Parenteral Drug Delivery Flashcards
Why do we need modified release injectables?
- short acting injections have limitations for chronic care products
- improved safety and/or efficacy with modified release formulations
- improved patient compliance as you reduce the injection frequency
- cost reduction
- allows bolus delivery for some drugs that would otherwise require slow iV infusion
Why do we use injectables?
~15% of current drug delivery market are injectable prodcuts
-there is increasing potential requirements due to the rapid biotechnology revolution
What is drug release?
-process by which a drug leaves a drug product and is subjected to ADME, eventually becoming available for pharmacologic action
What is drug release related to?
First step: Dissolution
Diffusion
What is diffusion in terms of drug release?
Transport of drugs from the dosage form matrices into the absorption site
What is drug release controlled by?
Physicochemical properties of the drug and delivery system
It is also controlled by the biological system
What are the fundamental parameters governing the diffusion process?
The variables in fick’s law:
Temperature, viscosity of medium, radius of molecule, distance to absorption site, concentration of the drug, diffusion coefficient
What parameters affect the dissolution rate?
The variables in the Noyes whitney equation:
Diffusion coefficient
Surface area of solid
Solubility of solid
Concentration of solute in the bulk at time t
Thickness of the diffusion layer
How can parenteral modified release delivery systems be achieved?
- dissolution controlled depot
- adsorption type depot
- partition controlled depot
- esterification type depot
- encapsulation type
- insitu solidifying depots
What is dissolution controlled release?
Form of MR Pareneteral preparation that is
- aqueous based
- can also be oil based, but will mean slower release due to dissolution and partitioning differences
- Decreases the release/absorption rate by reducing the drug dissolution rate of the tissue fluid E.g. Suspensions of macrocrystals or micronised particles such as long acting penicillin and insulin
- dissolution and hence absorption can be controlled to produce long acting products like depot antipsychotics (Depixol), depot hormones (Depo-Provera), depot anticancer agents (Elingard)
What are adsorption type depot formulations?
- a from of MR parenteral preparation which forms a depot in the muscle mass from which the drug is slowly absorbed
- C Max is usually seen within 1-2hours
- only free rug is available for absorption
- e.g. Diptheria vaccine containing antigens bound to Al(OH)3 gel
What are esterification type depot formulations?
-A form of MR parenteral drug formulation where bioerodable esters of drugs are formulated within an oily vehicle which forms a reservoir at the injection site.
What are encapsulation type depot preparations?
- A form of modified release parenteral drug formulation
- the drug is encapsulated or dispersed in biodegradable/bioadsorbable polymers or macromolecules. It forms colloidal particle spheres, capsules and ‘somes’
What are examples of biodegradable or bioabsorbable polymers or macromolecules used in encapsulation type depot preparations?
- gelatin
- dextran
- lactide/glycolide copolymers
- phospholipids,
- long chain fatty acids
- glycerides
What are examples of the particle spheres, capules or ‘-somes’ that encapsulation type depot preparations use?
- solid lipid nanospheres
- niosomes
- liposomes
These are considered as carriers
What are in-situ solidifying depots?
- e.g. gels
- these stay as a free flowing liquids at ambient conditions and solidify in the body as a result of potential triggers such as pH, temperature, ions or hydration
Where are in-situ solidfying depots injected?
-either Subcutaneously or intramuscularly
What is the process of drug release for a esterification type depot formulation?
- the drug ester partitions from the reservoir to the tissues
- the ester bioerodes to release the drug which prolongs the drug action
What is an example of an esterification type depot formulated drug?
- Fluphenthixol deconate is formulated in oil.
- It is given as a single 10mg/kg IM injection which lasts 10 days. -Onset of action occurs within 24-40 hours
- the depot is administered every 2-4 weeks
What are examples of advanced carrier-based parenteral products?
- microspheres
- microcapsules
- polymeric or solid lipid nanoparticles
- liposomes/PEGylated liposomes,
- drug polymer conjugates
- dendrimers
What are dendrimers?
-highly branched, star shaped macromolecules
What are co-polymer based gels?
- These ABA or ABC co-polymers are also called triblock polymers and have properties where they are micelles at room temperature but form a gel when heat is applied.
- This occurs due to the restructuring of molecules to become a micellular network which can form a gel.
- not all micelles can do this.
What is an example of an ABA triblock copolymer?
poloaxmers
What are Carrageenan based thermal gels?
- a family of linear sulfated polysaccharides extracted from red edible seaweeds
- these form a gel when temperature is lowered
- like starch, which becomes a thicker solution when dispersed in cool water and chilled, when these polysaccharides are dissolved and cooled down in the presence of salt, a gel is formed.
Why is choosing a gel base important?
the formulation of the gel depends on the nature of the polymer we are using.
What process must drug particles in an oil based solution and suspension require?
dissolution followed by partition
What process must carrier systems undergo?
erosion
What process must gel systems undergo?
erosion of the base before absorption
What process must complex/conjugated drugs undergo?
drug complex dissociation
What is the engineering approach?
when a pharmaceutical agent is encapsulated within or attached to a polymer or lipid, drug safety and efficacy can be greatly improved and new therapies are available
What is the engineering approach used to treat?
cancers.
-parenteral routes of delivery are essential to maintain the ‘engineered’ features of the delivery systems
What are the advanced features of the engineering approach compared to conventional dosage forms?
- improves therapeutic effectiveness
- lowers systemic toxicity of the drug
- potentially reduces irritancy at active site
What are the reasons behind the advantages of the engineering approach compared to conventional dosage forms?
- more consistent drug concentrations in blood
- site specific drug delivery
- long circulating (favourable distribution)
What are the different types of targeted drug delivery?
- passive targeting
- active targeting
- other targeting mechanisms
When is passive targeting used?
- for small molecules e.g. nanosized drug particles for tumours
- results in an enhanced permeability and retention effect in tumours
What are the features of tumours which allow us to passively target them?
- leakage of vasculature
- relatively suppressed lymphatic system.
When is active targeting used?
- when a carrier molecule is required.
- these can be recognised by a specific cell type such as a tumour
What does active targeting invovle?
- surface modification to incorporate an antigen or specific antibodies
- attachment of cell receptor specific ligands such as folic acid.
What are other targeting mechanisms?
- mechanisms which only release the drug when exposed to specific microenvironments like changes in temperature.
e. g. therma; sensitive liposomes
What are examples of advanced drug delivery systems in the market?
- CALEYX which are sterically stabilised liposomes of doxorubicin. They have a long plasma half life and reduced toxicity
- MYOCET which are liposomes containing doxorubicine citrate. It is a small sized liposome with reduced toxicity
- ABRAXANE which is a protein bound paclitaxel nanoparticle formulation.
What is Abraxane?
- the first albumin bound taxane particle of ~130nm that takes advantage of albumin.
- albumin is an insoluble protein and acts as the body’s key transporter of nutrients and other water-insoluble molecules
- albumin selectively accumulates in tumour tissues
What is long circulation?
-where there is a circulating reservoir containing the drug in the blood compartment by essentially reducing the drug’s body distribution
How is long circulation achieved?
- the carrier surface has to be altered to optimise drug targeting and to achieve prolonged circulation times
- often done with PEGylation
- this also avoids rapid rclearance by the reticuloendothelial system
What is PEGylation?
the covalent coupling of non toxic, hydrophilic polyethylene glycol to pharmaceutical ingredients of the carriers.
What is the result of lon-circulation and passive targeting using PEGylated liposomes of doxorubicin?
an overall increased efficacy and reduced toxicity.
