DRUG DELIVERY
SYSTEMS
PROTEIN AND PEPTIDE
DRUG DELIVERY Presented by
PUJITHA R,
M.Pharmacy I Sem
Department of Pharmaceutics,
College of Pharmacy, Madras Medical College, Chennai
www.DuloMix.com
CONTENTS
• Introduction
• Barriers for protein delivery
• Formulation of delivery systems of protein and other
macromolecules
• Evaluation of delivery systems of protein and other
macromolecules
• References
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PROTEINS
• The term Protein is derived from a Greek word “Proteios” meaning
“holding first place”.
• These are high molecular weight compound, Nitrogen-rich most
abundant substances present in animals and plant system.
• Protein is the basic constituent of the cytoplasm of the cell.
• Proteins are the linear chains of amino acids that are held together
by covalent linkages called “Peptide bonds”
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Difference between proteins
and peptides
PROTEINS PEPTIDES
50 and > 50 amino acids 20-50 amino acids
Secondary structure is likely stabilized Primary structure
by disulphide bonds. Ex: insulin, beta
sheets
Secondary, tertiary and quaternary Secondary sequence not found in
structures are present chain length having 20 amino acids.
No tertiary and quaternary structure
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Structure of proteins
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Structure of proteins
• PRIMARY STRUCTURE:
The simplest level of protein structure, primary structure is simply the
sequence of amino acids in a polypeptide chain.
• SECONDARY STRUCTURE:
The peptide backbone of the protein structure will fold onto itself, to give this
unique structure.
This folding of the polypeptide chains happens due to the interaction between the
carboxyl group along with the amine group of the peptide chains.
α-helix and β-pleated sheets are the two kinds of shapes formed in secondary
structure.
Other types are β bends(β turns, reverse turns), non-repetitive secondary
structures, Super secondary structures(Motifs)
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α-helix :
This structure resembles a coiled spring and is secured by hydrogen
bonding in the polypeptide chain.
β-pleated sheets:
This structure appears to be folded or pleated and is held together
by hydrogen bonding between polypeptide units of the folded chain that
lie adjacent to another.
• TERTIARY STRUCTURE:
It refers to the comprehensive 3-D structure of the polypeptide chain
of a protein.
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Types of bonds that hold a protein in its tertiary structure includes:
1) HYDROPHOBIC/ HYDROPHILIC INTERACTIONS:
❑ The ‘R’ group of the amino acid is either hydrophobic or hydrophilic.
❑ The amino acids with hydrophilic ‘R’ groups will seek contact with aqueous
environment.
❑ The amino acids with hydrophobic ‘R’ groups will avoid water and position
themselves towards the centre of the protein.
2) HYDROGEN BONDING:
❑ It occurs in between the polypeptide chain and amino acid ‘R’ groups helps
to stabilize protein structure.
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3) IONIC BONDING:
❑ Occurs between the positively and negatively charged ‘R’ groups that come
in close contact with one another.
❑ Occurs due to protein folding.
4) DISULFIDE BRIDGES:
❑ Foldings can result in covalent bonding between ‘R’ groups of cysteine
amino acids leading to disulfide bridges.
5) VAN DER WAALS FORCES:
❑ Assist in stabilization of protein structure.
❑ All these forces contribute to the bonding that occurs between molecules.
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• QUATERNARY STRUCTURE:
It refers to the structure of a protein macromolecule formed by
interactions between multiple polypeptide chains.
Each polypeptide chain referred to as a subunit.
Proteins with quaternary structure may consist of more than one of the
same type or different type of protein subunit.
• Domains:
The term domain is used to represent the basic units of protein
structure (tertiary) and function.
A polypeptide with 200 amino acids normally consists of two or more
domains.
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CLASSIFICATION OF PROTEINS:
• Based on biological function
• Based on source
• Based on shape
• Based on composition and solubility
• Based on location in the living cells
• Based on post translational modifications
• Based on nutrition
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1. Based on biological function
• Enzymes- DNA and RNA polymerase, Lipase
• Hormones- Insulin, Glucagon, Endorphine and Enkephalins
• Transport proteins- Cytochrome-C, Serum Albumin, Haemoglobin
• Respiratory pigments- Haemoglobin, Myoglobin
• Defense proteins or Antibodies (Immuno proteins)- IgG, IgM, IgE, IgD, IgA, Interferon, Fibrin
• Structural proteins- Collagen, Elastin, Keratin
• Contractile or motile proteins- Actin, Myosin
• Receptors- Trans-membrane proteins
• Signalling proteins- GTPase
• Storage proteins- Egg ovalbumin, milk casein, Ferretin.
• Toxins- Snake venom, Ricin
• Catalytic proteins- Alkaline phosphatase
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2. Based on source:
• Animal proteins- meat, eggs, milk
• Plant proteins- Pulses, seeds, grains, nuts.
3. Based on shape:
• Globular or corpuscular proteins- Cytochrome C, Blood proteins, Serum albumin,
Glycoproteins, Antibodies (Immunoglobulins), Hemoglobin, Hormones, Enzymes, Nutrient
proteins. (soluble)
• Fibrous or Fibrillar proteins- Collagens, Elastins, Fibroins, Keratin (insoluble)
4. Based on composition and solubility:
• Simple proteins or Holoproteins- Protamines and Histones, Albumins, Globulins, Prolamines,
Gluletins, Scleroproteins or Albuminoids.
• Conjugated or complex proteins or Heteroproteins- Metalloproteins, Chromoproteins,
Glycoproteins, Phosphoproteins, Lipoproteins, Nucleoproteins, Mucoproteins.
• Derived proteins- Proteans, Metaproteins or Infraproteins, Proteoses, Polypeptides,
Peptones, Coagulated proteins. MywPwhwar.DmualoGMuiidx.ec.oCmom
5. Based on location in the
living cell:
• Membrane proteins
• Internal proteins
• External proteins
• Viral proteins
6. Based on post-translational modifications:
• Native proteins
• Glyco proteins
• Cleaved proteins
• Protein with Disulfide bonds
• Protein complexes
• Chemically modified proteins
• Prions
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7. Based on nutrition:
• Complete proteins- Egg albumin, Caesin
• Partially incomplete proteins- wheat and rice proteins
• Incomplete proteins- Gelatin, Zein
BIOLOGICALLY IMPORTANT PEPTIDES:
1. Glutathione : tripeptide
2. Thyrotropin releasing hormone (TRH) : tripeptide
3. Oxytocin : nonapeptide
4. Vasopressin (ADH) : nonapeptide
5. Angiotensins : decapeptide
6. Methionine encephalin : pentapeptide
7. Bradykinin and kallidin : nona and decapeptides, respectively.
8. Aspartame : dipeptide
9. Gastrointestinal hormones : Secretin, Gastrin
10. Peptide antibiotics : GramicMidywP
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IMPORTANCE OF PROTEIN
DRUG DELIVERY
• The proteins and peptides are very important in biological cells.
