Protein and peptide drug delivery.pptx

Different routes for the protein and peptide drug delivery (Oral, Buccal, Nasal, Transdermal, Parental and pulmonary)

1. Protein And Peptide Drug Delivery S ystem PRESENTED BY: MEGHA ASSISTANT PROFESSOR

2. Delivery of Peptide and Protein Drugs

3. Routes Oral route Buccal Route Nasal Route Pulmonary Route Parenteral Route Transdermal Route Rectal Route

4. Oral Route

5. 1) ORAL ROUTE :- Oral route is the most popular route of delivery from the patient’s point of view. Main advantages of this route are convenience , acceptability and high patient compliance. The main barriers to successful oral delivery of protein and peptides are similar to that of traditional drug candidates , but these are more pronounced in the case o f peptide/protein moieties. The main barriers to effective oral delivery are :- Poor intrinsic permeability of peptides/proteins across biological membranes . Susceptibility to enzymatic attack by intestinal proteases and peptidases . Rapid post-absorptive clearance. Physical instability like aggregation and adsorption.

6. Chemical modification Penetration Enhancer Carrier System Enzyme Inhibitor Amino acid modification Lipidation Liposomes Emulsion Lipid Based Polymer based Hydrogels Nanoparticles Various approaches that are developed for delivery proteins and peptide drugs

7. a). CHEMICAL MODIFICATION :- The Chemical Modification of Protein and Peptide Drug is Important to Improve the Enzymatic Stability as well as Membrane Permeations. a.1) Amino acid modification:- Post-translational modifications can occur on the amino acid side chains or at the protein's  C-or  N-  termini .They can extend the chemical repertoire of the 20 standard amino acids by modifying an existing  functional group  or introducing a new one such as phosphate . Phosphorylation is a very common mechanism for regulating the activity of enzymes and is the most common post-translational modification. Amino acid (polar) Phosphorylation Amino acid ( non-polar)

8. a.2) Lipidation:- Attachment of lipid molecules to the protein structure. Hydrophobic groups for membrane localization:- Myristoylation , attachment of  myristate. Palmitoylation , attachment of  palmitate. Isoprenylation or  prenylation, the addition of an isoprenoid  group. Cofactors for enhanced enzymatic activity:- Lipoylation, attachment of a  lipoate functional group. F lavin  moiety may be covalently attached.

9. b) Penetration Enhancer:- Peptide/protein drug moieties, due to their molecular size, often require penetration enhancers to achieve therapeutically significant levels of luminal absorption. Penetration enhancers is responsible for the Disruption of the Mucosal Barriers. Surfactant Polysorbate , SLS, Pluronic F-68 Chelating agent EDTA Bile salt sodium cholate and deoxycholate Mucoadhesive polymeric system Thiomers , Cellulose derivatives Other example Fatty acids, Phospholilpid

10. C) Carrier System:- This strategy is particularly applicable in the case of poorly absorbed peptides/proteins, which are unstable in the Gastro intestinal (GI) lumen and their targeting to a specific tissue or organ is to be affected. The proper designing of the delivery system not only protects the drug from gastrointestinal degrading components in the physical environment of the formulation prior to absorption , but also localized the drug at or near the cellular membrane to maximize the driving force for passive permeation. C.1) lipid based carrier system:- C.1.1) Liposomes :- L iposomes are spherical, self-closed structure formed by one or several lipid bilayer with an aqueous phase inside.

11. Liposomes are biocompatible and can both entrap and protect the protein and peptide in their internal core. To deliver liposomes to the brain, they can be firstly modified into long circulation vesicles by decreasing particle size (< 100 nm) or by linking polyethylene glycol (PEG) chains to their surface. Method of Preparation Liposome

12. C1.2) Emulsion:- An emulsion is a well-blended mixture of two immiscible liquids such as oil and water in the presence of emulsifying or surface-active agents . Multiple emulsions such as oil in-water-in-oil (O/W/O) and water-in-oil-in-water (W/O/W) emulsions are often used for delayed or controlled drug release. Self-nanoemulsifying drug delivery systems (SNEDDS) have received considerable attention as a promising alternative to orally administered emulsions due to their high physical stability and ease of manufacture. SNEDDS consist of oils, surfactants, co-solvents/co-surfactants, and drugs. Compared to conventional W/O/W emulsions, SNEDDS have some advantages as an oral delivery system for protein drugs in terms of better stability, better oral bioavailability, and easier particle size control.

