Pareneteral Drug Delivery Flashcards
What are specialised routes of parenteral administration?
Intrathecal Intra cardiac Intra arterial Intra cisternal (= intramammary) Intra articular
What are parenteral preparations?
Sterile preparations intended for administration by injection, infusion or implantation in the human an or animal body
I.e. By other means than through the GIT particularly referring to IV, SC and IM routes
What is the relationship between the main parenteral route of administrations and the skin layer they penetrate?
IM = deepest = into the muscle and vein IV = vein SC = subcutaneous tissue ID= shallowest = into the dermis
Where are intrathecal drugs injected?
The composite hydrogel is injected at the site of injury and remains localised between the arachnoid and pia meter, releasing the drug load into the spinal cord.
What is subcutaneous administration?
Administration beneath the skin, hypodermic
What is intravaneous administration?
Administration within or into a vein or veins.
What is intravenous bolus?
Administration within or into a vein or veins all at once
What is intramuscular administration?
Administration within a muscle
Why are drugs administered pareneterally?
Drugs may be very inefficient or unreliable for oral absorption
Drugs may be easily destructed or inactivated in GIT
They may be subjected to extensive mucosal or FPM following oral administration
There may be a clinical need in par articular medical conditions for rapid, assured high blood and tissue levels.
What important drugs are available as Pareneteral dosage forms?
Biotechnology drugs like insulin and other proteins and peptides, several penicillin and cephalosporin antibiotics, heparin.
Many anticancer products used principally as parenterals
Smoke general anaesthetics like profolol
What are the advantages of parenterals?
Rapid onset of action Predictable and high bioavailability Avoids GIT and problems Avoids FPM Reliable in very ill or comatose patients
What are the disadvantages of Pareneterals?
Psychological fears of needles Pain and discomfort of injections Difficult to counteract incorrect dose Need for strict asepsis/sterilisation Risk of tissue damage
What are the different packaging options for parenterals?
Single dose containers including ampoules or single dose vials
Multi dose containers which contains about 10 usual doses of the injection,
Self sealing rubber septum to allow multiple dosing without contamination.
Small volume and large volume parenteral injections (IV bags)
Where are IV formulations injected into?
They are directly injected into the circulation via either a peripheral or central vein
What are the advantages of IV injections?
Extremely rapid and predictable response
Maximum availability (100%)
Achieves Cmax at ~4 mins
Rapid dilution by circulating blood, therefore general good tissue tolerance to the vein wall.
When are IV infusion and bolus injections given?
Large volumes can be given by IV infusion
Small volumes can be given by bolus injection
How can the volume of blood passing an injection site be predicted?
The average diameter of small veins is 0.2cm
The velocity of the blood flow in small veins is 10cm/s
And you have injected 2mL of the formulation over 30s.
The amount of blood passing through = area of small vein x velocity of blood flow x 30 seconds.
This is 9.42mL of blood passing through that vein in the 30 seconds you have injected the drug.
To find how much the formulation has been diluted by the blood flow, you divide the final volume by the volume you added (2mL+9.42mL)/2mL = 5.6 times
What are the risks/limitations of the IV route?
Drug shock Haemolysis Air embolism Thrombosis Phlebitis Extravasation
Why is drug shock a risk of the IV route?
If the drug is administered too rapidly it may cause excessive drug concentration at the target organ.
Why is haemolysis a risk of IV route.
May cause the lysis of red blood cells
Why is air embolism a risk of the IV route?
Air bibles in a blood vessel can occlude blood flow
Why is thrombosis a risk of the IV route.
This is a condition in which a vein is clogged off by a blood clot or foreign matter resulting in decreased blood flow.
Why are only drugs in aqueous or hydroalcoholic solutions given by IV route?
This is to minimise thrombosis
What is phlebitis?
Inflammation of the vein wall leading to possible thrombus formations
Often caused by particulate matter in the injected formulation or irritancy of the formulation. This reaction is mediated by prostaglandins.
Why is phlebitis a risk of the IV route?
Damages the vein may be due to excessive administration at the one site
What is extravasation?
This occurs during IV infusion where drugs are accidentally infused into the surrounding tissue.
Caused by leakage of the vein due to brittle veins, or direct exposure.
Why is extravasation a risk of the IV route?
It may cause inflammation and tissue leison
What are the administration sites of the SC route?
Arms,
Legs
Abdomen
What is the maximum volume to be administrated via the SC route?
