Approaches for delivery of protein, peptides & vaccines

1. Different approaches for
delivery of protein,
peptides & vaccines
PRESENTED BY : SHIKHA SINGH
ROLL NO :160617009
UNDER THE GUIDANCE OF: DR. M SREENIVASA REDDY
PROFESSOR & VICE PRINCIPAL
MCOPS MANIPAL UNIVERSITY

2. CONTENTS
Introduction of protein & peptides
Challenges in delivery of protein & peptides
Different approaches for delivery of protein & peptides
Introduction of vaccines
Delivery systems used to promote the uptake of vaccines
Controlled release micro-particles for vaccine development
Conclusion
References
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3. INTRODUCTION
What are proteins & peptides?
Proteins are relatively large molecules with complex structure
Peptide chains in peptides & proteins are seldom linear & adapt a variety of specific folded 3D patterns &
conformations
All peptides & proteins are polymers of amino acids connected via amide linkages referred to as peptide
bonds
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4. CHALLENGES IN DELIVERY OF PROTEIN &
PEPTIDES
DEGRADATION
1.1.
PHYSICAL
1.Denaturation 1.Aggregation 1.Adsorption 1.Precipitation
2. CHEMICAL
1.Deamination 1.Oxidation 1.Proteolysis
1.Disulphide
exchange
1.B-elimination
POOR STABILITY
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5. Conti…
1.3. BARRIERS
Enzymatic Barriers
Hydrolytic cleavage
Intestinal Epithelial
Capillary Endothelial
Blood Brain barrier
4. FOOD PROTEIN INTOLERANCE
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6. APPROACHES FOR DELIVERY OF PROTEIN
& PEPTIDES
Oral route
Buccal route
Nasal route
Transdermal route
Pulmonary route
Parenteral route
Ocular route
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7. Oral route
Barriers
Poor intrinsic permeability of peptides/proteins across biological
membrane
Susceptibility to enzymatic attack by intestinal proteases &
peptidases
Rapid post-absorptive clearance
Physical instability like aggregation & adsorption
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8. Approaches for oral delivery of protein & peptide drugs
Modification by chemical synthesis of Prodrug & its analogueApproach 1
• Eg PEG derivative Monosaccharide derivative
Use of enzyme inhibitorApproach 2
• Eg Metalloprotease inhibited by EDTA
Use of penetration enhancerApproach 3
• Eg EDTA, SLS
Carrier systemApproach 4
• Eg Nanocarrier, microparticle, Emulsion w/o/w & bioadhesive system
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9. Buccal route
Barriers for efficient drug absorption are
1. Mucus layer
2. Epithelial barriers
3. Peptidases in saliva & microbial flora
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10. Factors affecting buccal route
Molecular weight
Polarity
Conformation
Dissociation
Enzymatic
Chemical stability
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11. Approaches for buccal delivery of protein & peptides
Adhesive
tablets
Adhesive
patches
Absorption
promoters
Adhesive
gels
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12. Nasal route
Barriers to systemic absorption through nasal route
a) Extent of absorption varies with the mucus secretion & mucus turnover
b) Peptidases & proteases present in the mucus or associated with nasal membrane serve as
enzymatic barrier in protein/peptide absorption
c) Alteration in absorption profile in diseased conditions like allergic condition & chronic
rhinitis & URTI
d) Penetration enhancers & preservatives may damage mucosal cell membrane & may even
be ciliotoxic
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13. Type of dosage form
Nasal spray
Nasal drops
Aerosol
Various approaches for Nasal Delivery of peptide/protein drugs are:
◦ Viscosity modification - 0.6% HPMC
◦ PH modification – insulin permeates in acidic conditions
◦ Permeation enhancers – SLS
◦ Increase nasal blood flow
◦ Drug delivery design
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14. Transdermal route
Limitations of Transdermal Route for peptide/protein Delivery are:
A low rate of permeation for most protein drugs due to their
1. Large molecular weight
2. Hydrophilicity & lipophilic nature of the stratum corneum
High intra & inter patient variability
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15. Approaches for transdermal delivery of protein & peptides
Approaches:
1. Iontophoresis - insulin, vasopressin
