8 - Parenteral Flashcards
Advantages of parenteral administration?
- fast action
- complete/better absorption
- predictable outcomes
- drug targeting
Disadvantages of parenteral administration?
- short action
- invasive administration
- poor patient compliance
- hospital visits
- high cost
What are “dispersed systems” ?
- a thermodynamic, interfacial system in which one component is dispersed in the other
- pharmaceutical colloids in nature
- stability, interfacial phenomena, mass transfer
- higher quality requirements that counterpart preparations for oral delivery
- complex and expensive formulation
List 3 dispersion types
1) Lyophilic
2) Lyophobic
3) Association
Dispersion type:
Describe Lyophilic
a soluble dispersed phase in a continuous phase as in emulsions
Dispersion type:
Describe Lyophobic
an insoluble dispersed phase in a continuous phase as in suspensions
Dispersion type:
Describe Association
a soluble dispersed phase that is also “self-assemble” in a continuous phase as in liposomes
List different depot formulations
- suspensions (aqueous or oil)
- IM or SC administration
- drug reservoirs
- controlled drug release rate from injection site
- prolonged therapeutic effects
What is the difference between dissolution and solubility?
Dissolution: how fast is that compound going to dissolve (relates to rate)
Solubility: does not relate to rate, just how much is going to dissolve in the solvent
Describe dissolution depots
- salts and complexes with low solubility
- suspensions of microcrystals
- slow drug dissolution from formulation or into biological fluid
- dissolution could be alone or in combination with vehicle
The _____ the particle size, the more the depot (deposit?)
larger
What are adsorption depots?
- drug-absorbent binding
- unbound absorption
- continuous equilibrium
- force of binding and ratio of drug vs. absorbent
- aluminum hydroxide gels
Describe esterification depots
- bioconvertible prodrugs (esters)
- interfacial partition and prodrug bioconversion
- relatively easy formulation and manufacture
- actual commercial products
Describe encapsulation depots
- microcapsules, microparticles, liposomes, nanoparticles
- polymers or macromolecules
- barrier permeation or biodegradation
- novel drug delivery systems
- complex procedures
Describe injectable emulsions
- aqueous and oil phases
- emulsifiers
- internal and external phases
- W/O or O/W or W/O/W or O/W/O
- drug can be in either phase
What kind of parenteral nutrition can be given for terminally ill patients?
amino acids, dextrose, electrolytes, minerals, vitamins, fatty acids
*can also have parenteral preparations for candidates with poor or no solubility in water
Describe multiple emulsion
- hydrophilic & hydrophobic emulsifiers
- W/O/W or O/W/O
- two internal phases
- more stable
Describe microemulsion
- small particles (< 1000 nm)
- transparent
- most parenteral emulsions belong to this category
Most parenteral emulsions belong to which category?
microemulsion
Describe some characteristics of emulsions
- Internal phase: stability, solubility
- Sustained release
- Drug targeting
- Particle size/stability
List some side effects of emulsions
- Emboli in lung/liver/kidney/brain
- Headache/fever/chill/BP change/liver damage
List some physicochemical requirements of emulsions
- stable
- uniform
- sterile
List some biological requirements of emulsions
- endotoxin-free
- non-antigenic
- low side effects
- metabolizable
List some practical requirements of emulsions
- storage tolerance
- easy processing
- reasonable cost
List an example of an emulsifier
- Lecithins
- Pluronic
- phosphatidylcholine
- glycerol/propylene glycol
- polysorbate
List examples of oil phases
- soybean oil
- safflower oil
What is the aqueous phase?
water for injection
What other components of emulsifiers are controlled by other additives?
- pH
- osmolarity
- viscosity
- oxidation
- microbial growth
What does microfluidization do?
decreases particle size
What factors are considered in quality control?