• There is better understanding of the role of regulatory proteins in the
pathophysiology of human diseases.
• Lack of proteins and peptides causes diseases like Diabetes mellitus.
• Nowadays r-DNA technology and Hybridoma techniques are also used in
protein and peptide based pharmaceuticals.
• Improved analytical methods have promoted the discovery of numerous
hormones and peptides that have found applications as
biopharmaceuticals in the pharmaceutical field.
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FUNCTION OF PROTEINS
AND PEPTIDES
• Transport and storage of small molecules. Eg: Ferretin
• Oxygen carrier Eg: Haemoglobin.
• Some proteins serve as important structural elements of the body,
Eg: Hair, wool and collagen, an important constituent of connective
tissue.
• Co-ordinated motion through muscle contraction
• Mechanical support from fibrous proteins.
• Generation and transmission of nerve impulses.
• Enzymatic catalysis.
• Immune protection through antibodies.
• Control of growth and differentiation through hormones.
• Associated with genes, herMeywPdwhwairt.DmaualroGMyuii dxf.eca.oCmcomtors.
APPLICATIONS:
• Erythropoietin used for production of RBC.
• Tissue -Plasminogen activator is used for heart attack, stroke.
• Bradykinin increases the peripheral circulation
• Somatostatin decrease bleeding in gastric ulcer.
• Gonadotropin induce ovulation.
• Insulin maintain blood glucose level.
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MARKETED FORMULATIONS:
• FREEZE DRIED FORMULATION:
Eg:- Metrodin(i.m),
Pergonal (i.m),
Elspar (i.m/i.v),
Glucagon( i.m/i.v/s.c)
• READY TO USE FORMULATION:
Eg:- Lupron(s.c),
Calcimar(s.c)
• SR FORMULATION:
Eg:- Lupron(i.m)
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NEWER APPLICATIONS
• Goserelin is administered as a subcutaneous implant. Along with Leuprolide acetate (Lupron
Depot), it was one of the first polymer systems to have received FDA approval for controlled
release of a peptide. This drug is available in a 3.6-mg biodegradable and biocompatible
sterile white to cream-colored 1-mm by 1.5-mm cylinder about the size of a grain of rice
preloaded into a special single-use syringe The drug is dispersed in a matrix of d, l-lactic acid
and glycolic acid copolymer.
• Histrelin (Vantas) Implant is a sterile non-biodegradable, diffusion-controlled reservoir drug
delivery system designed to deliver Histrelin continuously for 12 months upon SC
implantation. It contains 50 mg of Histrelin acetate, a synthetic nonapeptide analog of the
naturally occurring gonadotropin-releasing hormone (GnRH) or luteinizing hormone–
releasing hormone (LH-RH). The device must be removed after 12 months, and another
implant may be inserted to continue therapy. The sterile implant contains a 50-mg Histrelin
acetate drug core inside a non-biodegradable, 3.5 cm by 3 mm cylindrically shaped hydrogel
reservoir that also contains stearic acid.
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– The hydrogel reservoir consists of a hydrophilic polymer cartridge composed of 2-
hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, trimethylolpropane
trimethacrylate, benzoin methyl ether, Perkadox-16, and Triton X-100. It is packaged in a
glass vial containing 2 mL of 1.8% sodium chloride solution and is primed for release upon
insertion.
• Leuprolide Acetate (Lupron, Lupron Depot-Ped, Lupron Depot-3 Month)
– Leuprolide is a synthetic GnRH analog. Like the naturally occurring LH-RH, initial and
intermittent administration of this drug stimulates the release of LH and FSH from the
anterior pituitary. As with goserelin, continuous administration of leuprolide suppresses the
secretion of LH and FSH, with a concomitant drop in testosterone concentrations and
subsequent medical castration. The usual adult dose for prostatic carcinoma is a
subcutaneous injection of 1 mg per day. There is also a monthly (every 28 to 33 days) depot
intramuscular injection.
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– The 7.5-mg strength is used for prostatic carcinoma. The powder for intramuscular injection
is reconstituted with a special diluent composed of d-mannitol, purified gelatin, d,l-lactic
and glycolic acid copolymer, polysorbate 80, and acetic acid.
– Lupron should be refrigerated until dispensed, but patients may store the product at room
temperature (no more than 30°C, or 86°F). The product should be protected from light and
the vial stored in the carton until use. Following reconstitution, the suspension is stable for
1 day. However, because the product has no preservative, it should be discarded if not used
immediately.
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• Viadur Implant
– The Viadur (leuprolide acetate) implant is a sterile, nonbiodegradable, osmotically driven
miniaturized implant designed to deliver leuprolide acetate for 12 months at a controlled rate.
It contains 65 mg of leuprolide (as 72 mg of the acetate), which is a synthetic nonapeptide
analog of naturally occurring GnRH or LH-RH. After 12 months, the implant must be removed,
and another may be inserted if indicated.
– Viadur is indicated in the palliative treatment of advanced prostate cancer. The drug is
dissolved in 104 mg of dimethyl sulfoxide. The reservoir houses a polyurethane rate-controlling
membrane, an elastomeric piston, and a polyethylene diffusion moderator. The contained
osmotic tablets are composed of sodium chloride, sodium carboxy methyl cellulose, povidone,
magnesium stearate, and sterile water for injection. PEG fills the space between the osmotic
tablets and the reservoir. The implant weighs about 1.1 g. As aqueous fluid diffuses through
the membrane and is slowly taken up by the osmotic tablets, the piston will move and force
out a controlled amount of the drug through the diffusion moderator orifice
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STABILITY PROBLEMS WITH
PROTEINS AND PEPTIDES
• Physical instability (non-covalent)
• Chemical instability (covalent)
PHYSICAL INSTABILITIES :
1. DE-NATURATION:
• If de-naturation is reversible, then the protein molecule can be refold to
its original form.
