Peptide and Protein Delivery by Injection

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  • Created by: LBCW0502
  • Created on: 20-11-19 14:50
What are biologics? (1)
A wide range of products - therapeutic proteins, monoclonal antibodies, vaccines, blood/components, somatic cells, gene therapy, tissues, blood products, peptides. Can be composed of sugars/proteins/nucleic acids/complex combinations
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What are biologics? (2)
Might be living entities such as cells and tissues. Isolated from a variety of natural sources - human, animal or micro-organism, may be produced by biotechnology methods and other cutting-edge technologies
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What are biologics? (3)
FDA definition - blood derived products, vaccines, in vivo diagnostic allergenic products, immunoglobulin products, products containing cells/microbes, most protein products applicable to prevention/treatment/cure of disease/condition of humans
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Why are biologics used? (1)
Very potent molecules. Have the ability to bind with high specificity and affinity to a wide variety of molecules (targets - proteins and DNA). Highly specific protein-protein interactions, highly selective for their targets
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Why are biologics used? (2)
Improved patient outcomes e.g. RA and cancer. Unique complex 3D conformation (specific to target). Less of drug will interact with other targets (reduce S/E)
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Describe features of small drug molecules (1)
Chemically synthesised, low mwt, known structure (easily identified or characterised). Less sensitive to environment. Absorption across biological membrane generally satisfactory (exceptions exist)
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Describe features of small drug molecules (2)
Not necessary to use aseptic principles from initial manufacturing steps. Variable specificity, may not be very high
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Describe features of biological products/biologics (1)
Biotechnology products, high mwt (macromolecules e.g. insulin mwt 5000 Da), structure complex/not easily identified or characterised, very sensitive to environment (acid, heat, enzymatic degradation)
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Describe features of biological products/biologics (2)
Very poorly absorbed across biological membranes, susceptible to microbial contamination, necessary to use aseptic principles from initial manufacturing steps, target specificity very high (e.g. antibodies). LRO5 (>500 mwt, poor absorption)
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Describe features of biological products/biologics (3)
Issues with absorption (not possible to use oral route, majority of biologics will be injectables). Emerging use of biologicals for diseases
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What are the issues facing formulation of peptide and protein therapeutics? (1)
Large and complex 3D structures. Requires proper folding and conformational stability for proper function. Stability issues due to manufacturing conditions, transportation and storage (vaccines, fridge/freezer conditions)
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What are the issues facing formulation of peptide and protein therapeutics? (2)
Biological environment (e.g. presence of enzymes, acid)
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What are the formulation issues with injectable biologics? (1)
Need very concentrated formulations/required protein doses (100s of mgs). Injection of 1 mL in a single self-administered dose used
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What are the formulation issues with injectable biologics? (2)
Viscosity is a key factor in syringe-ability (force required inject a given solution at a given rate via a chosen needle length and gauge). Flow through a hollow needle is inversely proportional to viscosity
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What are the formulation issues with injectable biologics? (3)
Formulations with a high viscosity can lead to high injection forces and long injection times (both parameters proportional to viscosity)
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Viscosity of a biologic solution for injection is independent on what? (1)
Biologic drug itself, concentration, formulation temperature, formulation pH, type of excipients, excipient concentrations. High protein concentration formulations have viscosities higher than the viscosity of water
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Viscosity of a biologic solution for injection is independent on what? (2)
Monoclonal antibodies, viscosity increase to >50-100 mg/mL
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What is syringe-ability?
Refers to the force required to inject a given solution at a given rate via a chosen needle length and gauge. Flow through a hollow needle is described by the Hagen-Poiseuille equation
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How is the reduction in the viscosity of biologic formulations achieved? (1)
The creation of formulations with lower viscosities is advantageous. Approaches include addition of hydrophobic salts or inorganic salts or addition of amino acids lysine or arginine
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How is the reduction in the viscosity of biologic formulations achieved? (2)
Approaches to reduce viscosity by adjusting pH/ionic strength are limited (influences stability of protein)
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What are the most commonly used ways of delivering biologics?
IV, IM (painful injection) and SC (preferred choice for administration - minimal skills, least invasive)
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Describe features of subcutaneous delivery of biologics (1)
Drugs administered via SC can reach systemic circulation either by uptake of blood capillaries or by lymphatic vessels. Compounds with mwt <16 kDa can reach systemic circulation via blood capillaries
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Describe features of subcutaneous delivery of biologics (2)
Protein therapeutics with higher mwt exhibit limited transport into blood capillaries and enter systemic circulation via an indirect route through lymphatics. Bioavailability not very high (<40%)
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What are the reasons for low bioavailability for biologics?
