DRUG DELIVERY SYSTEM (DDS) : M.PHARM INTRODUCTION FUNCTIONS OF PROTEINS AND PEPTIDES MAIN BARRIERS OF EFFECTIVE ORAL DELIVERY APPROACHES FOR ORAL DELIVERY OF DRUGS

1. PROTEIN AND PEPTIDE DELIVERY
THROUGH ORAL ROUTE
PRESENTED BY :
AKHILAA
1st YEAR M PHARM
PHARMACEUTICS
NGSMIPS

2. CONTENTS
 INTRODUCTION
 FUNCTIONS OF PROTEINS AND PEPTIDES
 MAIN BARRIERS OF EFFECTIVE ORAL DELIVERY
 APPROACHES FOR ORAL DELIVERY OF DRUGS
 CONCLUSION
 REFERENCES
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3. INTRODUCTION
 Proteins are the high molecular weight mixed polymer of alpha amino acids
joined together with Peptide linkages. In protein mainly contain carbon, nitrogen,
oxygen and sulphur molecules.
 Peptides are the condensation product of alpha amino acids.
 Proteins and peptides are used because of following reasons;
o The protein and peptide are important in biological cells.
o Lack of proteins and peptides cause diseases like Diabetes mellitus.
o Diabetes mellitus is caused due to the lack of protein called Insulin.
o Now a days R-DNA technology and hybridoma technique also used in protein
and peptide-based pharmaceuticals.
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4. Functions of Protein and Peptide :
 Transport and storage of small molecules and biological molecules.
 Coordinated motion via muscle contraction.
 The mechanical support from fibrous protein.
 Generation and transmission of nerve impulses.
 Enzymatic catalysis in biochemical reaction.
 The immune protection through antibodies.
 The control of growth and differentiation via hormones.
Examples:
• Erythropoietin is mainly used for production of RBC.
 The protein Tissue plasminogen activator is used for Heart attack, Stroke.
 Oxytocin is used in management of labour plain.
 Bradykinin increases the peripheral circulation.
 Somatostatin decrease bleeding in gastric ulcer.
 Gonadotropin induce ovulation.
 Insulin maintains blood sugar level.
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5. ORAL ROUTE OF DRUG DELIVERY
 Encapsulated protein or peptide with microsphere of approximately 10-micron diameter are used for oral
delivery.
Example: Insulin, Heparin
 MAIN BARRIERS IN EFFECTIVE ORAL DELIVERY:
 Poor intrinsic permeability of peptides/ proteins across biological membranes due to their large molecular
size and hydrophilic nature.
 Susceptibility to enzymatic attack by intestinal proteases and peptidases and digestion into their consistent
amino acids that lack the biological activity of the parent polypeptides.
 Rapid post-absorptive clearance.
 Physical instability like tendencies to aggregate and / non-specifically adsorbed to a variety of physical and
biological surfaces.
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6. Fig 1. Various barriers to oral absorption of Peptides
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7. APPROACHES FOR ORAL DELIVERY OF PROTEINS AND PEPTIDES
Approach Typical examples
Modifications by chemical synthesis of
prodrugs and analogues
PEG derivatives, monosaccharide derivatives.
Use of enzyme inhibitors Bacitracin, chymostatin, aprotinin, soyabean
trypsin inhibitor
Use of penetration enhancers EDTA, sodium deoxycholate, sodium lauryl
sulphate, oleic acid
Carrier systems w/o/w emulsions, emulsomes, nano- and
microparticles, bio adhesive systems
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8. 1

9.  Modifications by Chemical Synthesis of Prodrugs and Analogues
 The strategy of altering the peptide/protein structure by reversible (prodrug) or irreversible (analogue) chemical
modification is aimed to modify physiochemical properties of drugs such as lipophilicity, charge, molecular size,
solubility, configuration, isoelectric point, chemical stability, enzyme lability and affinity to carriers without
compromising on the inherent pharmacological properties of parent drug.
 This modification assists in manipulating the pharmacokinetic parameter, improves the therapeutic value of the
parent drug by facilitating membrane permeation and providing stability against degradation and thereby altering
bioavailability.
 The chemical modification of peptide /protein with PEG is a novel approach to obtain functionalized bioconjugates
with better resistance to proteolytic degradation, increased solubility, reduced immunogenicity and antigenicity and
low toxicity.
