Parenterals 2 Flashcards
What constitutes a large volume parenteral (LVP)
- it is packaged in volumes larger than 100 mL
- single dose units
- packaged in class or plastic
- never preserved with antimicrobial agents
- primarily used for volume and electrolyte replacements by IV route
- maximum volume 1000 mL
- usually administered continuously at a rate set in mL/h
What variance does homeostatic mechanisms maintain total body water at?
within 1%
What is the daily intake of fluid for adults?
50 ml/kg
What can the fluid balance be upset due to?
- den be upset due to reduced intake or unusual lose (shock. third spacing, trauma)
What are the most common components in fluid?
-sodium chloride and dextrose (D-glucose monohydrate)
What are some things that can commonly cause electrolyte unbalances?
- vomiting, dehydration, diarrhea, and trauma
Must electrolyte solutions be diluted before they are added to an LVP?
Yes, they must be
Can electrolytes be used to restore pH?
Yes, they can be
What are the ways that drugs are administered to reach a stable concentration?
- some drugs require continuous administration following a loading dose to maintain therapeutic serum levels
- may be added to LVP and infused but compatibility and stability must be considered
- when given IV rate is also an issue since some toxicities are related to serum concentration
What are blood products and what are they used for?
- many blood products are given as LVP
- albumin, fresh frozen plasma, whole blood
- not used for drug admin
- managed by Canadian blood services
What are some examples of LVP-like products which are not meant for IV administration but must also be sterile and particulate and pyrogen free?
- peritoneal dialysis solutions
- parenteral nutritional solutions
- irrigation solutions
What are small volume parenterals?
- injectable products packaged in volumes of 100 mL or less
- formulation required knowledge of physical, chemical and biological properties of drug and applications of this knowledge
- must determine the: route of administration, selection of the vehicle, required added substances, and an appropriate container and closure
If the dose requires volumes greater than ___ the IM route is not useful
10 mL
If drug is ___ to tissues IM route is contraindicated
irritating
If drug requires ____ IV is not practical
prolonged release
What consideration is taken when selecting a vehicle?
- generally may be aqueous, aqueous with co-solvents or non-aqueous
- aqueous is most desirable but drug stability is often an issue here
- water physiologically compatible and high dielectric constant and polarity allow dissolution of ionizable functional groups and hydrogen bonding facilitates dissolution of alcohols, aldehydes, ketones and amines
What would the purpose of co-solvents be?
- aids with solubility and stability
- non-polar substances have limited solubility in water and a co-solvent such as alcohol, glycerol, propylene glycol or polyethylene glycol may be required to effect solution
- co-solvents prevent chemical degradation especially by hydrolysis
What are some of the disadvantages of co-solvents?
- tissue irritation
- dilution may cause the drug to come out of the solution
- potential toxicities if given in a larger dose
What is the purpose of a surfactant?
- solubility may be increased by the use of non-ionic surfactants such as Span, Tween, Cremophor
- these are generally used in a concentration of 0.05 to 0.5%
- ionic surfactants are not generally used due to irritation or damage to the membranes
Cyclodextrins are oligomers of ____
glucose
How do cyclodextrins work?
they exert their effects by forming stable inclusion complexes
- amphipathic with the exterior being hydrophilic while interior is hydrophobic
Oil vehicles in injections are especially good for what?
- to provide prolonged or sustained release due to depot formation in the muscle tissue
(can also emulsify using surfactants to form product which can be given IV)
What are some of the purposed of added substances in a product?
- helps with safety, efficacy, elegancy, stability
What do these extra added substances include?
Buffers
Antioxidants
Antimicrobial agents
Toxicity adjusters
What are buffers used for?
- may be used to enhance stability and/or solubility but also to resist pH changes or storage
- buffers should have the capacity to maintain pH yet should adjust pH to that of aloof (pH=7.4) following administration
What can a pH above 9 cause?
- can cause tissue necrosis
What can a pH below 3 cause?
can cause pain and phlebitis
What does a buffer generally consist of? What are some common buffers?
consists of a weak acid or a base along with its salt
- common buffers are citrate, acetate, phosphate and tromethamine
Then buffer may alter properties of the product such as…?
- solubility and stability
Degradation of ____ increases in the presence of citrate
thiamine (vit B1)
Degradation of ____ increases in the presence of phosphate
phenethicillin
___ will precipitate in the presence of phosphates at certain pH values
calcium
What are some common methods of preventing oxidation?
- chelating agents
- protection from light
- replacement of air with inert gas, a slightly acidic pH or via the addition of antioxidants
How do antioxidants prevent the compound from oxidation?