1) pH = 6.6 - 6.8
2) Particle size = 0.2 - 0.5 micro meters
3) Surface charge (stability related, higher is preferable)
4) Stability
- Physical: particle change, creaming, coalescence, separation
- Chemical: Drug activity, hydrolysis, oxidation, pH change
- Microbiological: bacterial/fungal growth
Parabens are ______
preservatives
Describe administration of parenterals
- mostly IV injection (could be SC or IM I think)
- components of total nutrient admixture
- hospital applications
- storage in fridge for better stability
- incompatibility likely if admixing inappropriately
Hospital Dispensing:
IV lipid emulsions can be administered in combo with _____ and ____ _____
dextrose and amino acids
Hospital Dispensing:
____ are generally not added to the admixtures, with rare exceptions (ex. heparin, insulin, ranitidine)
Drugs
Hospital Dispensing:
What is the major concern?
physical stability
ex. phase separation, precipitation
Describe Injectable Suspensions
- Insoluble drug particles
- Aqueous or non aqueous medium
- Suspending agents
- Most difficult formulation in terms of stability and production
Why are injectable suspensions the most difficult to formulate?
- drugs with limited aqueous solubility
- solubilization with pharmacological or toxicological compromise
- requirements for sustained drug release
- requirements for long-term local drug effects
Characteristics of injectable suspensions?
- Increase drug stability profiles due to insolubility
- Controlled release action
- Depot release
- Formulation stability issues
- Difficulty in formulation and production
- Discomfort to patients
- Dose accuracy
List some physicochemical requirements of injectable suspensions
- stable
- uniform
- sterile
List some biological requirements of injectable suspensions
- pyrogen-free
- non-irritating
- low side effects
List some practical requirements of injectable suspensions
- resuspendability
- syringeability
- injectability
- easy production
- easy administration
What is syringeability?
- passing through needles
- no clogging
- dose accuracy
- less than 5 micro meters
- 0.5-5% solids
What is injectability?
- good flow
- even pressure
- clogging-free
- less discomfort
- viscosity-related
- excipient-related
Injectable suspensions:
What are some flocculating/suspending agents?
- surfactants
- polymers/colloids
- electrolytes
Injectable suspensions:
What is a wetting agent?
surfactant
Injectable suspensions:
Contain _______ to prevent microbial growth
preservatives
Injectable suspensions:
What are some stabilizers
- antioxidants
- chelating agents
Injectable suspensions:
What are some adjustors?
- buffering agents
- tonicity agents
Injectable suspensions:
What are some solvents?
either water or oil
What are some requirements for oils for injection?
- pure
- biodegradable
- IM injection only as a vehicle
- IV injection as an emulsion
- mainly for steroids, hormones and vitamins
What are some types of oils for injection
- soybean oil
- safflower oil
- peanut oil
- cottonseed oil
- corn oil
- olive oil
- sesame oil
- apricot kernel oil
What is included in chemical quality control?
- active ingredients
- degradation
- preservatives
What is included in biological quality control?
- sterility test
- pyrogen test
- preservative action
What is included in physical quality control?
- resuspendibility
- sedimentation
- syringeability
- crystal growth
- size distribution
- zeta potential
- rheology
- pH
- dissolution
What are pyrogens?
Fever-inducing agents
-Can cause a rise in temp of more than 0.6 degrees celsius
Pyrogens can result in ____ and _____
shock and death
What is an example of a pyrogen
bacterial LPS
Describe administration of injectable suspensions
- Mostly IM and SC injections
- slow/controleld release actions
- withdrawal from the ampoules
- discomfort to injection site
- not co-administered with other medications
Describe what pharmaceutical implants are
- devices in dermal/subdermal tissues for extended period of time
- sustained drug release profiles
- alternatives for long-term drug uses
- surfical implant and removal
Good characteristics of pharmaceutical implants?
- long-term actions
- steady drug concentrations
- one administration
- various release mechanisms
- compliance
Bad characteristics of pharmaceutical implants?
- surgical procedures
- complications
- difficult retrieval
- inflexibility
- complex production
- high unit cost
What is the objectives/purpose of pharmaceutical implants?
- delivering controlled drug release
- simplifying administration procedure
- minimizing medical implications
- reducing unauthorized misuse
- improving patient compliance
Pharmaceutical implants can either be permeation-controlled, diffusion-controlled or partition-controlled:
Describe premeation-controlled
- rate-controlling polymer membrane
- permeation in/out of the system
Pharmaceutical implants can either be permeation-controlled, diffusion-controlled or partition-controlled:
Describe diffusion-controlled
- polymer matrix
- insoluble polymers
- diffusion in/out of the system
What is Norplant 2?