• When it is irreversible, then unfold proteins fails to regain their original
structure.
• Factors involved:
Solvents used, pH alteration , changes in ionic strength, temperature
fluctuations.
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2. ADSORPTION:
• Surface adsorption of proteins and peptide reduces the concentration of drug available for
its function.
• Both proteins and peptides are amphiphilic molecules and thus gets adsorb at interfaces
like air-water, air-solid.
• Adsorption occurs during purification, formulation, storage and /or delivery.
• When adsorbed protein subjected to desorption they get desorbed leaving their
hydrophilic residues exposed leading to unexpected aggregation and precipitation
3. AGGREGATION & PRECIPITATION:
• The extent of aggregation and precipitation of protein molecule depends upon the relative
hydrophilicity of surfaces to which the polypeptide or protein are in contact with.
• Presence of large air-water interface accelerates these processes.
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CHEMICAL INSTABILITIES:
1. DE-AMIDATION:
• There is hydrolysis of the side chain amide linkage of an amino acid residue leading to
the formation of free carboxylic acid.
• The produced carboxylic acid leads to conversion of a neutral residue to negatively
charged residue and primary sequence isomerisation.
2. OXIDATION:
• Oxidation occurs at side chains of histidine, lysine, tryptophan, thyronine residues in
proteins.
• Occurs during isolation, synthesis and storage of proteins.
• Even atmospheric oxygen induces auto-oxidation.
• Oxidation of amino acid residues is followed by loss of biological activity.
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3. PROTEOLYSIS:
• Proteolysis occurs on exposing the proteins to harsh conditions such as prolonged
exposure to extreme pH or high temperature or Proteolytic enzymes.
• Bacterial contamination is the most common cause of proteases
• Proteolysis is avoided by storing the proteins in cold under sterile conditions.
4. DISULFIDE EXCHANGE:
• Breaking and reformation of disulfide bonds result into an alteration in 3D structure
followed by reduced activity.
• Disulfide exchange is in more case of molecules having large number of disulfide bonds.
• This reaction occurs in neutral or alkaline medium.
• Accelerated by thiols which are generated by disulfide linkage
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5. RACEMISATION:
• With an exception of glycine, all amino acids are chiral.
• Their racemisation will lead to increase in susceptibility of peptide bonds toward proteolytic
enzymes.
• Racemisation is catalysed in neutral and alkaline medium by thiols generated through disulfide
exchange.
DENATURATION OF PROTEINS:
➢ The phenomenon of disorganization of native protein structure is known as denaturation.
➢ Denaturation results in the loss of secondary, tertiary and quaternary structure of proteins.
➢ This involves a change in physical, chemical and biological properties of protein molecules.
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BARRIERS TO PROTEIN &
PEPTIDE DELIVERY
• In-vitro stability barriers
• Metabolic or enzymatic barriers
• Absorption barriers
• Chrono-phamacological barriers
• Distribution and excretion barriers
1. In-vitro stability barriers:
Peptides and proteins possess an inherent instability due to the chemical reactivity of
certain amino acids, which results in degradation reactions such as transpeptidation, side-chain
hydrolysis, di-keto piperazine formation, disulphide exchange, oxidation and racemization.
Stability is affected by environmental factors, pH, organic acids, ionic strength, metal ions,
detergents, temperature, pressure, interfaces and agitation and also highly susceptible to
lyophilisation.
Peptide and protein instability in-vitro is manifested by the tendency of such molecules to
undergo self-association in solution, resulting in the formation of multimers and in the extreme,
aggregation and precipitation. MywPwhwar.DmualoGMuiidx.ec.oCmom
Eg: Insulin exists predominantly as hexameric aggregates at pH 7, which are too large to be absorbed.
Proteins tend to denature in-vitro depending on the specific protein and solution properties
such as temperature, pH and salt concentration.
Eg: Human Chorionic Gonadotrophin undergoes substantial and irreversible interfacial denaturation
above pH 11.
Proteins also tend to adsorb at interface.
2. Metabolic barriers(Enzymatic barriers):-
Degradation of potential peptides and protein drugs involves hydrolytic cleavage of peptide
bonds by proteases or by chemical modifications.
▪ Hydrolytic cleavage of peptide bonds by processes, such as insulin-degrading enzyme,
Angiotensin-converting enzymes and Renin.
▪ Chemical modification of protein such as phosphorylation by kinases, oxidation by Xanthine
oxidase or Glucose oxidase.
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• Several methods to modify peptide structure to improve metabolic stability are:
• Substitution of an unnatural amino acids in the primary structure.
• Introduction of conformational constraints.
• Reversal of the direction of the peptide backbone.
• Acylation and alkylation of the N-terminal.
• Reduction of the C-terminus, formation of an amide.
3. Absorption barriers:-
The absorption barriers for protein and peptides include enzymatic barriers and the physical
barrriers such as hydrophobic membranes and tight inter-cellular junctions at the epithelium.
Proteins and peptides are generally too large for transport via paracellular route, unless the
integrity of the tight junctions is disturbed by the use of permeation enhancers.
Passive diffusion across lipid membranes is also not possible since the molecules are too large
and too hydrophilic to penetrate the lipid membrane barriers.
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• Active transport mechanisms exist in the GIT and other epithelial sites for absorption of the di
and tri peptides.
• Proteins and large peptides may be transported across cells via endocytic processes.
4. Chrono-pharmacological barriers:-
For optimal drug delivery, the following drug input factors are to be considered:
➢ Circadian and other rhythms of predictable period.
➢ Modulations on minute-to-minute basis, in response to nutrient delivery, physical activity and
metabolic stress.
➢ Pulsatile release patterns of many endogenous peptides and protein.
➢ Complex feedback control mechanisms which affects the release and biological effects of many
endogenous peptides and protein.
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5. Distribution and excretion barriers:-
After a therapeutic peptide or protein is administered, unwanted drug disposition may occur,
which results in the need to use large dose to compensate the drug wastage.
Unwanted distribution may also cause toxic side effects, resulting from drug action at non-
therapeutic sites.
Premature excretion may arise if small, high potent therapeutic peptides are cleared rapidly
through the kidneys, before reaching the target sites.
