PROTEIN AND PEPTIDE DRUG DELIVERY-SEMINAR-97-2003-final2

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PROTEIN AND PEPTIDE DRUG DELIVERY SYSTEM:

PROTEIN AND PEPTIDE DRUG DELIVERY SYSTEM 1

CONTENTS:

CONTENTS INTRODUCTION TO PROTEINS AND PEPTIDES ROUTES OF ABSORPTION PROPERTIES OF PROTEINS AND PEPTIDES CONSTRAINTS (POTENTIAL PROBLEMS) IN DELIVERY OF PROTEINS AND PEPTIDES PHARMACEUTICAL APPROACHES INCORPORATION INTO DRUG DELIVERY MATRIX STABILITY ASPECTS OF PROTEINS AND PEPTIDES RECENT ADVANCES IN DELIVERY OF THERAPEUTIC PROTEINS AND PEPTIDES REFERENCES 2

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3 INTRODUCTION Proteins are the most abundant organic macromolecules of the living system. The term was firstly used by Berzelius. The term “Protein” is derived from a Greek word Proteios – means holding the first place. Proteins are the linear chains of amino acids that are held together by covalent linkages called “ Peptide bonds”. Proteins occur in every part of cell & constitute about 50% of cellular dry weight. A Dutch chemist Mulder used the term “Proteins” in 1838 for the high molecular weight ,nitrogen rich & most abundant substances present in animals & plants.

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ENDOGENOUS PROTEINS AND PEPTIDES : These plays an important role in the regulation and integration of life processes. e.g. 1) Haemoglobin ,myoglobin, etc. affect the transport of oxygen within the body. 2) In the form of skin ,hairs, muscles , etc. proteins hold together ,protect and provide structure to the body of a multi-cellular organism. 3) Enzymes ,hormones and antibodies, etc. catalyze ,regulate and protect the body chemistry. 4

ROUTES OF ABSORPTION :

ROUTES OF ABSORPTION Most pharmaceutical proteins and peptides are formulated as solution or suspensions and delivered by invasive route such as IM, IV, or SC Injections but these routes have their own DEMERITS Poor patient compliance . Pain and discomfort associated with these routes. Inconvenience to treat the pediatric patients. 5

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The oral route presents a series of advantages towards other drug delivery systems like .. It is most convenient route of drug administration. Avoidance of pain and discomfort associated with injections. Higher patient compliance. Elimination of possible infections caused by the use or reuse of needles. 6 ROUTES OF ABSORPTION

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7 However still designing oral protein and peptide drug delivery have poses a persistent challenge to the formulation scientists because of their several unfavourable physicochemical properties like … Large molecular size. Susceptibility to enzymatic degradation. Short plasma half-life. High immunogenicity. Tendency to undergo aggregation. Adsorption and denaturation . Less bioavailability..(less than 1%) The challenge is here to improve the oral bioavailability from less than 1% to at least 30-40 %. The other routes that have been tried with varying degrees of success are : Oral, Buccal, Intranasal, Pulmonary, Transdermal, Ocular and Rectal.. challenges

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ABSORPTION PROPERTIES : 1) Molecular weight and size. 2) Conformation and Stereospecificity . 3) Immunogenicity. PHYSICOCHEMICAL PROPERTIES : 1) Solubility and partition coefficient. 2) Aggregation and hydrogen bonding. 8 PROPERTIES OF PROTEINS AND PEPTIDES

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The oral administration of protein and peptide drugs faces two formidable potential problems during their oral absorption : Metabolic degradation of therapeutic proteins and peptides by variety of proteolytic enzymes. Poor membrane permeability. 9 CONSTRAINTS (POTENTIAL PROBLEMS)

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Chemical Modification : (Prodrug approach) a) Amino acid modification. b) Hydro phobization. Use of enzyme (protease ) inhibitors. Use of absorption enhancers. Formulation vehicles. Mucoadhesive polymeric systems. 10 PHARMACEUTICAL APPROACHES

