Lorna (Biologics delivery) Flashcards
Biologics delivery
Can only be delivered through injections because if oral then they would be degraded by the stomach as they are protein based.
The issues this creates are with the pharmacy, patient acceptability and adherence to therapy
Biologics delivery by injections: viscosity issue
- The need for very concentrated formulations is often crucial because the required proteins doses are often on the order of hundreds of milligrams while an injection of 1mL in a single, self-administered dose has historically been regarded as the upper threshold of acceptability.
- Viscosity is a key factor in syringeability (force required to 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.
- Formulations with a high viscosity can lean to high injection forces and long injection times since both parameters are proportional to viscosity.
-The creation of formulations with lower viscosities is therefore advantageous.
- Approaches to achieve this include the addition of hydrophobic salts or inorganic salts or the addition of amino acid lysine or arginine.
- However, the approaches to reduce viscosity by adjusting pH and/or ionic strength are typically limited, as these influence the stability of the protein as well
(Protein can be hard to inject as it is gelatinous. If shaken it will also go frothy. Need to consider viscosity and stability in injections).
Injections of biologics
Viscosity of a biologic solution for injection is dependant on
- biologic drug itself (larger dug is more viscous)
- its concentration
- formulation temperature
- formulation pH
- type of exipients
- exigent concentrations
High protein concentration formulations of biologics have viscosities typically much higher than the viscosity of water.
For monoclonal antibodies, the viscosity usually increases exponentially at a concentration of >50 to 100mg/mL.
Viscosity and syringeability
Syringeability refers to the force required to inject a given solution at a given rate via a chosen needle length and cause.
Flow through a hollow needle is described by the Hagen-Poiseuille equation.
Structural complexity
- Biopharmaceutical drugs offer the advantages of high specificity and potency compared to small molecules.
- These features arise form their macromolecular nature, which provides the structural complexity that is often required for specificity.
- However, this structural complexity also makes them some of the most challenging molecules to formulate and deliver.
- The efficacy and safety of therapeutic proteins is affected by their secondary, tertiary, and quaternary structures.
Disadvantages
- Loss of activity in response to environmental triggers such as moisture or temperature which can occur during storage.
- The high molecular mass of biopharmaceutical drugs creates delivery challenged- a substantial reduction in permeability across biological barrier such as mucosal membranes
- Delivery to intracellular targets is also challenging due to their poor membrane permeation
Injection-mediated delivery of biologics
The most commonly used ways of delivering biologics:
- Intravenous
- Intramuscular
- Subcutaneous injections
SC route is a more convenient method of administration so is more likely.
SC route has been approved for the administration of therapeutic proteins including insulin and human growth hormone and a number of MAbs.
Subcutaneous delivery of biologics
- Drugs administered by the SC route can reach the systemic circulation either by uptake by blood capillaries or by lymphatic vessels depending on size.
- Compounds with molecular weights <16 kDa can reach systemic circulation via blood capillaries. Anything bigger than this will go through lymphatic system.
- Protein therapeutics with higher molecular weights exhibit limited transport into the blood capillaries and enter systemic circulation via an indirect route, through the lymphatics.
- Bioavailability is not necessarily high. Reasons for low bioavailability:
- Degredation at the injection site by proteolysis
- Blood and lymph flow at the site of SC injectionUptake of macromolecules from the site
- For monoclonal antibodies, rates of endocytosis and recycling through the interactions with the neonatal Fc receptor.
Challenges in the design of injectable formulations
- Key challenges lie in overcoming instability of the biologic.
- Caused by aggregation, deamination, isomerisation, hydrolysis, oxidation and denaturation.
(- The drug starts to unfold so they hydrogen bond together and it is no longer functional as there is too much concentration of the aggregated protein.) - The tendency of a biological drug to exhibit these structural modification depends on the properties of the molecule and the environmental factors.
- It is crucially important to understand the circumstances by which protein stability is compromised.
- A number of agents have been developed to increase stability of biologics.
Strategies that increase the stability of biologics
- Kinetic stability can be increased by introducing hydrophobic mutations, disulphide bonds, salt bridges, and metal ions at the protein surface to stabilise and rigidify regions involved in local unfolding.
- A popular strategy to prevent aggregation is addition of sugars or salts to the protein solution. these solutes are thought to be preferentially excluded from the surface of the protein, therefore favouring a compact state
- Polymers, amino acids, and non-ionic surfactants are also used to decrease aggregation
- Their use requires careful consideration in terms of local toxicity and potential immunogenicity
Storage of biologics
- Storing proteins in solution at low temperatures generally extends their shelf-life.
- Proteins can be denatured at low temperatures in the liquid phase, but, cold denaturation is generally reversible, unlike most high-temperature denaturation.
- Freezing offers lower temperatures, but repeated cycles of freeze-thawing can strongly stimulate aggregation.
- Another approach is to restrict protein mobility by freeze-drying or lyophilisation (separation of liquid water from a solution frozen to ice by vacuum sublimation, leaving the solutes in an anhydrous or almost anhydrous state).
- This is not without challenges as differential precipitation of buffers or other solvent compositions during freezing can lead to pH changes that irreversibly inactivate proteins
Distribution and elimination of biologics
Distribution
- In comparison to small molecules, biologics such as MAbs have a relatively limited distribution, owing to their size, charge, and tight target binding.
- MAb drugs are distributed to peripheral tissues by paracellular and/or transcellular movement following IV dosing or by absorption after parenteral injections.
Clearance
- Biologics with a molecule weight <69 kDa are mainly cleared by renal excretion
- mAbs are eliminated mainly via intracellular lysosomal proteolytic degradation which occurs throughout the entire body.
Most mAbs exhibit long half lives (3-4 weeks) primarily due to FcRn-mediated antibody recycling
Improving pharmacokinetics of biologics
Regardless of the type of injection, many biopharmaceutical drugs (with few exceptions, such as monoclonal antibodies) are rapidly cleared from the body, meaning that frequent injections are required.
Several strategies have been developed to address this challenge
- Microparticles
- Nanoparticles
- Depot injections
- Injectable modified peptides and proteins
Depot injections
- The most commercially successful example of a biopharmaceutical drug delivered as a depot injection is the luteinising hormone releasing hormone (LHRH) agonist - goserelin acetate.
- Contains a synthetic decapeptide analogue LHRH
- Contained in a PLGA rod
- In jetted SC into the anterior abdominal wall every 3 months
Injectable modified peptides and proteins
- Most macromolecules that are smaller than 60 kDA are cleared from the body via renal filtration
- Renal clearance can be reduced by increasing the size of macromolecules or by making other modifications to the macromolecule resulting in reduced renal clearance
- Chemical modification with hydrophilic polymers can increase the hydrodynamic radius
- This reduces or eliminates glomerular filtration this extending the circulating half-life and reducing injection frequency
- Polyethlene glycol (PEG) polymer is currently the most commonly employed material for this
PEGylation of biological molecules
- PEGylation can negatively affect the binding of a molecule to its receptor due to steric hindrance
- However, optimal design of molecules can minimise this effect
