Parenteral Drug Delivery Flashcards
What are the advantages to depot injections?
Reduced drug dose
Decreased side effects
Enhanced patient compliance
Improved therapeutic outcomes
What are the most commonly used techniques in the development of parenteral sustained for controlled release formulations?
Use of viscous, water-miscible vehicles (e.g., aqueous solutions in gelatin, polyvinylpyrrolidone (PVP))
Use of water-immiscible vehicles, such as vegetable oils, plus water-repelling agent, such as aluminum monostearate
Formation of thixotropic suspensions
Use of water-insoluble drug derivatives, such as salts, complexes and esters
Formation of polymeric microspheres or microcapsules, such as lac tide-glycoside copolymers
Formation of liposomes
Coadministration of vasoconstrictors
What are the different types of release mechanisms of parenteral formulations?
Dissolution-controlled depot
Adsorption-type depot
Encapsulation-type depot
Esterification-type depot
What is dissolution-controlled depot?
The drug absorption rate in this type of depot formulations is controlled by the slow dissolution of drug particles in the formulation or in the tissue fluid surrounding the formulation.
Not zero-order kinetics
Example: penicillin G procaine, penicillin G benzathine
What is adsorption-type depot?
This depot preparation is formed by binding drug molecules to adsorbents such as aluminum hydroxide gel. Only unbound, free drug is available for absorption. As soon as the unbound drug molecules are absorbed, a fraction of the bound drug is released to maintain equilibrium
Example: some vaccines
What are encapsulation-type depots?
This depot preparation is prepared by encapsulating drug solids within a biodegradable or bioabsorbable permeation barrier or dispersing drug particles in a diffusion matrix. Drug release rate is controlled by permeation rate of the barriers or biodegradation rate of the macromolecules
Example: microcapsules, liposomes, microbeads
What are esterification-type depot?
This type of formulations is produced by esters flying the drug to form a bioconvertible prodrug ester and then preparing it in an injectable. The drug absorption rate is controlled by the interfacial partitioning of the drug esters from the reservoir to the tissue fluid and the bioconversion of the inactive drug esters to active drug molecules
Example: fluphenazine enanthate, nandrolone decant ate, testosterone 17beta-cypionate
What are the advantages of injectable emulsions?
They incorporate drugs within the internal phase (contributes to sustained release)
Prolonged delivery can be achieved through the use of multiple emulsions
They can be used for site specific delivery (delivery drugs to phagocytic cells of the reticuloendothelial system for treatment of parasitic/infectious diseases)
What all needs to be considered when developing an injectable emulsion
Oil phase Emulsifier Aqueous phase The pH Particle size Surface charge Stability
What are the most commonly used oils for injectable emulsions?
Long chain triglycerides from vegetable sources (soybean oil, safflower oil)
What is the most important thing to check in the oils for injectable emulsions?
The purity of the oils; they must be purified to remove undesirable components (peroxides, pigments, thermal or oxidative decomposition products, aflatoxins, herbicides, pesticides)
What are the limitations in choosing an emulsifier?
Risk of toxicity (hemolytic reactions)
What is the most common emulsifier used in injectable emulsions?
Natural lecithin (mixture of phosphatides obtained from egg yolks and soybean sources). It is metabolized the same way as fat and is not excreted in the kidneys
Why do various substances need to be added to the aqueous phase?
To adjust or control osmolarity, pH, oxidation and microbial growth
What is a good choice for controlling the osmolarity of the aqueous phase?
Glycerol
What is used to adjust the pH?
A small quantity of sodium hydroxide is used to adjust the pH to approximately 8.0 prior to sterilization (autoclaving causes hydrolysis of glycerine and phosphatide, producing free fatty acids, reducing the pH)
How does particle size affect stability and toxicity?
Particles greater than 4-6 um are known to increase the incidence of emboli and blood pressure changes
Particles ranging from 0.5-1.0 um are utilized more rapidly by the body
Smaller particles size (200-500 nm) also leads to formulations with the highest physical stability
How does surface charge affect stability?
Ionized lipids have a favorable effect on emulsion particle size and stability through an increase in the surface charge and bilayer thickness of phospholipid films. A reduction in the electrical charge can increase the rate of flocculation and coalescence
What indicates physical instability?
Particle size changes Flocculation Creaming Coalescence Oil separation
What indicates chemical instability?
