1. PROTEIN/PEPTIDE DRUG DELIVERY
SYSTEM
Presented by
J.sowmya latha
m.pharm(p’ceutic
s)
256212886042,
MRCP.
Under the guidence
of
Mrs.yasmin begum
M.pharm(ph.D)

2. Protein Formulations
1
• Protein sequence modification (site
directed mutagenisis)
• PEGylation
2
• Proteinylation
• Microspher encapsulation
3
• Formulating with permeabilizers

3. Site Directed Mutagenesis
E343H
 Allows amino acid substitutions at specific sites in a protein
i.e. substituting a Met to a Leu will reduce likelihood of
oxidation.
Protein engneering(size,shape,etc).

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

5. PEGylation
CH-CH-CH-CH-CH-CH-CH-CH-CH-CH
| | | | | | | | | |
OH OH OH OH OH OH OH OH OH OH
+

6. 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

7. Proteinylation
Protein drug
+
scfc (antibody)

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

9. Drug Delivery
Route of
administration
parenteral Non-parenteral

10. Parenteral Delivery of Proteins
• For the systemic release of the protein and
peptides parenteral route is the most efficient
route.
• This is the best choice to achieve the therapeutic
activity.
• Mainly three types of administration are used:
 Intravenous
 Intramuscular
 Subcutaneous

11. Advantages and Disadvantages

12. The drug carrier systems employed for defined and
controlled delivery of drug through this route are :-
particulates
Cellular carriers
pumps
• Microspheres
• Emulsions
• liposomes
• erythrocytes
• Mechanical
• Osmotic
• Controlled release

13. Particulates:
A)Microspheres:
 These are solid spherical particles in the size range of few tenths
of micrometer to several hundreds micrometer containing
dispersed drugs in either solution or microcrystalline form.
 They can be targeted to a particular organ or a specific part of a
organ o to a selective intracellular site. Passive targeting can be
achieved by cellular uptake or local injection.
 Active targeting can be achieved by conjugating receptor-specific
moieties like monoclonal antibodies.

14. ADVANTAGES:
 They can be administered subcutaneously,
intramuscularly.
 By using an appropriate technique they can be
prepared cheaply.
DISADVANTAGES :
 Drug release may be poorly defined. They have to
pass successfully the biological and cellular barriers.
 They may interact or form complexes with the blood
components.

15. B) LIPOSOMES:
• These are spherical vesicles formed when
phospholipids are allowed to swell in aqueous media.
• As their structure resembles to cell membranes,
Liposome can serves as a depot releasing the drug
slowly.
• Liposome protect the entrapped peptide from
enzymatic degradation on intravenous administration.
• They can passively deliver peptide to a particular site.

16. ADVANTAGES:
 Flexibility in size, shape and structure. Relatively
non toxic disposition.
 Ability to encapsulate both hydrophilic and
lipophilic peptide or protein.
DISADVANTAGES:
 The constituent phospholipids have tendency to
interact with proteins.
 Proteins susceptible to aggregation may affect the
stability of liposome.

17. 2) CELLULAR CARRIERS:
Peptides and proteins can be encapsulated in erythrocytes to
achieve their prolong release and target.
ADVANTAGES:
Biodegradability Non immunogenic Large circulation life Large
quantity of drug can be encapsulate in small volume of cell.
Offers enzymatic protection to the drug.
LIMITATION:
Long term storage is problematic.

18. 3) PUMPS:
 The primary driving force for delivery is the pressure
difference .
 Pressurizing the reservoir by osmotic or direct mechanical
actuating can generate this difference to affect the drug
release.
 The pump can either be implanted or externally portable.
 The ideal pump should have :
 1 Wide range of delivery rate.
 2 Accurate, precise and stable delivery.
 3 Compatibility of drug with internal pump components.
 4 Monitoring of status of pump should be easy.
 5 Protection against overdose and leakage.
 6 Long reservoir life.

19. NON PARENTERAL ROUTE OF
ADMINISTRATION
Oral Route of Administration:
 oral route is most popular route from patient point of view.
 Advantages:
 1.Convenience
 2.Acceptibility
 3.High patient compliance
Disadvantages
 The systemic bioavailability of protein and peptide drug
by this route is generally less than 2%.
 Very less permeability through oral mucosa. Potential
degradation by strong acids and proteolytic enzymes.

