protein and peptide drug delivery system

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PROTEIN AND PEPTIDE DRUG DELIVERY SYSTEM SUBMITTED BY: Gunjan M.Pharmacy -I PGIMS

Protein and peptide : 

Protein and peptide Protein are the most abundant macromolecule in the living cells. The name protein is coined from the greek word- Protos , meaning “first” or “foremost”. Proteins - Chains of same 20 amino acids but in different combinations and sequences, each joined together by a specific type of covalent bond. Protein > 50 amino acids Peptide < 50 amino acids Function of a protein determined by its non-covalent 3D structure.

Classification of Proteins: 

Classification of Proteins According to their biological roles - Enzymes – Catalyses virtually all chemical reactions i.e. pepsin - Transport proteins i.e. Hemoglobin of erythrocytes - Contractile or Motile proteins i.e. Acting and Myosin - Structural proteins i.e. Collagen - Defense proteins i.e. Immunoglobulin and Antibodies - Regulatory proteins i.e. insulin - Nutrient and storage proteins i.e. Ovalbumin

Challenges with Proteins: 

Challenges with Proteins Very large and unstable molecules Structure is held together by weak non-covalent forces Easily destroyed by relatively mild storage conditions Easily destroyed/eliminated by the body Hard to obtain in large quantities

Problem with Proteins (in vivo – in the body) : 

Problem with Proteins (in vivo – in the body) Elimination by B and T cells Proteolysis by endo / exo peptidases Small proteins (< 30 kD ) filtered out by the kidneys very quickly Unwanted allergic reactions may develop (even toxicity) Loss due to insolubility/adsorption

Problem with Proteins (in vitro – in the bottle) : 

Problem with Proteins (in vitro – in the bottle) Noncovalent Covalent - Denaturation - Deamidation - Aggregation - Oxidation - Precipitation - Disulfide exchange - Adsorption - Proteolysis

Noncovalent Processes: 

Noncovalent Processes Denaturation Adsorption Aggregation Precipitation

Covalent processes: 

Covalent processes Deamidation - conversion of Asn-Gly sequences to a-Asp- Gly or b-Asp- Gly Oxidation - conversion RSR’ to RSOR’, RSO 2 R’ or RSO 3 R’ (Met & Cys ) Disulfide exchange - RS - + R’S-SR’’ goes to RS-SR’’ + R’S - ( Cys ) Proteolysis - Asp-Pro, Trypsin (at Lys) or Chymotrypsin (at Phe /Tyr)

Parenteral Route Of Administration: 

Parenteral Route Of Administration For the systemic release of the protein and peptides parenteral route is the most efficient route. This is the best choice to achieve the therapeutic activity. Mainly three types of administration are used: 1) Intravascular 2) Intramuscular 3) Subcutaneous

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Advantages: 1) Fast absorption. 2)Avoid first pass metabolism and proteolytic degradation. Disadvantages: 1) Short duration of biological action. 2)Stimulate immunogenic response. 3) Inability to transport

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The drug carrier systems employed for defined and controlled delivery of drug through this route are :-

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1)Particulates: A)Microspheres: these are solid spherical particles in the size range of few tenths of micrometer to several hundreds micrometer containing dispersed drugs in either solution or microcrystalline form. They can be targeted to a particular organ or a specific part of a organ o to a selective intracellular site. Passive targeting can be achieved by cellular uptake or local injection. Active targeting can be achieved by conjugating receptor-specific moieties like monoclonal antibodies.

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ADVANTAGES: They can be administered subcutaneously, intramuscularly. By using an appropriate technique they can be prepared cheaply. DISADVANTAGES : Drug release may be poorly defined. They have to pass successfully the biological and cellular barriers. They may interact or form complexes with the blood components.

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B) LIPOSOMES: These are spherical vesicles formed when phospholipids are allowed to swell in aqueous media. As their structure resembles to cell membranes, Liposome can serves as a depot releasing the drug slowly. Liposome protect the entrapped peptide from enzymatic degradation on intravenous administration. They can passively deliver peptide to a particular site.

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ADVANTAGES: Flexibility in size, shape and structure. Relatively non toxic disposition. Ability to encapsulate both hydrophilic and lipophilic peptide or protein. DISADVANTAGES: The constituent phospholipids have tendency to interact with proteins. Proteins susceptible to aggregation may affect the stability of liposome.

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2) CELLULAR CARRIERS: Peptides and proteins can be encapsulated in erythrocytes to achieve their prolong release and target. ADVANTAGES: Biodegradability Non immunogenic Large circulation life Large quantity of drug can be encapsulate in small volume of cell. Offers enzymatic protection to the drug. LIMITATION: Long term storage is problematic.

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3) PUMPS: The primary driving force for delivery is the pressure difference . Pressurizing the reservoir by osmotic or direct mechanical actuating can generate this difference to affect the drug release. The pump can either be implanted or externally portable. The ideal pump should have : 1 Wide range of delivery rate. 2 Accurate, precise and stable delivery. 3 Compatibility of drug with internal pump components. 4 Monitoring of status of pump should be easy.

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5 Protection against overdose and leakage. 6 Long reservoir life. PUMPS ARE OF THREE TYPES: Mechanical pump Osmotic pump Controlled release micro pumps

Controlled release pump: 

Controlled release pump

NON PARENTERAL ROUTE OF ADMINISTRATION: 

NON PARENTERAL ROUTE OF ADMINISTRATION Oral Route of Administration: oral route is most popular route from patient point of view. Advantages: 1.Convenience 2.Acceptibility 3.High patient compliance

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Disadvantages The systemic bioavailability of protein and peptide drug by this route is generally less than 2%. Very less permeability through oral mucosa. Potential degradation by strong acids and proteolytic enzymes.

