pharmaceutics exam 3 Flashcards
what are solutions
what may solutions be
“Liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents”.
Solutions may be,
- Oral
- Otic
- Opthalmic
- Topical
What is the maximum concentration to which a solution can be prepared with that agent and solvent?
Attractive forces- what do they cause molecules to do
Repulsive forces- what does it cause molecules to do
Dipolar molecules-
Hydrogen bonding-
in solution, are there are attractive or repulsive forces
what do you want a balance of
what atoms of hydrogens move close to
what molecules also form hydrogen bonds
Solute must dissolve – attractive forces cause molecules to cohere and adhere to each other based on their attractiveness
Repulsive: prevents the molecules from interpenetrating each other
In a solution, there are both but if they are equal then the potential energy is minimal – do not have too many attractive or repellent forces and that’s when the solution is most stable and dissolved
Want a balance of both attractive and repulsive forces
Dipolar molecules align to each other based on negative and + end
Hydrogen atoms move in close to electronegative atoms (i.e., F, O, N)
Hydrogen bonds exist also with
Esters, Carboxylic acids, Aldehydes, Polypeptides
How to improve solubility conditions
What options are available to pharmacists?
what consists of 0.03% iodine
can use:
Different solubilizing agents
Different chemical salt form of medicinal agent
Alteration of the pH of a solution
Partial or whole substitution of a solvent
Example; 1g of iodine granules in 3,000 mL (0.03% iodine)
Alternative: dissolve in Potassium Iodide, Sodium Iodide
Iodine Topical Solution, USP (contains 2% iodine, 2.4% sodium iodide)
How do you make sure that solute gets into solution:
what do undissolved solutes need to do
in dissolved solution, what does the solvent have a higgher affinity for
How do you make sure that solute gets into solution: excipients – additives to improve solubility.
Example: pure water, can add some alcohol
Undissolved solute: water/solvent needs to overcome the balance of attractions between the solute molecules (so the affinity for one molecule for another); solvent needs to be able to overcome the solute-solute attraction to make a solute-solvent attraction
- (easier to do for monovalent molecules or molecules where at least ine atom is monovalent than a molecule that is multivalent).
- Need to overcome the attraction of the solute
In dissolved, the solvent has a higher affinity for the solute and was able to overcome the solute-solute attraction
Want a solute-solvent interaction.
The potential energy is a mimimum and you have a more stable solvent
When the exact solubility is not known (or has yet to be
determined), general expressions of relative solubility may be used.
what are they and how many are there
what is the unit
what do you need to do if you have more and more insoluble particles
Very Soluble <1
Freely Soluble 1-10
Soluble 10-30
Sparingly Soluble 30-100
Slightly Soluble 100-1000
Very Slightly Soluble 1,000-10,000
Practically Insoluble >10,000
or Insoluble
all in parts per whole
More and more insoluble: need more and more solvent
what Factors influence solubility
what is a positive heat of solution
what is a negative heat of solution
Temperature:
- “Positive heat of solution”
pH of the solution:
Weak acids or weak bases
Physical agitation:
Extent to which solvent passes over solute
Particle size:
Finer the powder, greater the surface area, the more rapid dissolving process
Most drugs have a positive heat of solution so they dissolve with heat. Some might have a negative heat of solution, and do not dissolve and this makes things worse
Solubility: Beneficial considerations
are salts more or less soluble in water
what are organic bases most soluble in
is alcohol more or less lipophlic
Salts of organic compounds are more soluble in water compared to their organic base counterparts.
Organic bases are more soluble in organic solvents
Like prefers like
For atropine 455.0 mL of water for 1 g of drug
For atropine sulfate 0.5 mL of water for 1 g of drug
Alcohol is more of a lipophilic environment so molecules might dissolve better.
