THE CHEMISTRY OF DRUG DELIVERY SYSTEMS

THE CHEMISTRY OF

DRUG DELIVERY SYSTEMS

Dr. Lê Thành Dũng

Org Chem Eng Group

Faculty of Chemical Engineering

Tel: 38647256 ext. 5681

Email: [email protected]

OBJECTIVES

On the completion of this course, the student should be able

to have a deep understanding of the chemical aspects of

drug delivery systems that have recently attracted attention

from the chemistry and chemical engineering community.

EVALUATION

Seminar: 70%

Final exam: 30%

Students have to work in group for the preparation and the presentation

of their seminar subject. Evaluation will be given based on individual

contribution (preparation, discussion), the oral presentation and the

answers to the questions.

Students will receive a publication on drug delivery system at least one

week before the day of the exam. The exam questions will be based on

the given article.

REFERENCES

1. Martin Malmsten, Surfactants and polymers in drug delivery,

Marcel Dekker, New York, 2002

2. Glen S. Kwon, Polymeric drug delivery systems, Taylor &

Francis Group, New York, 2005

3. Ram B. Gupta, Uday B. Kompella, Nanoparticle technology for

drug delivery, Taylor & Francis Group, New York, 2006

4. Publications in Elsevier, Royal Society of Chemistry, American

Chemical Society, Wiley InterScience journals…

CONTENTS

1. Generalities of drug delivery

2. Liposomes as drug delivery systems

3. Polymers and polymeric systems for drug delivery

4. Dendrimers for drug delivery

GENERALITIES OF

DRUG DELIVERY

DRUG DELIVERY SYSTEM

A drug delivery system is a formulation or a device that safely

brings a therapeutic agent to a specific body site at a certain

rate to achive an effective concentration at the site of drug

action.

Definition:

Roles:

Carry

Transport

Protect

Distribute

Enhance body retention, the efficacy of the treatment

ROUTES OF DRUG ADMINISTRATION

Topical delivery

ORAL DELIVERY

(GASTROINTESTINAL ADMINISTRATION)

ORAL DELIVERY


Advantages:

safest

most convenient

most economical

Disadvantages:

poorly absorption of large, highly charged molecules

degradation of drug by stomach acid, various enzymes in

the GI tract

ORAL DELIVERY


Dosage forms:

liquids (rapid aborsoped)

dispersed systems: emulsions, suspensions

solids (less absorped): powders, tablets, caplets, capsules

controlled release drug delivery systems

PARENTERAL ADMINISTRATION

IM: into a muscle (intramuscular)

IV: into a vein (intravenous)

SC: under the skin (subcutaneous)

ID: into the skin (intradermal, intracutaneous)

TRANSDERMAL ADMINISTRATION

Advantages:

solution for drugs that can not be administered by oral delivery

reliability, precision of dosage

time control of the onset of action

Disadvantages:

discomfort

possibility of infection

tissue damage

administration by trained personel

MUCOSAL DRUG DELIVERY

Advantages:

avoid the first-pass effect of

drug cleareance

ORAL MUCOSAL ROUTE

Sublingual delivery

Classification:

Buccal delivery

Local delivery

Sublingual delivery Buccal delivery Local delivery

Surface area: 100 cm2

SUBLINGUAL AND BUCCAL DELIVERY

Sublingual delivery Buccal delivery

High permeability Less permeability

Higher rate of absorption Low rate of absorption

Higher drug bioavailability Low drug bioavailability

Rapid onset of action Sustained-release approaches

Constantly washed by saliva Relatively immobile

More permeable drug Less permeable drug (peptides)

Not include penetration enhancers Normally include penetration enhancers

What do you know about saliva?

Saliva: protective aqueous fluid, 1% organic & 99% inorganic

materials

Salivary pH: 5.5 – 7 depending on the flow rate

Flow rate increases [HCO3] increases pH increases

Daily salivary volume: 0.5 – 2 L

Oral cavity is a water-rich environment

Selection of hydrophylic matrices as drug carriers

PULMONARY ADMINISTRATION

Large mucosal surface of respitory system for drug absorption

« Taking advantage of the body’s ability to transfer large molecules

through the lung is a better way to deliver drugs than sticking people with

needles » Patton, Chemtech 1997, 27, 34

PULMONARY ADMINISTRATION

Advantages:

larger surface area (70 m2)

very fast onset of action (comparable to intravenous route)

Disadvantages:

lack of reproducibility of the administered dose

variable rate of absorption of drug at different regions

TRANSDERMAL AND TOPICAL ADMINISTRATION

STRUCTURE OF THE SKIN



Epidermis structure:



Stratum corneum structure:

Penetration barriers: lipid self-assemblies in the stratum

corneum (10%)


PERMEABILITY ENHANCEMENT

By surfactant-based formulations (penetration enhancers,

liposomes,…):

By hydration of the stratum corneum:

Surfactant-based formulations can interact with lipids and alter

their structure enhance drug penetration

Water can interact with the polar headgroups of lipids through hydrogen

bonding loosen the lipid packing the lipid region becomes more fluid

Enhance drug penetration

PENETRATION ENHANCEMENT

Barry, Int. J. Cosmet. Sci. 1988, 10, 281

PENETRATION (PERMEABILITY) ENHANCERS

Definition:

Compounds that promote the absorption of drugs through the

skin or mucosae, usually by reversibly altering the permeability of

the barrier.

Characteristics:

Non toxic

Pharmacologically inert

Immediate in action

Reversible in action

Chemically & physically compatible with the drug and with the

skin/mucosae

Cosmetically acceptable


Common penetration enhancers:

Aprotinin

Dextrans


Common penetration enhancers:

SELECTION OF ROUTE OF DRUG

ADMINISTRATION

Affects the onset and duration of drug action

Depends on the desired drug concentration profiles to be

achieve, patient and disease

Ex: Administration of nitroglycerin

Oral 53%

Inhalation

32%

Transdermal

8%

Injectable/

Implant 3%

Ocular 2%

Nasal 2%

GLOBAL DRUG DELIVERY MARKET BY

ADMINISTRATION MODE

CLASSIFICATION OF DRUG DELIVERY SYSTEM

By the way of delivery:

Targeted drug delivery systems: deliver drug to a desired

body location, organ, tissue, specific cells…

Controlled-release drug delivery systems: preprogramed

drug release.

By the route of delivery:

Topical (local) drug delivery systems: drugs are delivered

locally to the target organ/tissue without entering the

systemic circulation.

Systemic drug delivery systems: drugs are delivered to

the whole body via the general blood circulation

DIFFERENT KINDS OF DRUG

Tablets, pills Capsules Suppositories

Creams

Ointments Liquids Aerosols Injectables

Repeat administration

Fluctuation of drug concentration in the body

DRUG RELEASE PROFILE

FLUCTUATION IN DRUG CONCENTRATION

1 2 3 4

A 1

A 2

A 3

A 4 Drug concentration

Frequencies of dosing

B

Toxic level

Adverse side effects

Therapeutic range

Minimum effective concentration

No therapeutic range

A1, A2, A3, A4: series of multiple doses of a conventional drug delivery system

B: ideal drug concentration profile

PRODRUG

Prodrug is an inactive precursor of a drug.

Prodrug reconversion occurs in the body inside a specific

organ, tissue or cell.

What is a prodrug?

Prodrug = Drug + Drug delivery system

How to design a prodrug?

Increase solubility or absorption

Increase chemical and metabolic stability

Mask irritation or taste

MAIN TYPES OF PRODRUGS FOR

TARGETED DRUG DELIVERY

(a): Classic prodrugs: prodrugs are transformed into one or

more active substances inside the cell

(b): Two or more substances react to form the active drug under

specific intracellular conditions

(c): Advanced forms of prodrugs containing 3 components

CLASSIC PRODRUGS

Reconversion by the cleavage of a chemical bond

(normally by enzymes in the targeted cell)

Ex: Sulfasalazine for the treatment of inflammatory bowel disease

Colonic bacteria

5-aminosalicylic acid

sulfapyridine

active moiety

Azo modification

PRODRUGS OF TYPE (b)

Ex:

Indole-3-acetic acid

+ Horseradish

peroxidase Cytotoxic products

No toxicity No toxicity

ADVANCED FORMS OF PRODRUGS

Carrier: binding other components and altering the

physicochemical properties (ex solubility) of prodrug

Targeting moiety: enhancing the specific activity of the drug

on targeted cells

decreasing adverse side effects on

healthy tissues

Reconversion by the cleavage of a chemical bond

(normally by enzymes in the targeted cell)

ADVANTAGES OF PRODRUG OF TYPE (c)

The conditions of drug release can be precisely controlled by

modifying the bonds and each constituent

Prevent the degradation of the active component, reduce its

total body clearance

Release the drug inside targeted cells


Micelles

Liquid crystalline phases

Liposomes

Microemulsions

Emulsions

Polymers and dendrimers

Nanoparticles

Hydrogels

LIPOSOMES IN DRUG DELIVERY

WHAT ARE LIPOSOMES?