13. Protein SNEDDS

14. C.2) Polymer Based Carrier System:- C.2.1) Hydrogels :- Hydrogels are three-dimensional polymeric networks composed of cross- linked hydrophilic and biocompatible polymers, which also exhibit a thermodynamic compatibility with water allowing them to swell in aqueous media. Among various polymers, 2-hydroxyethyl methacrylate, ethylene glycol dimethylacrylate, N-isopropyl acrylamide, acrylic acid, methacrylic acid (MAA), polyethylene glycol (PEG) and polyvinyl alcohol (PVA) are commonly used in hydrogels for protein delivery. Alginate and xanthan gum-based hydrogel systems seem to be suitable for protein delivery via the oral route of administration.

15. C.2.2) Nanoparticles:- Nanoparticles are solid, colloidal particles consisting of macromolecular substances that vary in size from 10 nm to 1000 nm. Typically , the drug of interest is dissolved, entrapped, adsorbed, attached and/or encapsulated into or onto a nano matrix . P olymers are used in the preparation of nanoparticles:- P olylactic acid (PLA ), P olylactic-co-glycolic acid(PLGA) Chitosan G elatin , Polymethylmethacrylates P oly-alkyl-cyanoacrylate.

16. D) Enzyme Inhibitor:- In addition to direct modifications, another method to increase oral peptide bioavailability is to coadminister with enzyme inhibitors. These enzyme inhibitors are usually more effective in the large intestine than the small intestine due to the large quantity and variety of proteases in the small intestine. Insulin with enzyme inhibitor (Aprotinin, bacitracin, betatin) which result in significance reduction in insulin digestion and improve in its intestinal absorption profile Enzyme inhibition compound Metalloprotease EDTA Aminopeptidases Bestain & Bacitracin Metalloendoprotease Phosphoramidon Cystinyl Proteases Papain, Endopeptidase

17. Buccal Route

18. Buccal membrane has numerous elastic fibers in the dermis, which is another barrier for diffusion of drug across the buccal membrane. The barriers for efficient drug absorption are: Mucus layer covering the oral epithelium. Epithelial barriers. Peptidases in the saliva and the mucus layer and microbial flora. The buccal peptide absorption is assumed to be via passive absorption mechanism. Various parameter that influence the extent of buccal peptide absorption are molecular weight, polarity, conformation, dissociation and enzymatic and chemical stability. 2.) Buccal Route :-

19. various strategies employed for Buccal Delivery Adhesive tablets Adhesive patches Adhesive gels a.) Adhesive Tablets:- Buccal tablets are small, flat and oval, with a diameter approximately 5-8 mm. They soften , attach to the mucosa, and are retained in position until dissolution and release is complete. These tablets can be applied to different sites in the oral cavity, including the palate,the mucosa lining the check, as well as between the lip and the gum.

20. b). Adhesive Gels :- Viscous adhesive gels have been designed for local therapy using polyacrylic acid and polymethacrylate as gel forming polymers . Gels are reported to prolong residence time on the oral mucosa to a significant level. This not only improves absorption but also allows for sustained release of the active principle. C). Adhesive Patches :- Patches are laminates consisting of an impermeable backing layer, a drug- containing reservoir layer from which the drug is released in a controlled manner, and a bioadhesive surface for mucosal attachment.

