SEMINAR

ON
PROTEIN AND PEPTIDE DRUG DELIVERY
By
M.NAGESHWAR RAO,
M. Pharmacy , I YEAR II SEM

Under the guidance of

M.Vijayalaxmi, M. Pharm.(Ph.D)
Assistant professor ,
TEEGALA.KRISHNAREDDY COLLEGE OF PHARMACY,
SAROOR NAGAR, HYDERABAD, 506009

CONTENTS

Protein & Peptides.

Structure of protein.

Classification of protein.

Importance of protein and peptide drugs.

Advantages and disadvantages and stability problems.

Parenteral delivery of protein and peptide drug delivery.

non parenteral delivery of protein and peptide drug delivery.

Marketed formulations .

Conclusion.

References.
2

INTRODUCTION
PROTEINS : Proteins are the large organic compounds

made of amino acids arranged in a linear chain and joined

together by polypeptide bonds.
PEPTIDES: These are short polymers formed from the
linking, in a defined order of amino acids.

STRUCTURE OF PROTEIN
There are four types.
Primary structure- The amino acid sequence.
Secondary

structure-

structures stabilized by

Regularly

repeating

local

hydrogen bond.

Tertiary structure-Three dimensional

structure of

polypeptide
Quaternary

structure-The

structure

formed

by

several protein molecules (polypeptide chains).

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Classification of
Proteins
According to their biological roles

Transport
proteinsi.e.
Haemoglobin
of
erythrocytes
Contractile or Motile proteins- i.e. Actin and
Myosin
Structural proteins- i.e. Collagen in bones

Defense proteins- i.e. Immunoglobulin's and

Antibodies
Regulatory proteins- i.e. insulin
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WHY PROTEIN AND PEPTIDE DRUGS ?

The protein and peptides are very important

in biological cells.
Lack of proteins and peptides causes diseases
like Diabetes mellitus.
Diabetes mellitus is caused due to the lack of
protein called INSULIN.
Now a days R-DNA technology and hybridoma
techniques also used in protein and peptide
based pharmaceuticals.
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Advantages of protein and

peptide drug delivery system

Erythropoietin used for production of RBC.

Tissue plasminogen activator is used for Heart

attack, Stroke.
Oxytocin maintain labor pain.
Bradykinin increases the peripheral circulation.
Somatostatin decrease bleeding in gastric ulcer.
Gonadotropin induce ovulation.
Insulin maintain blood sugar level.
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Advantages of protein and peptide drugs

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.
Drug delivery can be controlled precisely.

DISADVANTAGES OF PROTEIN AND PEPTIDE

DRUGS
Large molecular size
Susceptibility to enz. Degradation
Short plasma half life
Ion permeability
Immunogenicity
Aggregation
Denaturation etc

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Stability problems:
(in vivo in the body)

Elimination by B and T cells

Proteolysis by endo/exo peptidases
Small proteins filtered out by the kidneys

very quickly
Unwanted allergic reactions may develop

(even toxicity)
Loss due to insolubility/adsorption
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12

Commonly used excipients For

solving physical and chemical stability problems

Excipients

Function

Example

Surfactants

Prevent denaturation
and aggregation
Antiaggregatory
Stabilize protein
against denaturation

Polysorbate 20, 80

Albumin
Sugars

Cryoprotectants

24 Jan. 2010

Stabilize protein
against very cold
condition
Modern College of Pharmacy, Pune

Serum albumin
Mannitol,
propylene glycol,
Sucrose, Lactose
Sugars, Amino
acids, Amines,
polyols, Salts
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Absorption of proteins &peptides:

Penetration of proteins into mucosal

membranes:
Achieved by two mechanisms
1) Tran cellular: Enhancers increases
trancellular permeability of proteins and
peptide drugs by affecting membrane lipids
and proteins.
Various enhancers used in this pathway:
Dimethyl maleate
NSAID
MONOGLYSERIDES

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Para cellular pathway:

Enhances the penetration of proteins and

peptides by increasing the permeability of

para cellular pathway by increasing the pore
size of mucosal membrane.
Various enhancers used :
EDTA
N- acyl amino acids.
N- acyl collagen derivatives.