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A chemical modification of protein and peptide drugs improves their enzymatic stability and membrane permeation. Also , it can be used for minimizing the immunogenicity. Prodrug approach includes : 1) Amino acid modification. 2) Hydrophobization . 11 PRODRUG APPROACH (CHEMICAL MODIFICATION)

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A ) AMINO ACID MODIFICATION : Modification of individual amino acids by the substitution of D- amino acid with the L-amino acid can significantly alter physiological properties of proteins and peptides. e.g. Desmopressin and Deaminovasopressin are the two analogs of vasopressin, former involves deamination of first amino acid and replacement of last L- arginine with D- arginine to give Deaminovasopressin . It contributes to enhanced membrane permeability and enzymatic stability. 12 PRODRUG APPROACH (CHEMICAL MODIFICATION)

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B ) HYDROPHOBIZATION : By surface modification using the lipophilic moieties. e.g. NOBEX INSULIN by PALMITOYLATION. Conjugation of insulin to 1,3-dipalmitoylglycerol at free amino acid groups of glycine , phenylalanine and lysine to form mono and dipalmitoyl insulin having facilitated transfer of insulin across mucosal membrane of large intestine and improved stability against intestinal enzymatic degradation. 13 PRODRUG APPROACH (CHEMICAL MODIFICATION)

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The whole GIT and liver tend to metabolize proteins and peptides into smaller fragments of 2-10 amino acids with the help of variety of proteolytic enzymes (proteases ). So protease inhibitors are co-administered with proteins and peptides to alter the environment for maximum enzyme stability to supress proteolytic activity. They are of 4 major types : Aspartic proteases ( pepsin,rennin ,etc. ) Cystinyl proteases ( papain, endopeptidase ) Serinyl proteases ( thrombin, trypsin ) Metallo proteases ( carboxypeptidase ) 14 USE OF ENZYME (PROTEASE) INHIBITORS

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15 Sr. No. Protein Protease inhibitor Results 1. Insulin Aprotinin . Significant reduction in insulin digestion. 2. Insulin Camostat mesilate . Improvementin activity profile of drug. USE OF ENZYME (PROTEASE) INHIBITORS

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Penetration enhancers are the formulation components that temporarily disrupt the mucosal barrier to improve the permeation of large macromolecular substances like proteins and peptides. following classes of compounds are commonly used : Surfactants- Polysorbate , SLS, Pluronic F-68. Chelating agents- EDTA. Fatty acids-Sodium caprate . Mucoadhesive polymers- Thiomers , cellulose derivatives. Phospholipids- PC. 16 USE OF PENETRATION ENHANCERS

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MECHANISMS OF ACTION OF PENETRATION ENHANCERS Detergents and surfactants increases the transcellular transport of drugs by disrupting the structure of lipid bilayer rendering the cell membrane more permeable. Calcium Chelators believe to exert their action by complex formation with calcium ions ,thus passing through the tight junctions (TJ’s) and facilitate paracellular transport of hydrophilic drugs. Fatty acids have been shown to improve paracellular absorption by phospholipase C activation and upregulation of intracellular Ca + , leading to contraction of actin-myosin filaments and opening of TJ’s. 17 USE OF PENETRATION ENHANCERS

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The oral delivery of therapeutic proteins and peptides can be successfully achieved by using various carrier systems like : Dry emulsions Microspheres Liposomes Nanoparticles 18 FORMULATION VEHICLES

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S/O/W multiple emulsion of Insulin : Solubilization into oil phase can avoid degradation of proteins. Coating of insulin molecule with a llipophilic surfactant enhance permeation through intestinal mucosa. Drawbacks : Physical-chemical instability on long term storage. Reqirement for storage at low temperature. 19 FORMULATION VEHICLES

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DRY EMULSIONS : To overcome the problem of instability on long term storage, multiple emulsions are now-a days replaced by dry emulsions. Dry emulsions can be prepared by : Spray drying Lyophillization Evaporation Using pH –responsive polymers like HPMCP, dry emulsions can be enteric coated and site specificity is achieved. 20 FORMULATION VEHICLES

