Protein and Peptide drug delivery system

1. PROTEIN AND PEPTIDE
DRUG DELIVERY SYSTEM
1
,
By: Dr. Manish Kumar
Professor, MM College of Pharmacy, MM (DU), Mullana.
Ambala, Haryana

2. CONTENT
S
I. Protein & Peptides
II. Structure of protein
III. Classification of protein
IV. Drug delivery system
V. Stability testing
VI. Conclusion
VII. References
2

3. 1. PROTEIN & PEPTIDES
 PROTEINS: Proteins are the large organic compounds
made of amino acids arranged in a linear chain and joined
together by peptide bonds.
Protein > 50 amino acids
 PEPTIDES: These are short polymers formed from the
linking, in a defined order of amino acids.
peptide < 50 amino acids
3

4. CONTINUE….
 Why protein and peptide are used;
 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.
4

5. CONTINUE…
ADVANTAGES
 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. 5

6. CONTINUE…
FUNCTIONS
 Transport and storage of small molecules.
 Coordinated motion via muscle contraction.
 Mechanical support from fibrous protein.
 Generation and transmission of nerve impulses.
 Enzymatic catalysis.
 Immune protection through antibodies.
 Control of growth and differentiation via hormones 6

7. 2. STRUCTURE OF PROTEIN
The structure of protein divided in to four types:
1. Primary structure : The amino acid sequence.
2. Secondary structure: Regularly repeating local structures
stabilized by hydrogen bond.
3. Tertiary structure : Three dimensional structure of
polypeptide.
4. Quaternary structure: The structure formed by several
protein molecules (polypeptide chains).
7

8. CONTINUE…
8

9. 3. CLASSIFICATION OF
PROTEIN
 Depending on the number of amino acids they are classified
as follows:
 Polypeptides protein
 Oligopeptides protein
 Fibrous proteins
 Globular proteins
 Oligo meric proteins
9

10. 4. DELIVERY OF PROTEINS
DRUG DELIVERY CLASSIFICATION
Pulmonary Parenteral Transdermal
Implants Ocular Nasal
Miscellaneous Oral
Route of Administration
PEGylation Pro-drug Polymer depot
Drug Modification
Drug Delivery
10

11. CONTINUE…
Parenteral routes of administration;
 Parenteral route is most efficient way for systemic delivery
of proteins and peptides.
 This is the best choice to achieve therapeutic activity
 Mainly 3 routes of administration
 Intravascular
 Intramuscular
 Subcutaneous
11

12. CONTINUE…
Advantages
Route of delivery for 95% of proteins
Allows rapid and complete absorption .
Avoids first pass metabolism
Disadvantages
Problems with overdosing, necrosis
Local tissue reactions/hypersensitivity
Everyone hates getting a needle
12

13. CONTINUE…
INTRAVENEOUS ROUTE:
 Excessively metabolized and tissue drug bound at the site of
IM can be administered by this route such as Insulin ,
Interferon etc.
DISADVANTAGES:
Causes pain, tissue necrosis and thrombocytopenia.
ADVANTAGES: Antibiotics can be administered.
13

14. CONTINUE…
 INTRAMUSCULAR ROUTE:
 Gamma globulins given by this route are proved to have
long-term protection from hepatic infection. some drugs
given by this route include long acting insulin, GH.
DISADVANTAGES:
Not used for all proteins and peptide drugs because of
metabolism of drugs at the site of injection.
14

15. CONTINUE…
 SUBCUTANEOUS ROUTE;
 Controlled release is obtained from implantable polymeric
devices.
 These are prepared from crossed linked polymers which are
biocompatible and biodegradable e.g. Poly lactic acid.
Release of Insulin, bovine serum albumin, LH was prolonged
by this route.
15

16. 4. PARENTERAL DRUG DELIVERY SYSTEM
 Polymer based drug delivery system.
 Liposome based drug delivery system.
 Hydro gel based drug delivery system.
 Emulsion based drug delivery system.
PUMPS:
 Implantable infusion pumps
 Mechanical pumps
16