Oxidation and hydrolysis of the oil or emulsifier
Change in pH value
Increase in free fatty acid content or rancidity of the oil
What is an injectable suspension?
Injectable suspensions are heterogeneous systems consisting of a solid phase dispersed in a liquid phase that may be either aqueous or nonaqueous. They should be sterile, pyrogen free, stable, resuspendable, syringeable, injectable, isotonic and non-irritating
What needs to be considered when formulating an injectable suspension?
Flocculating/suspending agents Wetting agents Solvent system Other excipients Syringeability/injectability Resuspendibility
What do flocculating agents do?
A controlled flocculation approach uses a flocculating agent to form a loosely bound aggregate or flocs in a manner that settles but rapidly redispersed easily upon agitation
What are common flocculating agents?
Electrolytes
Surfactants
Hydrophilic colloids
What is an alternative to a flocculating agent?
A suspending or thickening agent that keeps the dispersed particles in a deflocculated state (limited in parenteral use due to viscosity)
Why are wetting agents important?
Wetting of the suspended ingredient(s) is one of the most important aspects of the injectable suspension because the hydrophobic powders are often suspended in aqueous systems. Wetting agents reduce the contact angle between the surface of the particle and the wetting liquid
What are other excipients included in injectable suspensions?
Preservatives
Tonicity agents
Antioxidants
Chelating agents
What is one of the most successful parenteral formulations?
Depot preparations. After SC or IM injection, they can form a depot at the site of injection. The depot acts as a drug reservoir that releases the drug molecules continuously at a rate determined by the characteristics of the formulation
An implantable controlled release drug delivery system must fulfill one or more of the following requirements:
To facilitate and maximize patient compliance with a therapeutic regiment over an extended time period required for effective treatments
To deliver drug at a controlled rate throughout treatment period, with maximal dose-response-duration relationship and minimal potential adverse effects
To be readily implanted or inserted without major surgical procedures on the patients
To be free of potential medical complications without necessary supervision by medical personnel
To possess minimal risk of misuse or unauthorized termination of medication by nonmedical personnel
To be readily retrievable by medical personnel when necessary
To be manufactured with simple processing and low cost
What are the different types of medical implant formulations?
Membrane permeation controlled devices Matrix diffusion controlled devices Membrane-matrix hybrid devices Microreservoir partition controlled devices Osmotic pressure activated devices Vapour pressure activated devices Magnetically activated devices
How do matrix permeation controlled devices work?
The drug reservoir is encapsulated within a capsule-shaped or spherical compartment that is totally enclosed by a rate-controlling polymeric membrane
How do matrix diffusion controlled devices work?
The drug reservoir is formed by omogenous dispersion of drug solid particles throughout a lipophilic or hydrophilic polymer matrix
How do membrane-matrix hybrid devices work?
There is constant drug release rate maintained by the permeation-controlled system, while minimizing the risk of dose dampening from the reservoir compartment
How do microreservoir partition controlled devices work?
There is a suspension of drug crystals in an aqueous solution of water-miscible polymer. It will further form a homogenous dispersion of millions of discrete, unleachable, microscopic drug microreservoirs in a polymer matrix
How do osmotic pressure activated devices work?
Drug reservoir (solution or semisolid formulation) is contained within a semipermeable housing with controlled water permeability. Drug release rate is controlled by water permeability, surface area and thickness of the semipermeable membrane
How do vapour pressure activated devices work?
The drug reservoir (solution) is contained inside an infusate chamber. By a freely-movable bellows the infusate chamber is is physically separated from the vapour pressure chamber, which contains a vaporizable fluid such as fluorocarbon. The fluorocarbon vaporizes at body temperature and creates a vapour pressure, which can force the drug solution out of the system
How do magnetically activated devices work?
A magnetic wave-triggering mechanism is incorporated into the device, and drug can be triggered to release at varying rates depending on the magnitude and the duration of electromagnetic every applied. Under non-triggering conditions, this implantable device releases drugs at a controlled basal rate by diffusion alone. By applying an external magnetic field, the drugs are activated by the electromagnetic energy to release from the device at a much higher rate of delivery
What is a liposome?
A structure consisting of one or more concentric spheres of lipid bilayers separated by water or aqueous buffer compartments.
What are multilamellar vesicles?