20. Various strategies have been attempted for effective delivery of
proteins and peptides drugs through oral route. Some of them
are as follow:
MODIFICATION BY CHEMICAL
SYNTHESIS:
• This modification assist in manipulating the pharmacokinetic
parameters to improve the therapeutic value of the parent drug.
• This can be done by:
• 1)Irreversible (analogue)
• 2)Reversible (prodrug)

21. Enzyme Inhibitors: Aprotinin, camostat mesylate, Bacitracin
.
Penetration Enhancer: SLS, EDTA, Fatty acids.
Carrier System : This strategy is particularly applicable in case of
poorly absorbed ,the drugs which are unstable in G.I.lumen.
Example: Liposome and sub micro emulsion

22. Buccal Route of Administration
The drugs are absorbed through oral mucosa i.e. occur in non
keratinized sections.
ADVANTAGES:
 1)It is close resemblance to oral route seems well acceptable to
the patients.
 2)Can attached and remove without any pain or discomfort.
 3)It is worth considerable when penetration enhancers are
used.

23. The inherent problem with these dosage form is the risk of drug loss
by accidental swallowing leads to less administration time.
The various strategies employed for Buccal delivery:
 1)Adhesive tablets
 2)Adhesive gels
 3)Adhesive patches
 4)Absorption promoters

24. Nasal Route of Administration
 The nasal route has been chiefly employed for producing local
action on mucosa.
 This mucosa is more permeable compare to the oral mucosa.
 The nasal absorption of protein and peptide can be via special
diffusion and special targeted mechanism i.e. 1-20%
Example: Insulin and Human growth hormone.
Advantages:
 Convenient ,simple and practical way of drug administration.
 High vascular permits better drug absorption. First pass
metabolism can be avoided. Rapid onset of action.
Disadvantages:
 Long term usage causes toxicity.
 Enzymatic barrier, size of protein and peptide drug reduce the
systemic bioavailability.
•

25. Number of approaches are available for achieving effective
delivery of protein and peptide drug. Those are:
 VISCOSITY MODIFICATION
Eg:Hydroxy propyl methyl cellulose
 MEMBRANE TRANSPORTER
Eg:Surfactant( SLS)
 ENZYME INHIBITOR
Eg:Bestatin, Amastatin pH MODIFICATION Insulin exhibit
highest solubility in acidic medium

26. TRANSDERMAL ROUTE OF
ADMINISTRATION
 This is a topical medication.
 In this the drug is absorb through skin. Example: Insulin,
Vassopressin.
ADVANTAGES :
 Better and improved patient compliance.
 Drug with short half life can also administer.
 Administration of drugs with low therapeutic index.
 Controlled administration is possible.

27. DISADVANTAGES:
Low rate of permeation of these drugs because of large molecular
weight.
High lipophilicity and hydrophilicity of stratum corneum of skin.
Number of approaches are available for achieving effective
delivery of protein and peptides. Those are:
 1)IONOPHORESIS: induces migration of ions or charged
molecules when the current is allowed to flow through an
electrolyte medium.
 2)PHONOPHORESIS: thermal effect of ultrasonic waves
alters the physical structure of skin and enhance permeability.
 3)PENETRATION ENHANCER: Oleic acid and Surfactant.
4)PRODRUG: Modification in the ph ysiochemical properties
of drug like lipophilicity and charge will enhance the
permeability of the drug.

28. PULMONARY ROUTE OF
ADMINISTRATION
o Respiratory track offers an alternative site for systemic non
invasive delivery of protein and peptide drugs Alveoli and lungs
are the absorption site(90%).
o Drugs are absorbed through lungs by simple diffusion and carrier
mediated transport.
ADVANTAGES:
 Provide a direct route to systemic circulation.
 Safe route even in patient with lungs disease.
 Decrease in dose requirement.
 Fast absorption. Patient compliance.

29. DISADVATAGES:
Only small amount of drug can be administered.
 Inflammation and edema can be observed.
Degree of bioavailability is less due to presence of hydrolytic
enzymes in lungs. Most of the drug administer at upper part of
the lung area with low systemic circulation.
RECTAL ROUTE OF ADMINISTERATION
 Rectum is highly vascularised body cavity. The rectal mucosa is
devoid of any villi.
 These drugs are in the form of gel and dry powders.
 Example: Insulin, Gastrin and Calcitonin.
ADVANTAGES:
 Large dose can be administer.
 Avoid first pass metabolism.

30. Occular route of administration
To treat infections and enzymes used to promote wound healing.
a. Bacitracin
 The drug is applied topically to the eye for a variety of
conditions, including eyelid burns and corneal superficial
punctate keratits .It is also used to treat optic neuritis.
 Commercial bacitracin is a mixture of at least nine bacitracins,
which is used for its antibacterial activity

31. b. Chymotrypsin
Chymotrypsin is used clinically in the eye for enzymatic
intracarpsular lens extraction.
c. Cyclosporine
Cyclosporine are a group of biologically active metabolites
produced by Fungi. When cyclosporine A is administered by
nonocular route in rats, it produces significant blood levels, but it
can not be detected in tissues.