First described by Bangham and Horne after their study of lipid

phase structures in the electron microscope in 1964

Bangham, Horne, J. Mol. Biol. 1964, 8, 660

Liposomes are concentric bilayered vesicles in which an

aqueous volume is entirely enclosed by a membraneous lipid

bilayer mainly composed of natural or synthetic phospholipids

Liposomes are formed spontaneously when lipids are dispersed

in an aqueous medium (auto-assembly)

Why liposmes are used in drug delivery ?

Phospholipid bilayer

Aqueous cavity Polar head group

Hydrophobic tail

Storage ability of hydrophilic substances in the aqueous cavity

and hydrophobic drugs in the membrane

Similarity of structure to phospholipid membranes in living cells

Avoid the hydrolytic degradation of drugs in water

Reduce the RES uptake due to the rapid clearance of drugs

from bloodstream circulation (especially in intravenous administration)

Phospholipid bilayer

Aqueous cavity Polar head group

Hydrophobic tail

CELL MEMBRANE AND LIPOSOME

SIZE OF LIPOSOMES

Atoms Molecules Proteins Virus Bacteria Cells

Size of nanoparticles

Size of liposomes varies depending on how they are prepared

Size of liposomes

STRUCTURAL COMPONENTS OF LIPOSOMES

The main components of liposomes are phospholipids and

sterols

Phospholipids are the major strutural components of

biological membranes such as cell membranes

The most common phospholipids in biological membranes:

Phosphoglycerides

Sphingolipids

PHOSPHOGLYCERIDES

R1, R2 = fatty acid chain

R3 Phosphoglycerides

Phosphatidylcholine (PC)

Phosphatidylethanolamine (PE)

Phosphatidylserine (PS)

Phosphatidylglycerol (PG)

Phosphatidic acid (PA)

Phosphatidylinositol (PI)

SPHINGOLIPIDS

Sphingosine

Sphingolipids

N-acylsphingosine, ceramide

R1 = fatty acid chain

R1 = fatty acid chain

R2 = polar head group

STEROLS

Basic core of sterols

Cholesterol

Fluidity buffer for membrane with respect to temperature

Hydroxyl group in position 3 allows functionalization by various

functional groups

INFLUENCE OF CHOLESTEROL

ON THE STABILITY OF LIPOSOMES

Reduce the membrane permeability of phospholipid bilayers

Needham and Nunn, 1990

Grit and Crommelin, 1993

Increase the stability of liposomes in vitro and in vivo

Cholesterol is added in lipid mixtures used to produce

liposomes in concentrations of 30-50 mol%

almost non-polar increase hydrophobic interactions in the

phospholipid bilayers drecrease the fluidity of the membrane

SELF-ASSEMBLY PROPERTIES OF

AMPHIPHILIC COMPOUNDS

Depend on the geometry of amphiphilic molecules

Direct micelle

Inverse micelle

Lamellar phase

or vesicle

SELF-ASSEMBLY PROPERTIES OF

AMPHIPHILIC COMPOUNDS

Structure of the aggregate can be predicted from

packing parameter

P = V

a l

V: total volume of the molecule

a: maximum cross sectional area of the head group

l: length of the hydrophobic chain

P = V

a l

Spherical micelles

Globular micelles

Cylindrical micelles

Vesicles

Lamellar phase

Lamellar phase

Inverse micelles

CLASSIFICATION OF LIPOSOMES

Liposomes are classified depending on their size

Liposomes SUVs - Small

Uni-lamellar Vesicles

LUVs - Large

Uni-lamellar Vesicles

MLVs – Multilamellar

Large Vesicles

Diameter

(nm)

20- 100 100 - 500 > 500

Cross

section

PREPARATION OF LIPOSOME

DELIVERY SYSTEM

By the lipid film rehydration method

Minko et al. J. Appl. Physiol. 2002, 93, 1550

Pakunlu et al. Pharm. Res. 2003, 20, 351

Phospholipids

+

Drug solution

1. CHCl3

2. Evaporation to

a thin film

Dry lipid film Buffer (pH = 7.4)

agitation

MLVs

Sonication

22 kHz

SUVs Filters

SUVs of

homogenous size

Lipid-soluble drug Water-soluble drug

PHYSICOCHEMICAL PROPERTIES

OF LIPOSOMES Phase transition

Temperature (Tc)

Gel phase (solid) Liquid crystalline phase (fluid)