- this is why for drugs that are not as soluble in water, alcohol is used as an alternative
“like dissolves like”
wha do solvents need in order to dissolve
what are organic molecules most soluble in and what is the exception
what are examples of polar groups
do halogens increase or decrease solubility and why
what happens in Cl or F is added
Solvents having chemical structures most similar to the solute will most likely dissolve it.
For i.e., organic compounds are more soluble in organic solvents compared to in water.
One exception is if organic compound has polar functional group.
Polar groups are:
OH, CHO, COH, CHOL, CH2OH, COOH,
NO2 and SO3H – dissolve well in water
In general, halogen atoms decrease solubility
–Because of an increase in MW without proportionate increase in polarity
If Cl or F is added, then there is more MW without the proportional increase in polarity which is why the single addition of a Cl or F does not improve solubility but actually decreases it
Inorganic MOLECULES
what does monovalent mean
If cation and anion of an ionic compound are monovalent, what is easily overcome
what is you have two ions
what happens in the catiion and anion are multivalent
how much solubility is there for this
are ammonium and quaternary ammonium salts water or lipid soluble
what kind of molecules are water insoluble
If cation and anion of an ionic compound are monovalent, solute-solute attractive forces are easily overcome by the solvent. Not very strong
(i.e., NaCl, LiBr, KI).
Same is true if one of the two ions in an ionic compound is monovalent (i.e., BaCl2, MgI2)
If both the cation and anion are multivalent, the solute-solute interaction may be too great to overcome (i.e., CaSO4, BaSO4) by the solvent
This results in POOR WATER SOLUBILITY
Ammonium and quaternary ammonium salts are water soluble
Phosphates, Carbonates, Silicates, Borates, and Hypochlorites are water insoluble (except for their alkali metal salts and ammonium salts).
organic MOLECULES
molecules what number of polar functional groups is sufficient to solubilize chain lengths with how many carbons
what is more soluble: branched or straight chains
how does MW affect water solubility
what is can increase in structural similarity between solutes result in
Molecules having one polar functional group is sufficient to solubilize chain lengths consisting of 5 carbons
Molecules having branched chains are more soluble than corresponding straight-chain compounds
Water solubility decreases with increase in molecular weight (like with adding F, increase in MW without proportional increase in solubility)
Increased structural similarity between solute and solvent = increased solubility (remember: “like dissolves like”)
Solvents for liquid preparations
Alcohol, USP: Ethyl alcohol, ethanol, C2H5OH
A primary solvent for many organic compounds
When mixed with water = hydroalcoholic mixture
Alcohol USP is 94.9% to 96.0% C2H5OH by volume, when determined at 15.56 °C
15.56 °C (U.S. government standard temp. for alcohol determinations).
Dehydrated Alcohol, USP contains not less than 99.5% C2H5OH.
Want to promote solute, solvent interactions
add ethyl alcohol to be a part of solution
Dehydrated: less water
for drugs not soluble in water, what is a suitable alternative and why
what are examples of insoluble agent
when alcohol is too much, what can be used
are the limits of alcohol content for For children < 6 years, 6-12 and 12+
For drugs not soluble in water, alcohol is preferred as a suitable alternative due to its miscibility in water and ability to dissolve many water insoluble agents.
For e.g., Drug agents, flavorants, antimicrobial preservatives.
When alcohol content is too much, glycerin and glycols can be used to reduce total amount of alcohol needed.
FDA proposed for manufacturers of OTC oral drug products
For children < 6 years of age alcohol limit is 0.5%
For children 6 to 12 years of age, limit is 5%
For children over 12 years of age & adults limit is 10%
Diluted Alcohol, NF
how is it prepared
since liquids tend to contract, what is the final volume
what is diluted alcohol useful for
Prepared by mixing equal parts of alcohol USP with purified water
Since liquids tend to contract during mixing the final volume is generally 3% less than what otherwise should be expected.
For example, if 50 mL of each component is combined the result is 97 mL.
