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Micelles

Dendrimer

Dendrimers are three-dimensional macromolecules with a basic structure that resembles trees,
i.e., they possess a root based on a core molecule with 2+ symmetry to which the dendritic
trees (dendrons)

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Dendrimer synthesis

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Application

Liposome

Structural control over size and shape of drug or imaging-agent cargo space
Biocompatible, nontoxic polymer/pendant functionality
Precise, nanoscale container and/or scaffolding properties with high-drug- or highimaging-agent-capacity features
Well-dened scaffolding and/or surface modiable functionality for cell-specic
targetingmoieties
Lack of immunogenicity
Appropriate cellular adhesion, endocytosis, and intracellular trafcking to allow
therapeutic delivery or imaging in the cytoplasm or nucleus
Acceptable bioelimination or biodegradation
Controlled or triggerable drug release
Molecular-level isolation and protection of the drug against inactivation during
transitto target cells
Minimal nonspecic cellular and blood-protein-binding properties
Ease of consistent, reproducible, clinical-grade synthesis

Phospholipids

What is a liposome?

Polar Head Groups

Spherical vesicles with a phospholipid bilayer

Hydrophilic

Three carbon glycerol

Hydrophobic

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Cell Membrane

Uses of Liposome
Chelation therapy for treatment of heavy
metal poisoning
Enzyme replacement
Diagnostic imaging of tumors
Cosmetics
Study of membranes
Drug Delivery

Why Use Liposomes in Drug Delivery?

Drug Targeting
Inactive: Unmodified liposomes gather in specific tissue
reticuloendothelial system

Active: alter liposome surface with ligand (antibodies,

enzymes, protein A, sugars)

Why Use Liposomes in Drug Delivery?

Drug Targeting
Pharmokinetics - efficacy and toxicity
Protection
Release modified

Physical: temperature or pH sensitive liposomes

Directly to site

Modes of Liposome/Cell Interaction

Adsorption

Fusion

Endocytosis

Lipid transfer

Classes of Liposomes
Conventional

Long circulating

Immuno

Cationic

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Current liposomal drug preparations

Liposomal Formulation of AmB

Phospholipid:AmB ratio

Type of Agents
Examples
Duanorubicin,
Doxorubicin*, Epirubicin
Anticancer Drugs
Methotrexate, Cisplatin*, Cytarabin
Anti bacterial
Triclosan, Clindamycin hydrochloride,
Ampicillin, peperacillin, rifamicin
Antiviral
DNA material
AZT
Enzymes
cDNA - CFTR*
Radionuclide
Fungicides
Vaccines

AmB

Hexosaminidase A
Glucocerebrosidase, Peroxidase
In-111*, Tc-99m
Amphotericin B*
Malaria merozoite, Malaria sporozoite
Hepatitis B antigen, Rabies virus glycoprotein

*Currently in Clinical Trials or Approved for Clinical Use

Cholesterol - only few %moles

Lipid

Exact Mechanism of liposomes not understood

Diffusion
Lipid transfer

Decrease in toxicity
No decrease in effectiveness of drug against fungi

Problems with Liposomal Preparations

of Drugs

High cost
Lack long term stability (short shelf life)
Low Pay Load - poor encapsulation
Possibility of new side effects

Self emulsifying drug delivery

systems (SMEDDS / SNEDDS)

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Biopharmaceutical classification
system (BCS)

Introduction
Oral route most convenient
User-friendly
Cost-effective

Class II
permeability

First step for absorption is solubilization

Approximately 40% of new chemical entities
exhibit poor aqueous solubility

Class I

Low solubility

High solubility

High permeability

High permeability

Class IV

Class III

Low solubility

High solubility

Low permeability

Low permeability

solubility

Lipid Formulation Classification System

(LFCS)
Type

Type

Type

Type

Type

II

III A

III B

IV

Oil

SEDDS

Non-dispersing;
requires
digestion

without watersoluble
components

SEDDS/SMEDDS
with watersoluble
components

SMEDDS with
water-soluble
components
and low oil
content

Oil-free
formulation
based on
surfactants and
cosolvents

Structure of O/W emulsions

Macroemulsion

Structure of emulsions
Macroemulsion

Microemulsion

Cloudy

Clear

Require a large input of energy

Formed spontaneously

Thermodynamically unstable

Stable

Microemulsion

Critical differences SMEDDS/SNEDDS

Microemulsion

Thermodynamically stable
(equilibrium)

Strongly affected and broken-up by

temperature changes and/or
dilutions

Exhibit a large range of structures

Preparation
Spontaneous emulsification

Nanoemulsion
Thermodynamically unstable (nonequilibrium)
Kinetics of destabilization is very slow
kinetically stable
Remain stable in conditions of stress
Preparation

