Protein and peptides drug delivery systems- An Overview in Pharmaceutical field

1. PROTEIN AND PEPTIDE DRUG
DELIVERY
VINOTH R
2061010003
M.Pharm (IP) – 1st Semester

2. CONTENTS
 Introduction
 Structure
 Drug Delivery Techniques
 Pumps
 Challenges in Drug Delivery
 Barriers for Protein Delivery
 Manufacturing Process
 Stability Testing
 Instability
 Physical Instability
 Chemical Instability
 Marketed Drugs
 Market research
 References

3. 3
Amino
Acids Peptides Proteins
What are Proteins and Peptides?
Introduction:

4. Peptides
 Endocrinology
(Hormones)
 Neurotransmitters/
Neuromodulators
 Anti-Tumour Agents
 Antibiotics
Proteins
 Transport Proteins
 Structural Proteins
 Defence Proteins
 Regulatory Proteins
 Nutrient Proteins

5.  The use of therapeutic proteins to replace or supplement endogenous protein
molecules has been a long established treatment for diseases such as
diabetes, growth hormone deficiency, and haemophilia.
 Protein and peptide drugs are either natural in origin or synthetically
produced using recombinant DNA technology or from transgenic animals.
 Proteins and peptides are rapidly degraded in the gastrointestinal tract due to
the harsh pH and enzymatic environment, resulting in poor oral bioavail-
ability.

6. Structure:
 Proteins and peptides consist of simple building blocks called amino acids,
which are linked together by peptide bonds.
 A peptide bond is formed by the nucleophilic addition of the primary amine
of one amino acid to the electropositive carboxylate carbon of the other
amino acid
Amino acid1

7. DELIVERY TECHNIQUES
 Polymer based drug delivery system.
 Liposome based drug delivery system.
 Hydro gel based drug delivery system.
 Emulsion based drug delivery system.
PARENTERAL DRUG DELIVERY SYSTEM
PUMPS
 Implantable infusion pumps
 Mechanical pumps

8. POLYMER BASED DRUG DELIVERY SYSTEM
Polymers are used as carriers in this drug delivery system.
Characters of polymers
 It should be biodegradable.
 It should be bio compatible.
 Non-toxic.
Types of polymers
Natural polymers
Synthetic polymers

9. LIPOSOME BASED DRUG DELIVERY
 Spherical vesicles with a phospholipid bilayer
 Liposome's are microscopic vesicles composed of one or more
aqueous compartments.
 Liposome’s in Proteins delivery
 Example: Lecithin used in controlled drug release
LIPOSOME IN PEPTIDE DRUG DELIVERY
 Bleomycin : A peptide with anti tumor activity, reduces normal
tissue toxicity

10.  Soluble in both organic and aqueous media.
 Liposome’s are important for targeting drugs directly to the liver, and brain.
 Lipsosomes easily crosses blood brain barrier. Example: Dopamine
converted to L-Dopa.
 Used as a vehicles for vaccines.
 Less stable , easily susceptible to oxidation.
 Hence liposome’s are replaced by noisome an alternate for liposome’s
Advantages of liposome drug delivery
Disadvantages

11. HYDROGEL BASED DDS
 Hydrogels are three dimensional networks of hydrophilic polymers that are insoluble
 Hydro gels are polymers which have the ability to swell in water .
 Biodegradable hydro gels are used, due to its biocompatibility .
 Examples: Hydroxy methylacrylate, used to minimize mechanical irritation to
surrounding tissue.
EMULSION BASED DELIVERY
 Emulsions can be used for parenteral drug delivery of proteins and peptides used to
prolong the release of drug.
 E.g. subcutaneous administration of muramyl dipeptide in a w/o emulsion. It is
used to potentiate immune system .

12. CELLULAR CARRIERS
 Protein and peptides can be incorporated in erythrocytes to achieve the prolong
release or targeting.
 Resealed erythrocytes as delivery system for c-reactive protein, and mainly used
to target liver and spleen.
PUMPS
Types of pumps:
1) IMPLANTABLE PUMPS
 Drug is implanted subcutaneously, and delivered by I.V infusion.
 Pumps are filled with drug through a septum with a needle.
 Pumps deliver drugs to central vein for 7-14 days a constant rate.
.

13. 2) MECHANICAL PUMPS
 Easily manipulated to deliver protein and peptide drugs.
Example: insulin has been successfully delivered by portable syringe

14. Challenges In Delivery
1. Chemical, physical and enzymatic instability
2. Pre systemic degradation
3. Provokes immunogenic response
4. High molecular size
5. Short plasma half life
6. Specialized transport mechanism
7. Inability to transport efficiently to extravascular sites

15. Barriers For Protein Delivery
Various barriers in delivery of proteins are:
1. Enzymatic barrier
2. Intestinal epithelial barrier
3. Capillary endothelial barrier
4. Blood brain barrier

16. Manufacturing processes of Protein Based Drug Delivery System
A typical manufacturing process of protein solution involves
1. Freeze the bulk drug substance (therapeutic protein).
2. Formulation (dilution and addition of excipients).
3. Filtration for removing any particulate matter and/or sterilization.
4. Filling of drug product in vials or syringes.
5. Inspection of filled vials or syringes for the presence of any particulate
matter.
6. Labelling and packaging.
7. Storage and shipment of drug product.
Use of a delivery device for drug administration to the patient