 PEGylation imposes certain barrier to clinical application by increasing molecular size, restricting distribution from
blood to target tissues and decreasing receptor-binding affinity.
 For improving oral bioavailability, lipid conjugates with phospholipids have been proposed. Phospholipids provide
unique interface between lipophilic acyl region and hydrophilic biomolecules.
 Lipid conjugates have significant towards protein/peptide with improved stability, bioavailability and barrier
permeation characteristics.
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10. Parent drug Chemical modification approach Result
Insulin Modified with fatty acids lipophilic derivatives have,
increased bioavailability
Tetragastrin (TG) Fatty acylation Degradation clearance of TG
on the apical membrane was
improved
Lutenizing
hormone
releasing
hormone
Conjugated to lipoamino acids and
lipopeptides
Bioavailability improved
Methionine
Enkephalin
Metkephamid Orally inactive
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11.  Use of enzyme inhibitors
Drug Enzyme inhibitors Results
Insulin Aprotinin, Bacitracin, Bestatin,
camostatmesilate, sodium glycolate.
Significant reduction in
insulin digestion and
improvement in its intestinal
absorption profile
Insulin Camostat mesilate Plasma glucose levels
decreased in a dose-
dependent manner.
Vasopressin
and its
analogues
Aprotinin Improvement in the activity
profile
Eel calcitonin Camostat mesilate Significant improvement in
calcitonin delivery
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12.  Use of Penetration Enhancers
Penetration
enhancers
Mechanism Examples
Chelating agents Form complexes with proteins, and these
complexes act on the tight junctions between
epithelial cells, thereby decreasing the resistance
to solute transit by paracellular pathway
Citric acid, EDTA, salicylates
Bile salts Increase the membrane fluidity by decreasing the
viscosity of the mucous layer adhering to mucus
surfaces, inhibit peptidases and solubilises the
drug.
Sodium deoxycholate, sodium
glycolate, sodium taurocholate.
Surfactants Facilitates the leaching of proteins from the
membrane
Polyoxyethylene-20-cetyl ether,
polyoxyethylene-9-lauryl ether
Fatty acids Disturbs the membranes interior and interacts with
the polar head of phospholipids
Oleic acids
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13.  The mechanisms involved in intestinal permeation through transcellular route by absorption enhancers
are:
o Interaction of absorption enhancer (e.g., mixed micelles, salicylic acid) with membrane lipid
protein leads to membrane perturbation followed by an increase in permeability. Saturated fatty
acid with same carbon atom shows fluid micelles and better result, when compared to unsaturated
fatty acid.
o Disorder of membrane status by decrease in membrane nonprotein thiol, e.g., diethyl maleate,
salicylic acid.
 The mechanism involved in intestinal permeation through paracellular route by absorption enhancers
are:
o Chelation between enhancer and Ca++/Mg++ around tight junction which force water through by
osmosis, enhancing paracellular absorption of water-soluble drug.
E.g., EDTA, bile acids.
o Activation of junctional actomyosin contraction.
E.g., glucose, amino acids.
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14.  Carrier system
 Lipid carriers and emulsions:
o It is way to circumvent membrane barrier and thereby promoting the uptake of difficult class
of therapeutics.
o Common type of lipid vesicles are liposomes.
o Liposomes comprises bilayer with aqueous core, both lipid soluble and water-soluble drugs
can be encapsulated.
o The main problem associated with the liposome for oral delivery is poor stability profile.
o They are susceptible to dissolution by intestinal detergent like bile salts and to degradation by
intestinal phospholipases.
o The liposomes stability in the g.i.t can be enhanced by creating cross linked network in the
liposomal membranes.
o Polymerised liposomes using 1,2–Di (2,4 – octadecadienoyl)-sn-glycerol -3-
phosphorylcholine (DODPC) have been developed for the stability.
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15.  Emulsomes:
o It is lipoidal drug delivery vehicle and it is prepared by higher concentration
of Lecithin (5-10%).
o The internal phase of emulsomes remain to be solid or quasi-solid at ambient
temperatures.
o It is prepared by emulsification at elevated temperature where ordered
biphasic dispersion is stabilized by addition of lecithin in high quantity.
o The internal phase may contain entrapped protein /peptide macromolecules
and could be cultivated as nanospheres with surface resembles the
chylomicrons.