High-energy methods, e.g. high pressure

homogenizers
Low-energy methods, spontaneous
emulsification

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Excipients - Oil

Preparation of SMEDDS / SNEDDS

Oil (lipophilic
component)

Microemulsions

Surfactant

Strictly identical whatever

the order in which
compounds are mixed

Characteristics
Co-solvent
(hydrophilic
component)

Solubilize lipophilic drug

Nanoemulsions

Only formed if surfactants

are mixed first with the
oily phase

Natural Oils (Triglyceride)

Corn oil
Soya oil

Maisine (Glycerylmonolinoleat)
Capmul (Glycerylmono- and
dicapylate/caprate)
Miglyol
(Glyceryltricaprylate/caprate)

Micro-/Nano-emulsion

+GI fluid

Excipients - Surfactants
Effects

Excipients - Co-solvents

Examples
Characteristics

Effects

O/W Microemulsion

Improve drug dissolution

Must be orally acceptable;

safety

Increased intestinal epithelial

permeability

Tween 80 (Polyoxyethylene
(80) sorbitan monooleate)

Surfactant concentration can

be reduced

Help to dissolve hydrophilic

surfactant

Non-ionic; less toxic

Increased tight junction

permeability

Cremophor RH40 (PEG-40

hydrogenated castor oil)

Not mandatory

Help to dissolve the drug in

the lipid base

Inhibited p-glycoprotein drug

efflux

Labrafil M 1944 CS (PEG-6glyceryloleat)

Alcohol and other volatile cosolvents can migrate into

shells of capsules

Supports spontaneous
formation of microemulsions

Examples

Non-ionic

High HLB (8-18)

Concentration 30 60 %
(w/w)

Examples

Semisynthetic Lipids (Mono-, Diand Triglycerides)

SMEDDS / SNEDDS

Order is very important

Characteristics

Transport via the intestinal

lymphatic system

Edible oils are not frequently

used due to their poor ability
to dissolve drugs

Always self-emulsifying

Effects

Polyethylene glycol
Propylene glycol
Ethanol
Glycerol

May cause moderate

reversible changes in intestinal
wall permeability
May irritate GI tract

Potential mechanisms

SMEDDS / SNEDDS

Grea ter chemical /

enzyma tic s tability

Advantages of SMEDDS / SNEDDS

Reduced gastrointestinal
meta bolism

Improve in oral bioavailability

Enha nced drug

di s solution

Ease of manufacture and scale-up

Grea ter i nterfacial a rea

for a bs orption

Enha nced drug

a bs orption

Mi cro- /Na no-emulsion

Enha nced drug
permeation

Ability to deliver peptides that are prone to enzymatic hydrolysis in GIT

No influence of lipid digestion process

Reduced drug efflux

Enha nced lymphatic
tra ns port

Enha ncement in oral

bi oa vailibilty

Reduced hepatic
meta bolism

Reduction in food effects

Increased drug loading capacity

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Advantages over emulsion

Characterization

Stability

Easily stored

Particle size

Smaller size

Emulsion: 0.2 10 m
SMEDDS/SNEDDS: 2 100 nm

Can be filled in Hard/Soft gelatin capsules

Can be autoclaved

Polarity
Zeta potential
Drug precipitation / stability on dilution
(Pseudo) ternary phase diagrams

Pharmaceutical applications
How to differ micro- from nanoemulsions?
Microemulsion

Nanoemulsion

Dynamic light scattering

Dynamic light scattering

Dilution decrease the size

Dilution have no influence

on droplet size

Temperature change
Strongly affect structure
Phase separation

Temperature change
No immediate effect on
structure

Ciclosporin
(cyclosporine)
BCS class IV
Immuno-suppressive
Cyclic nonribosomal
peptide

Sandimmune
Sandimmune Neoral
(Optoral)

Pharmaceutical applications
Future aspects
Physiological bile flow

Without bile

Supersaturable SMEDDS

Solid SMEDDS

Stabilize drug in temporarily

superstated phase

Leakage problem with hard

gelatin capsules

Polymeric precipitation inhibitor

(e.g. HPMC)

Disadvantages of soft gelatin

capsules in manufacturing
process

Reduced level of surfactants

Reduce toxic effects of
surfactants (GI side effects)
Mechanism is poorly understood

Incorporation of liquid selfemulsifying ingredients into

powder
Tablets, pellets

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Take-Home messages

SMEDDS/SNEDDS
are a promising tool for
the oral delivery of
hydrophobic drugs
Compromise between toxicity and self-emulsification
ability must be find
Keep in mind the difference between micro- and
nanoemulsions