For humans, it is approx 1mL
What are common drugs administered via the SC route?
Vaccines
Insulin
Adrenaline
What are the absorption features of the SC route?
Slower onset and longer duration than IM or IV
This is preferred for some drugs like insulin.
Total absorption may be <100% (due to some metabolism in the skin layers)
Absorption into the lymphatics occurs preferentially compared to the IM route this is because the lymphatic system is more developed in have SC layers
What is IM drug administration ?
Injection into a muscle tissue
What is the maximum volume injected via IM route?
4 mL but usually only inject 0.5~2mL
What are the principal injection sites of IM administration?
Gluten (butt)
Deltoid (upper arm)
Vastus lateralis (lateral thigh)
What are the absorption features of the im route?
There is a formation of a depot in the muscle mass from which the drug is slowly absorbed.
Cmax within ~1-2hiurs
Second fastest in onset of systemic action due to vascular supply differences
Dissolution and absorption can be controlled - potential for long acting products like in suspension
due to changing particle size, and crystal forms
What are the major problems associated with SC and IM injections that should be considered during formulation design?
Injection site reactions
Drug precipitation at the injection site
What are injection site reactions?
These include
Pain on injection (irritancy of the drug or solvent, or incompatible pH/tonicity)
Inflammation
Tissue damage (which can be direct cell injury or a consequence of inflammation)
Nicolau syndrome which is pain, skin discolouration and necrosis following an IM injection. Associated with diclofenac, ibuprofen, tetracycline, benzathine penicillin, lidocaine
What is post injection drug precipitation ?
Precipitation of the drug after it is injected.
This can occur to poorly water soluble drugs if the drug is solubilised in water-solvent based formulations
This can occur after SC, IM and even IV injections
Why does post injection drug precipitation occur?
The solvent is absorbed more rapidly than the drug.
The solvent is diluted with the tissue fluid resulting in the drug concentration in vivo to exceed its solubility
What is the equation of drug solubility in water solvent systems?
Log S = fσ + log Sw
Where s = solubility in water - solvent systems
f = co-solvent fraction
σ = solubilisation capacity of the solvent.
Sw = solubility in water
Where are IV formulations injected into?
They are directly injected into the circulation via either a peripheral or central vein
What are the advantages of IV injections?
Extremely rapid and predictable response
Maximum availability (100%)
Achieves Cmax at ~4 mins
Rapid dilution by circulating blood, therefore general good tissue tolerance to the vein wall.
When are IV infusion and bolus injections given?
Large volumes can be given by IV infusion
Small volumes can be given by bolus injection
How can the volume of blood passing an injection site be predicted?
The average diameter of small veins is 0.2cm
The velocity of the blood flow in small veins is 10cm/s
And you have injected 2mL of the formulation over 30s.
The amount of blood passing through = area of small vein x velocity of blood flow x 30 seconds.
This is 9.42mL of blood passing through that vein in the 30 seconds you have injected the drug.
To find how much the formulation has been diluted by the blood flow, you divide the final volume by the volume you added (2mL+9.42mL)/2mL = 5.6 times
What are the risks/limitations of the IV route?
Drug shock Haemolysis Air embolism Thrombosis Phlebitis Extravasation
Why is drug shock a risk of the IV route?
If the drug is administered too rapidly it may cause excessive drug concentration at the target organ.
Why is haemolysis a risk of IV route.
May cause the lysis of red blood cells
Why is air embolism a risk of the IV route?
Air bibles in a blood vessel can occlude blood flow
Why is thrombosis a risk of the IV route.
This is a condition in which a vein is clogged off by a blood clot or foreign matter resulting in decreased blood flow.
Why are only drugs in aqueous or hydroalcoholic solutions given by IV route?
This is to minimise thrombosis
What is phlebitis?
Inflammation of the vein wall leading to possible thrombus formations
Often caused by particulate matter in the injected formulation or irritancy of the formulation. This reaction is mediated by prostaglandins.
Why is phlebitis a risk of the IV route?
Damages the vein may be due to excessive administration at the one site
What is extravasation?
This occurs during IV infusion where drugs are accidentally infused into the surrounding tissue.
Caused by leakage of the vein due to brittle veins, or direct exposure.
Why is extravasation a risk of the IV route?
It may cause inflammation and tissue leison
What are the administration sites of the SC route?
Arms,
Legs
Abdomen
What is the maximum volume to be administrated via the SC route?