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MywPwhwar.DmualoGMuiidx.ec.oCmom
DRUG DELIVERY SYSTEMS FOR PROTEINS
& OTHER MACROMOLECULES
PARENTERAL NON – PARENTERAL
ROUTES ROUTES
1. Microspheres 1) Oral delivery
2. Hydrogels 2) Buccal route
3. Liposomes 3) Nasal route
4. Solid – lipid 4) Ocular route
nanoparticles (SLNs) 5) Transdermal route
5. PEGylation 6) Pulmonary route
6. Pumps 7) Rectal route
8) Vaginal route
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PARENTERAL ROUTE
➢ Parenteral route is most efficient way for systemic delivery of proteins and peptides.
➢ This is the best choice to achieve therapeutic activity for protein and peptide drugs.
➢ Mainly 3 routes of administration:
• Intravenous
• Intramuscular
• Subcutaneous
➢ Others include intra-articular, intraperitonial and intrathecal use.
➢ Controlled release drug delivery system produces prolongation of biological activity.
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SIGNIFICANCE:
✓ Major route of choice for protein/peptides.
✓ Targeting to specific receptors can improve the therapeutic efficacy of the drug.
✓ Pulse delivery is preferred, which avoids the down regulation of receptors caused by continuous
administration.
✓ Faster onset of action on IV administration.
DISADVANTAGES:
❑ Fast clearance of drugs.
❑ Generation of immune responses and other undesirable deleterious side effects and interactions
when administered in high dosage levels.
❑ Due to short half-life of proteins, frequent injections are required and thus patient compliance is
poor.
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PHARMACEUTICAL APPROACHES
TO PARENTERAL DELIVERY
A) MICROSPHERES:
❖ Various bio-degradable polymers have been investigated for preparation of microspheres as
depot formulation.
❖ The bio-degradable microspheres are used to deliver small molecules, proteins and
macromolecules.
❖ There are three manufacturing techniques for protein containing microspheres namely,
w/o/w technique, phase separation methods and spray drying.
B) HYDROGELS:
❖ Hydro gels are 3 D hydrophilic polymeric networks having capacity to absorb large quantities
of water.
❖ Dextran based hydro gels are used for controlled release of pharmaceutically active proteins.
❖ To form a gel it needs to undergo cross linking either by chemically or physically.
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❖ Eg: Gel formulation of cross linked polyacrylamide-polyvinyl pyrrolidone is used to achieve
the prolong release LH, Ig etc.,
❖ Reproducibility of release kinetics is poor and improved by using low temperature solvent
casting method.
C) LIPOSOMES:
❖ Liposome is the most sophisticated way to prepare controlled release protein and peptide
pharmaceuticals.
❖ The protein/peptides localize on the liposomal surface instead of being entrapped inside the
liposomes, hence they are available for binding to its receptor molecules and express the
biological activity.
❖ Incorporation of peptide into the liposome also significantly enhanced the circulation time of
the peptides.
❖ Eg: Asialofeutin, Ricin A chain, Depo – foam
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D) SOLID LIPID NANO-PARTICLES(SLN):
❖ SLN are colloidal particles composed of bio-degradable lipid matrix that is solid at body
temperature and exhibit size range of 100-400nm.
❖ SLN shows excellent physical stability, protection from degradation, controlled drug release,
site specificity.
❖ One disadvantage associated with SLN is low drug loading capacity but it can be improved by
Nano structured lipid carriers(NLC) and Lipid drug conjugate nanoparticle (LDC).
E) PEGylation:
❖ PEG is non-toxic, linear or branched polymer and has been approved by the FDA for use in
foods, cosmetics and pharmaceuticals.
❖ Chemical conjugation with PEG is one of the most successful techniques to prolong the
residence time of protein drugs in the blood stream.
• Drug macromolecules are covalently linked to the polyethylene glycol (PEG) polymer
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❖ The advantages of PEGylation for protein molecules are:
– Enhanced bio-availability
– Decreased dosing frequency
– Decreased degradation by metabolic enzymes
– Increased efficacy
– Improved safety profile
– Reduction or elimination of protein immunogenicity
– Improved drug solubility
– Improved drug stability
❖ Eg: PEG-L-asparaginase (Oncaspar)
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6. 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 at constant rate.
7. MECHANICAL PUMPS
❖ Easily manipulated to deliver protein and peptide drugs.
❖ Eg: Insulin has been successfully delivered by portable syringe.
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NON-PARENTERAL ROUTE
• Several biopharmaceuticals have undergone extensive developments (other than injections)
towards alternative administration routes, particularly peptide hormones such as Insulin,
Vasporessin, Calcitonin and Leutenizing hormone releasing hormone, Human growth
hormone and Interferon α.
• Studies indicated that oral bioavailability of most peptides and proteins are <1%. However,
exceptions exist Eg: Cyclosporine – lipophilic cyclic peptide with 11 amino acids used as an
immunosuppressant can have 50% bioavailability when administered in suitable vehicles.
• Transmucosal routes of drug delivery (i.e., the mucosal linings of nasal, rectal, vaginal, ocular
and oral cavities) offer distinct advantages over peroral administration for systemic effects
like by-pass of first pass effects and avoidance of pre-systemic elimination within the GIT.
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1. ORAL DELIVERY
❖ Oral route is the most convenient method of drug delivery since it has the following advantages
✓ Avoidance of pain and discomfort associated with injections
✓ Elimination of possible infections caused by inappropriate use or reuse of needles
✓ Patient compliance
✓ Less expensive to produce
✓ No need to maintain strict sterile conditions as in case of parenteral production.
DISADVANTAGES:
❑ Poor intrinsic permeability.
❑ Susceptibility to enzymatic degradation.
❑ Short plasma half life, Rapid post absorptive clearance.
❑ Physical instabilities like tendency to aggregate, denature or non-specifically adsorbed to variety
of physical and biological surfaces.
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PHARMACEUTICAL APPROACHES
TO ORAL DELIVERY:
• Chemical modification
• Enzyme inhibitors
• Penetration enhancers
• Formulation vehicle
• Muco-adhesive polymeric system
A) CHEMICAL MODIFICATION(PRODRUG APPROACH):
❖ This method is important to improve the enzymatic stability as well as membrane permeations.
❖ It is applicable for reducing the immunogenicity.
❖ The chemical modification includes two types:
– Amino acid modification
– Hydrophobization
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AMINO ACID MODIFICATION:
• Here the substitution of D-amino acid and L-amino acid is important to alter the physiological
properties of protein and peptide drug delivery system.
