oral drug delivery proteins
TRANSCRIPT
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Strategies for oral delivery of proteins and peptides
Presented by:-Mr. Mane Avinash A.M.Pharm sem.-ÍÍDept. of Pharmaceutics
Guided by:-Mr. Galgatte U.C.Associate Professor Dept. of Pharmaceutics
P. E. SOCIETY’S MODERN COLLEGE OF PHARMACY NIGDI,PUNE,44
2015-16
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Peptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is known as an amide bond or a peptide bond.
INTRODUCTION
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Proteins are large organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues
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Primary structure- The amino acid sequence.
Secondary structure- Regularly repeating local structures
stabilized by hydrogen bond.
Tertiary structure- The three dimensional structure of the
polypeptide.
Quaternary structure-The structure formed by 2 or more
polypeptide chains associated by non covalent forces.
STRUCTURE OF PROTEIN
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1. Erythropoietin used for production of RBC.
2. Tissue plasminogen activator is used for Heart attack, Stroke.
3. Oxytocin maintain labor pain.
4. Bradykinin increases the peripheral circulation.
5. Somatostatin decrease bleeding in gastric ulcer.
6. Gonadotropin induce ovulation.
7. Insulin maintain blood sugar level.
ADVANTAGES
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1. Transport and storage of small molecules.
2. Coordinated motion via muscle contraction.
3. Mechanical support from fibrous protein.
4. Generation and transmission of nerve impulses.
5. Enzymatic catalysis.
6. Immune protection through antibodies.
7. Control of growth and differentiation via hormones.
FUNCTIONS
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1. Elimination by B and T cells.2. Proteolysis by endo/exo peptidases.3. Small proteins filtered out by the kidneys very
quickly.4. Unwanted allergic reactions may develop (even
toxicity).5. Loss due to insolubility/adsorption.
PROBLEMS WITH PROTEINS(in vivo – in the body)
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Encapsulated peptides or proteins in amino acids with microspheres of approximately 10 micron in diameter , used for oral delivery.
Example: Insulin and heparin.Orally administered insulin produces hypoglycemic
effect .
ORAL ROUTE
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The ease of administration and higher degree of patient compliance with oral dosage forms are the major reasons for preferring to deliver proteins and peptides by mouth.
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protection against the metabolic barrier in GIT absence of a carrier system for absorption of
peptides with more than three amino acids Proteins are labile due to susceptibility of the
peptide backbone to proteolytic cleavage Prodrug approach
olefenic substitution, d‐amino acid substitution, dehydro amino acid substitution, carboxyl reduction
Problems associated with oral delivery
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1. Amino acid modifications Metkephamid, an analog of methionine
encephalin with substitution of glycine by l-alanine ₂and modified methionine, readily penetrated across the nasal mucosa with 54% bioavailability relative to subcutaneous administration but was orally inactive
Maximising oral protein and peptide absorption
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2. Hydrophobization Hydrophobization of peptides may be attempted by two
approaches. The first is peptide backbone modification to include more of hydrophobic amino acids; the second would be covalent conjugation of a hydrophobic moiety—for example, a lipid or polymeric tail.
Increasing the hydrophobicity of a peptide or protein by surface modification using lipophilic moieties may be of particular benefit to trans cellular passive or active absorption by membrane penetration or attachment, respectively; or it may simply aid in the increased stability of the protein.
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EXAMPLE lipophilic modification of TRH by covalent
conjugation of lauric acid to this tripeptide (Lau-TRH). The derivative was more stable in rat plasma and was rapidly converted to TRH in the intestinal mucosal homogenate.
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Formulating for delivery through the gastrointestinal (GI) tract requires a multitude of strategies
To alter the environment for maximum solubility and enzyme stability of protein by using formulation excipients such as buffers surfactants and protease inhibitors
To promote absorption through the intestinal epithelium
Strategies for oral delivery
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Barriers to the absorption of drug in the intestine
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Bonding of (PEG) and alkyl groups fatty acid radicals to produce desired amphiphilic oligomers oligomers are conjugated to proteins or peptides to obtain desired amphiphilic products can resist excessive degradation of protein or
peptide drugs technology reduces self‐
association, increases penetration and increases compatibility with formulation ingredients than parent drug
Nobex technology
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Nobex conjugation technology
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Oral delivery is the most sought after route of administration for most of the drugs and pharmaceutical products, which depends on the drug’s molecular structure or weight
Transport mechanism of macromolecules
Peroral route: promises and pitfalls
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(A) Transport mechanism of bio drug through the intestinal epithelium membrane,
(B) Probable mechanism of penetration enhancer,
C) enzyme inhibitors, (D) Representative mechanism of prodrug
absorption and its activation.