2. Phonophoresis – insulin, erythropoietin
3. Penetration enhancer - Oleic acid, dimethylsulphoxide
4. Prodrugs – TRH, LHRH
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16. Pulmonary route
Particles that reach the alveoli can be absorbed into the systemic circulation, avoiding first
pass metabolism & the harsh conditions of the gut
The deep lung delivery offers the following benefits:
Provides a direct route to the circulation
Reduction in dose requirement up to 50 fold & thus a cost effective option
Fast absorption
Safe route for drug entry even in patients with lung diseases
No triggering of immune functions
Increased patient compliance with a minimum of discomfort & pain
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17. Major challenges in pulmonary drug delivery
Variation in absorption rates due to variation in epithelial line thickness under physiological
condition
Delivery to the lung should be precise & consistent at every inspiration
Site of dose deposition to the deep lung
Aerodynamics of aerosolized particles
Reproducibility in dose deposition
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18. Parenteral route
It is major route of choice for delivery of protein & peptide drug
The parenteral drug delivery system includes IV, IM, subcutaneous, intraperitoneal,
intratheacal routes, etc
 Drug carrier system employed for definite & controlled delivery of drug through this route are
1. Particulates
2. Soluble carriers
3. Miscellaneous system
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19. Drug carrier system
A. Particulates
1. microspheres
2. nanoparticles
3. nanoparticles
4. liposomes
5. emulsions
6. cellular carriers
B. Soluble carriers (macromolecules)
C. Miscellaneous
1. Self-regulated
2. systems Pump
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20. Ocular route
Viscosity of formulation play important role to increase contact time & increase
bioavailability of the drug
Various polymer used in ophthalmic preparation the first approach in ocular drug delivery
system is that to prolong contact time by incorporating various polymer
Eg :PVA, PVP, MC, CMC, HPMC, other bioadhesive polymer eg carbopol, sodium alginate, etc
Barrier to ocular route is
1. Tear dilution
2. Lacrymal drainage
3. Protein binding
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21. Approaches for ocular delivery of protein & peptides
Approaches:
1. Ocular inserts
2. Absorbable gelatin sponge
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22. Company Product name Technology Formulation product
Apollo Life Science Oraldel Nanoparticles Tablet Insulin, TNF-blocker
Emisphere Eligen
Penetration
enhancers
Tablet Calcitonin, insulin
Nobex/Biocon HIM2 Pegylation Liquid
Insulin, enkephalin,
calcitonin
Generex Oral–Lyn ™
Penetration
enhancers
Spray devices ,
aerosol particles
Insulin, Macrotonin
Provalis PLC Macrulin™
Lipid based
microemulsion
Emulsion
Insulin, Salmon
calcitonin
NOVEL TECHNOLOGIES:
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23. NAME PRODUCT COMPANY STATUS
Exubera Inhaled insulin powdered Pfizer & CO FDA approved
Aerodose Inhaled insulin solution
Aerogen and diestro
medical system
Phase 2 completed
HIIP Inhaled insulin powdered Eli lilly & CO In Phase 2
Rapid mist oralin Mouth spray for buccal delivery Generex biotechnology Completed phase 2 trials
Emisphere tablet Emisphere Phase 2 completed
NIN-058 tablet
Nobex corporation and
glaxosmithkline
Phase 2 in progress
Patch Insulin patch
Altea development
corporation
Phase 1
EXAMPLES OF MARKET TRENDS
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24. VACCINE DRUG DELIVERY SYSTEM
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25. INTRODUCTION
A vaccine is a biological preparation that improves immunity to a particular disease
A vaccine typically contains an agent that resembles a disease-causing microorganism & is
often made from weakened or killed forms of the microbe, its toxins or one of its surface
proteins
Vaccines can be prophylactic or therapeutic
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26. DELIVERY SYSTEMS USED TO PROMOTE
THE UPTAKE OF VACCINES
1. ABSORPTION ENHANCERS
Increases absorption by enhancing membrane permeation, rather than increasing solubility
Also termed as permeation enhancer
Absorption enhancers are functional excipients included in formulations to improve the