Dilute alcohol is a useful hydroalcoholic solvent in various pharmaceutical processes and preparations
Rubbing Alcohol
how much ethyl alcohol does it have
To discourage oral ingestion each, how much of a certain solution is added to each ____mL of solution – how does it taste
what is the denaturant that is employed called
what is it made of
Rubbing alcohol contains about 70% ethyl alcohol by volume, remaining is water, denaturants (with or without color additives and perfume oils and stabilizers).
To discourage oral ingestion each 100 mL must contain not less than 355mg of sucrose octa-acetate (or 1.4 mg of denatonium benzoate) which has a bitter taste and discourages internal use.
Internal Revenue Service- U.S. Treasury Department, the denaturant employed is called Formula 23-H
8 Parts (by volume) of acetone
1.5 Parts (by volume) of methyl isobutyl ketone
100 parts (by volume) of ethyl alcohol
Glycerin, USP (Glycerol)
A clear syrupy liquid with a sweet taste
Miscible in water and in alcohol
Glycerin is naturally viscous, but can be made less viscous by heating
Can be used as a preservative or stabilizer
Can also be used for internal applications in addition to external use
Isopropyl rubbing alcohol
how much isopropyl alcohol does it have
where is it used
how much of it is used to prepare diabetc needles and syringes
what is a rubefacient and what is its mechanism
Isopropyl rubbing alcohol, ~70% isopropyl alcohol.
Remaining components are water (with or without colorants), stabilizers and perfumes.
Used externally as *rubefacient and soothing rub vehicle for topical purposes.
To prepare diabetic needles and syringes for hypodermic injections of insulin, a commercially available ~91% isopropyl rubbing alcohol is used also.
- “A rubefacient is a substance for topical application that produces redness of the skin e.g. by causing dilation of the capillaries and an increase in blood circulation”
Propylene glycol, USP
Viscous liquid, miscible in alcohol and water
Relatively nontoxic liquid that is practically colorless, odorless, and tasteless.
Used as a solvent for flavors, extracts, drugs, food antioxidants as well as a heat transfer medium
Can substitute for glycerin in pharmaceutical formulations
Purified Water, USP, H20
Must meet U.S. Public Health Service regulations with respect to bacteriologic purity.
Drinking water should be,
Clear, colorless, odorless, neutral or slightly acidic or alkaline.
Tap water not acceptable for manufacturing or extemporaneous compounding
Contains 0.1% of solids per 100 mL of evaporated H2O
Possible chemical incompatibilities between solids and drug agent could result.
Signs that chemical incompatibilities have occurred
Precipitation, discoloration, effervescence
Preparation of solutions
usually, which is greater amount of solute or solvent
how are pharmaceutical preparations expressed
what are
W/V
V/V
W/W
what are the unfavorable interactions
usually, the amount of solute is far less than the amount of solvent
pharmaceutical preparations are expressed in percent strength
W/V:
percent weight in volume
- solids in liquids
V/V:
percent volume in volume
liquids in liquids
W/W: percent weight in weight
- solids in semisolids
unfavorable interactions to know:
- Liquid pharmaceuticals for oral administration to patient usual dose = 5 (one teaspoonful), 10, 15 mL (one tablespoon).
Purified Water, USP, H20
how is it obtained/what kinds are there
how many impurities does it have in comparison to drinking water
when evaporated how much is in solid form
what is it used for
Distillation, Ion exchange treatment, reverse osmosis
As a result, fewer impurities than drinking water
When evaporated no more than 0.001% total solid (1 mg of solids per 100 mL of water)
Used in the preparation of aqueous dosage forms (except for IV administered drug substances)
Considerations for pharmacists
some chemical agents do what
what can you do
Some chemical agents take longer to dissolve.
what you can do to help with this
- Apply heat
- Reduce particle size of the solute
- Use a solubilizing agent
- Apply vigorous agitation
Which of the following would suggest that your newly prepared solution contains chemical incompatibilities?
A) Effervescence
B) Discoloration
C) Precipitation
D) A and B only
E) A, B and C
All of them!