For humans, it is approx 1mL
What are common drugs administered via the SC route?
Vaccines
Insulin
Adrenaline
What are the absorption features of the SC route?
Slower onset and longer duration than IM or IV
This is preferred for some drugs like insulin.
Total absorption may be <100% (due to some metabolism in the skin layers)
Absorption into the lymphatics occurs preferentially compared to the IM route this is because the lymphatic system is more developed in have SC layers
What is IM drug administration ?
Injection into a muscle tissue
What is the maximum volume injected via IM route?
4 mL but usually only inject 0.5~2mL
What are the principal injection sites of IM administration?
Gluten (butt)
Deltoid (upper arm)
Vastus lateralis (lateral thigh)
What are the absorption features of the im route?
There is a formation of a depot in the muscle mass from which the drug is slowly absorbed.
Cmax within ~1-2hiurs
Second fastest in onset of systemic action due to vascular supply differences
Dissolution and absorption can be controlled - potential for long acting products like in suspension
due to changing particle size, and crystal forms
What are the major problems associated with SC and IM injections that should be considered during formulation design?
Injection site reactions
Drug precipitation at the injection site
What are injection site reactions?
These include
Pain on injection (irritancy of the drug or solvent, or incompatible pH/tonicity)
Inflammation
Tissue damage (which can be direct cell injury or a consequence of inflammation)
Nicolau syndrome which is pain, skin discolouration and necrosis following an IM injection. Associated with diclofenac, ibuprofen, tetracycline, benzathine penicillin, lidocaine
What is post injection drug precipitation ?
Precipitation of the drug after it is injected.
This can occur to poorly water soluble drugs if the drug is solubilised in water-solvent based formulations
This can occur after SC, IM and even IV injections
Why does post injection drug precipitation occur?
The solvent is absorbed more rapidly than the drug.
The solvent is diluted with the tissue fluid resulting in the drug concentration in vivo to exceed its solubility
What is the equation of drug solubility in water solvent systems?
Log S = fσ + log Sw
Where s = solubility in water - solvent systems
f = co-solvent fraction
σ = solubilisation capacity of the solvent.
Sw = solubility in water
What are the consequences of post injection precipitation?
Delayed or potentially poor absorption due to slow redissolution. The bioavailability will no longer be 100%, and clinical failure is likely to occur.
Injection site reactions due to prolonged drug exposure, abrasive effect of precipitates and the presence of neutrophils and macrophages
What are the conventional parenteral formulations?
Solutions
Emulsions (o/w and w/o)
Suspensions
What are the parenteral formulations in order from fastest release?
Solution (fastest)
Aqueous suspension
Emulsion
Oleaginous suspension (slowest)
What are the events that must occur before the drug is absorbed into the blood?
Emulsions (oil based solutions) must partition into injection site. They may bind to tissues and precipitate, or they may redissolve to be absorbed through the biomembrane.
Carriers and devices undergo matrix erosion partitioning into solutions at the injection site to be absolved.
Suspensions and nano crystals need to dissolve into solutions to be absorbed.
Oil based suspensions need to dissolve or partition into solutions to be absorbed
Complexes and conjugated drugs need to undergo a drug comples dissociation into solutions to be absorbed
How are parenteral solutions prepared?
By dissolving the rug and excipients, adjusting the pH, sterile filtration (via a 0.22μm membrane) followed by aeseptic filling.
Large and small volume parenterals which do not contain a preservative just be terminally sterilised by auto claving. If they are sensitive to heat, they can be sterilised by the filter methods, radiation or gaseous methods, however they can’t be sensitive to light
How are parenteral suspensions prepared?
By mixing sterol powder and vehicle or by mixing them prior to use
Syringeability and inject ability are the critical flow properties for parenteral suspensions (Textureanalyser analyses the force which is required to push the suspension out of the syringe.)
Dissolution and absorption can be controlled to produce long acting products
What are the long acting suspension products of parenteral dosage forms?
Zinc insulin, penicillin G procaine
Depot antipsychotics like Depixol
Depot hormones like Depo Provera
Depot anticancer agents like Eligard
How are parenteral emulsions prepared?
W/o and o/w emulsions can be used for local injection, but w/o emulsions cannot be used for IV.
Formulation options are restricted through very limited stabilisers and emulsifiers suitable for parenteral preparations
What is intralipid?