• Eg: Desmopressin and Deaminovasopressin are the two important analogs of vasopressin. The
former involves deamination of first amino acid and replacement of last L arginine into the D
arginine to give Deaminovasopressin.
HYDROPHOBIZATION:
• It is having an important approach for the lipophilic moieties.
• Eg: Nobex Insulin by the palmitoylation conjugation of the Insulin molecule to the 1,3
dipalmitoylglycerol containing a free amino acid groups of glycine, phenylalanine and lysine
molecule to form this insulin.
• This facilitates the transfer of insulin across the mucosal membrane of the large intestine and
is important to improve stability against enzymatic degradation.
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B) ENZYME INHIBITORS(PROTEASES):
❖ GIT and liver play important role in metabolization of the protein and peptides into
smaller fragments of 2- 10 amino acids with the help of a variety of proteolytic enzymes.
❖ Protease inhibitors are co-administered with protein and peptide to alter the environment
for enzyme stability to suppress the proteolytic activity.
❖ Types of protease inhibitors:
Aspartic proteases – Pepsin , Renin
Cystinyl proteases – Papain, Endopeptidase
Serinyl proteases – Thrombin, Trypsin
Metallo proteases – Carboxypeptidase
C) PENETRATION ENHANCERS:
❖ These are responsible for the disruption of mucosal barriers and applicable to improve the
membrane permeations of large macro-molecular substances like proteins and peptides.
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❖ Classes of permeation enhancers:
– Surfactant( Polysorbate, SLS)
– Chelating agent( EDTA)
– Fatty acids( Sodium caprylate)
– Mucoadhesive polymeric systems( Thiomers, cellulose derivatives)
– Phospholipids
❖ Mechanism of penetration enhancers:
▪ Detergent and surfactant molecules- Disrupt the structure of lipid bi-layer and thus
increases the transcellular transport of drug material.
▪ Calcium chelates- Complex formation of calcium ions and passing through tight junctions,
facilitates paracellular transport of hydrophilic drugs.
▪ Fatty acids- Phospholipase C activation and up-regulation of intracellular calcium ions,
leading to contraction of actin myosin filaments. Thus improves the paracellular transport.
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D) FORMULATION VEHICLES:
❖ The protein and peptide drug delivery system is important for the oral delivery of proteins and
peptides which can be successfully achieved by using various carrier systems like,
– Dry emulsion
– Microspheres
– Liposomes
– Nanoparticles
1. DRY EMULSION:
• It is an important application in drug delivery systems to prevent the instabilities of the long term
storage of multiple emulsions.
• Dry emulsion is prepared by the spray drying, lyophilisation and evaporation techniques.
• In dry emulsion preparation, pH responsive polymers like Hypromellose phthalate(HPMCP) is
important for the emulsion to be enteric coated and site specificity is achieved.
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2) MICROSPHERES:
• The uniform distribution of drug in oral drug delivery of proteins and peptides achieved by
microspheres.
• The pH responsive microspheres are used to prevent proteolytic degradation in stomach and
upper portion of small intestine.
3) LIPOSOMES:
• Liposomes are the small microscopic vesicles in which the aqueous volume is entirely enclosed
by membrane composed lipid molecules.
• Liposome improves physical stability and increases membrane permeability but to improve the
stability of liposomes, GI-resistant lipids or polymers are used.
MywPwhwar.DmualoGMuiidx.ec.oCmom
4) NANOPARTICLES:
• Nanoparticles are developed as particulate carriers for oral protein and peptide drugs.
• The proteins and peptides encapsulated in the nanoparticles are less sensitive to enzyme
degradation and increases intestinal epithelial absorption.
E) MUCO-ADHESIVE POLYMERIC SYSTEMS:
❖ The muco-adhesive polymeric system is important to prevent the problem associated in pre-
systemic metabolism or first pass metabolism and maintain its therapeutic efficacy.
❖ Here the residence time of the drug at the site of action is increased or drug clearance rate is
decreased.
❖ Examples of muco-adhesive polymers are thiomers, polyacrylic acid derivatives, cellulose
derivatives.
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2. NASAL ROUTE:
• This route has been chiefly employed to provide local action on the mucosa.
• The nasal route is relatively more permeable to peptides as compared to other routes like
transdermal or oral.
• This route has been used to administer pituitary hormones like Vasopressin and Oxytocin for
many years.
• Nasal sprays are reported to mainly deposit in the atrium while the nasal drops spread more
extensively and therefore, their clearance is more rapid and are absorbed to a lower extent.
• The absorption of various drugs through the nasal mucosa are increased with the use of
absorption enhancers such as Cyclodextrins, Phospholipids, bioadhesive powder systems and
Chitosan.
• Commonly this route used for topically active drugs to alleviated histaminic symptoms in nasal
cavity.
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ADVANTAGES:
✓ Convenient, simple and practical way of drug administration, especially for the very old,
young, blind and debilitated patients.
✓ The high vascularization permits better drug absorption.
✓ First pass metabolism can be avoided.
✓ Rapid onset of action
DISADVANTAGES:
❑ Extent of absorption varies with the mucous secretion.
❑ Muco-ciliary clearance rate being of the order of 15 mins represents a physical and temporary
barrier.
❑ Peptidases and proteases present in the mucous or nasal membrane serve as enzymatic
barriers in protein/peptide absorption.
❑ Penetration enhancers and preservatives may damage mucosal cell membrane and may even
be ciliotoxic. MywPwhwar.DmualoGMuiidx.ec.oCmom
PHARMACEUTICAL APPROACHES
TO NASAL DELIVERY:
A) VISCOSITY MODIFICATION:
❖ Half the time of clearance could be increased significantly by using solution with higher
viscosity because the clearance time from the nasal cavity can be delayed.
B) pH MODIFICATION:
❖ Usually the lowest solubility of peptides and proteins is found at their isoelectric point.
❖ Solubility can be increased by adjusting the pH further away from the isoelectric point of a
particular peptide.
C) INCREASE NASAL BLOOD FLOW:
❖ Enhancement in nasal peptide absorption has been reported with an increase in local nasal
blood flow.
❖ Histamine, Prostaglandin E and β-adrenergic agonists are vasoactive agents which are known
to enhance.
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D) DISSOACIATION OF AGGREGATION:
❖ Proteins are prone to form higher order aggregates in solution
❖ Eg: In case of insulin, at pH 7 it exists as hexameric aggregates so failed to cross the nasal
membrane.
