25-therapeutic application of peptides-1 .ppt

Part Two Biopharmaceuticals as therapeutic agents 1 Learning objectives • Factors that must be considered for protein drug delivery • Learn about the routes of administration available for protein drug delivery • Learn about recombinant protein as therapeutic agents with examples • Learn about s...

Part Two Biopharmaceuticals as therapeutic agents 1 Learning objectives • Factors that must be considered for protein drug delivery • Learn about the routes of administration available for protein drug delivery • Learn about recombinant protein as therapeutic agents with examples • Learn about synthetic proteins/peptides as therapeutic agents with examples. 2 Key factors to be considered in Protein drug delivery Protein structure Physicochemi cal factors Physiological factors • Molecular size • Shape & conformation • Charge • Solubility • Partition coefficient • Aggregation • Stability • pH • Digestive enzymes • Permeability barrier • Secretion • Phagocytic clearance Routes of administration option for protein drugs Routes of administration * Relative Proteolytic Activity of Biological Tissues Intestinal > Rectal > Buccal > Nasal > Pulmonary > Vaginal > Dermal * Relative Permeability of Epithelial membranes Intestinal > Pulmonary > Nasal > Vaginal > Rectal > Corneal > Buccal > Transdermal Comparison Route Pros Transderm • Low proteolytic activity • Avoidance of first pass al metabolism • Controlled release possible • Fast absorption Nasal • Lower proteolytic activity than GI • Avoidance of first pass metabolism Buccal Cons • Poor absorption • Poor bioavailability • Reproducibility • Short residence time • Low bioavailability • Low bioavailability • Lower proteolytic activity than GI • Avoidance of first pass metabolism • Lower proteolytic activity than GI • Low Rectal • Partial avoidance of first pass bioavailability effect • Reproducibility Pulmonary • Fast absorption • Lower proteolytic activity than GI • of first pass * Intestinal route Avoidance is NOT feasible due to the GIT proteolytic enzymes metabolism • Reasonable bioavailability Strategies to Increase Protein Bioavailability  Barrier Permeability - Penetration enhancers - Tight-junction permeability enhancers - Enzyme inhibitors (EDTA)  Enzymatic Degradation - Prodrugs - Liposomes, nanoparticles Recombinant Proteins 8 Insulin • In early 1920s insulin was called “Isletin” and it was isolated from animals (e.g. pigs – porcine insulin) to treat DM at that time. • In the 1930s, H.C. Hagedorn, a chemist from Denmark added adding protamine and zinc to produce longer-acting animal insulins (later called Neutral Protamine Hagedorn (NPH) insulin). • In 1978, the first recombinant DNA human insulin was prepared by David Goeddel and his colleagues (of Genentech) by utilizing and combining the insulin Aand B- chains expressed in Escherichia coli. 9 • In 1982, the first insulin utilizing rDNA technology, Humulin R (rapid) and N (NPH, intermediate-acting), were marketed by Eli Lilly - USA • Lispro was the first short-acting insulin analog approved in 1996. followed by Insulin Aspart in 2000. Then insulin glargine, approved in 2000. Then Insulin Glulisine in 2004 and Insulin Detemir, approved in 2005. • “Exubera” is the first inhaled insulin, was developed by Sanofi-Aventis and Pfizer and marketed by Pzifer in 2006. Withdrawn due to failed gain acceptance from patients 10 Micro-organisms used in Insulin productions 11 Insulin preparations in Oman Insulin (human insulin) – no modifications in structure – protamine added Insulin analogues (mutated) – selected amino acids were replaced/substituted ** The most common way to administer insulin is through SC injection. 12 Recombinant human erythropoietin (EPO) • It was an immediate success in treating the anaemia of chronic renal failure. • Therapy with EPO has also been considered for the anaemia associated with many disorders including cancer, multiple myeloma, myelodysplasia, HIV infection and chemotherapy. • It has become a drug of abuse amongst athletes who derive benefit from the increased oxygen carrying capacity of the resultant polycythaemia. • Darbepoetin alfa (Aranesp) is a recombinant EPO analogue approved by FDA in 2003. 