Signs that chemical incompatibilities have occurred
Precipitation, discoloration, effervescence
From slide 21 :)
Dry Mixtures for Solution
it contains everything for formulation except what
after reconstitution, where should it be placed, and for how long
with any remaining amounts, what should the pharmacist tell the patient?
what are examples of this
what needs to be done for oral powders
Dry mixtures for solution contain all of the required components of the formulation (i.e, colorants) EXCEPT the solvent.
Following reconstitution using required volume of liquid solution, it should be stored in the refrigerator for a period not to exceed what’s written on label.
Typically 7 to 14 days
Pharmacist to instruct patient to discard remaining
Examples are,
Cloxacillin Sodium for Oral Solution, USP- an anti-infective antibiotic
Penicillin V Potassium for Oral Solution, USP- an anti-infective antibiotics
Potassium Chloride for Oral Solution, USP- a potassium supplement
For oral: powder that needs to be reconstituted
Oral Solutions
When will a pharmacist be required to dispense a commercially prepared oral solution?
- commercial
- pediatric
- bulk
When will a pharmacist be required to dispense a commercially prepared oral solution?
When necessary to dilute a commercial preparation
When necessary to prepare a pediatric solution by reconstitution of a dry powder
When necessary to extemporaneously compound an oral solution from bulk components
Ex: 1 Oral Rehydration Solutions
what can lead to dehydration and/or death
what can rapid fluid loss lead to
depeltion of what ions results from this as well
what kind of solutions are effective for this problem
Bodily fluid loss (such as with diarrhea) can lead to dehydration and/ or death.
5 million children < 4 years old die from diarrhea annually worldwide.
The rapid fluid loss can lead to loose, watery stools and dehydration.
Depletion of sodium, potassium, and bicarbonate ions results as well.
Oral rehydration solutions are effective with volume depletion of 5 to10%
of body weight.
Ex: 2 Oral Colonic Lavage Solution
what is it used for
how long must you be on a _____ diet
what must you take the night before
what is an alternative drink for this procedure
Preparation of the bowel for colonoscopy
Clear liquid diet for 24-48 hrs prior to procedure
Oral laxative (i.e., magnesium citrate or bisacodyl) night before; cleansing enema 2 to 4 hours prior.
Poor compliance can be a problem, but often not.
Hospital stays are sometimes recommended to monitor the period prior to procedure
Alternative to this procedure:
PEG-3350-Electrolyte Solution
Oral administration of balanced solution of electrolytes with polyethylene-glycol.
Ex: 2 Oral Colonic Lavage Solution
adult dose of soln
how much soln before GI procedure
how fast should the patient consume the solution
when will the first BM be
what is the drinking regimen
Adult dose: 4 L of solution before GI procedure.
Patient should rapidly consume 240 mL of solution every 10 minutes until all is consumed.
First bowel movement will occur within 1 hr.
Different regimens
3 hrs drinking, 1 hr waiting to complete waste removal
Ideally, NO food intake 3 to 4 hrs prior to procedure
Definitely, NO food intake 2 hrs prior to procedure.
Product is to be stored in refrigerator after reconstitution
Formulation:
PEG-3350 236.00g
Sodium sulfate 22.74g
Sodium bicarbonate 6.74g
Sodium chloride 5.86g
Potassium chloride 2.97g
Ex.3: Sodium Citrate and Citric Acid Solution
what are the components
useful for patients requiring what?
Official Solution:
Sodium citrate 100 mg/mL
Citric acid 67 mg /mL
Dose 10 to 30 mL, up to 4 times daily
Useful for patients requiring alkaline urine
For example, uric acid with urinary tract
Or, gout therapy- to reduce crystallization of urates
Syrups
how much alcohol
what are the standard components
what is the purpose of this dosage form
Alcohol content
- very little if any
Standard components
- purified water
- sucrose
- flavoring agents
- coloring agents
- therapeutic agents
Purpose of dosage form
- pleasant tasting vehicle for extemporaneous preparations
- added to the standard formula for medicated syrups
- To be added to the preparation of standard formula for medicated syrups (syrups containing medicinal agents).