❖ Satisfactory nasal absorption of insulin was observed with sodium deoxycholate which causes
the dissociation of insulin hexamer to diamers and monomers.
E) MEMBRANE TRANSPORT ENZYME INHIBITION:
❖ Penetration enhances like bile salts, surface active agents and chelating agents are reported
to increase the nasal absorption of proteins and peptides.
❖ Thus the bile salts effects both the permeability of nasal mucosa and inhibit the activity of
leucine amino peptidase and thereby enhance the absorption of insulin.
MywPwhwar.DmualoGMuiidx.ec.oCmom
3. OCULAR ROUTE:
• Drugs instilled into the pre-corneal cavity can reach the systemic circulation through blood
vessels underlying the conjuctival mucosa or through overflow of drug solution into the
nasolachrymal drainage system followed by absorption through the nasal mucosa.
• Advanced drug delivery systems have been developed with the intervention of optimizing and
controlled delivery of ocular therapeutics to the target sites, either by increasing its penetration
across the mucosa or by prolonging the time of carrier with the ocular surface.
ADVANTAGES:
✓ Delivery of proteins and peptides through ocular inserts.
✓ Avoids first pass metabolism
✓ Protein/peptide administration through conjunctiva.
MywPwhwar.DmualoGMuiidx.ec.oCmom
DISADVANTAGES:
❑ Existence of physiological barriers like tear dilution, lachrymal drainage and protein binding.
❑ Low capacity for transport.
❑ Ocular peptidases forming enzymatic barrier.
❑ Poor permeability for the large, hydrophilic molecules through a membrane.
PHARMACEUTICAL APPROACHES TO OCULAR DELIVERY:
▪ Pro drug design
▪ Addition of protease inhibitors
▪ Use of penetration enhancers
▪ Novel nano particulate delivery systems.
MywPwhwar.DmualoGMuiidx.ec.oCmom
4. BUCCAL ROUTE:
• The oral mucosa has a rich blood supply and is permeable to many biological agents.
• The bioavailabilities or relative potencies of intraorally administered peptides are quite low unless
permeabilizers are used.
• The buccal peptide absorption is assumed to be through passive absorption mechanism.
• A number of dosage forms are available that are to be administered via buccal route that can be
used to deliver protein/peptides, however, the conventional means include aqueous solutions,
buccal or sublingual tablets, capsules.
• Various parameters that influence the extent of buccal peptide absorption are,
– Molecular weight
– Polarity & Conformation
– Dissociation
– Enzymatic and chemical stability
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ADVANTAGES:
✓ It is robust and comparatively much less sensitive to irreversible irritation even on long term
treatment.
✓ Absence of enzymatic barrier to protein/peptide absorption.
✓ Well acceptable to the patients.
✓ Improved patient compliance is anticipated due to the easy accessibility and administration.
✓ It is worth consideration when penetration enhancers are to be employed.
DISADVANTAGES:
❑ Epithelial barrier
❑ Risk of drug loss by accidental swallowing or by the salivary washout.
❑ Do not allow drinking and are a handicap for speaking.
❑ Control release cannot be achieved.
MywPwhwar.DmualoGMuiidx.ec.oCmom
PHARMACEUTICAL APPROACHES
TO BUCCAL DELIVERY:
A) FORMULATION COMPOSITION:
❖ Eg: Insulin could not be effectively absorbed when using a simple disk shaped dosage form
prepared by direct compression of insulin in a mixture of HPC and carbopol .
❖ Buccal absorption was achieved by using a dome shaped two phase mucosal adhesive
device prepared by dispersing insulin crystals with sodium glycocholate, an absorption
promoter.
B) SELF-ADHESIVE BUCCAL PATCH:
❖ It is feasible to deliver peptide based pharmaceuticals such as oxytocin, vasopressin and
insulin.
C) Use of bio-adhesive polymers for the delivery of bio-actives.
D) Use of polymeric and lipid novel DDS.
E) Addition of penetration enhancers and protease inhibitors.
MywPwhwar.DmualoGMuiidx.ec.oCmom
5. TRANSDERMAL ROUTE:
❖ With an insight into the percutaneous absorption into the skin, it is now evident that, through
this route, benefits of iv drug infusion can be closely negotiated avoiding its inherent hazards.
❖ Mechanical abrasion, chemical enhancers are used to increase permeability of the drug into
the skin.
ADVANTAGES:
✓ Elimination of hepatic first pass metabolism.
✓ Avoidance of toxic effects since controlled administration is possible.
✓ Drugs with shorter half life can be administered.
✓ Drugs with lower therapeutic indices is possible.
✓ Skin contains amino-peptidases, which exhibit less enzymatic activity than other proteolytic
enzymes in the GIT, so bioavailability of peptide drug delivered is increased when compared
to oral administration.
MywPwhwar.DmualoGMuiidx.ec.oCmom
✓ Well accepted for hormone-replacement therapy, smoking cessation, pain management.
✓ Termination of therapy can be simply affected by removing the topical device.
DISADVANTAGES:
❑ Low rate of permeation for most of the protein drugs, due to their arge molecular weight and
hydrophilicity and lipophilic nature of the stratum corneum layer.
❑ Significant inflammation is unacceptable for chronic transdermal delivery of protein
therapeutics.
MywPwhwar.DmualoGMuiidx.ec.oCmom
PHARMACEUTICAL APPROACHES
TO TRANSDERMAL DELIVERY:
A) IONTOPHORESIS:
❖ In this technique, membrane transport facilitates of charged molecules depend on their
ionic characters.
❖ To undergo iontophoresis, the peptide/protein molecules must carry charge and this can
achieved by controlling pH and ionic strength of solution.
❖ Heat generated during this process can cause de-naturation.
❖ Eg: insulin- improved delivery
B) PHONOPHORESIS:
❖ In this method ultra-sound is applied through a coupling agent to the skin The drug
absorption is enhanced through thermal effect of ultrasonic waves and subsequent
temporary alterations in the physical structure of skin.
❖ Thus it makes the bio membrane permeable to the drug.
MywPwhwar.DmualoGMuiidx.ec.oCmom
❖ The limitation of this technique is that it causes de-naturation due to elevated temperature
or mechanical disruption of the structure of protein/peptide.
❖ Eg: INF-γ (low frequency ultra-sound used. Improvement in trans-dermal delivery)
C) PENETRATION ENHANCERS:
❖ Without permeation enhancers lower bioavailability is achieved when these routes are
used.