Better ability of self-assembly

Higher permeability to aqueous solution

Tc depends on the properties of lipids:

polarity

structure of fatty acid chain (length, level of unsaturation,

branching, presence of cycles)

adsorption of ions or proteins

Viniegra et al. Int. J. Biochem. 1984

Papahadjopoulos et al. Biochim. Biophys. Acta. 1973

INCORPORATION OF DRUGS IN LIPOSOMES

Through a drug concentration gradient

Before the formation of liposomes

Through a pH gradient

Drug: weak base

ACTIVE LOADING OF DRUG INTO PREFORMED

LIPOSOMES BY pH GRADIENT

ACTIVE LOADING OF DRUG INTO PREFORMED

LIPOSOMES BY pH GRADIENT

Drug = weak base:

Doxorubicin

Adriamycin

(cancer chemotherapy)

Vincristine

(cancer chemotherapy)

CHARACTERIZATION OF LIPOSOME SYSTEMS

Properties of liposomes Analysis

Physical size, shape and its distribution Cryo-TEM

Laser light scattering

Size exclusion chromatography (SEC)

NMR

Stability Dynamic light scattering (DLS)

Surface charge, zeta potential Free flow electrophoresis

Extent of drug entrapped Size exclusion chromatography (SEC)

NMR

Entrapped volume/lipid weight

NMR

Carboxyfluorescene

Lamellarity

Cryo-TEM 31P NMR

Phase transition temperature (Tc) Differential scanning calorimetry (DSC)

Purity of phospholipids Thin layer chromatography (TLC)

HPLC

NMR

CHARACTERIZATION OF LIPOSOME SYSTEMS

Light scattering techniques

NMR

Cryogenic transmission electron microscopy (Cryo-TEM)

Differential Scanning Calorimetry (DSC)

Drug release

Fluorescene spectroscopy

CONTROL OF LIPOSOME FORMATION BY NMR

By 31P solid-state NMR:

DSPC:DPPE-PEG2000:cholesterol = 60:15:25 mol%

High PEG-lipid content

C. Leal et al. J. Colloid Interface Sci. 2008, 325, 485


DSPC:DPPE-PEG5000:cholesterol = 78:4.5:17.5 mol%

65C

Low PEG-lipid content




DSPC:DPPE-PEG2000:cholesterol = 67:8:25 mol%

65C

Intermediate PEG-lipid content




DSPC:DPPE-PEG2000:cholesterol

65C


The higher the PEG-lipid content, the smaller the micelles are


M. Delcea et al. http://arxiv.org/abs/0904.1662v1, 2009

By 1H NMR:


DOPC lipid in chloroform

DOPC vesicles in HEPES buffer

Also confirmed by DOSY NMR

M. Delcea et al. http://arxiv.org/abs/0904.1662v1, 2009

By 1H NMR:


The higher the line width, the bigger the molecules are

DMPG vesicles in HEPES buffer

Also confirmed by DOSY NMR

DMPG lipid in chloroform

EVALUATION OF LIPOSOME SIZE BY

DIFFUSION NMR SPECTROSCOPY

The (mean) hydrodynamic radius R of a particle can be derived

from the diffusion coefficient D by the Stokes-Einstein equation:

Principles:

D = kBT

6R

D: (translational) diffusion coefficient

kB: Boltzmann constant

T: absolute temperature

: solvent viscosity

In general, by measuring D, these informations can be obtained:

effective size

binding phenomena, association constant

aggregation

molecular interactions Y. Cohen et al. Angew. Chem. Int. Ed. 2005, 44, 520

DIFFUSION ORDERED SPECTROSCOPY (DOSY)

– NMR CHROMATOGRAPHY

Means for “virtual separation” of compounds

One axis is the chemical shift, the other is that of the diffusion

coefficient

2D DOSY spectrum

Y. Cohen et al. Angew. Chem. Int. Ed. 2005, 44, 520



D 10-11 m2/s

D 10-12 m2/s





CPEG: PEG-lipid content in the liposomes

DLIP/1012, DMIC/1012: micelle and liposome diffusion coefficients x 1012

dLIP, dMIC: micelle and liposome diameters

dPCS: liposome diameters obtained by photon correlation spectroscopy

MIC: fraction of micelles

EVALUATION OF DRUG ENCAPSULATION BY


Y. Cohen et al. Angew. Chem. Int. Ed. 2005, 44, 520

Principles:

Drug size << liposome size

In free state: Ddrug >> Dliposome

In encapsulated state: Ddrug Dliposome

The quantity of drug encapsulated in liposomes can be

evaluated

CRYOGENIC TRANSMISSION ELECTRON

MICROSCOPY (CRYO-TEM)



Information:

Size (nm µm) and shape of complex structures in the solution

state

Applications:

Identify new morphologies and phases in the solution state

Characterize the interplay between different objets in solution

Used as complement to scattering techiniques:

to improve the modeling of scattering data

to discern the polydispersity in size and shape of

assembled structure

characterize intermediate structures

Zhong and Pochan, Polym. Rev. 2010, 50, 287



Advantages:

Zhong and Pochan, Polym. Rev. 2010, 50, 287

characterize in situ, in the solution state

without the need of modeling as required in scattering

techniques (neutron, X-ray, light scattering)

Disadvantages:

heavy technical skills for sample preparation and observation



Sample preparation:

place a drop of sample onto an EM-grid

remove excess solution by a filter paper, leaving a thin film of

the solution on the EM-grid

Plunge rapidly the grid into liquid ethane held just above the

freezing point (cooled by liquide nitrogen) to vitrify the sample

and avoid sample’s crystallization

Transfer the vitrified sample at low temperature to the

microscope



Sample preparation:

CRYO-TEM IMAGES OF LIPOSOMES FORMED BY

EPC : CHOLESTEROL = 60 : 40 MOL%

Edwards et al. Biophys. J. 1997, 73, 258

EPC: egg yolk lecithin

Liposomes have spherical shapes

Ice crystal deposited on the

sample surface after vitrification

100 nm




elongated or tube-shaped liposomes

segregation of the lipid and cholesterol

components

100 nm




revert back to a spherical shape

100 nm

Crystalline particles


DSPC/CHOLESTEROL

Without PEG2000-DSPE Without 5% PEG2000-DSPE


DSPC: 1,2-distearoylphosphatidylcholine

PEG2000: polyethylene glycol, M = 2000 Da

DSPE: 1,2-distearoylphosphatidylethanolamine

DIFFERENTIAL SCANNING CALORIMETRY (DSC)

Principles:

both sample and reference are maintained at nearly the same

temperature

the difference in the amount of heat (Cp) required to increase

the temperature of the sample and the reference is measured

as a function of temperature

through comparison between the sample and the reference,

melting and other transitions in liposome systems are monitored

DIFFERENTIAL SCANNING CALORIMETRY (DSC)

Principles:

DSC FOR DPPC/CHOLESTEROL SYSTEMS

Ladbroke et al. Biochim. Biophys. Acta 1968, 150, 333

Pretransition Chain melting

DRUG RELEASE

Principles:

Through the release of a component encapsulated in liposomes,

information relating to the permeability of the lipid bilayers can

be obtained.

Frequently used methods:

carboxyfluorescene self-quenching

ethidium intercalation with DNA

DRUG RELEASE

FLUORESCENE SPECTROSCOPY

Informations:

localization of a solubilized molecule in a lipid membrane in a

liposome (by measuring the fluorescene anisotropy)

fluorescene anisotropy degree of orientation localization

FLUORESCENE SPECTROSCOPY

Fluorescene anisotropy <r> of 4-heptadecyl-7-hydroxycoumarin (HC)

and 1,6-diphenyl-1,3,5-hexatriene (DPH) in egg

phosphatidylcholine/cholesterol liposomes vs. temperature

HC with 5% PEG-PE

HC without 5% PEG-PE

DPH with 5% PEG-PE

DPH without 5% PEG-PE

DPH HC

Silvander et al. Langmuir 2000, 16, 3696

LIPOSOMES IN DRUG DELIVERY

Advantages:

Structural similarity to cell membrane structures

Capacity to encapsulate both water-soluble and oil-soluble drugs

Disadvantages:

Complicated preparation

Sterilization difficulties

Poor storage stability

Poor solubilization capacity for more hydrophobic drugs

Difficulties to control the drug release rate

INTRAVENOUS ADMINISTRATION

Problems:

Rapid elimination of drug carriers from bloodstream circulation

by the reticuloendothelial (RES) system low bioavailability

Accumulation of drugs in RES-related tissues (liver, spleen,

marrow) local toxicity

UPTAKE OF DRUG CARRIERS – PHAGOCYTOCIS

Drug carriers Adsorption of serum proteins

(opsonins) at the surface

Uptake by macrophage Engulfment of

drug carriers

macrophage

Drug carrier

EFFECTS OF THE SURFACE OF DRUG CARRIERS

ON THE PHAGOCYTOSIS

More hydrophobic particles

Hig

her

RE

S u

pta

ke o

f dru

g c

arr

iers

More highly charged particles

Tabata et al. Adv. Polym. Sci. 1990, 94, 106

ZETA POTENTIAL – A MEASURE OF CHARGES OF

SUSPENDED PARTICLES

Double layer

Gouy layer

UPTAKE OF DRUG CARRIERS – PHAGOCYTOCIS

Dependence of phagocytocis on properties of drug carriers:

Size

Surface:

hydrophobicity

charge

chemical functionality

The adsorption of serum protein can be reduced by

modifying the structure of phospholipids

PHOSPHOLIPID STRUCTURE AND THE SERUM

PROTEIN ADSORPTION

Chonn et al. J. Biol. Chem. 1992, 267, 18759

Ganglioside GM1 (zero charge)

Sphingomyelin SM (zero net charge)

Liposomes containing:

Phosphatidylcholine PC (zero net charge)

Phosphatidylinositol PI (one negative charge, shielded by an outer group)

Diphosphatidylglycerol DPG (two negative charge)

Phosphatidic acid PA (two negative charge)

Ganglioside GM1

Sphingomyelin SM

Phosphatidylcholine PC

Phosphatidylinositol PI

Diphosphatidylglycerol DPG

Phosphatidic acid PA

ADSORPTION OF SERUM PROTEINS

DRIVING FORCES

Electrostatic interaction

Hydrophobic interaction

Van der Waals interaction

Interactions that drive the adsorption:

Modification of liposomes by adding poly(ethylene glycol)

(PEG) or poly(ethylene oxide) (PEO) chains

PEG PEO

EFFECTS OF LIPOSOMES CONTAINING

PE-PEO PHOSPHOLIPIDS

PEO750-PE

PEO2000-PE

PEO5000-PE

Uncoated liposomes

Higher

accumulation of

liposomes in

bloodstream

Mori et al. FEBS Lett. 1991, 284, 263


PE-PEO PHOSPHOLIPIDS

PEO750-PE

PEO2000-PE

PEO5000-PE

Uncoated liposomes

Higher

uptake of

liposomes

in liver and

spleen

Mori et al. FEBS Lett. 1991, 284, 263


PE-PEO PHOSPHOLIPIDS - SUMMARY

longer bloodstream circulation time (higher bioavailability)

decrease of accumulation in RES-related tissues

increase of accumulation in tissues not related to the RES

reduction of adverse side effects (lower toxicity)

INTRAVENOUS ADMINISTRATION – TARGETING

Target the drug carriers to a specific tissue or cell

Increase the drug bioavailability

Reduce adverse side effects

Prodrug structure:

PEO-modified liposomes are used to protect targeting moiety

and assure a long circulation time

EFFECTS OF PEO-MODIFIED LIPOSOMES IN

TARGETING DELIVERY

Binding to mouse

pulmonary artery

endothelial cells

PEO-modified liposomes functionalized with relevant antibodies

PEO-modified liposomes functionalized with an irrelevant antibodies

Uncoated liposomes Holmberg et al. J. Liposome Research 1990, 1, 393

TOPICAL ADMINISTRATION

Why liposomes are used in topical administration?

To overcome the barrier properties of the stratum corneum

Penetration enhancers may result in an increased systemic

drug level or even toxic effects

Highly deformable liposomes (transfersomes or elastic

liposomes) can transfer various kinds of drugs (different in

lipophilicity and molecular weight, proteins, peptides)


Two main routes of penetration:

Maghraby et al. Eur. J. Pharm. Sci. 2008, 34, 203

transappendageal pathway

transepidermal pathway

through the sweat glands

across the hair follicles

intercellular route

transcellular route

Driving force for penetration:

osmotic gradient


Transappendageal pathway:



Transepidermal pathway:



Passage of transfersomes through the stratum corneum:

1/10 transfersome diameter


Edge activators to produce elasticity of transfersomes:

destabilizes the lipid bilayer

increases deformability of the liposome

surfactant nature (sodium cholate, deoxycholate, dipotaasium

glycyrrhizinate…)

POLYMERS AND POLYMERIC

SYSTEMS FOR DRUG DELIVERY

OVERVIEW

Kim et al. Eur. J. Pharm. Biopharm. 2009, 71, 420

Controlled release

Polymeric drug

delivery system

Targeted delivery

Sustained release

Triggered release

Prodrug Enhanced

permeability and retention (EPR)

Targeting ligands

Triggered targeting

Hydrogels Smart polymers,

stimuli-sensitive hydrogels

Polymer-drug conjugates

Polymeric liposomes

and micelles

Smart polymers

Polymeric liposomes

and micelles

COMPARISON AMONG CONTROLLED DRUG

RELEASE SYSTEMS

Kim et al. Eur. J. Pharm. Biopharm. 2009, 71, 420

HYDROGELS

Definition:

Polymeric material that has the ability to absorb > 20% of its

weight of water (or biological fluids) and still maintain a distinct

3D structure

History:

1960: Wichterle & Lim first proposed the use of hydrophilic

networks of poly(2-hydroxyethyl methacrylate) (PHEMA) in

contact lenses

Wichterle & Lim. Nature 1960, 185, 117

extended to various biomedial & pharmaceutical applications

HYDROGELS

Structure:

Tridimensional network consisting of physical or chemical

cross-links ( branch)

Chemical (covalent, ionic)

cross-links, irreversible

Physical (entanglement,

hydrogen, VDW)

cross-links, reversible

Properties:

Insoluble (3D cross-linked network)

Infusible

Hydrophilic (presence of OH, COOH, CONH2, HSO3)

Swell in water

DIFFERENCE BETWEEN GEL AND HYDROGEL

Linear polymer

strands

Aqueous gel

Hydrogel

Polymer strands

dissolve in water

Polymer strands

swell in water

Physical network, weak interaction

Entanglement, hydrogen, VDW cross-links

Reversible

Soluble, fusible, dissolve in water

Chemical network

Covalent cross-links

Irreversible

Insoluble, infusible, swell in water

PREPARATION OF HYDROGEL-BASED


Gupta et al. Drug. Discov. Today. 2002, 7, 569

Chemical, physical

or radiation

cross-linking

Synthesis

Purification

Drying

Air/freeze drying

Drug loading

Filtration &

rinsing Drying

SYNTHESIS OF POLYMERS

By condensation polymerization of monomers (release of

H2O, NH3, HCl)

By free radical polymerization of monomers containg double

bond, through chain reaction with 3 stages

Ex: M < 20 000 Da poly(ethylene glycol) (PEG)

M > 20 000 Da poly(ethylene oxide) (PEO)

Initiation (thermal, photochemical, free radical or ionic)

Propagation

Termination

POLYMERIZATION PROCESSES FOR THE

PREPARATION OF HYDROGELS

Bulk polymerization

Suspention polymerization

Emulsion polymerization

Monomers + cross-linking agent + initiator hydrogels whose

morphologies depend on the mold used

Drops of monomer & initiator are dispersed in a concentrated

aqueous saline solution hydrogel beads

Emulsificaiton methods spherically shaped hydrogels

MONOMERS USED IN THE PREPARATION

OF SYNTHETIC HYDROGELS

=

COPOLYMERS

Constitued from different types of monomers ( homopolymers)

Chainings Name Notation Properties

ABBBABBAABAA Statistical (random)

copolymer

P(A-co-B) New material, properties

intermediate of PA & PB

ABABABABABAB Alternating copolymer P(A-alt-B) New material, properties

intermediate of PA & PB

AAAAAABBBBBB Block copolymer P(A-b-B) Superposition of

properties of PA & PB

Graft copolymer P(A-g-B) Superposition of

properties of of PA & PB,

for interface problems

To modify mechanical properties & swelling property (of

hydrogels)

COPOLYMERS – EXAMPLES

Hydrogels P(HEMA-co-MMA) PHEMA P(HEMA-co-VP)

Water content in

swelling state

less intermediate higher

more hydrophilic than MMA

HYDROPHILIC POLYMERS USED IN

PREPARATION OF HYDROGELS

Hamidi et al. Adv. Drug. Deliv. Rev. 2008, 60, 1638

CROSSLINKING METHODS USED IN HYDROGELS

Hamidi et al. Adv. Drug. Deliv. Rev. 2008, 60, 1638

Crosslinking methods

Chemically crosslinked Physically crosslinked

Crosslinking by radical polymerization

Crosslinking by high energy irradiation

Crosslinking using enzymes

Crosslinking by chemical reaction with

complementary groups

Crosslinking with aldehyde

Crosslinking with addition reaction

Crosslinking by condensation reaction

Crosslinking by ion interaction

Physically crosslinked hydrogels

from amphiphilic block and graft

copolymers

Crosslinking by crystallization

Crystallization in

homopolymer systems

Crosslinking by

stereocomplex formation

CROSS-LINKING AGENTS USED IN THE

SYNTHESIS OF HYDROGELS

RELATIONSHIP BETWEEN STRUCTURE AND

PROPERTIES OF HYDROGELS

CHARACTERIZATION PARAMETERS

FOR HYDROGELS

Gupta et al. Drug. Discov. Today. 2002, 7, 569

DEGREE OF SWELLING

capacity of hydrogels to absorb water or aqueous solution

Information:

%S =

%S: % age swelling

Ws: weight of the swollen gel

Wd: weight of the dry gel

diffusional properties of a solute through the hydrogel

% age swelling:

Ws Wd

Wd 100%

FACTORS THAT CONTROL THE

DEGREE OF SWELLING

Nature of monomers

Type & density of cross-link

Temperature

Ionic strength

pH of the hydration medium

FACTORS THAT AFFECT THE

DEGREE OF SWELLING

Hydrophilicity of monomers increases % S increases

Hydrogels P(HEMA-co-MMA) PHEMA P(HEMA-co-VP)

Water content in

swelling state

less intermediate higher

E.g.