- membrane-matrix hybrid
- both permeation and diffusion
Pharmaceutical implants can either be permeation-controlled, diffusion-controlled or partition-controlled:
Describe partition-controlled
- dispersed drug microreservoirs
- drug partition through the system
What is an osmotic pump?
- osmotic-producing agnet
- universal formulation
- custom-made possible
Describe “Magnetic Activated”
- In vivo device
- In vitro control
- Both triggering and nontriggering
- Prototype
Describe the Application of magnetic activated
- decreasing use in humans
- research-based studies in animals
- long-term drug studies
- veterinary applications
Why are liposomes used in cosmetics?
Liposomes are lipid based and our skin has a high percentage of lipids so this will increase absorption
*If you apply lipids to other lipids (like dissolves like) and there will be a higher amount of drug delivery
What are liposomes?
- A structure consisting of lipid bilayers (to mimic our skin for best drug delivery) separated by aqueous compartments (vesicles)
- Heterogeneous disperse systems
- Wide particle size distribution
- Phospholipids and cholesterol
List the 3 types of liposome vesicles
- large unilaminar vesicle
- small unilaminar vesicle
- multi-laminar vesicle
What does sonication do?
breaks up particles
What does a vortex do?
causes high vibration rates and shakes the products to reduce particle size
What does reverse phase evaporation do?
solubilizes in an organic solvent, add water at higher temp allowing it to boil off
What does the french press method do?
uses high pressure to push particles through filter
Bonus question on exam!!!!
What was the car brand used in the asthma commercial?
Volvo
Bonus question on exam!!!!
Something about how tumours can be used to enhance drug delivery??
- tumor’s vasculature is very good
- has enhanced permeation and retention effect
______ = stabilizer of liposomes
Cholesterol
Using products with liposomes does scare some people about increasing their cholesterol. Is this a legitimate concern?
No - the amount of cholesterol used is very minimal
How does cholesterol stabilize liposomes?
- Decreases bilayer fluidity/viscosity
- Reducing membrane permeability
- Minimizes interaction with biological fluids
________ = naturally existing, abundant in vivo
Cholesterol
Cholesterol is also _______, ________, and ________
biocompatible, biodegradable and bioabsorbable
How are liposomes eliminated from the body?
- through the liver, but not in the traditional sense
- If it does get to liver or blood, immune cells with recognize liposomes and will start ingesting it
- macrophages of the liver with ingest liposomes and render them useless
- *they are going to the target tissue but not being effective because they are getting ingested
???? doesn’t really make sense, but that’s all I wrote down
What are some other components in liposomes?
-polymers, surfactants, stabilizers
What are liposomes used mainly in?
cosmetic and topical liposomes formulations
Caution use of liposomes in ??
parenteral formulations due to safety concerns
Where do hydrophilic drugs load?
aqueous compartments
Where do lipophilic drugs load?
within lipid bilayers
Where do amphipathic drugs load?
depending on PC
Where do large molecules load?
surfaces
Overall, drug loading in liposomes is relatively ____
low
Describe “Drug Entrapment”
- Entrapment dependent on internal volume
- Charged lipids increase volume by repulsion
- Diluted solutions show higher entrapment
- Drug leachability is common with liposomes
Liposomes:
In vitro fate of particle size?
- physical stability
- uniformity
- drug loading
Liposomes:
______ particle size distribution is preferable
Narrower
Liposomes:
In vivo fate of particle size?
- interaction with blood components
- uptake by tissues and cells
Liposomes:
_____ targeting possible by sorting particle size
Specific
What is the typical formula of a liposome?
- Egg lecithin 45%
- Phosphatidylserine 9.9%
- Cholesterol 45%
- Vitamin E 0.1%
Describe physical in vitro stability of liposomes
- dynamically instable
- particle aggregation
- particle fusion
- phase change (don’t want fusion or phase change)
- drug leaching
*don’t want aggregation or it to break apart
Describe chemical in vitro stability of liposomes
- hydrolysis
- oxidation
- pH
- membrane permeability
- drug delivery
-environmental related (light, air, temperature, etc)
Describe in vivo stability of liposomes
- various interactions in vivo
- instability due to protein transfer
- size and preparation related
- drug loss dramatic
- specific targeting possible but mechanisms not well studied and understood (leaky vasculature is a proposed theory)
- biggest challenge for medical application
Why do we create stealth liposomes?