32. 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.
 Drug delivery can be controlled precisely.

33. Vaginal route of administration
 The vaginal preparations currently on the market contain
topicaly effective agents.
 Anti-microbial agents:eg;metronidazole
 Estrogenic steroids such as estroidal for restoring the
normal physiology of vaginal mucous.
Advantages:
 The feasibility of self administration
 The possibility of prolonged retention of drug delivery
system.
 The potential avoidance of hepato gastro intestinal first pass
elimination.
 Minimizatio of proteolytic degradation.

34. Recent advances in protein drug delivery
 Polymeric drug delivery
 Microencapsulation
 Polymer scaffolds
 Magnetic targeted carrier
 Liposomes
 Hydrogel based drug delivery

35. Polymeric drug delivery
 Frequency of doses reduced
 Drug utilised more effectively
 Drug stabilised inside the polymeric matrix
 Reduced side effects
 Possibility of dose dumping
 Deactivation of drug inside the polymer

36. Release Mechanism
 Diffusion of drug out of the polymer
o o o
o o o
o o o
o
o o o
o o
 Drug Release by Polymer
Degradation
Hydrolysis
Enzymatic (Phosphotases;
Proteases etc.)

37. Microsphere Drug delivery
• Process involves encapsulating protein/peptide drugs in small
orous particles for protection from “insults” and for sustained
release.
Release mechaism:
• Hydrophyllic(i.e gelatin)
-best for burst release
Hydrophobic(i.e PLGA):
-good sustained release(esp vaccines)
-tends to denature proteins.
Hybrid (amphaphatic):
-good sustained release
-keeps proteins native/active

38. Microsphere Drug delivery
• Two types of microspheres
Nonbiodegradable
e.g, ceramic particles
polyethylene co-vinyl acetate
polymethacrylic acid/PEG
Biodegradable (preferred)
e.g, gelatin
polylactic-co-glycolic acid
(PLGA)

39. Polymer scaffolds
 Incorporate drug in to polymer matrix.
 Protection of drug from enzymatic degradation particularly
applicable to protein and peptide drugs.
 Release drug at knwn rate over a prolonged duration.
 Drug dispersed or dissolved in suitable polymer.
 Diffusion of drug through pores of polymer.

40. Magnetic Targeted Carriers (MTCs)
 Microparticles, composed of
elemental iron and activated
carbon
 Drug is adsorbed into the
MTCs and transported
The particles serve as delivery
vehicles to the area of the tumor
for site-specific targeting

41. Liposomal Drug Delivery
Spherical vesicles with a phospholipid bilayer
 E.g, Bleomycin encapsulated in
thermo sensitive liposome enhanced
antitumor activity and reduced normal
tissue toxicity.
s.C injection of –vely cherged liposomes
produced a prolonged hypoglycemic
effect in diabetic dogs.
 Liposome have recently been used
successfully as vehicles for vaccines.

42. Hydrogel Based Drug Delivery
Hydrogels are three dimensional networks of hydrophilic
polymers that are insoluble

43. Hydrogel Based Drug Delivery
Hydro gels can swell as a result of changes in pH,
Temperature.
R
O
N N
O
R
H H
R = polymer backbone
R
O
NH2
+
O
H H
H2O
e.g Insulin,it has been incorporated in hydro gels and
investigated by researches effectively.

44. conclusion
 Protein and peptide pharmaceuticals are very important class
of therapeutic agents.
 Their emergencies on the clinical & therapeutic horizon has
intensified the investigation for their convenient & effective
delivery through noninvasive route.
 The additional challenges for the pharmacist is the designing
& development of viable delivery system for non parenteral
administration of protein and peptide drugs.

45. References
• Novel drug delivery systems,second edition,reviced and
expanded,YIE CHIEN,pg no;631 to 723
• Controlled drug delivery systems concepts and advances
by S.P.VYAS,ROOP K.KHAR(controlled protein delivery
pg no:503 to 566.
• Robinson, R. Joseph. Controlled Drug Delivery :
Fundamental &application, Second edition, Mercel
Dekkar, USA, pg no:7-14.
• Jain N.K., Progress in Controlled & novel Drug delivery
system. CBS publication; Delhi, 195.
• Gupta H, Sharma A. Recent trends in protein and peptide
drug delivery systems. Asian J Pharm 2009;3:69-75.