absorption of a pharmacologically active drug
Ex: skin permeation enhancers include non-ionic surfactants which cause changes in the
intracellular proteins of stratum corneum & increase permeability by this mechanism
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27. 2. LIPOSOMAL DELIVERY SYSTEMS
Liposomes are composed of phospholipid bilayers capable of entrapping hydrophilic moieties
in the aqueous compartment & hydrophobic moieties in the lipid bilayers with cholesterol
imparting rigidity to the bilayer
Liposomal vaccines based on viral membrane proteins (virosomes) have been approved as
products in Europe for hepatitis A & influenza
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28. 3. ORAL IMMUNIZATION
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29. Controlled release micro-particles for vaccine development
PLGA (polylactide co-glycolic acid) is used as a biodegradable micro particle for vaccine
delivery due to the abundance of data & information on its properties, uses & role in on going
studies
Factors that effect the release pattern are:
1. Molecular weight of compound- greater the mol. Wt. greater the bond, larger time to
degrade
2. Chemical composition of co-polymer- release of the peptide was prolonged when
microspheres made of copolymer containing higher proportion of polylactide
3. Size of the microspheres- greater the particle size longer the time to collapse, delays the
release of antigen
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30. Peptide based vaccines
A peptide vaccine is a type of subunit vaccine in which a peptide of the original pathogen is
used to immunize an organism
These types of vaccines are usually rapidly degraded once injected into the body, unless they
are bound to a carrier molecule such as a fusion protein
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31. Nucleic acid based vaccines
Use of nucleic acid-based vaccines is a novel approach to immunization that elicits immune
responses similar to those induced by live, attenuated vaccines
Nucleic acid vaccines have been shown to elicit both antibody and cytotoxic T-lymphocytes
responses to diverse protein antigens
ADVANTAGES:
 Simplicity of the vector
 The ease of delivery
 Duration of expression
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32. DNA vaccines
DNA vaccination is a technique for protecting an organism against disease by injecting it with
genetically engineered DNA to produce an immunological response
These are the third generation vaccines & are made up of a small, circular piece of bacterial
DNA (called plasmid) that has been genetically engineered to produce one or two specific
proteins (antigens) from a pathogen
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33. RNA vaccines
 Recent studies have demonstrated that mRNA formulated in liposome's & administered sub-
cutaneously or intravenously, effectively generated antibody & act directed against the
encoded protein
However, the difficulty & expenses of large scale RNA production & the relative instability of
mRNA compared to DNA might render RNA vaccines an impractical means of immunization
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34. CONCLUSION
The promise of peptides and proteins will lead to drug innovation and discovery, and
challenge the ingenuity of pharmaceutical developers to develop novel delivery methods for
present and future therapies
Although various vaccines have been successfully developed for several diseases, research is
still in progress to develop vaccines for life threatening diseases like cancer , AIDS etc
Novel vaccine delivery systems need to be developed in order reduce morbidity and mortality
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35. REFERENCES
1. Controlled drug delivery concepts and advances. By S.P.Vyas, Roop K. Khar, Vallabh
Prakashan, 1st edition, Page No: 503-70
2. Progress in controlled and novel drug delivery system, N. K. Jain, CBS publishers &
distributors, 1st edition, page no. 184-208
3. D. Sesardic and R. Dobblaer, European union regulatory developments for new vaccine
adjuvants and delivery systems, vaccine 22 (2004), pp. 2452-2456
4. Samantha Jilek, Hans P. Merkle, Elke Walker. “DNA- Loaded biodegradable microparticles
as vaccine delivery systems and their interaction with dendritic cells”, Page 378
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