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Protein &peptide Drug Delivery

D R U G D E L IV E R Y C L A S S IF IC A T IO N

D r u g D e li v e r y

R o u te o f A d m in is t r a ti o n

P u l m o n a ry

P a re n te ra l

T ra n sd e rm a l
I m p la n ts

D r u g M o d i f ic a ti o n

M is c e ll a n e o u s
O c u la r

O ra l

P E G y la t io n

P ro -d ru g

P o ly m e r d e p o t

N asal
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Non parenteral routes of administration

Oral route.
Nasal route.
Polumnory route.
Buccal route.
Transdermal route.
Ocular route.

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Parenteral drug delivery systems:

Polymer based drug delivery system.
Liposome based drug delivery system.
Hydro gel based drug delivery system.
Emulsion based drug delivery system.

Pumps :
1) Implantable infusion pumps
2) Mechanical pumps

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Advantages and Disadvantages of parenteral route:

Advantages

19

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.
And non-toxic.
Two types of polymers are used widely
1)natural polymers
2)synthetic polymers
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Proteins:
1) Natural polymers: Collagen , hemoglobin and gelatin.
2) Synthetic polymers: mainly poly esters like PLA and

PGA are used widely.

Peptides: Calcitonin, somatostatin are formulated as
peptide in polymeric drug delivery system.
In vivo Biodegradation: Homogenous hydrolytic chain
cleavage mechanisms.
Example: PGA, During cleavage of PGA no.of carboxyl
groups increases.
Disadvantages: Lack of purity, easily contaminated with
microorganisms.

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Liposome based drug delivery:

Liposome's are microscopic vesicles composed of

one or more aqueous compartments.

Liposomes in Proteins delivery :
Example: Lecithin used in controlled drug release.
Liposomes in peptide drug delivery:
Bleomycin : A peptide with anti tumor activity,
reduces normal tissue toxicity.
Negatively charged liposome's produces a
prolonged hypoglycemic effect in diabetic drugs,
which are injected by subcutaneous injection.

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Advantages of liposome drug delivery system

Soluble in both organic and aqueous media.
Liposomes are important for targeting drugs

directly to the liver, and brain. Lipsosomes

easily crosses blood brain barrier.
EXAMPLE: Dopamine converted to L-Doapa
Used as a vehicles for vaccines.
Disadvantages:
Less stable , easily susceptible to oxidation.
Hence liposomes are replaced by noisome an
alternate for liposomes.
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Hydro gel based drug delivery system:

Hydro gels are polymers which have the

ability to swell in water .

Biodegradable hydro gels are used, due to its
biocompatibility .
Examples: Hydroxymethylacrylate,used to
minimize mechanical irritation to surrounding
tissue.
Advantages: Low interfacial tension between
hydro gel surface and aqueous solution has
found to minimize protein adsorption and cell
adhesion.
Disadvantage: Difficulty to achieve

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Emulsions 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 .

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Pumps:
Pumps :

Types of pumps:
1) Implantable infusion 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.
2) Mechanical pumps: Easily manipulated to deliver
protein and peptide drugs.
Example: insulin has been successfully delivered by
portable syringe.
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Non parenteral routes of drug delivery:

Parenteral route is not properly achievable,

hence other routes are preferred.

1) Oral route.
2) Rectal route.
3) Nasal route.
4) pulmonary route.
5) Buccal route.
6) Transdermal route.
7) Ocular route.
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Oral route:
Encapsulated peptides or proteins in amino

acids with microsphere of approximately 10

micron in diameter , used for oral delivery.
Example : Insulin and heparin.
Orally administered insulin produces
hypoglycemic effect .
Disadvantages: Acid catalyzed degradation in
stomach.
Proteolysis in GIT.