- Medicated syrups are commercially prepared from individual components (i.e., purified water, sucrose, flavoring agents, coloring agents, therapeutic agents, etc…).
elixirs
how much alcohol
what are the standard components
what is the purpose of thiis dosage form
Alcohol content
- 10-12%
Standard components
- alcohol and water, additives: glycerin, propylene glycol, colorants, flavorants
Purpose of dosage form
- Nonmedicated elixirs used as vehicles
- Medicated elixirs used to exert drug effect
orally used
sprays
how much alcohol does it have
what is the purpose of the dosage form
- how is it ofetn administered and why
- what are one-way pumps used for
- what is the dosage form for
Alcohol content
- very little if any
Standard components
- can have antibiotics and antihistamines
Purpose of dosage form
- Often administered intranasally to relieve nasal congestion and inflammation
applied in the nose to relieve nasal congestion
- apply drugs systemically and quickly
- one-way pump sprays prevent the drawback of particles in the bottle, nothing can go inside the product to contaminate it
- One-way pump sprays, developed to deliver drugs to the nose. Used for prescription and non-prescription medications.
- dosage form for the nasopharyngeal tract or to the skin
tinctures
how much alcohol
what are the standard components
what is the purpose of this dosage form
Alcohol content
- 15% - 80%
Standard components
- vegetable materials
- alcohol and water
Purpose of dosage form
- - to dissolve inorganic compounds due to high amount of alcohol
What is another name for Syrup NF? Discuss the composition. When are preservatives used?
simple syrup is another name
- made of purified water and sucrose, medicate syrup add on flavoring agents, coloring agents, therapeutic agent
- preservatives are used to prevent microbial growth and to ensure their stability during their period of use and storage.
What is a tincture? What importance does the alcohol content serve (be specific)?
Alcoholic or hydroalcoholic solution; high [ ] of plant extract
- high alcohol helps to dissolve inorganic compounds and help preserve
What are the major components of Ophthalmic solutions?
- for eye drops have to be sterile
- some have preservatives and some do not
- buffer
What are the reasons for buffering an ophthalmic solution?
To achieve greater comfort to the eye (because if too acidic, would be irritating for people that cannot produce tears)
To render the formulation more stable
To enhance aqueous solubility
To enhance the drug’s bioavailability
To maximize preservative efficacy
Why is the viscosity of the (ophthalmic) solution important?
Increasing the viscosity of the solution will improve the duration that the eye is exposed to the drug, compared to when a less viscous substance is employed.
- more viscous stays on the eye longer
A patient has dry eye (no tear production), how may this affect ophthalmic drug therapy?
want eye drop content to stay on eye as much as possible, so make eye drops more viscous because we want it to stay on the eye
- Tears can neutralize any excess hydrogen and hydroxyl ions introduced with the medicated solution. So the eye drop cannot be acidic.
- Tears can prevent any discomfort associated with use of medicines; most agents are weakly acidic (and have a weak buffering capacity). So patient is not able to prevent discomfort because they do not have tears and so eye drop cannot be overstimulating or acidic because they cannot prevent discomfort
Syrups
what is it
for non-medicated use, what is it used for
this vehicle (syrup) is meant to be added to what
how are medicated syrups prepared?
What are the two forms that it can come in
“Concentrated aqueous preparations of sugar (or a sugar substitute) with or without a flavoring agent and medicinal substances”
Non-medicated (flavored vehicles)
Intended Purpose:
Pleasant-tasting vehicles to be added to extemporaneously compounded preparations
To be added to the preparation of standard formula for medicated syrups (syrups containing medicinal agents).