17. 17

18. PARENTERAL ROUTES OF ADMINISTRATION
 Parenteral route is most efficient way for systemic delivery
of proteins and peptides.
 This is the best choice to achieve therapeutic activity.
 Mainly 3 routes of administration
 INTRAVASCULAR
 INTRAMUSCULAR
 SUBCUTANEOUS
18

19. • Route of delivery for 95% of proteins
• Allows rapid and complete absorption .
• Avoids first pass metabolism
Advantages
• Problems with overdosing, necrosis
• Local tissue reactions/hypersensitivity
• Everyone hates getting a needle
Disadvantages
19

20. INTRAVENEOUS ROUTE
 Excessively metabolized and tissue drug bound at the
site of IM can be administered by this route.
EX: Insulin, Interferon.
DISADVANTAGES:
 Causes pain, tissue necrosis and thrombopenia.
ADVANTAGES:
 Antibiotics can be administered.
20

21. INTRAMUSCULAR ROUTE
 Gamma globulins given by this route are proved to have
long-term protection from hepatic infection.
 some drugs given by this route include long acting insulin,
GH.
DISADVANTAGES:
 Not used for all proteins and peptide drugs because of
metabolism of drugs at the site of injection.
21

22. SUBCUTANEOUS ROUTE
 Controlled release is obtained from implantable polymeric
devices.
 These are prepared from crossed linked polymers which are
biocompatible and biodegradable.
EX: polylactic acid
 Release of Insulin, bovine serum albumin, LH was
prolonged by this route.
22

23. PARENTERAL DRUG DELIVERY SYSTEM
 Polymer based drug delivery system.
 Liposome based drug delivery system.
 Hydro gel based drug delivery system.
 Emulsion based drug delivery system.
PUMPS:
 Implantable infusion pumps
 Mechanical pumps
23

24. 24

25. POLYMER BASED DRUG DELIVERY SYSTEM
polymers are used as carriers in this drug
 Pug delivery system.
CHARACTERS OF POLYMERS
 It should be biodegradable.
 It should be bio compatible.
 And non-toxic.
Two types of polymers are used widely
 natural polymers
 synthetic polymers
25

26.  Natural polymers: Collagen , hemoglobin and gelatin.
 Synthetic polymers: mainly poly esters like PLA and PGA are
used widely.
 Diffusion of drug out of the polymer
 Drug Release by Polymer Degradation
26
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27. 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’s 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.
27

28. ADVANTAGES OF LIPOSOME DRUG DELIVERY
 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.
DISADVANTAGES
 Less stable , easily susceptible to oxidation.
 Hence liposome’s are replaced by noisome an alternate for
liposome’s.
28

29. 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: Hydroxymethylacrylate, used to minimize
mechanical irritation to surrounding tissue.
29

30. 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.
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.
30

31. 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.
2. MECHANICAL PUMPS
 Easily manipulated to deliver protein and peptide drugs.
Example: insulin has been successfully delivered by portable
syringe.
31

32. NON PARENTERAL ROUTES OF ADMINISTRATION
Parenteral route is not properly achievable, hence other routes
are preferred.
 Oral route.
 Rectal route.
 Nasal route.
 Pulmonary route.
 Buccal route.
 Transdermal route.
 Ocular route
32

33. 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.
33

34. TRANSDERMAL ROUTE OF ADMINISTRATION
 This is topical medication.
 Drug is absorbed through the skin.
EX: Insulin, vasopressin
ADVANTAGES:
 Controlled administration of drug is possible.
 Improved patient compliance.
 Drugs with short half lives can be administered.
DISADVANTAGES:
 High intra and inter patient variability.
 Low permeation because of high molecular weight.
 Hydrophilicity and lipophilicity of stratum corneum. 34