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Rectal route:
Insulin is administered in rectal route.
Advantages:
Reduction in first pass metabolism.
Rapid systemic absorption.
Safe and convenient for neonates and infants.
Withdrawal of drug easy , incase of adverse

effects.

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Nasal route:
Nasal mucosa allows the effective systemic absorption of

protein and drugs, which are susceptible to gastro

intestinal degradation when administered orally.
Advantages:
Drugs administered by nasal route directly enters into
systemic circulation. Nasal mucosa prevents destruction of
peptides.
Disadvantages: Peptide activity is present in nasal cavity ,
that leads to destruction of amino acid sequence.
Example : Leuprolide-Metered dose inhaler suspension.

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Pulmonary route :
Lungs are attractive site for protein drug

delivery becauseA) large surface area of lungs approximately

100mtrsquare in adults.
B) Rapid absorption of drug into blood stream
through alveoli.
Advantages : By using mechanical system
powders are derived.
Example : Albumin was largely absorbed with
in 48 hours.
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Buccal route:
Mucoadhesive dosage forms can be used for

buccal route.
Adsorption enhancers like salicylates or a
surfactant is used for protein and peptide delivery
through buccal route.
Example:
Oxytocin , vasoprocin , insulin, are reported to be
absorbed through buccal mucosa . And adhesive
gel, patches , tablets are used.
Insulin is absorbed through buccal mucosa in the
presence of sodium glycolate.

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Transdermal route:
For transdermal delivery of drugs is followed

by iontophoresis , phonophoresis , and

prodrug phenomenon.
Iontophoresis: Used for local and systemic
delivery of proteins and peptides. In this an
electric current is used to drive the molecules
across the skin surface.
Example: Transport of insulin using
iontophoresis.
Phonophoresis: The absorption is enhanced
by thermal effect of ultrasonic waves and
subsequent alteration of physical structure of
skin surface.
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Ocular route:
In this route enkephalins , thyrotrophin

releasing hormones ,luteinizing hormones

,glucagon and insulin are administered.

34

Formulation aspects:
Storage:
Refrigeration
Packaging
Additives
Freeze-Drying

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Protein Formulations
1

36

PEGylation
PEG is a non-toxic, hydrophilic, FDA
approved, uncharged polymer
Increases in vivo half life
Decreases immunogenicity
Increases protease resistance
Increases stability

37

Proteinylation
Attachment of additional or secondary
(nonimmunogenic) proteins for in vivo protection
Cross-linking with Serum Albumin
increases in vivo half life
Cross-linking or connecting by protein
engineering with antibody fragments
38

Formulation with
permeabilizers
Salicylates (aspirin)
Fatty acids
Metal chelators (EDTA)

39

Marketed formulations
Product

Formulation

Route

Indication

Lupron

Sterilized lyophilized
microspheres Contains
Leuprolide acetate.

i.m

Prostatic
cancer

Pitressin tannate

Vasopressin tannate in
peanut oil.

i.m

Antidiuretic

H.P. Acther gel

Adrenocorticotropic harmone
in gelatin

i.m. , s.c.

Endocrine
cancer

Sandostatin-l
depot

Octreotide

i.m.

Neurotropin

Growth harmone

i.m .

Drowsiness

Conclusion :
Protein and peptide based pharmaceuticals are

rapidly becoming a very important class of

therapeutic agents and are likely to replace many
existing organic based pharmaceuticals in the
very near future.
Peptide and protein drugs will be produced on a
large scale by biotechnology processes and will
become commercially available for therapeutic
use.

41

Reference:
Robinson, R. Joseph. Controlled Drug

Delivery : Fundamental &application,

Second edition, Mercel Dekkar, USA, Page
no.7-14.
N.K.Jain, Progress in Controlled & novel
Drug delivery system. , Page no.183-195.

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Thank
you
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