Degradation at injection site by proteolysis. Blood and lymph flow at the site of SC injection. Uptake of macromolecules from site. For monoclonal antibodies, rates of endocytosis and recycling through interactions with neonatal FcRn
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Describe features of distribution of biologics (1)
Limited distribution due to size, charge, tight target binding. Distribution of small molecules not confined to central blood component (higher apparent Vd, similar to total blood volume). Administration of IV insulin - rapidly cleared
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Describe features of distribution of biologics (2)
mAB drugs distributed to peripheral tissues by paracellular and transcellular movement
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Describe features of the clearance of biologics
Biologics rapidly cleared (requires frequent injections). Biologics with mwt <69 kDa are mainly cleared by renal excretion)
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Describe the clearance of mABs (1)
Eliminated via intracellular lysosomal proteolytic degradation (occurs throughout entire body). Most mAbs exhibit long half lives (3-4 weeks). Primarily due to FcRn mediated antibody recycling
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Describe the clearance of mABs (2)
Taken up by receptors, enter lysosome, cycled back into the lumen/blood, uptake and cycling protects monoclonal antibody from degradation, has along half-life e.g. treatment for inflammatory diseases (daily administration not required)
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How can be PK of biologics be improved?
Microparticles, nanoparticles, depot injections, injectable modified peptides and proteins. Can affect drug PK by enabling sustained release of the drug, nanoparticles offer targeting capability
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Describe features of depot injections
E.g. LHRH agonist, goserelin acetate. Contains synthetic decapeptide analogue of LHRH. Treatment of prostate cancer, breast cancer, endometriosis. PLGA rod. Injected via SC into anterior abdominal wall every 3 months, slow release of PLGA/drug
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Describe features of injectable modified peptides and proteins (1)
Most macromolecules that are smaller than 60kDa are cleared from the body via renal filtration. Renal clearance can be reduced by increasing size of macromolecules or made other modifications to reduce renal clearance
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Describe features of injectable modified peptides and proteins (2)
E.g. hydrophilic polymers increase the hydrodynamic radius. Reduces or eliminates GFR, extends circulating half life and reduce injection frequency. PEG used
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Describe features of injectable modified peptides and proteins (3)
Attach polymer to drug molecule (conjugation) – to avoid clearance via the kidneys e.g. PEG (hydrophilic, available in different mwt, non-toxic, not pharmacologically active, inert)
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Describe features of PEGylation of biological molecules
Can negatively affect the binding of a molecule to its receptor due to steric hindrance. Optimal design of molecules can minimise this effect. Need to ensure there isn't interference in pharmacological action
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State features of neonatal Fc receptor recycling (1)
Approaches that exploit neonatal Fc receptor (FcRn) recycling pathway have also been developed to increase the half-life of macromolecules. This involves the creation of genetic fusions between the macromolecule and the Fc region of IgG
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State features of neonatal Fc receptor recycling (2)
Results in many approved products, including the blockbuster drug, entanercept (advantages, disadvantages slide)
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What are the advantages of microparticles?
Controlled release can be achieved. Delivery is possible using SC injections
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What are the disadvantages of microparticles?
Burst release can occur, cause potential for local toxicity and wastage. Burst release associated with adverse events related to peak serum exposure
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What are the advantages of depot injections?
Same parent drugs can be formulated in several dosage forms (weekly, monthly). Delivery technology can be applied to a large number of compounds. Lower burst release. Avoids requirement for reconstitution/suspension
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What are the disadvantages of depot injections?
Larger gauge needle can be required for injections or incisions need to be made into the skin
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What are the advantages of nanoparticles?
Targeted delivery - small size allows enhanced permeation into tumours and retention in tumours. Has high adjuvancy for vaccine applications
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What are the disadvantages of nanoparticles?
Non-specific uptake in reticuloendothelial system organs. Immunotoxicity can occur
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Describe the different states of association of insulin (1)
Naturally occurring insulin in beta cells self-associates into dimers. Three dimers combine with two Zn ions to form a hexameric complex (adaptation for maximal storage capacity within beta cell)
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Describe the different states of association of insulin (2)
Insulin from these hexamers (released by exocytosis from beta cells) is converted to biologically active monomers which enters the blood stream and act on insulin receptors at target tissue
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Describe features of the formulation and release issue (1)
If insulin is injected IV, it will rapidly to inactivated by peptidases. To achieve a more sustained activity, insulin is injected SC into interstitial space.