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Various strategies have been attempted for effective delivery of proteins and peptides drugs through oral route. Some of them are as follow: MODIFICATION BY CHEMICAL SYNTHESIS: This modification assist in manipulating the pharmacokinetic parameters to improve the therapeutic value of the parent drug. This can be done by: 1)Irreversible (analogue) 2)Reversible (prodrug)

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Enzyme Inhibitors: Aprotinin, camostat mesylate, Bacitracin. Penetration Enhancer: SLS, EDTA, Fatty acids. Carrier System : This strategy is particularly applicable in case of poorly absorbed ,the drugs which are unstable in G.I.lumen. Example: Liposome and sub micro emulsion.

Buccal Route of Administration: 

Buccal Route of Administration The drugs are absorbed through oral mucosa i.e. occur in non keratinized sections. ADVANTAGES: 1)It is close resemblance to oral route seems well acceptable to the patients. 2)Can attached and remove without any pain or discomfort. 3)It is worth considerable when penetration enhancers are used.

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The inherent problem with these dosage form is the risk of drug loss by accidental swallowing leads to less administration time. The various strategies employed for Buccal delivery: 1)Adhesive tablets 2)Adhesive gels 3)Adhesive patches 4)Absorption promoters

Nasal Route of Administration: 

Nasal Route of Administration The nasal route has been chiefly employed for producing local action on mucosa. This mucosa is more permeable compare to the oral mucosa. The nasal absorption of protein and peptide can be via special diffusion and special targeted mechanism i.e. 1-20% Example: Insulin and Human growth hormone.

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Advantages: Convenient ,simple and practical way of drug administration. High vascular permits better drug absorption. First pass metabolism can be avoided. Rapid onset of action. Disadvantages: Long term usage causes toxicity. Enzymatic barrier, size of protein and peptide drug reduce the systemic bioavailability.

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Number of approaches are available for achieving effective delivery of protein and peptide drug. Those are: VISCOSITY MODIFICATION Hydroxy propyl methyl cellulose MEMBRANE TRANSPORTER Surfactant( SLS) ENZYME INHIBITOR Bestatin, Amastatin pH MODIFICATION Insulin exhibit highest solubility in acidic medium

TRANSDERMAL ROUTE OF ADMINISTRATION: 

TRANSDERMAL ROUTE OF ADMINISTRATION This is a topical medication. In this the drug is absorb through skin. Example: Insulin, Vassopressin. ADVANTAGES : Better and improved patient compliance. Drug with short half life can also administer. Administration of drugs with low therapeutic index. Controlled administration is possible.

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DISADVANTAGES: Low rate of permeation of these drugs because of large molecular weight. High lipophilicity and hydrophilicity of stratum corneum of skin.

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Number of approaches are available for achieving effective delivery of protein and peptides. Those are: 1)IONOPHORESIS: induces migration of ions or charged molecules when the current is allowed to flow through an electrolyte medium.

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2)PHONOPHORESIS: thermal effect of ultrasonic waves alters the physical structure of skin and enhance permeability. 3)PENETRATION ENHANCER: Oleic acid and Surfactant. 4)PRODRUG: Modification in the ph ysiochemical properties of drug like lipophilicity and charge will enhance the permeability of the drug.

PULMONARY ROUTE OF ADMINISTRATION: 

PULMONARY ROUTE OF ADMINISTRATION Respiratory track offers an alternative site for systemic non invasive delivery of protein and peptide drugs Alveoli and lungs are the absorption site(90%). Drugs are absorbed through lungs by simple diffusion and carrier mediated transport.

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ADVANTAGES: Provide a direct route to systemic circulation. Safe route even in patient with lungs disease. Decrease in dose requirement. Fast absorption. Patient compliance.

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DISADVATAGES: Only small amount of drug can be administered. Inflammation and edema can be observed. Degree of bioavailability is less due to presence of hydrolytic enzymes in lungs. Most of the drug administer at upper part of the lung area with low systemic circulation.

RECTAL ROUTE OF ADMINISTERATION: 

RECTAL ROUTE OF ADMINISTERATION Rectum is highly vascularised body cavity. The rectal mucosa is devoid of any villi. These drugs are in the form of gel and dry powders. Example: Insulin, Gastrin and Calcitonin. ADVANTAGES: Large dose can be administer. Avoid first pass metabolism.

SITE SPECIFIC DELIVERY: 

SITE SPECIFIC DELIVERY The objective of selective delivery and targeting are: Optimal delivery of drug to specific cell and diseased site. Reduction in the potential for side-effects. Protection of the drug from the body or vice-versa until the drug reaches its site of action. To improve the risk/benefit ratio.

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Drugs can be targeted to the lymphatic system. In case of drug overdo drug absorption can be terminated. Reduced proteolytic degradation. The improved systemic bioavailability of protein and peptide drugs due to co-administration of absorption enhancer. EXAMPLES : Surfactant, salicylate and EDTA.

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The site specific delivery can be achieved by: 1) MACROMOLECULAR DRUG CARRIERS Polylysine, polyethylene glycol. 2) SOLUBLE POLYMER CONJUGATES Polyethylene glycol, Poly-l-aspartic acid 3) PARTICULATE CARRIERS Liposome, Emulsions, Stabilized micellar system.

Storage (additives): 

Storage (additives) Addition of stabilizing salts or ions (Zn + for insulin) Addition of polyols (glycerol and/or polyethylene glycol) to solubilize Addition of sugars or dextran to displace water or reduce microbe growth Use of surfactants (CHAPS) to reduce adsorption and aggregation

Storage (Freeze Drying): 

Storage (Freeze Drying) Freeze liquid sample in container Place under strong vacuum Solvent sublimates leaving only solid or nonvolatile compounds Reduces moisture content to <0.1%

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Thank you