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16.  Particulate carriers:
o The particulates employed as delivery vehicle can be replicating and non-replicating in
nature.
o The replicating system comprise of attenuated or genetically modified strains of viruses or
bacteria, which continue to propagate in vivo after administration, e.g., genetically
engineered vaccinia virus and attenuated strains of Salmonella.
o Non replicating particulate systems are polymeric particles and lipid containing particles.
They encapsulate the drug within the particle and thereby lend a protective cover to them in
the hostile GI environment.
o They should maintain certain criteria before they can be utilized as oral delivery vehicle like:
 Resistant to degradation in the GI tract and thus protect encapsulated drug from
degradation.
 The particle should be absorbed to ensure delivery of the encapsulated drug to their in
vivo target.
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17.  Bioadhesive system:
o To delay the transit through the intestine.
o Carbopol and carbophil are reported to interact non-specifically with the
mucus layer over the intestinal epithelial cells.
o Bioadhesive systems, by virtue of their mucoadhesive property intensify the
contact between the dosage form and intestinal mucosa and thereby assist the
drug to exert its effect at high concentration within a restricted area.
o Due to increased contact to the absorbing mucosa a steep concentration is
maintained and this leads to decrease in the diffusional path length and
increase in the absorption and local delivery of drug.
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18.  Combination strategies:
o Combining two or more strategies that can act together to counter the barriers can be
beneficial.
o Eudragit L 100 insulin microspheres containing protease inhibitors (aprotinin), Bowman-Birk
inhibitors (BBI), chymostatin (CS) and trypsin inhibitor (TI) were designed.
 Competitive Oral Delivery Technology:
Peptide transport system
 A specific carrier system, the intestinal peptide transporter or Dipeptide transporter, is
reported to exit for the uptake of dipeptide from intestine.
 This is a sodium independent mechanism and is responsible for acquiring nutrient.
 Transport of antibiotic like amino cephalosporin is known to occur through this route.
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19.  Vitamin B12 Coated Nanoparticles
o Vitamin B12 transport system has limited capacity.
o VB12 linkage is itself does not offer protection against proteolysis in the stomach and small
intestine.
o An approach to counter these problems is to employ nanoparticles as carrier for drug this
could amplify the uptake system 103 to 106 fold and the drug moiety is protected in
gastrointestinal milieus.
o Another benefit could be that the peptide/protein moiety to be delivered need not be linked to
the vitamin B12 directly.
o This would potentially benefit in case of peptide molecules like Hirudine and Vasopressin.
o Uptake and transport of VB12 coated nanoparticles performed by Caco-2 cells have
demonstrated a 2-4-fold enhancement in uptake and transcytosis of nanoparticle across the
cells.
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20. CONCLUSION
Oral delivery of peptides and proteins for the therapeutic treatment of disease is now possible.
These drugs can make the passage through the intestinal tract, through the luminal barriers and into
the bloodstreams. The new and relevant approaches are also developed to make protein and peptide
pharmaceuticals commercially viable and therapeutically useful.
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21. REFERENCES
1. Vyas S.P, Khar R.K, Controlled Drug Delivery. 2nd ed. Delhi: Vallabh Prakashan, 2012; P: 492-512.
2. Jain N.K, Progress in Controlled and Novel Drug Delivery Systems. New Delhi: CBS Publishers and
Distribution Pvt. Ltd, 2013; P: 195-198.
3. Patel S, Jani Pooja, Manseta P, Pharmaceutical approaches related to systemic delivery of protein and
peptide drugs: An overview. Int. J. Pharm. Sci. Rev. Res. Vol 12, Issue 1, January -February 2012; Article-
007.
4. P. Muralidhar, S Babajan, E Bhargav. An overview: Protein and Peptide based Drug Delivery. Int. J. Pharm.
Sci. Rev. Res., 42(1), January -February 2017; Article No. 29, P: 169-178.
5. Soltero R, Ekwuribe N. The oral delivery of protein and peptide drugs. Drug formulations and delivery,
P:106-110.
6. Sagar Kishor Savale, Protein and Peptide Drug Delivery System. World J Pharm Pharm Sci. Volume 5, issue
4, 724-742.
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22. THANK YOU
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