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Describe features of the formulation and release issue (2)
Usually insulin is injected as hexamers in SC use from which monomers are absorbed through capillaries. Insulin release dictated by level of aggregation
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Describe features of the formulation and release issue (3)
Soluble human insulin consists of hexamers which dissociate into dimers and monomers at the injection site. Lag phase between injection of hexamers and availability of biologically active dimers/monomers at target tissues
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Describe features of the formulation and release issue (4)
Soluble human insulin given 30 mins before a meal. Insulin peak after SC injection of regular insulin is too late/not high enough. Short acting insulin analogues developed to overcome flaws in PK of regular human insulin
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Describe the insulin diffusion into capillaries
Insulin monomers and dimers enter the capillary system at a faster rate than hexamers. Only monomeric or dimeric insulin is biologically active at the insulin receptor. Speed of hexamer dissociation determines PK/PD profiles of insulin preparations
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What are the two different categories of insulin analogues?
Rapid acting insulin analogues (rapid dissociation of hexamers to monomers, rapid absorption through capillaries, reverse for basal insulin analogues) and long acting insulin analogues (insulin glargine and insuline detemir)
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Describe features of rapid acting insulin analogue modifications (1)
These modifications weaken the propensity for insulin to self-associate through charge repulsion at sites where insulin monomers would normally associate to form dimers. Results in rapid absorption of monomers from SC tissue at the time of injection
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Describe features of rapid acting insulin analogue modifications (2)
These insulin analogs enter the bloodstream within minutes, important to inject them within minutes of eating
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Describe features of long-acting insulin analogues (1)
Insulin glargine is modified to shift the isoelectric point (pH at which there is no net charge) towards more neutral pH. Makes insulin less soluble at physiological pH, promotes precipitation following SC injection
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Describe features of long-acting insulin analogues (2)
Individual insulin units, through enzymatic action are absorbed into bloodstream through endothelium. Slow break up of insulin cluster gives insulin glargine its long action
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Describe features of non-invasive delivery of peptides and proteins (1)
Despite proliferation and use in clinic, no real developments in non-invasive delivery technologies. Administration currently limited to injection due to negligible absorption from mucosal surfaces
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Describe features of non-invasive delivery of peptides and proteins (2)
Injections less accepted by patient (painful/expensive to manufacture/administer). Non-invasive delivery of biotherapeutics (oral route) considered a panacea in drug delivery
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Describe features of non-invasive delivery of peptides and proteins (3)
Becoming more important with wider use of biotherapeutics and multiple drug regimens in an ageing population
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Describe the rationale for oral delivery (1)
Convenience/compliance. Less costly non-sterile oral dosage forms. Reduction in healthcare costs associated with switch from injection to oral administration (Vit B12, estimated to amount 37-64%)
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Describe the rationale for oral delivery (2)
More physiological route for some drugs/possibly better outcomes. Commercial patent extensions
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What are the biological barriers for biologicals in oral administration? (1)
Acids and enzymes (gut lumen), poorly permeable (intestinal epithelium), enzymes (intestinal metabolism), first pass effect (liver) - to get to systemic circulation
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What are the biological barriers for biologicals in oral administration? (2)
Physiologic variables - gastric motility, pH at absorption site, area of absorbing surface, mesenteric blood flow, presystemic elimination, ingestion with/without food. Poor bioavailability, most peptides/proteins have oral administration of <1%
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Describe features of absorption enhancement strategies (1)
Mucoadhesive polymers prolong residence time of complexed protein drug at mucosal surface. Surface active permeability enhancers compromise cell membrane integrity (membrane-impermeable protein drug crosses epithelial barrier)
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Describe features of absorption enhancement strategies (2)
TJ opening where paracellular space is increased, improving paracellular access of protein molecules. Exploit epithelial transcytotic mechanisms by conjugating the drug (or drug carrier) to a ligand that is transported transepithelially via the route
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Describe features of absorption enhancement strategies (3)
Modes of permeability enhancer action - article. (Recent progress in oral delivery of peptides/proteins e.g. GLP-1 analogue, treatments for diabetes, OP, acromegaly etc)
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Comments

Allen Swift

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Peptide delivery by injection is a common method used to introduce peptides into the body for example BPC-157, a synthetic peptide known as Body Protection Compound-157, is often administered via injection for research purposes.

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