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1. Enzyme inhibitors (protease inhibitors)2. Absorption enhancers (permeation
enhancers)3. Mucoadhesive polymeric systems4. Novel carrier systems5. Prodrug strategies
Formulation approaches for oral delivery of proteins and peptides
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Sr.no.
Approach Examples Effects on bioavailability
Drawbacks
1 Absorption enhancers
Bile salts, fatty acids, Surfactants (anionic, cationic)
Enhanced bioavailability by increased membranepermeation
Available transport systems of both proteins/peptides and undesirable molecules in GIT
2 Enzyme inhibitors
Sodium glycocholate, camostate mesilate
Resisted enzymes degradation in stomach and intestines
Produced severe side effects in the treatment of chronic diseases such as diabetes, etc.
3 Mucoadhesive polymeric systems
Thiolated polymer
Site–specific delivery and improved membrane permeation
Limitation due to the mucus turnover in absorption sites (intestine)
4 Prodrug strategies
Phenyl propionic acid
Prodrug permeabilityimproved 1608fold than parent drug
Lack of methodology, structuralcomplexity, stability problem of protein
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Desmopressin acetate (DDAVP) is a synthetic analogue of 8 arginine vasopressin: ant diuretic hormone. Marketed by Aventis pharmaceutical and is approved for diabetes insipidus.0.16 % bioavailable
Novartis and Roche pharmaceutical market cyclosporine (small lyophilic mol. For graft rej.) 30% bioavailability
Oral peptides today(Application)
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Aim: Design and In Vitro Characterization of
Buccoadhesive Drug Delivery System of Insulin
Preparation Method: A buccoadhesive drug delivery system of
Insulin was prepared by solvent casting technique and characterized in vitro by surface pH, bio adhesive strength, drug release and skin permeation studies. Sodium carboxymethyl cellulose-DVP was chosen as the controlled release matrix polymer.
Case Study
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Result: it is concluded that the system is a
success as compared to the conventional formulations with respect to invasiveness, requirement of trained persons for administration and most importantly, the first pass metabolism.
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Company Product name
Formulation
Development phase
Product
Apollo Life Science
Oradell Tablet Clinical phase I b
Insulin, TNF-blocker
Emisphere Eligen Tablet Phase II Calcitonin, insulin, PTH, heparin
Nobex/Biocon
HIM2 Liquid Abandoned Insulin, enkephalin, calcitonin
Technologies for oral delivery of proteins under clinical development by companies.
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Company Product name
Formulation
Development phase
Product
Oramed ORMD-0801ORMD-0901
Capsule Phase I Insulin/Exenatide
Diasome pharmaceuticals
Hepatic-directedvesicles-insulin(HDV-1)
Tablet Phase II/III Insulin
Diabetology Capsulin Capsule Phase II Insulin
Merrion pharma (Ireland)with Novo-Nordisk
Vetsulin Matrix tablet Phase I Insulin and GLP-1 analogues
Chiasma (Israel)
Octreolin Suspension Phase I (phase I completed,phase III enrolling
Octreotide
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NAME OF PUBLICATI
ON
PUBLICATION NO.
TYPE DATE INVENTOR
Oral delivery of modified
transferrin fusion
proteins
US8129504 B2
Grant 6 march 2012
Christopher p.Prior ,
Homoyoun sodeghi,Andrew turner.
Peptide library and screening systems
US5432018 A
Grant Jul 11, 1995 William J. Dower, Steren
E.cwirla, Ronald
W.barrettPeptide
conjugateUS5442043 Grant Aug 15,1995 Takeda
chemical industries
PETENTS
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1. McNally Ej. protein formulation and delivery. In: Drug and the pharmaceutical sciences.2nd ed. New York: Marcel Dekker; 2000.p.99-125
2. Novel drug delivery system by Dr. D. K. Jain and Dr. D. T. Baviskar Nirali prakashan Page no.14.1-14.7
3. Agarwal, V., Khan, M.A., 2001. Current status of the oral delivery of insulin. Pharm. Tech. 25 (10), 76–90.
4. Antunes, F., Andrade, F., Ferreira, D., Morck, N.H., Sarmento, B., 2013. Models to predict intestinal absorption of therapeutic peptides and proteins. Curr. Drug Metab. 14 (1), 4–20.
5. Aoki, Y., Morishita, M., Asai, K., Akikusa, B., Hosoda, S., Takayama, K., 2005. Region dependent role of the mucous/ glycocalyx layers in insulin permeation across rat small intestinal membrane. Pharm. Res. 22 (11), 1854–1862.
References
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