Download Protein Pharmaceuticals (VI)

Protein Pharmaceuticals (VI)
“Formulation and Delivery”
Dr. Aws Alshamsan
Department of Pharmaceutics
Office: AA87
Tel: 4677363
[email protected]
Objectives of the Lecture
By the end of this lecture you will be able to:
1. Describe techniques for optimal protein
formulation
2. Realize the importance of delivery systems
for protein pharmaceuticals
3. Compare different delivery methods
Solving the problems
Microbial
Considerations
Additives
Storage
Formulation
Delivery
Solving the problems
Microbial
Considerations
Additives
Storage
Formulation
Delivery
Formulation
• Biotechnology products are generally sensitve and
have considerably short as compared to lowmolecular weight drugs.
• Optimal formulation is supposed to improve the
product stability in vitro and in vivo.
Site-Directed Mutagenesis
• Bioengineering process that creates a mutation as a
defined site in the DNA strand.
• Engineered proteins can be tailored for a specific
application or improved stability.
Site-Directed Mutagenesis
Site-Directed Mutagenesis
PEGylation
• Covalent attachment of PEG to another molecule
such as protein.
PEGylation
• Significantly increases in vivo half life
• Prevents from proteolytic enzymes degradation
Increase in size to reduce kidney
filtration
PEG
Protein
Decrease
accessibility
for proteolytic
enzymes and
antibodies
PEGylated proteins in the market
Brand Name
Drug name
Parent Drug
Indication
Approval Year
1990
Adagen®
Pegadamase
Adenosine deaminase
Severe combined
immunodeficiency
disease (SCID)
Oncaspar®
Pegaspargase
Asparaginase
Leukaemia
1994
PEG-INTRON®
Peginterferon-a2b
IFN-a2B
Hepatitis C
2000
PEGASYS®
Peginterferon-a2a
IFN-a2A
Hepatitis C
2001
Neutropenia
2002
Acromegaly
2003
Neulasta®
Pegfilgrastim
Somavert®
Pegvisomant
Macugen®
Mircera®
Cimzia®
Granulocyte-colony
stimulating factor
(GCSF)
Growth Hormone
antagonist
Age-related macular
degeneration
Epoetin beta-methoxy
Anemia associate with
Erythropoietin (EPO)
polyethylene glycol
Kidney disease
PEG-Certolizumab
Rheumatoid arthritis
Anti-TNF Fab
pegol
& Crohn’s disease
Pegaptanib
Anti-VEGFc aptamer
2004
2007
2008
Peptide Micelles
Hydrophilic block
Hydrophobic block
Peptide
O H
H3N+
H
R1
N
H
R2 H
N
O H
PEG
O H
R3
N
H
R4
O
O
CH-CH-CH-CH-CH-CH-CH-CH-CH-CH
| |
| | |
| |
| | |
OH OH OH OH OH OH OH OH OH OH
Solving the problems
Microbial
Considerations
Additives
Storage
Formulation
Delivery
Targeted Micelles
Liposomes
• Phospholipid bilayer
• Aqueous core
• 80-100nm in size
• Biocompatible
• Uni- or Multilamellar
• Could be easily functionalized
Liposomes
• Preferential retention in leaky vasculature e.g.
cancer
• Easily uptaken by macrophages
• Overcome by Stealth property (PEGylation)
Liposomes
Liposomes
Microspheres and Nanoparticles
• Encapsulation of a protein or peptide
inside a porous particle
• Constructed of Biodegradable,
Biocompatible polymer
– PLGA (FDA approved)
Microspheres and Nanoparticles
Microspheres and Nanoparticles
Polymeric Nanoparticle Uptake by
Human DCs: SEM image
Polymeric Nanoparticle Uptake by
Human DCs: Confocal Image
Protein Delivery
• Drugs could be
administered by several
routs:
– Parenteral (injections)
– Transdermal
– Oral
Parenteral
Parenteral Delivery
•
•
•
•
•
•
•
•
Route of delivery for 95% of proteins
Allows rapid and complete absorption
Allows smaller dose size (less waste)
Avoids first pass metabolism
Avoids protein “unfriendly zones”
Problems with overdosing, necrosis
Local tissue reactions/hypersensitivity
Everyone hates getting a needle
Oral (GI-MAPS®)
Transdermal Patches
• Proteins imbedded in a simple matrix with
appropriate additives
• Patch is coated with small needles that
penetrate the dermal layer
• Proteins diffuse directly into the blood stream
via capillaries
• Less painful form of parenteral drug delivery
Transdermal patch
Small Pins
Skin
Close-up of Patch Pins
Exubera (Inhaled Insulin)
• Exubera, a dry-powder form of insulin, is
inhaled with a special device similar to an
asthma inhaler
• Exubera normalized blood sugar levels as well
as injections did
• Patients taking inhaled insulin also reported
greater satisfaction and quality of life (for 18+
only)
• About 1/5 study subjects developed a mild
cough with inhaled insulin
• Product pulled in Oct. 2007
Pfizer
Oral (Oralin/Oral-Lyn) by GENEREX
It is not oral, it is
buccal
Oral Insulin (Oralin/Oral-lyn)
• Bucchal aerosol delivery system developed
by Generex (Approved in Ecaudor and India)
Oral Insulin (Oralin/Oral-lyn)
• Insulin is absorbed through thin tissue layers
in mouth and throat
• Insulin is formulated with a variety of
additives and stabilizers to prevent
denaturation on aerosolization and to stabilize
aerosol particles
Oral insulin by NOBEX
• Conjugate the lysine
residue with
amphiphilic oligomer
• Alkyl chain + PEG
• Enhance stability in vivo
• Hydrolysis of oligomer
release the native
structure
• Phase II clinical trial
(2004)
Future Delivery
Future Delivery (Biocapsule)
• Encapsulation of insulinsecreting cells
(insulinoma)
• Immune components
physically excluded
• Glucose molecules pass
freely
• Insulin is secreted in
response to glucose
Biocapsules
Protein Pharmaceuticals
Now you are able to:
Describe techniques for optimal protein
formulation
Realize the importance of delivery systems for
protein pharmaceuticals
Compare different delivery methods
Next Lecture
• Biotechnology-based
vaccines