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LECTURE 8 – Materials for Drug Delivery

Fundamentals of Medical Materials 334221 BME - Technion
Dr. Yosi Shamay
Definitions

Pharmaceutical formulation is the process in

which different chemical substances, including the
active drug, are combined to produce a final
medicinal product.
Drug delivery refers to approaches, formulations,
technologies, and systems for transporting a
pharmaceutical compound in the body as needed to
safely achieve its desired therapeutic effect.

Wikipedia
Role of Formulation and Drug Delivery
in Pharmacokinetics + Pharmacodynamics?
Pharmacokinetics: Therapeutic Window
Pharmacokinetics: Therapeutic Window
Pharmacokinetics: Therapeutic Window
Drug Types
 Routes of Administration

Topical/Transdermal
Rectal or Vaginal
Pulmonary
Oral
Parenteral (Injectable)
Pharmacokinetics Differs
by Route of Administration
Route of Administration
Affects Drug Distribution
Oral Administration
Pills
– Antiquated single-dose unit; round,
produced by mixing drug powder with
syrup and rolling into shape

Tablets
– Oblong or disk-like shape, produced
through mechanical pressure; filler
material provides mass; starch or
carbonates facilitate
disintegration
 Oral Administration (Cont’d)

Coated Tablets: Tablet covered by a “shell” (wax, highly

specialized polymers = Eudragit®) to facilitate swallowing,
cover bad taste or protect active ingredient from stomach
acid
 Oral Delivery (Cont’d)
Matrix Tablets: Drug is embedded in inert “carrier” meshwork for
extended or targeted (intestinal) release

Capsules: Oblong casing (Gelatin); contains drug in liquid, powder

or granulated form
Troches or Lozenges: Sublingual Tablets Intended to be held in the
mouth until dissolved
Goal of Controlled Drug Release

Drug Concentration

Time
Drug Concentration

Time
Controlled Drug Release - Depot
Dissolution Rate of
Homogenous Matrix System
Example: How Oral Drug Formulation
Modulates Release Rate
Time-Release

Ethylcellulose
hydroxypropyl methylcellulos

Povidone
Controlled Release Oral Formulations
Many of the long-acting medications have drug names that end with a two-letter suffix. For
example, CD (controlled dosing), SR (sustained release), LA (long-acting), XR (extended
Percutaneous Drug Formulation
Pulmonary Formulations
Inhalation anesthetics (Hospital use only)
Nebulizers (mostly propellant operated)dispense defined amount of
Aerosol (= dispersion of liquid or or solid particles in a gas)
Size of aerosol particles determines depth of penetration into the
respiratory tract:
>100 μm: Nasopharynx
10-100 μm: Trachea, bronchii
<10 μm: Bronchioli, alveoli

Stabilizers: Polysorbates 
 Parenteral Drug Administration

Advantages:
100% “Absorption”
Drug enters general circulation without hepatic passage  No
first-pass hepatic elimination
Better bioavailability of hydrophilic drugs

Bioavailability/Speed of Absorption
Intravenous (i.v.): Fastest (infusions; cardio-vascular drugs)
Intramuscular (i.m.): Medium (anti-inflammatory; antibiotics)
Subcutaneous (s.c.): Slowest (vaccines; insulin; depot
contraceptives)
 Solubilizing Insoluble Drugs for IV Injection

Kolliphor EL, formerly known as Cremophor

EL, is the registered trademark of BASF Corp.
for its version of polyethoxylated castor oil.
It is prepared by reacting 35 moles of ethylene
oxide with each mole of castor oil. 
-Improves drug solubility but exhibits side-
effects
-Paclitaxel (Taxol) is a non-soluble drug which
is given with Kolliphor
 Drug Binding to Plasma Proteins

 Primarily albumin (4.6g/100ml), also β-globulins and acidic

glycoproteins. Other specialized plasma proteins
(transcortin; thyroxin-binding globulin; etc.)
 Binding to plasma proteins is instantaneous and reversible.

• Of great importance, as
the free (=effective)
drug concentration
determines intensity of
response
• Binding to plasma
proteins is equivalent to
depot formulations
The Problem with Macromolecule
Delivery

 Elimination by B and T cells

 Proteolysis by endo/exo peptidases,
nucleases
 Small macromolecules (<30 kD) filtered out
by the kidneys very quickly
 Unwanted allergic reactions may develop
(even toxicity)
 Loss due to insolubility/adsorption
Macromolecule Formulation

 Protein sequence modification (site directed

mutagenisis)
 PEGylation
 Proteinylation
 Microsphere/Nanosphere encapsulation
 Formulating with permeabilizers
Site Directed Mutagenesis
(Protein Engineering)

E343H
Site Directed Mutagenesis

 Allows amino acid substitutions at specific sites

in a protein
 i.e. substituting a Met to a Leu will reduce
likelihood of oxidation
 Strategic placement of cysteines to produce
disulfides to increase Tm
 Protein engineering (size, shape, etc.)
PEGylation