❖ Lower bioavailability is due to poor mucosal permeability.
❖ Eg: Sodium tauroglycocholate, Oleic acid, dimethyl sulfoxide, surfactants are used but
causes skin irritation and thus it is limited in usage.
MywPwhwar.DmualoGMuiidx.ec.oCmom
6. PULMONARY ROUTE:
• The respiratory tract offers an alternative site foe systemic, non-invasive delivery of
proteins.
• It is used in case of diseases which cannot be treated using medication and which require
macromolecular drug therapies.
ADVANTAGES:
✓ Reduction in dose requirement upto 50 folds and hence, cost effective.
✓ Safe route for drug delivery even in patients with lung diseases.
✓ No triggering of immune function.
✓ Increased patient compliance with minimum pain and discomfort.
DISADVANTAGES:
❑ Most of the drug is delivered to the upper lung, an area where the systemic absorption is
less.
❑ Variation in absorption rates due to variation in epithelial line thickness under physiological
conditions. MywPwhwar.DmualoGMuiidx.ec.oCmom
PHARMACEUTICAL APPROACHES
TO PULMONARY DELIVERY:
A) LIPOSOMES:
❖ Liposomal aerosols are one of the good formulation due to several advantages like
sustained release, prevention of irritation, reduced toxicity, improved stability.
❖ Lipid composition, size, charge, drug-lipid ratio, method of delivery are dependent on the
release rate, drug carrying capacity and deposition of liposomes in lungs.
❖ Insulin liposome- hypoglycemic effect have been significantly enhanced by the intra-
tracheal delivery (Dipalmitoyl phosphatidylcholine:cholesterol – 7:2)
B) LIPID-BASED MICROPARTICLES:
❖ Lipid-based hollow-porous micro particles named Pulmo-spheres, were loaded with Ig-G
delivered into upper and lower respiratory tract, triggers local and systemic immune
responses.
MywPwhwar.DmualoGMuiidx.ec.oCmom
C) MICROSPHERES:
❖ Microspheres are physically and chemically more stable than liposomes and allow
higher drug loading.
❖ Therefore, they are useful carrier systems for proteins and peptides.
❖ Microspheres delivery depends on the
preparation technique,
delivery device,
polymeric material chosen.
MywPwhwar.DmualoGMuiidx.ec.oCmom
7. RECTAL DELIVERY:
• In the rectum, the upper venous drainage system is connected to the portal system, whereas
the lower venous drainage system is connected directly to the systemic circulation by the
iliac veins and the vena cava.
• On co-administration with absorption promoting adjuvant the hepatic first pass metabolism
is bypassed, proteolytic degradation is reduced and thus improve systemic bioavailability of
the protein drug.
• Eg: Insulin micro-enema co-administered with sodium 5-methoxy salicylate promotes the
rectal absorption of insulin.
• With an increase in the molecular weight of a compound, its lymphatic uptake is favoured.
ADVANTAGES:
✓ Avoids first pass metabolism.
✓ Suitable for drugs that can cause nausea/vomiting and those which irritate the GI mucosa on
oral administration.
✓ Large dose of drugs can be administered.
MywPwhwar.DmualoGMuiidx.ec.oCmom
✓ Offers an opportunity of target drug delivery to the lymphatic circulation.
✓ Faster onset, higher bioavailability, shorter peak and shorter duration than the oral route.
✓ Drugs can be easily inserted and retained into the Rectum.
DISADVANTAGES:
❑ Luminal pressure exerted by the rectal wall limits absorption.
❑ pH, buffer capacity, surface tension, viscosity of the rectal fluid are to be considered during
formulation.
❑ Tight intercellular junctions of the columnar epithelium of the rectal mucosa limits the
absorption and bioavailability of peptides and proteins.
PHARMACEUTICAL APPROACHES TO RECTAL DELIVERY:
❖ pH modification
❖ Use of polymeric and lipid novel delivery systems.
❖ Addition of bioadhesives /penetration enhancers/protease inhibitors or surfactants
MywPwhwar.DmualoGMuiidx.ec.oCmom
8. VAGINAL DELIVERY:
• It is one of the alternative routes for the systemic delivery of the proteins because of the
relatively high permeability of the vaginal epithelium.
• Prolonged contact of the drug with the vaginal mucosa can be easily achieved than at other
absorption sites like Rectum or Intestinal mucosa.
• Vaginal permeability is strongly influenced by variation in the serum Oestrogen level.
• Vaginal route is useful for administration of LHRH & its synthetic analogs, especially when a
low but long lasting release of gonadotropins is required.
ADVANTAGES:
✓ Large surface area, rich blood supply.
✓ Lipophilic substances penetrate more rapidly than hydrophilic substances through the
vaginal membrane.
✓ Beneficial for chronic administration of protein and peptide pharmaceuticals.
MywPwhwar.DmualoGMuiidx.ec.oCmom
DISADVANTAGES:
❑ Restricted absorption of hydrophilic drugs. Eg: Progesterone (lipophilic) penetrates more
rapidly than Mannitol (hydrophilic).
❑ Menstrual cycle-associated vaginal changes.
❑ Genital hygiene issues.
❑ Coitus interference.
❑ Variable drug permeability and local side effects.
PHARMACEUTICAL APPROACHES TO VAGINAL DELIVERY:
❖ Muco-adhesive or bio-adhesive polymers
❖ pH or temperature sensitive polymers.
❖ Liposomes
❖ Nano-emulsions
❖ Vaginal inserts
❖ Hydrogels MywPwhwar.DmualoGMuiidx.ec.oCmom
EVALUATION OF PROTEIN AND
PEPTIDE DRUG DELIVERY SYSTEM
➢ Many tests are required for stability of protein products to assure the identity, purity, potency
and stability of formulation.
➢ Due to complexity of proteins bioassay are required to assess the potency of the formulation.
➢ In case of in-vitro bioassays response of cells to hormones and growth factors is monitored.
➢ In case of in-vivo bioassay pharmacological response of animals to proteins is monitored.
Eg: Bioassay of insulin in rabbits.
1. UV SPECTROSCOPY:
• Proteins containing amino acid residues such as phenylalanine, tyrosine, tryptophan can be
detected by UV Spectroscopy.
• This method can be used for in-process quality control.