21. Formulation of Mucoadhesive buccal Film Formulation of Mucoadhesive buccal Film API Bioadhesive polymer Plasticizer Penetration Enhancer Backing membrane Agarose chitosan gelatin hyaluronic acid Polyacrylates polyoxyethylene glycerol, propylene glycol, PEG 400, castor oil Polysorbate EDTA sodium cholate and deoxycholate Thiomers Cellulose derivatives carbopol magnesium stearate HPMC HPC CMC

22. Nasal Route

23. 3.) Nasal Route:- Generally, the intranasal route is suited for the intermittent delivery of highly potent peptide/protein drugs having low molecular weight . Peptidal drug moieties like calcitonin, ACTH, and interferon are reported to have appreciable absorption through nasal mucosa. Nasal route is chiefly use to delivery of protein drug. Barriers to systemic absorption through nasal route :- Extent of absorption varies with the mucus secretion and mucus turnover . Peptidases and proteases present in the mucus or associated with nasal membrane serve as enzymatic barrier in protein/peptide absorption. Types of Dosage Form Nasal Spray Aerosol Nasal Drops

24. Various approaches for Nasal Delivery of peptide/protein drugs Increase nasal blood flow Permeation enhancer and enzyme inhibitor Dissociation of Aggregation pH Modification Viscosity modification a.) Viscosity modification :- The clearance time from the nasal cavity can be delayed by using solutions with higher viscosity. For example the half time of clearance could be increased significantly with 0.6 % of hydroxypropyl methylcellulose.

25. b). pH Modification:- Peptides and proteins usually exhibit the lowest solubility at their isoelectric point. Thus, by adjusting the pH further away from the isoelectric point of a particular peptide, its solubility can be increased. For example nasal absorption of insulin was observed with sodium deoxycholate, that insulin is capable of crossing the nasal membrane in an acidic medium . Examples of buffer used in nasal spray sodium phosphate, Sodium citrate, citric acid. c). Dissociation of Aggregation:- Proteins are likely to form higher-order aggregates in solution. For instance at pH 7.0, protein exists in solution chiefly as hexameric aggregates

26. Protein fails to cross the nasal membrane. Sodium deoxycholate disrupts the formation of protein hexamer or dissociation of protein hexamer to dimer or monomer. d). Permeation enhancer and enzyme inhibitor :- They increase the fluidity of the lipid bilayer membrane and open up aqueous pores as a result of calcium ion chelation . Peptidase inhibitors enhance the absorption by suppressing peptidase activity in both the mucus and mucosal cells . Enzyme inhibitor Permeation enhancer EDTA Bile Salts Polysorbate EDTA sodium cholate and deoxycholate Thiomers Cellulose derivatives

27. e). Increase Nasal flow:- With an increase in local nasal blood flow an enhancement in nasal peptide absorption has been reported. This occurs due to concentration gradient of peptide passive diffusion . Vasoactive agents, which are known to enhance nasal blood flow, include histamine, prostaglandin E1 and beta-adrenergic agonist. Different nasal delivery systems like drops, sprays and inhalers have variable results in terms of intensity, duration of effect. Nasal drops produce far greater pathologic changes and faster clearance than the nasal sprays and inhalers. Metered dose aerosol and metered dose pump can achieve accurate dose dispensation and good distribution in the nasal cavity. Delivery system :-

28. Transdermal Route

29. 4.) Transdermal Route:- Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution . Advantages of Transdermal Route for peptide/protein Delivery are : Better and improved patient compliance. Elimination of hepatic first pass phenomenon. Controlled administration is possible and thereby avoidance of toxic effects. Also drugs with shorter half-life can be administered. Limitations of Transdermal Route for peptide/protein Delivery are : A low rate of permeation for most protein drugs due to their large molecular weight and hydrophilicity and lipophilic nature of the stratum corneum . High intra and inter patient variability.

30. Various approaches for Transdermal delivery Route of peptidal drugs Iontophoresis Sonophoresis Electroporation Microneedle technology a).Iontophoresis:- Iontophoresis is a method that induces migration of ions or charged molecules when an electric current is allowed to flow through an electrolyte medium.