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MICROSPHERES : pH responsive microspheres can be used as oral delivery vehicles for proteins and peptides thereby protecting them from proteolytic degradation in the stomach and upper portion of small intestine. In the basic environment of the intestine , the complex dissociate resulting in swelling of microspheres and rapid drug (insulin) release. NANOPARTICLES : Particles in the nanometric size range are absorbed intact by the intestinal epithelium and they are less prone to enzymatic degradation. Particle size ,surface charge and influence of surface ligand affect the uptake of nanoparticles in the GI tract.. 21 FORMULATION VEHICLES

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LIPOSOMES : ENCAPSULATION of insulin with the sugar chain portion of mucin and of PEG completely suppressed the degradation of insulin in the intestinal fluid whereas UNCOATED LIPOSOMES suppressed it only partially. Surface coating of liposomes with PEG or mucin gained resistance against dagestion by bile salts and increased stability in the GI tract. 22 FORMULATION VEHICLES

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These systems prevent the presystemic metabolism of the therapeutic proteins and peptides. Residence time of drug delivery system at the site of action is also increased by decreasing the drug clearance rate. e.g. Thiomers , polyacrylic acid derivatives and cellulose derivatives.The stronger mucoadhesive properties of thiomers are believed to be based on covalent bonds between thiol groups of the thiomer and cystein - rich domains of mucus glycoproteins . ( Higher amount of thiol groups =Stronger mucoadhesive properties.) 23 MUCOADHESIVE POLYMERIC SYSTEMS

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There are four methods for incorporaton of drugs into the delivery matrix : EMULSIFICATION EXTRUSION AND SPRAY DRYING POLYMERIZATION 24 INCORPORATION INTO DRUG DELIVERY MATRIX

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EMULSIFICATION : Water soluble drug is first dissolved in aqueous solution and the polymer is dissolved in organic solvent. The two solutions are then mixed with in an appropriate proportion to produce w/o emulsion. this primary emulsion is then emulsified into an aqueous solution containing an emulsifier to produce w/o/w emulsion. finally ,the organic solvent is removed from emulsion by evaporation under reduced pressure ,by filtration or by increasing the temperature . 25 INCORPORATION INTO DRUG DELIVERY MATRIX

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EXTRUSION : When extrusion or spraying is employed to form microspheres, the core material or matrix containing drug ,incorporated as solution or particulate is ejected from the orifice of a fine tube , syringe or nozzle to form micro droplets. The size of droplets depends upon : Properties of liquid. (melt, solution or suspension ) Orifice diameter. Jet velocity. 26 INCORPORATION INTO DRUG DELIVERY MATRIX:

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POLYMERIZATION : HYDROGELS -polymeric drug delivery systems. Preparation – by mixing monomer with the drug, an initiator and a cross-linking agent. e.g. Intravascular delivery of proteins via hydrogel system that is photo polymerized in-situ on the inner surface of blood vessels. Drawback : -radiation may have deleterious effect on the integrity of proteins. 27 INCORPORATION INTO DRUG DELIVERY MATRIX:

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PROTEIN DEGRADATION PATHWAYS : Two basic mechanisms : Physical Chemical In chemical degradation, the native structure of the protein is changed by modifications into the primary structure. In physical degradation, the native structure of the protein is changed by modifications into the higher order structures of proteins i.e. secondary, tertiary or quaternary structure. 28 STABILITY ASPECTS :

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PHYSICAL INSTABILITY : Denaturation is the primary sign of physical instability of proteins. In globular proteins, hydrophobic residues are buried in the interior and hydrophilic residues are available for interaction with the aqueous solvents. Denaturation refers to the loss of this globular structure which leads to protein unfolding. Denaturation may be caused by changes in the environment of the proteins such as temperature, pH , introduction of hydrophobic surfaces or by introduction of interfaces by the addition of organic solvents. 29 STABILITY ASPECTS :

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CHEMICAL INSTABILITY : The chemical instability of proteins and peptides is a result of following four types of reactions : Oxidation Deamination Peptide bond hydrolysis Disulphide exchange 30 STABILITY ASPECTS :