Nature of monomers:

Type & density of cross-link:

Cross-linking agents increase % S decreases


DEGREE OF SWELLING Temperature:

Lower critical

solution

temperature

(LCST)

Temperature

Swelling state Collapsed state

Upper critical

solution

temperature

(UCST)

Temperature

Swelling state Collapsed state


DEGREE OF SWELLING

Temperature-LCST:

Non associated

Structured water

Less structured

bulk

Aggregation

Bromberg et al. Adv. Drug. Deliv. Rev. 1998, 31, 197

Hydrophobic association is entropy controlled:

S > 0 G = H T S < 0


DEGREE OF SWELLING

Ionic strength & pH of the hydration medium:

Due to the presence of of weakly acid and/or basic functional

groups on the backbone

E.g. COOH, NR3

Ionization of the functional groups depends on the pH & on the

ionic strength of the external medium

Ionization of the functional groups leads to water uptake

properties (osmotic driving force)


DEGREE OF SWELLING

Ionic strength & pH of the hydration medium:

DRUG RELEASE MECHANISMS

FROM HYDROGELS

Drug release takes place by 3 mechanisms

diffusion-controlled

swelling-controlled (when diffusion of drug is faster than

hydrogel swelling)

chemically-controlled

hydrolytic/enzymatic cleavage of polymeric chain

reversible/irreversible reactions between the polymer

network and the releasing drug

DRUG RELEASE MECHANISMS –

DIFFUSION CONTROLLED

Molecular diffusion

Drug diffusion

DRUG RELEASE MECHANISMS –

DIFFUSION CONTROLLED

Passive diffusion of drug across hydrogel membranes can be

described by the Fick’s first law

J k

x = D

dC k

x

dx

D = kBT

6R (Stokes-Einstein equation)

: Flux of species k along x - direction J k

x

D: diffusion coefficient

C: concentration

J depends on the mesh sizes of swollen hydrogels (5-100 nm)

CONTROLLED-RELEASE HYDROGEL SYSTEMS

Time-controlled systems

E.g. copolymeric hydrogel disks for controlled release of

burenorphine (treating opioid dependence) by buccal route

Stimuli-induced release systems

STIMULI-INDUCED RELEASE SYSTEMS

Brannon-Peppas, MPB, 1997, 11, 34

pH-RESPONSIVE HYDROGELS

pH-RESPONSIVE HYDROGELS

PAA

PDEAEMA

TEMPERATURE-RESPONSIVE HYDROGELS

Bromberg et al. Adv. Drug. Deliv. Rev. 1998, 31, 197

DENDRIMERS FOR DRUG

DELIVERY

STRUCTURE OF DENDRIMERS

2D

3D

core

Branch point

periphery

cavity

4th generation

Generation: same external functional groups as starting molecule

SYNTHESIS OF DENDRIMERS

Divergent synthesis:

Coupling

3

Activation

6 Coupling

Activation

1st generation

2nd generation


Divergent synthesis – the first dendrimer: 1st generation

2nd generation

Vögtle F. et al. Synthesis 1978, 155

De Brabander E.M.M. et al. Angew. Chem. Int. Ed. Engl. 1993, 32, 1308


Divergent synthesis – PAMAM (PolyAMidoAMine):

Amine & ester

terminated poly(amidodamine)

dendrimers Tomalia D. A. et al. Macromolecules 1986, 19, 2466

Tomalia D. A. US. Pat. 4507466, 1985,


Convergent synthesis:

Dendron

Core

Dendrimer


Convergent synthesis – preparation of dendrons:

Coupling Activation

1st generation

Coupling

2nd generation


Convergent synthesis – Fréchet-type dendrons

(polyaryl ethers):

[G-1]-OH [G-1]-Br

[G-2]-Br

[G-3]-Br

Fréchet et al. J. Am. Chem. Soc. 1990, 112, 7638

Chem. Commun. 1990, 1010

Bn: Benzyl


Comparison between divergent & convergent synthesis:

Core

4 eq

12 eq

36 eq

1/3 eq

1/3 eq

1/4 eq

Divergent

construction

Convergent

construction

Terminal site

for monomer

connectivity

Focal site

for monomer

connectivity

Core

Peripheral region Void volume

Branch juncture

THE CHEMISTRY OF DRUG DELIVERY SYSTEMS

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