- often have higher oxidation potential than the drug and are preferentially oxidized
- used along or in combination
What compounds can you not use an antioxidant with?
you cannot use with LVP, intrathecal or intraocular injectables
There is a formation of ____ when bisulfites oxidize to sulfate
insoluble salts
There is a reaction of bisulphate with ____ functional groups
aldehyde
Like antioxidants, antimicrobial agents are not be to added to what?
LVPs, intrathecals, or intraocular injectables
Antimicrobial agents are to be avoided or used with caution in what group of people?
young children
What are some examples of tonicity adjusters?
- ideally, parenteral should be isotonic but often not possible since high drug concentrations are needed to keep the volume small
- can compromise by dilution the solution in an IV administration
- easiest method of determining the quantity of tonicity adjusters is not use NaCl equivalent method
- best to use the White-Vincent method if the product is buffered
What are some of the agents used as tonicity adjusters?
sodium chloride, dextrose, mannitol, and glycerol
The antimicrobial effectiveness test is in what USP?
USP 51
How does the antimicrobial effectiveness test work?
- product samples are inoculated with a controlled quantity of specific microorganisms
- test them compares the level of microorganisms found on a control sample vs the test samples over a period of 28 days
- the product in the original container is inoculated to provide between 1x10^5 and 1x10^6 colony forming units per mL of product (at various intervals, depending on the category, samples are taken and the number of cf. is determined using the plate-count method)
- any growth over the allotted amount for any of the indicated microorganisms means that the preservative in the product is not effective and the product fails the test
How many categories are there for the antimicrobial effectiveness test?
4
What does category 1 cover?
- parenterals, ophthalmics, otics, sterile nasal products made with aqueous bases or vehicles
What does category 2 cover?
- topically used products made with aqueous bases or vehicles, non-sterile nasal products, emulsion and products applied to mucous membranes
What does category 3 cover?
oral products other than antacids mad with aqueous bases or vehicles
What does category 4 cover?
antacids made with an aqueous base
What is the allotted bacteria and yeast/mold counts for category 1?
Bacteria: on day 7 not less than 1.0 log reduction from initial count, day 14 not less than 3.0 log reduction and on day 28 no increase from day 14
Yeast: on days 7,14,and 28, no increase from the original count
What is the allotted bacteria and yeast/mold counts for category 2?
Bacteria: on day 14, not less than 2.0 old reduction from initial count and on day 28 no increase from day 14
Yeast/mold: on days 14 and 28 no increase from the original count
What is the allotted bacteria and yeast/mold counts for category 3?
Bacteria: on day 14 not less than 1.0 log reduction from initial count and on day 28 no increase from day 14
Yeast/mold: on days 14 and 28 no increase from original count
What is the allotted bacteria/yeast/mold count for category 4?
on days 14 and 28 no increase from the original count
What function do containers for parenterals serve?
they facilitate manufacture, maintain product integrity (includes stability, sterility and freedom from particulates), allow inspection of product, permit shipping and storage, provide convenient clinical use
What are the three types of containers recognized by the USP?
- type 1: borosilicate and is the least reactive as measured by an alkalinity test run on powdered samples (the best but also the most expensive)
- types 2 and 3: soda lime glass with type 3 having been treated with sulphate, sulphate or sulphide to make it less reactive (type 2 is used for products which remain below pH 7.0 during shelf life)
- type 3 can be used for dry powders which require reconstitution and then are immediately removed
What kinds of glass is amber glass mostly used for?
used for products which are light sensitive
What must be determined before amber glass is used for a product?
need to determine that leaching does not occur over the shelf-life of the product
What is that USP chapter for specifying the testing of glass containers? Plastic containers? Performance testing containers?
USP chapter 660 = glass
USP chapter 661 = plastic
USP chapter 671 = performance testing
What does USP 660 test for?
tests light transmission, chemical resistance and tests for alkalinity
What are polymeric materials generally used for? What additives are generally used?
generally used for the rubber closures for parenteral products
- additives include accelerators, activators, plasticizers, etc
Specifications and tests for closures are described in which USP?
USP 381 - elastomeric closures for injections
What are some common problems with closures?
leaching of materials into the product, adsorption of product, particulate contamination from the container/closure combination
What are some of the physical properties important in the selection of closures?
- compression set: good plastic/elastic properties to ensure a good leak-proof fit
- flexibility: coring may occur when the needle passes through the closure
- hardness: soft enough to allow the easy passage of the needle. Route of administration must be considered - some routes require a narrow gauge
- water vapour transition: resistant to passage of water vapour
- resealability: reseal well when needle is withdrawn
- tackiness: do not want closures to stick together or clump
Plastics like ___ and ___ may be used for packaging parenterals
PVC and polyethylene
What are the advantages of plastics? Disadvantages?
Advantages: light weight, break resistant
Disadvantages: moisture and glass permeability, leaching and adsorption of drug material