13 Recombinant Interferons • Interferon beta–1a (Avonex) & Interferon beta–1b (Betaseron) has been licensed for use in relapsing remitting multiple sclerosis (MS). • It is believed that interferon-beta based drugs achieve their beneficial effect on MS progress via their anti-inflammatory properties. Studies have also determined that interferon-beta improves the integrity of the blood–brain barrier (BBB) which generally breaks down in MS patients, allowing increasing amounts of undesirable substances to reach the brain. 14 Recombinant human Growth Hormone (hGH) • Invistigations of clinical usage of hGH have focused on two major areas of hGH biologic action: 1) linear growth promoition and 2) modulation of metabolism. • hGH is commonly used for the long-term replacement treatment for children with classic growth hormone deficiency in whom growth failure is due to lack of adequate endogenous hGH secretion. • Recombinant hGH products: Genotropin and Humatrope 15 Recombinant Human Deoxyribonuclease I • Marketed as Pulmozyme. • It is an enzyme which selectively cleaves DNA. It hydrolyzes the DNA present in sputum/mucus of cystic fibrosis patients and reduces viscosity in the lungs, promoting improved clearance of secretions 16 ADVANTAGES AND DRAWBACKS of Recombinant Proteins • High activity, which usually means that small doses of peptide have to be administered. • Peptides are usually highly specific and have therefore relatively low systemic toxicity. They do not accumulate in the body as they have relatively short half-lives. • The total amount to be produced is relatively small (large scale production?). • The cost of their synthesis has been considered disadvantageous. 17 Synthetic Peptides 18 Somatostatin Analogues • Example: Octreotide (Sandostatin) is the synthetic analogue of somatostatin. • Uses: GIT disorders. • MOA: pharmacological action include: - inhibit secretion of many hormones. - reduce secretion of fluids by the intestine and pancreas. - reduce gastrointestinal motility and inhibit contraction of the gallbladder. - cause vasoconstriction in the blood vessels. 19 Vasopressin Analogues • Example: Desmopressin, • (des-amino-D-Arg8-vasopressin) (Minrin) • Uses: doctors prescribe desmopressin most frequently for treatment of diabetes insipidus, bedwetting, or nocturia. • MOA: Desmopressin works by limiting the amount of water that is eliminated in the urine. 20 Bivalirudin • It is synthetic analogue of Hirudin (a peptide found in the saliva of the medicinal leech) (Angiomax) • Uses: Used in emergency for angina and Myocardial Infarction. • MOA: Bivalirudin is a short, synthetic peptide that is potent, highly specific, and a reversible inhibitor of thrombin. It inhibits both circulating and clot-bound thrombin, while also inhibiting thrombin-mediated platelet activation and aggregation. 21 Pentafuside • The synthetic peptide T20/Pentafuside/ Enfuvirtide (Fuzeon) is a 36 amino acid peptide compound. • Uses: treatment of HIV infection. • MOA: It corresponds to amino acids 638 to 673 of HIV1(LA1) transmembrane protein, gp4. Pentafuside blocks HIV infection, uniquely, by preventing membrane fusion (i.e. fusion inhibitor), which is an essential process in viral replication. In preclinical/clinical studies it showed to block infection of cells by HIV and prevented the fusion of one HIV-infected cell with another. 22 Peptide antibiotics 1) Polymyxins (B1 and B2): Uses: Polymyxins is used as a topical preparation for local eye and ear infections. MOA: Polymyxins bind to the bacterial cell membrane and alter its structure, making it more permeable. The resulting water uptake leads to cell death. 23 2) Colistin / Polymexin E • Colistin (bactericidal effect) is occasionally given by injection/aerosol to treat Pseudomonas aeruginosa in patients with cystic fibrosis. It is also used orally in bowel sterilization regimens for neutropenic patients, as it is not absorbed. • Neisseria spp. and Helicobacter pylori bacteria are resistant to colistin. 24