O
O
+
O
O
PEGylation

 PEG is a non-toxic, hydrophilic, FDA approved,

uncharged polymer
 Increases in vivo half life (4-400X)
 Decreases immunogenicity
 Increases protease resistance
 Increases solubility & stability
 Reduces depot loss at injection sites
Poly Ethylene Glycol = PEG

Medicine
• PEG is the basis of a number of laxatives.   PEG is also used as
an excipient in many pharmaceutical products.
• When attached to various protein medications, polyethylene glycol
allows a slowed clearance of the carried protein from the blood.
• The possibility that PEG could be used to fuse axons is being
explored by researchers studying peripheral nerve and spinal cord
injury
Research
PEG is commonly used as a crowding agent in in vitro assays to mimic highly
crowded cellular conditions.
PEG is commonly used as a precipitant for plasmid DNA isolation and protein
crystallization.
PEG is used to fuse two different types of cells, most often B-cells and myelomas
in order to create hybridomas. César Milstein and Georges J. F. Köhler originated
this technique, which they used for antibody production, winning a Nobel Prize in
Physiology or Medicine in 1984.
The PEG Solubility Paradox
PEG modification = PEGylation
Pegaspargase-PEGylated L-asparaginase

•5-kDa linear PEG attached at multiple sites

•Indicated in acute lymphoblastic leukemia (ALL).
•Pegaspargase has a prolonged circulating half-life and low immunogenicity
unlike other L-asparaginase products produced in E. coli or Pectobacterium
carotovorum.
•The mean serum half-life of PEG-asparaginase is about 15 days as opposed
to the 24 h of the nonmodified E. coli enzyme and the 10 h of the Erwinia
chrysanthemi form.
•L-asparaginase is administered twice or three times weekly, pegaspargase is
administered once in two weeks and induces less toxic hypersensitivity, thus
improving patient compliance.  $980.00 vs $52.38 per injection
Pegfilgrastim (Neulasta®, Amgen)
PEGylated form of the recombinant human granulocyte colony-stimulating factor (GCSF)

• Produced from filgrastim (Neupogen®, Amgen) using Nektar

PEGylation technology.

• Minimizes problems associated with nonselective conjugation,. This

process leads to site-specific PEGylation at the N-terminal methionyl GCSF
residue of G-CSF, and improves the biological activity of filgrastim.
• Filgrastim is administered by injection daily for 2 weeks, whereas
pegfilgrastim requires only one injection per chemotherapy cycle.
• The side effects of pegfilgrastim are smaller than those of filgrastim;
they include splenic rupture, sickle cell crises, allergic reactions, and
anaphylaxis.
40kd
HTSDS = height standard deviation score IGF-1 = most commonly used biomarker
for GH activity
Microscophere (Nanoparticle) Encapsulation

100 m
Encapsulation
 Encapsulating macromolecule drugs into particles
(microparticles or nanoparticles) for protection from
degradation in the blood, liver, etc.
Types of Nanoparticles
 Nonbiodegradable
 ceramic particles
 metal or silica nanoparticles
 polyethylene co-vinyl acetate
 polymethacrylic acid/PEG
 Biodegradable (preferred)
 gelatin
 polylactic-co-glycolic acid (PLGA)
PLGA - Structure
Nanoparticle Release

 Hydrophilic (i.e. gelatin)

 best for burst release
 Hydrophobic (i.e. PLGA)
 good sustained release (esp. vaccines)
 tends to denature proteins
 Hybrid (amphipathic)
 good sustained release
 keeps proteins native/active
Permeabilizers (Adjuvants)

 Anything that is known to “punch holes” in the

intestinal lumen
 Salicylates (aspirin)
 Fatty acids
 Metal chelators (EDTA)
 Targeted Drug Delivery: Goals

1. Limit drug exposure in healthy

tissues?
2. Increase drug concentration in
disease sites?
Advanced Drug Delivery Systems

Langer et al, Nano Letters, 2012

Barriers
 To be absorbed and distributed, drugs must cross barriers
(membranes) to enter and leave the blood stream.
 Body contains two type of barriers which are made up of
epithelial or endothelial cells:
 External (Absorption Barriers): Keratinized epithelium (skin),
ciliated epithelium (lung), epithelium with microvilli (intestine),
etc.
 These epithelial cells are connected via zonulae occludens
(tight junctions) to create an unbroken phospholipid bilayer.
Therefore, drugs must cross the lipophilic membrane to enter
the body (except parenteral).
Problem in Cancer Drug Delivery: How to target a drug 47

to disseminated tumors in light of endothelial barriers?