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OXIDATION : Amino acid side chains of proteins and peptides are susceptible to oxidation by either atmospheric oxygen metal ions like copper or iron reagents such as hydrogen peroxide e.g. Methionine residues under acidic conditions are especially prone to oxidation by reagents like hydrogen peroxide ,producing methionine sulfoxide. It is an issue when hydrogen peroxide is used to sterilize formulation vessels or the formulation area. 31 STABILITY ASPECTS :

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DEAMINATION : The hydrolysis of an amide side chain of certain amino acid residues (like glutamine and aspargine ) is called as deamination. Some conditions like change in temperature and pH are shown to facilitate deamination of therapeutic proteins and peptides. PEPTIDE BOND HYDROLYSIS : e.g. When aspartic acid residues are heated to 90-100 0 C ,at pH 4 , the hydrolysis of Asp-X bond leads to the loss of biological activity . 32 STABILITY ASPECTS :

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DISULFIDE EXCHANGE : Many therapeutic proteins contain cystein residues that form disulfide bonds. These bonds are important components of the structural integrity of proteins. Incorrect linkages of these disulfide bonds often leads to a change in the three –dimensional structure of proteins and thereby it’s biological activity. 33 STABILITY ASPECTS :

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PEGylation : PEGylation, is a process of attaching the strands of the polymer PEG to most typical peptides fragments, that can help to meet the challenges of improving the safety and efficiency of many therapeutic macromolecules. It is widely used for the modification of proteins ,peptides , antibody fragments and oligonucleotides. Properties of PEG: Non-toxic. and non –immunogenic. Hydrophilicity. High flexibiity. 34 RECENT ADVANCES :

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ADVANTAGES OF PEGylation : Increased bioavailability. Optimized pharmacokinetics. Decreased immunogenicity. Decreased frequency of administration. MECHANISM OF PEGylation : Increases molecular weight of molecule. Increases drug solubility. Enhanced protection from proteolytic degradation. Reduced dosing . 35 RECENT ADVANCES :

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MATKETED PREPARATIONS AND APPLICATIONS : PEGylated interferon alpha -2a : In Hepatitis B PEGylated interferon alpha-2b : In Hepatitis C PEGylated liposome containing doxorubicin : in Cancer. 36 RECENT ADVANCES :

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Therapeutic proteins and peptides administered IV or SC are often cleared rapidly from the circulation and therefore need to be injected frequently in order to maintain therapeutic level in the blood. Various types of liposomal formulations have been utilized as drug delivery vehicles for sustained release of proteins and peptides like unilamellar or multilamellar vesicle systems but few deals with the mulltivesicular liposomes , called as “ DepoFoam particles .” The DepoFoam technology is capable of : Accomodating high drug loading and high recovery. High encapsulation efficiency Controlling the sustained delivery of macromolecular drugs. 37 Depo -Foam TECHNOLOGY :

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A unique feature of DepoFoam system is that inside each DepoFoam particle, discontinous internal aqueous chambers ,bounded by a continuous network of lipid membranes render a higher aqueous volume to lipid ratio and much larger particle diameter as compared to SUV’s or MLV’s. 38 Depo -Foam TECHNOLOGY : SUV. MLV DepoFoam.

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N.K. JAIN; Advances in Controlled And Novel Drug Delivery; Ist edition-2001 ; CBS Publishers And Distributors; 232-260 . U. SATYANARAYANA, U. CHAKRAPANI; Biochemistry ; IIIrd edition -2006; Uppala Authors And Publishers Interlinks ; 43-68. JAMES SWARBRICK ;ENCYCLOPEDIA OF P’CEUTICAL TECHNOLOGY ; IIIrd edition ; Vol. -1 ; 2713-2730. E. J. McNally ; Protein Formulation and Delivery ; Marcel-Dekker (P) ; Vol.99 ; 1-4 , 71-110, 239-243. 39 REFERENCES :

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www,ijpsonline.com www.pharmainfo.net www.asiapharmaceutics.info 4. www.academicjournals.org 40 WEB REFERENCES :

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