31. To undergo Iontophoresis protein/and peptide molecules must carry charge. To achieve this pH and ionic strength of solution are controlled. Protein/and peptide are repelled by the same charge on electrode and penetrate through the skin under the influence of electric current . The two electrodes are placed on the stratum corneum, one of the electrode drug is loaded (reservoir electrode) and current is applied which increased the permeability of skin and drug molecule flow through epidermis →→→ dermis→ papillary layer →→ subdermal tissue→→blood circulation Iontophoresis

32. b) Electroporation :- Electroporation utilizes very short pulses of high voltages (between 10 and 100 V) to perforate the skin. Similar to iontophoresis , application of electroporation breaches only the stratum corneum, characterizing it as another non-invasive method for drug introduction. Application of an electric current disrupts the structure of these lipids, allowing molecules to penetrate the skin. In addition, delivery of drug can be increased using this method by increasing the voltage, number of pulses and duration of pulses to levels still viewed as safe for the patient.

33. c). Sonophoresis :- Sonophoresis, also referred to as cavitational ultrasound, relies on the application of sound waves to the skin to increase its permeability. Sonophoresis achieves this task by targeting the lipid bilayers embedded in the stratum corneum. Sound waves, generally between 20–100 kHz, are believed to cause an increase in pore sizes on the skin (increased fluidity in these lipid bilayers), thus allowing drug penetration transcellularly through the stratum corneum

34. d). Microneedle technology:- Microneedle technology involves the use of small needles that create small pores in the skin, allowing drug passage across the outermost physical barrier. These microneedles are designed to breach only the stratum corneum. Methods :- One such method involves a two step approach, where the needles are used to puncture the skin to create pores, followed by topical administration of the drug. Another method includes coating the microneedles themselves with drugs, allowing the drug to then enter the body after the skin is treated with the needle. A third method includes encapsulating the drug in biodegradable microneedles, slowly releasing the drug as the needles degrade.

35. Microneedle Technique

36. Parenteral Route

37. 5.)Parenteral Route :- Parenteral mode of drug delivery has been the major route of choice for protein/peptide, owing to their poor absorption and metabolic instability when given by other alternative routes. The parenteral drug delivery system includes Intravenous, intramuscular, subcutaneous, intraperitoneal, intrathecal use. Carriers System Liposome Nano particles Microsphere Emulsion

38. MISCELLANEOUS Self regulated system On demand system Pump Mechanical pump Osmotic pump

39. a ). On Demand System :- Externally augmented demand delivery systems are particularly beneficial in the delivery of polypeptides like insulin . The device consists of an ethylene-vinyl acetate matrix with magnetic beads or cylinders. The magnetic beads alternately compress and expand the matrix in the presence of magnetic field . On exposure to external oscillating magnetic field the drug release was increased up to 30 times. On removal of the magnetic field, the drug release rates returned to normal.

40. b.)Pumps:- Pumps differ from other diffusion based system in that primary driving force for delivery is the pressure difference and not the concentration difference of the drug between the formulation and the surroundings. Pressurizing the drug reservoir, by osmotic action or by direct mechanical actuation, can generate this pressure difference to affect drug release. The pump can either be implantable or externally portable. b .1) Mechanical pumps:- Mechanical pumps are technically simple, rugged and can be easily manipulated to deliver Peptidal drugs in several different wave form. But the prime concerns are in terms of its susceptibility to mechanical failure, high power requirement and relatively large size.

41. b .2) Osmotic pumps:- Osmotic Pump have been used extensively for delivery of a large number of peptide/proteins drugs in animals. These pumps can be implanted subcutaneously. Some of the representative examples of drugs that have been delivered in osmotic pumps include insulin, ACTH, calcitonin, LHRH, growth hormone, neurotensin and vasopressin

42. C) Self regulated system:- Glucose sensor sense the Glucose level Transmit Signal to the insulin Pump Then sensor transmit signal to stop the insulin pump Insulin Pump deliver Insulin to infusion set

43. Thank You