• Protein aggregates scatter UV light and absorbance increases, hence UV Spectroscopy can be
used to monitor protein aggregation.
MywPwhwar.DmualoGMuiidx.ec.oCmom
2. LIQUID CHROMATOGRAPHY:
• To study the stability of proteins and peptides HPLC is an useful technique.
• Other methods include Normal phase HPLC, Reverse phase HPLC, Ion exchange
chromatography.
3. ELECTROPHORESIS:
• Most often used technique for protein products is sodium dodecyl sulphate polyacrylamide
gel electrophoresis (SDS-PAGE)
• Proteins are denatured by boiling in the SDS solution.
• All charges of protein are masked by negative charge of Dodecyl sulphate.
• Thus protein moves on polyacrylamide gel strictly on basis of size of protein molecule.
• This technique is useful for determining the molecular weight of proteins.
• For visualization of proteins on the gel reagents used are Silver nitrate, Coomassie brilliant
blue dye.
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4. THERMAL ANALYSIS:
• Differential Scanning Calorimetry (DSC) is gaining widespread use as a tool for investigating
transitions of confirmation as a function of temperature and more importantly the effect of
potential stabilizing excipients in a protein solution.
• The apex of endothermic peak is the transition temperature between native and partially
unfolded confirmations.
5. BIURET TEST:
• The compounds with peptide linkage undergoes this test.
• The structure of biuret is similar to that of peptides.
• Biuret reagent: Copper sulphate, Sodium hydroxide, Sodium- potassium tartarate
• The peptides in the presence of biuret reagent reduces copper to cuprous ions in alkaline
solutions and thus producing purple colour.
MywPwhwar.DmualoGMuiidx.ec.oCmom
• This coloured product is formed due to formation of coordination complex of cupric ions with
unshared electron pairs of peptide nitrogen oxygen of water.
6. BRADFORD PROTEIN ASSAY:
• The Bradford protein assay measures the concentration of protein by adding Coomassie dye
to the sample under acidic conditions.
• When proteins bind with the Coomassie dye, the sample changes from brown to blue colour.
• The level of blue can then be measured by using a spectrophotometer to determine the
concentration of protein.
• Measure the absorbance at 595 nm to get the result.
MywPwhwar.DmualoGMuiidx.ec.oCmom
SOME PROTEIN AND PEPTIDE
BIOPHARMACEUTICAL DRUGS
DRUG INDICATION TARGET LOCATION FORMULATION
Calcitonin Osteoporosis Calcitonin receptors Nasal spray, solution for
on the surface of injection
osteoclasts
Corticotrophin Diagnosis of Cell surface receptors on Injectable gel
adrenocortical adrenal cells
deficiency
Cyclosporine Organ transplant Bind cyclophilin, an Surfactant
prophylaxis intracellular protein solubilized solution
regulator in T cells for injection, capsules,
ophthalmic emulsion
Desmopressin Diabetes insipidus Vasopressin v1 and Oral tablet,
v2 receptors on renal intranasal, solution
epithelial cells and for injection
vascular smooth
Muscle
MywPwhwar.DmualoGMuiidx.ec.oCmom
Contd…..
DRUG INDICATION TARGET LOCATION FORMULATION
Alteplase, tPA Pulmonary embolism, Activates Powder for injection
(Activase) acute myocardial Plasminogen in a
infarction, ischemic vessel clot
Stroke
Interferon alfa-2a Chronic myelogenous Type 1 interferon Prefilled syringes of
(Roferon) leukemia, hairy cell receptor on infected solution for injection
leukemia cells, tumor cells,
immune cells
Etanercept Rheumatoid arthritis Binds tumor necrosis Powder for injection,
(Enbrel) factor in synovial fluid, solution for injection
Plasma
Pegaspargase Acute lymphocytic Depletes L-asparagine PEGylated protein
leukemia around lymphoid tumor solution for injection
cells lacking
MyP ar Aspargine synthetase
wwhw.DmualoGMuiidx.ec.oCmom
Contd…..
DRUG INDICATION TARGET LOCATION FORMULATION
Adalimumab Ankylosing Binds tumor necrosis factor Solution for
(Humira) spondylitis, Crohn’s α in synovial fluid, plasma injection, prefilled
disease, psoriasis, and other inflamed tissues syringes, pens
rheumatoid arthritis
Bevacizumab Cancers, macular Binds to vascular Solution for injection
(Avastin) degeneration, endothelial growth
Diabetic retinopathy factor on tumor or
retinal endothelial cells
Certolizumab Crohn’s disease, Binds tumor necrosis factor PEGylated powder
Pegol rheumatoid arthritis α in synovial fluid, plasma for injection
and other
inflamed tissues
Trastuzumab Breast cancer HER2 protein on the Powder for injection
(Herceptin) surface of breast, colon
and ovarian cancer cells
MywPwhwar.DmualoGMuiidx.ec.oCmom
REFERENCES
• Fundamentals of Biochemistry by J.L. Jain, 6th revised and enlarged edition,
2005.
• Biochemistry by U. Satyanarayana, Revised reprint 2007.
• Ansel’s pharmaceutical dosage forms and drug delivery systems, 10th edition,
2013.
• Textbook of biochemistry for medical students by D.M. Vasudevan,
6th edition, 2011.
• Handbook of Pharmaceutical dosage forms by S.P. Vyas, A.K. Goyal, 1st edition,
2002.
• Progress in novel and controlled drug delivery systems by N.K. Jain, 2008.
• Drug delivery and targeting for pharmacists and pharmaceutical students by
Anya.M. Hillery, special Indian edition.
MywPwhwar.DmualoGMuiidx.ec.oCmom
REFERENCES
• Pharmaceutics by Shelley Chambers Fox, Remington education.
• International Journal of Current Pharmaceutical Research –
Peptides and proteins in pharmaceuticals by
Ratnaparkhi M.P., Chaudhari S.P., Pandya V.A, a review article, 2010.
• Asian journal of pharmaceutics – Review article on Recent trends in protein
and peptide drug delivery systems by Himanshu gupta, Aarti sharma, 2010.
• World journal of pharmacy and pharmaceutical sciences, Protein and
peptide DDS by Sagar Kishore Savale (www.wjpps.com ), a review article,
2016.
• Research journal of pharmacy and technology – Protein and peptide drug
delivery – a brief review by L. Srinivas, 2019.
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MywPwhwar.DmualoGMuiidx.ec.oCmom