Active Targeting:

Cancer cells Endothelial cells

Controlled Drug Release Strategies - Depot or Particle

www.worldclimatereport.com
 HPMA-E-selectin Binding Peptide (P-Esbp)
polymer conjugates
 Esbp is a 12 amino acid sequence: DITWDQLWDLMK known to bind
E-selectin in the low nanomolar (nM) range.

Design: E-selectin targeted

HPMA copolymer conjugated
with pH sensitive Doxorubicin
or labeled with FITC

(DITWDQLWDLMK)

or FITC
 50
Synthetic Route for Drug-Polymer-Peptide Conjugate
DOX-HPMA-Esbp
The binding affinity of P-(Esbp)-FITC is three orders of magnitude
relative to free Esbp

Binding to immobilized E-selectin. Binding to IVEC cells upon activation

Scrm P-(Scrm)-FITC

Esbp, IC50 5μm

P-Esbp
IC50 6nm

Flow Cytometry
ELISA

Shamay et al., Biomaterials., 2009, 30(32):6460

The rate of P-(Esbp)-FITC internalization was significantly higher in
TNF-activated IVECs

Representative confocal fluorescence images of IVECs incubated with FITC labeled

HPMA-peptide copolymers and LysoTracker-Red DND99.
Shamay et al., Biomaterials., 2009
P-Esbp-HzBoc inhibits adhesion of B16 melanoma to the lungs
A. B.

C.

Non-Treated Pre-Treated
with P-Esbp

B16F10 cells were injected IV to mice 40min after treatment with P-Esbp-
HzBoc. Lungs were examined after 15 days
In-vivo anti-tumor activity of targeted polymer on murine
Lewis Lung Carcinoma (3LL) tumors

Growth rate of 3LL tumors

E-selectin targeted HPMA copolymer DOX conjugate
enhanced tumor growth inhibition compared to
non-targeted HPMA copolymer-bound DOX

P-DOX

P-(Esbp)-DOX

Survival of C57BL/6 mice

Drug in a single
iv injection

E-selectin targeted HPMA copolymer DOX conjugate

prolonged the mean survival of mice relative to P-DOX P-(Esbp)-DOX
control groups

drug
55
 Nanoparticle Development
Nanoprecipitation Method with Ultra-
DLS
Stabilizers:
Organic Phase:
Hydrophobic
t
Drugs in DMSO en
10-20 mg/ml r em
su
ea
M TEM/SEM
ze IR783
Si
(published in Nature
Materials 2018)
Size Exclusion Particle shape/size
Chromatograph
y
Dr HPLC
ug
Sephadex-G25 Co
nt
e nt
Aqueous phase:
Dye Ultra-
Stabilizer
2mg/ml in Sodium
 Strategy for Targeting KI’s

Kinase inhibitors properties Delivery requirements:

1) Very hydrophobic 1) Need to work with multiple drugs

2) Reversible inhibitors 2) High drug loading efficiency

3) Administrated daily 3) Rapid, scalable synthesis

Drug core : Nanocrystals or

Colloidal aggregates
Washed

Coated with
polyelectrolyte
Which Coating?
Fucosylated, Sulfated Polysaccharide Binds to P-
Selectin
Fucoidan

MW: 20kd-300kd

High affinity to P-selectin (~20nM)

Radiotherapy induces P-selectin in tumor vasculature
Structural element for building nanoparticles

Shamay et al. Science Trans Med.

2016 et al . Nature Communications. 201
Mizrachi and Shamay
 Fucoidan Nanoparticles Bind to Irradiated
Endothelial Cells
Paclitax
el
Sorafeni Ultra-sonication
b
MEK162
BYL719

Endothelial Cells (Radiation)

Red = nanoparticles
Green =membrane
Blue=DAPI

Shamay et al. Science Trans Med.

Nanoparticles Bind to P-selectin on Tumor
Spheroids
SEM

Shamay et al. Science Trans Med.

 Targeting PI3K pathway in HNSCC
P-selectin DAPI
BYL719 - PI3K inhibitor

Cal33 mouse tumor model

Head and Neck Cancer

Pathway inhibition
pS6

Mizrachi and Shamay et al.

Nature Communications.
RT Increases Nanoparticle Localization
Microneedles

Prausnitz et al, Nature Medicine, 2012

Glucose-Responsive Smart Insulin Delivery

w/ 400 mg/dL glucose w/ 100 mg/dL glucose

https://www.youtube.com/watch?v=e1xX88oJF-M

Gu et al, ACS Nano, 2013

Wireless Microchips for Controlled Drug Delivery

Michael Cima Robert Langer

Antibodies As Biomaterials
Fluorescent labeled Antibodies

Anti-EGFR-FITC in lung
cancer cells
Antibody Drug Conjugates (ADC)
 Brentuximab vedotin

Anti-CD30
 Case Report in Hodgkin’s Lymphoma:

DHAP (dexamethasone, cytarabine and cisplatin)

IGEV (ifosfamide, gemcitabine, vinorelbine and prednisone),