Liposomes containing multiple lipid bilayers
What are small unilamellar vesicles (SUVs)?q
Vesicles containing only a single Hilary with diameters ranging from 25-50nm (produced by sonication of MLVs)
What are large unilamellar vesicles (LUVs)?
Liposomes with a single lipid bilayer with a size range of 100-500 nm
What are the materials used in preparation of liposomes?
Phospholipids
Sterols
What are the most abundant glycerol phosphatides
Phosphatidylcholine (aka lecithin)
Phosphatidylethanolamine
What are the roles of cholesterol in liposome structures?
Decreasing the fluidity of microviscosity of the bilayer
Reducing the permeability of the membrane to water soluble molecules
Stabilizing the membrane in the presence of biological fluids such as plasma
What affects the location of the drug within a liposome?
The location is based on the partition coefficient of the drug between the aqueous compartments and lipid bilayers
The maximum amount of drug that can be entrapped within a liposome is dependent on what?
On its total solubility in each phase
What is the most frequently used lipid for liposome formulation?
Lecithin
When is sphingomyelin used?
To produce more rigid liposomes
When is Phosphatidylserine used?
To produce more charged liposomes
What is alpha-tocopherol used for?
To prevent oxidation
What are different liposome preparation methods?
Hydration method
Solvent injection method
Reverse phase evaporation method
What is the hydration method?
Introduction of an excess volume of aqueous buffer to a thin film of lipids under reduced pressure
What is solvent injection method?
Injection of lipids dissolved in an organic solvent (e.g. Ether, ethanol) into a vast volume of buffer solution
What is reverse phase evaporation method?
Formation of a water-in-oil emulsion of phospholipids and buffer in excess organic phase followed by removal of the organic phase under reduce pressure
What are the 3 approaches to control the particle size distribution of liposome preparations?
Fractionation of the size of interest from a heterogeneous liposome preparation
Homogenization of a liposome dispersion to yield a population of smaller vesicles with a narrow size distribution
Extrusion of a heterogeneous preparation through capillary pore membranes of known pore diameter to yield an average size that approximates the pore diameter
In what areas is the most promising liposomal drug delivery?
Site-specific delivery (especially disease states involving RES) Site-avoidance delivery Sustained or controlled release Passive drug targeting Gene therapy
What are nanoparticles?
Colloidal particles with a size smaller than 1 mm
What is the different between nanocapsules and nanospheres?
Nanocapsules have a core-shell structure (a reservoir system)
Nanoparticles represent a matrix system
What are the materials commonly used to make nanoparticles?
Poly(lactic acid) (PLA)
Poly(lactic-co-glycolic acid) (PLGA)
Cellulose derivatives (ethyl cellulose, cellulose acetate)
Natural polymers (gelatin, sodium alginate)
Polymerization of monomers (alkyl methacrylate monomers, alkyl cyanoacrylate monomers, acrylamide monomers)
How are the two techniques used to prepared nanoparticles classified?
Formation from preformed polymers
Preparation through various polymerization reactions of monomers
What are the different methods to prepare nanoparticles
Emulsion-evaporation method Salting-out method Emulsion-diffusion method Precipitation method Preparation of nanocapsules
Explain the emulsion-evaporation method
The polymer is dissolved in a chlorinated solvent and emulsified in an aqueous phase containing a surfactant. The organic solvent is then removed under reduced pressure to form nanospheres
Explain the salting-out method
An electrolyte-saturated solution containing a hydro colloid is added to an acetone solution of polymer to form an O/W emulsion. Sufficient amount of water or an aqueous solution of PEG is added to allow complete diffusion of acetone into the aqueous phase, thus inducing the formation of nanospheres
Explain the emulsion-diffusion method
An aqueous gel of a hydrocolloid is added to a solution of polymer dissolved in benzyl alcohol to form a W/O emulsion. A large amount of water is added to the emulsion in order to allow the complete diffusion of the organic solvent into the water, leading to the precipitation of the polymer as nanospheres
Explain precipitation method
The polymer is dissolved in a water-miscible solvent and mixed into a non-solvent which leads to the precipitation of nanospheres
What are the different nanoparticle purification steps?
Ultracentrifugation Centrifugal ultrafiltration Cross flow filtration Gel permeation Dialysis
How are nanoparticles sterilized?
Gamma-radiation