Fat emulsions for parenteral nutrition
Stable emulsion
Low toxicity
Small droplet size (0.1-0.5μm is ideal as >3μm esi lots in thrombosis)
Clinical used for the reversal of local anaesthetic induced toxicity to the heart
How is intralipid used for the reversal of local anaesthetic induced toxicity to the heart?
In-vitro studies suggest that the lipid infusion creates a lipid phase, or “lipid sink,” in the plasma to which lipophillic drugs such as local anesthetics can partition into.
The second possible mechanism is reversal of mitochondrial fatty acid transport inhibition. Local anesthetics inhibit carnitine acylcarnitine translocase (CACT), an enzyme used in mitochondrial fatty acid metabolism and transport. Because fatty acids are involved in 80% to 90% of cardiac ATP synthesis, inhibition of CACT may contribute to cardiac toxicity.
Lipid infusion may increase the intracellular fatty acid content enough to overcome the inhibition of the CACT enzyme by the anesthetic.
What are novel parenteral drug deliver systems?
In situ gelling systems (depot forming) Carrier systems (lipopsomes)
Why are drugs incorporated into these novel parenteral drug delivery systems?
To increase duration of action
Provide selective delivery of drug to a specific site e.g. Tumour
Reduce unwanted side effects and adverse reactions due to selectivity
What are the considerations for safe and effective parenteral drug delivery?
Microbiological factors (sterile, free from bacteria and pyrogens)
Chemical stability (preventing hydrolysis and oxidation)
Solubility (including in hence formulation AND post injection)
Physiological compatibility (including pH, tonicity, drug concentration)
Syringeability and injectability (i.e. Viscosity in suspensions)
What are the commonly used additives for parenteral drugs?
Antioxidants - maintains chemical stability
Chelating agents
Antimicrobial agents (preservatives) - ensure sterility
Buffers - biocompatibility attributes free from irritation
Tonicity adjustment agents
Solubilising agents and surfactants - maintain solubility
Viscosity inducer - aids in parenteral administration
What is the main restriction to the type or amount of excipients used in parenteral formulations?
Safety issues
What is the role of antioxidants?
Maintain product stability by being preferentially oxidised.
Ascorbic acid and salts of sulfur dioxide (bisulfide, metasulfite, sulfite) are the most common antioxidants used in aqueous parenterals
What is the role of chelating agents?
To complex and inactivate materials like copper, iron and a zinc which catalyse oxidative degradation of drug molecules
E.g. EDTA derivatives and salts (citric and tartaric acids) also employed as chelating agents
What is the role of antimicrobial agents?
Inhibit the grown of microorganisms in
Multiple dose parenteral products
Single dose parenteral produces which are not terminally sterilised
E.g. Benzalklnium chloride Benzyl alcohol (low concentration)
What are some interactions between preservatives and other components of a formulation?
Partitioning into a micellular phase or an oil phase in n emulsion
Inclusion complexes with cyclodextrins
This will compromise the preservative efficacy
What is the role of a buffer?
Maintain pH as this is related to drug stability and solubility.
Better tissue tolerance.
The pH is usually 4-9 for injections.
Acetates, citrates, phosphates are buffering agents commonly used in parenteral products.
Amino acids may be used as a buffering agent for polypeptide injectables
What is tonicity ?
An osmotic pressure gradient of two solutions separate by a semipermeable membrane.
Why is isotonicity important for parenterals?
Avoids hemolysis or cede nation of RBC owing to hypotonic or hypertonic solutions respectively.
Dextrose and sodium chloride are commonly used tonicity adjustment agents
What is the role of surfactants?
These are used for wetting and to prevent crystal growth in a suspension.
They also provide acceptable suringeability.
E.g. Poly sorbates such as tween80, pluronic F127
What is the most widely used solvent for parenteral preparations?
Water for injection
What are the requirements for WFI?
Distillation of deionised
Free of contaminants (including microbes and other foreign particles)
Free of pyrogens
Why are water miscible solvents used in parenterals?
To enhance drug solubility and to serve as stabilisers
Glycerin, ethyl alcohol, propylene glycol, polyethylene glycol 300 are the most commonly used.
Why are mixed solvent systems commonly used in parenterals?
To reduce irritancy and toxicity
Why is sodium chloride injection USP used?
This is a sterile isotonic solution of sodium chloride in water for injection.
Does not contain antimicrobial agents
The sodium and chloride ion contents of each injection are approximately 154mEq of each per L
These are used to reconstitute medications for injection.
As a catheter or IV line flush to maintain patency