17. Many proteins are very unstable in solution and may not yield acceptable shelf
life, even under refrigerated (2°C-8° C) storage conditions
The capability of a particular formulation in a specific container/closure system to remain
within its physical, chemical, microbiological, toxicological and protective specifications.
Evaluates the effect of environmental factors on the quality of the drug
substance or a formulated product which is utilized for prediction of its shelf life,
determine proper storage conditions.
STABILTY TESTING
LYOPHILIZATION

18. General
Selection of Batches
Container Closure System
Specification
Testing Frequency
Storage Conditions
Stability Commitment
Evaluation
Statements/Labelling
On-going Stability Studies

19. INSTABILITY
Protein pharmaceuticals commonly exhibit both physical and chemical
instability, whereas chemical instability refers to modification of proteins via
bond formation (e.g., oxidation) or bond cleavage (e.g., deamidation), yielding
a new chemical entity.
PHYSICAL INSTABILITY
Physical instability refers to changes in the higher order structure that does not
include covalent bond cleavage or formation. Protein denaturation is a result of
change in higher order folding or conformation that commonly exhibits as a
change in the surface exposure of functional groups.

20. Denaturation :
Protein native structure represents the least overall thermodynamic free
energy of interaction of different residues of the polypeptide(s) with the
solvent (water) and with themselves
Aggregation and precipitation
Aggregation of proteins refers to nonreversible interaction and clustering
of two or more protein molecules. Protein aggregates may be soluble or
insoluble.

21. Surface adsorption
The adsorption of proteins and peptides to the surfaces of the container,
closure, or filter results from protein surface interaction with nonpolar
surfaces

22. CHEMICAL INSTABILITY
Chemical instability of proteins and peptides generally involves one or more
of the following chemical reactions
Hydrolysis
Proteolysis is the hydrolysis of the peptide bond between amino acids in a
peptide or protein. At an extreme pH and temperature, the peptide bond can
undergo rapid proteolysis resulting in protein degradation and/or
fragmentation
Deamidation
Deamidation is one of the main chemical degradation pathways of proteins in
which the side-chain linkage in a glutamine (Gln) or asparagine (Asn) residues
is hydrolyzed to form a carboxylic acid.

23. Oxidation:
Oxidation is one of the major causes of chemical degradation in proteins and
peptides. The functional groups in proteins that can undergo oxidation
include the following Sulfhydryl in cysteine (Cys), Imidazole in histidine
(His), Thiolether in methionine (Met), Phenol in tyrosine (Tyr), Indole in
tryptophan (Trp)
Racemization
Racemization can affect protein conformation. All amino acid residues except
glycine (Gly) are chiral at the carbon atom bearing the side chain and are
subject to base-catalyzed racemization

24. Di sulfide exchange
Di sulfide bonds provide covalent structural stabilization in proteins.
Cleavage and subsequent rearrangement of these bonds can alter the tertiary
structure, thereby affecting protein conformation, stability, and biological
activity
Maillard reaction
The use, or presence as impurities, of reducing sugars (e.g., glucose, lactose,
fructose, maltose, xylose) in a protein formulation can result in the Maillard
browning reaction, which involves nonenzymatic glycation of the protein at the
basic protein residues such as lysine, arginine, asparagine, and glutamine.

25. Drug Name Brand Name Indication
Atosiban acetate Antocin
(Jenburkt
pharmaceuticals Ltd.)
Delaying the birth in case of threat of
premature birth
Bacitracin Bacitracin,
Cortisporin, Neosporin
(Pfizer)
Infants with pneumonia and empyema
caused by staphylococci Bivalirudin
Calcitonin Miacalcin (Sebela
Pharmaceuticals)
Symptomatic Paget's disease for patients
unresponsive to alternate treatments
Dactinomycin Cosmegen (Dr.
Reddy’s Laboratories
Ltd.)
Wilms'tumor, childhood
rhabdomyosarcoma, Ewing's sarcoma and
metastatic
Lypressin Diapid (Novartis) Central diabetes insipidus, Cushing’s
syndrom
Marketed Protein and Peptide Drugs

26. Drug Name Brand Name Indication
Oxytocin Syntocinon (Novartis,
Karnataka Antibiotics and
Pharmaceuticals Ltd.)
Initiation or improvement of
uterine contractions
Somatostatin acetate Stilamin (Serum
International Ltd.)
Acute variceal bleeding
Vancomycin Vancocin (Eli Lilly and
Company, AstraZeneca)
Serious or severe infections caused
by susceptible strains of
methicillinresistant
Enfuvirtide Fuzeon (Roche India) AIDS/HIV-1 infection
Cyclosporine Gengraf, Neoral, Pulminiq,
Restasis, Sandimmun
(AbbVie Inc.)
Transplant (kidney, liver, and
heart) rejection, rheumatoid
arthritis, severe psoriasis.

27. Market Research For Proteins and Peptides

29. References
 Pharmaceutical Dosage Form and Drug Delivery Third Edition by Ram I. Mahato and
Ajit S. Narang CRC Press
 Jain NK. Progress in Controlled and Novel Drug Delivery System. CBS Publishers
and Distributors: New Delhi. 1st ed. 20004.
 Savale SK. PROTEIN AND PEPTIDE DRUG DELIVERY SYSTEM. WORLD
JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES; Volume 5,
Issue 4. 724-742 DOI: 10.20959/wjpps20164-6425.
 http://en.wikipedia.org

30. Thank You!!