35. Number of approaches are available for effective protein and peptide
drug delivery.
 They are
 IONTOPHORESIS
 PHONOPHORESIS
 PENETRATION ENHANCERS
 PRODRUG
 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. 35

36. PULMONARY ROUTE OF ADMINISTRATION
 Lungs are attractive site for systemic delivery of proteins
and peptides because of their enormous surface area(70
sq.m)
 Alveoli and lungs are the absorption sites.
 Drugs are absorbed through lungs by simple diffusion,
carrier mediated transport
36

37. ADVANTAGES:
 Decrease in dose requirement.
 Fast absorption
 Increased patient compliance
DISADVANTAGES:
 Inflammation may be observed in lungs.
 Degree of bioavailability was less due to hydrolytic enzymes
present in lungs
37

38. RECTAL ROUTE OF ADMINISTRATION
 Rectum is highly vascularised body cavity.
 Rectal mucosa is devoid of villi.
 Drugs are in form of suppositories, gel, dry powders.
EX: Insulin, calcitonin
ADVANTAGES:
 Reduced proteolytic degradation.
 Improved systemic bioavailability with co-administration of
absorption enhancers.
EX: surfactants
 Large dose can be administered.
38

39. OCULAR ROUTE
 In this route enkephalins, thyrotrophin releasing hormones
,luteinizing hormones ,glucagon and insulin are administered
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 , vasopressin , 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.
39

40. The drugs are absorbed through oral mucosa mainly through
the non-keratinized regions.
ADVANTAGES:
 It can be attached or removed without any discomfort and
pain.
 Well acceptability by patients.
 Drugs are absorbed rapidly.
DISADVANTAGES:
 Administration time is limited.
 Drug loss by accidental swallowing.
40

41. NASAL ROUTE OF ADMINISTRATION
 The nasal route has been employed for producing local action on
the mucosa which is more permeable compared to oral mucosa.
 Nasal absorption is through passive diffusion.
EX: Insulin, human growth hormone.
ADVANTAGES:
 Rapid onset of action
 First pass metabolism can be avoided
 Better drug absorption
DISADVANTAGES:
 Long-term usage causes toxicity.
 Size of proteins and peptide drugs reduces systemic
bioavailability. 41

42. PROTEIN FORMULATIONS
42
1
• Protein sequence modification (site
directed mutagenisis)
• PEGylation
2
• Proteinylation
• Microsphere encapsulation
3
• Formulating with permeabilizers

43. PEGYLATION
 PEG is a non-toxic, hydrophilic, FDA approved,
uncharged polymer.
 Increases in vivo half life.
 Decreases immunogenicity.
 Increases protease resistance.
 Increases stability.
43
CH-CH-CH-CH-CH-CH-CH-CH-CH-CH
|
|
|
|
|
|
|
|
|
|
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
+

44. PROTEINYLATION
 Attachment of additional or secondary (non-immunogenic) 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.
44
+
Protein drug scfc (antibody)

45. FORMULATION WITH PERMEABILIZERS
 Salicylates (aspirin)
 Fatty acids
 Metal chelators (EDTA)
45

46. STABILITY TESTING
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 a drug substance or a
formulated product which is utilized for prediction of its shelf life, determine proper
storage conditions.
 General
 Selection of Batches
 Container Closure System
 Specification
 Testing Frequency
 Storage Conditions
 Stability Commitment
 Evaluation
 Statements/Labelling
 On-going Stability Studies 46

47. 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.
 Their need in the clinical & therapeutic regions has
intensified the investigation for their convenient & effective
delivery through noninvasive system.
47

48. REFERENCES
 Controlled drug delivery concepts and advances by S.P vyas
& Roop k.khar Understanding the Fundamentals of
Peptides and Proteins
 By GARY HU (Bio processing journal -trends in
development in bio process technology)
 PEPTIDES AND PROTEINS IN PHARMACEUTICALS
RATNAPARKHI M.P.,* CHAUDHARI S.P., PANDYA V.A. I
nternational Journal of Current Pharmaceutical Research
48

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