This document discusses barriers to protein and peptide drug delivery. It begins by defining proteins and peptides, and describing their structures. It then outlines some of the main challenges to delivering these large molecule drugs, such as low permeability, enzymatic degradation, short half-lives, and barriers like the intestinal epithelium, capillary endothelium, and blood-brain barrier. Specifically, it notes proteins face enzymatic breakdown in the GI tract, must pass through tight cell junctions in the intestine and blood vessels, and generally cannot cross the blood-brain barrier due to its selective permeability. Overcoming these delivery challenges is important for utilizing proteins and peptides as therapeutics.

1. PROTEIN AND PEPTIDE DELIVERY
BARRIERS FOR PROTEIN DELIVERY
SUBMITTED BY,
PREETHA U PILLAI
1ST YEAR M PHARM

2. INTRODUCTION
 PROTEINS: Proteins are the natural polymer
molecules made of amino acids units and joined together
by polypeptide bonds (Protein > 50 amino acids)
 PEPTIDES: These are short polymers formed by
linking in a defined order of amino acids (peptide < 50
amino acids)

3. STRUCTURE OF PROTEIN
 Primary structure- Array of number and specific
sequence of amino acids in protein structure
 Secondary structure- Regularly repeating local
structures stabilized by hydrogen bond.
 Tertiary structure-Three dimensional structure of
functional protein
 Quaternary structure- Contains two or more
polypeptide chains associated by non-covalent forces

4. ROLE OF PROTEINS
 1. STRUCTURAL FUNCTIONS: Responsible for
strength of body including collagen, elastin found in
bone matrix, vascular system and other organs
 2. DYNAMIC FUNCTIONS: Acts as enzymes,
hormones, blood clotting factors, immunoglobulins,
membrane receptors, besides their function in genetic
control, muscle contraction.

5. PROTEIN AND PEPTIDE DRUG DELIVERY
 Comes under novel drug delivery system.
 Most abundant material of living system and biological cells
 Proteins and peptides are the main building blocks of life and are now
evolving as a very promising brand of therapeutic entities. Therapeutic
proteins have increased dramatically in number and frequency of use
since the introduction of first recombinant protein viz, human insulin, 25
years ago.
 Delivery of proteins in body have limited its use
 Due to rapid progress in biotechnology, as well as gene technology,
production of potential therapeutic peptides and proteins in commercial
quantities possible

6. ADVANTAGES
 The mode of delivery is convenient, i.e., eye drops.
 Systemic absorption is extremely rapid. • Avoid first-pass
metabolism.
 The formulation can be designed to prolong drug action
and/or reduce drug concentrations to achieve consistent
drug action with least side effects.
 The drug delivery can be controlled precisely

7. DELIVERY CHALLENGES
 Low permeability due to large molecular size
 Susceptibility to enzyme degradation
 Short plasma half life
 Immunogenicity
 Aggregation
 Denaturation
 Protein binding

8. BARRIERS FOR PROTEIN DELIVERY
 Enzymatic barriers
 Intestinal Epithelial Barrier
 Capillary Endothelial Barrier
 Blood Brain Barrier(BBB)

9. ENZYMATIC BARRIERS
 The enzymatic degradation is brought about mainly via two ways:
1.Hydrolytic cleavage of peptide bonds by processes, such as insulin-
degrading enzyme, angiotensinconverting enzymes and renin.
Proteolysis is an irreversible reaction and hence potentially causes
the of damage of the peptide and protein drug.
2.Chemical modification of protein such as phosphorylation by
kinases, oxidation by xanthine oxidase or glucose oxidase.
 It limits absorption of protein drugs from G.I tract

10. INTESTINAL EPITHELIAL BARRIER
 Serves as a barrier for transport of protein drugs across
the intestinal epithelium
 Several mechanisms that are involved in the transport of
peptide /protein drugs across the intestinal epithelium are
 A. Passive & carrier mediated transport
 B. Endocytosis & Transcytosis
 C. Paracellular Movement.

11.  A. Passive and carrier mediated transport:
• Active transport appears to be the predominant mechanism.
Accounts for the extensive absorption of di-and tripeptides
from small intestine
 B. Endocytosis and transcytosis
• Cellular internalization of peptides/proteins may occur by
Endocytosis whereby peptide /proteins, which are too large to
be absorbed by carrier mediated transport, are taken up.
• The Different pathways of Endocytosis involve
Phagocytosis(cell eating), Pinocytosis(cell drinking)

12. C. Paracellular movement:
 The transport of drugs through the junction between the
GI epithelial cells.
 Two mechanism involved in drug absorption are-
1.Permeation through tight junction of epithelial cells
(insulin)
2.Persorption
 The small intestine epithelial mucosa serves as a barrier
to the permeation of macromolecules

13. CAPILLARY ENDOTHELIAL BARRIER
 To cross the capillary endothelium the peptides/proteins
must pass between the cells or alternatively transverse
across the endothelial cells themselves.
 Solutes that transverse the endothelial cell membrane
may get modified or metabolized by cytoplasmic
enzymes.
 Thus, the endothelial passage poses metabolic or
enzymatic barrier to the solution passage.

14. BLOOD BRAIN BARRIER (BBB)
 The blood-brain barrier (BBB) represents a major obstacle to
the delivery of proteins to the brain compartment. It consists of
several barriers with the two that are best described being the
vascular BBB, and the blood-cerebrospinal fluid (blood-CSF)
barrier
 At both sites, the BBB is formed by a monolayer of cells that
are cemented together by tight junctions and have other
mechanisms that control or retard leakage of plasma into the
CNS.
 Allows passage of small, lipophilic, uncharged molecules and
gases. Large molecules like proteins do not pass the BBB
easily

16. REFERENCE
 Controlled Drug Delivery By Suresh P. Vyas and Roop K.
Khar 2nd Edition Page No;480-493
 www.wikepedia.org
 Recent trends in Protein and Peptide Drug Delivery System,
Himanshu Gupta, Aarti Sharma.