Trying to allow liposomes to hide from the immune system therefore they would be allowed to reach the target tissue !!!
Describe Stealth Liposomes
- polymer attachment
- “invisible” to immune system in vivo
- increased retention and stability
- more site-targeting
- challenging formulation
- the longer the stage in blood, the more it can target cancer cells
- want to increase half life therefore allowing more particles to reach target site (cancer tumor)
We need to sterilize nanoparticles, what is the max size of nanoparticles for filtration?
- 22 microns
* Anything small can be filtered as a form of sterilization
Sterilization of liposomes:
_____-_____ filtration for final sterilization
microbial-retentive
Sterilization of liposomes:
_______ should not affect liposome structure
filtration
Sterilization of liposomes:
_____ and ______ sterilization could compromise structure integrity and drug activity
thermal and radiation
Sterilization of liposomes:
______ manufacturing expensive and difficult in validation
Aseptic
Characteristics of liposomes?
- biocompatibility
- biodegradability
- small particles
- diverse drug loading
- parenteral use
- drug targeting
- instability
- high material cost
- large-scale production difficulties
What are the medical applications of liposomes?
- site-specific delivery
- site-avoidance delivery
- sustained/controlled drug release
- passive drug targeting to tumors
- protein/peptide/gene delivery
Describe nanotechnology
- Buzzword, promising potentials
- A broad range of topics: colloidal sciences, supramolecular chemistry, device physics, engineering, etc.
- Multidisciplinary and interdisciplinary
- More marketing strategies than actual applications
Pharmaceutical applications of nanotechnology?
- controlled release
- taste masking
- stability improvement
Food applications of nanotechnology?
- nutrient protections
- ingredient isolations
- odor/taste masking
Agriculture applications of nanotechnology?
- pesticides/fertilizers
- veterinary use
- chemical biodegradation
Commercial/industrial applications of nanotechnology?
- fragrance release
- detergent isolation
- thermal release
List some polymeric dispersions
- microcapsules
- microspheres
- nanocapsules
- nanospheres
- nanoparticles
Difficulties with nanoparticles?
- use of organic, toxic solvents
- operator protection
- environmental pollution/protection
- large-scale production
- production cost
Describe the separation of nanoparticles
- solvents
- free drugs
- polymers
- additives
Describe the purification of nanoparticles
- stability
- toxicity
- quality
- injectability
What is ultracentrifugation?
- spin it at high rates and separate particles
- once nanoparticles settle to the bottom, we can separation the organic solvent from it
How can the principle of dialysis be related to separation of nanoparticles
Put nanoparticles in the bag and spin it in the beaker.
Buffer = water in this case
(water is considered low salt/low solute)
Organic solvents want to come out of the bag (follow concentration gradient).
Dialysis bag is semi-permeable membrane and nanoparticles that are too big to leave the bag while everything else smaller than that is able to leave the bag
*just using a barrier (dialysis bag) to separate particles based on size
What is included in physical quality control?
- Size & distribution (dynamic light scattering)
- Morphology (SEM)
- Drug loading
- Drug release
- Physical states
What is included in chemical quality control?
- Drug activity (functional assays)
- Degradation (HPLC)
- Byproducts
- Additives (HPLC)
- Interactions
How can the drug be released from nanoparticles?
- Hydrophilic polymers facilitate faster drug release than lipophilic polymers
- Drug solubility, diffusivity, molecular weight and particle size influence drug release rate and extent
- Controlle released is achievable by formulation strategies
Drug can release by:
1) nanoparticles eroding
2) drug diffuses out of nanoparticles
3) temp changes could increase or decrease drug release
In vitro = ?
outside of body (test tube)
In vivo = ?
in the body
Describe in vitro studies
- interaction with blood components
- uptake by cells
- stability
- toxicity
Describe in vivo studies
- animal models
- drug targeting
- drug activity
- drug toxicity
- overall outcomes
Liposomes are ___ based
lipid
Nanoparticles are _____ based
polymer