Medicated syrups are commercially prepared from individual components (i.e., purified water, sucrose (the active substance in syrup), flavoring agents, coloring agents, therapeutic agents etc…).
can have medicated and non-medicated
syrups
how much alcohol does it have
what can be added to syrup and what must you be mindful of
what pH can the syrup medium be
what meds are usually used in syrup
Syrups contain very little (if any) alcohol so preferred by parents over other alternatives for their kids
If the drug is stable in solution it can be added to flavored syrup.
—Be mindful of unfavorable drug interactions
—what versatile drug substance
The syrup medium may be basic, acidic, or neutral, and should be selected with knowledge of drug stability in each. So can use syrup for any drug
The most frequently used medications in syrup form are,
Antitussive agents and Antihistamines
Opioid Analgesic
what is the active ingredient
what is the active ingredient’s concentration
what is it used for
Antihistamine, CHLOR-TRIMETON SYRUP OTC
what is the active ingredient
what is the active ingredient’ [ ]
what is it used for
Antiviral, NORVIR® (ritonavir)
what is the active ingredient
what is the active ingredient [ ]
what is it for
Antidepressant, Celexa (Forest)
what is the active ingredient
what is the active ingredient [ ]
what is it for
Opioid Analgesic, Demerol® Hydrochloride Syrup
Active agent: Meperidine HCL,
Concentration of active agent, 50 mg/5ml
For the treatment or relief of moderate to severe pain
Antihistamine, CHLOR-TRIMETON SYRUP OTC
Active agent: Chlorpheniramine maleate,
Concentration of active agent, 2 mg/5ml
For the prevention, treatment of allergic reactions
Antiviral, NORVIR® (ritonavir)
Active agent: Ritonavir
Concentration of active agent, 80 mg/ml
For the treatment of HIV
Antidepressant, Celexa (Forest)
Active agent: Citalopram hydrobromide
Concentration of active agent, 10 mg/5ml
For the treatment of depression (alternative to antipsycotic agents)
soothing, yummy taste, very stable over long period of time
Components of Syrups
what do syrups contain
what is not common to find in syrup
what can you add in low amounts and what thickness will it result compared to it in high amounts
what are the components of simple syrup and what is it considered to be
if you need to add antimicrobial preservatives or flavorants depends on what
for diabetic patients, what do you replace the sugar with
Most syrups contain:
- Purified water
- Sugar (usually sucrose)- typically 60 to 80%
—-Sorbitol, glycerin, and propylene glycol are all alternatives - Antimicrobial preservative?
- Flavorants?
- Colorants?
- Not uncommon to find the following in commercially prepared syrups,
—–Solubilizing agents, thickeners, stabilizers
add the low amount of sugar, will not be as thick compared to the high amount of sugar
simple syrup: 85 grams of sucrose to 100 mL of water, so much sucrose that it is a self-preservative
do I need antimicrobial preservatives or flavorants, depends on the amount of sucrose
For diabetic patients:
- replace sucrose with methyl cellulose to get the same viscosity but is tasteless then add artificial sweetener, this is equivalent to 60 to 80% sucrose
Preparation of Syrups
what are the 4 methods
- heat
- shake
- add
- percolation
One of 4 methods are generally employed,
- Solution of ingredients with aid of heat
- Solution of ingredients with agitation (no heat)
- Addition of sucrose to a prepared medicated (or to a flavored) liquid
1, 2 & 3 are preferred
- Percolation of either the source of the medicating substance or the sucrose. Ex. Ipecac syrup
Elixirs
what are they and are they usually flavored
if yes for what reason
what are non-medicated and medicated elixirs used for
are they easier to manufacture compared to syrups
are they as sweet as syrups
do they have a lot of sugar and what does it allow
what two componets in solution can it solubilize
what drug do you use when using an elixir
“Clear, sweetened hydroalcoholic (has water and alcohol) solutions intended for oral use, and are usually flavored to enhance their palatability.”
–Nonmedicated elixirs used as vehicles
–Medicated elixirs used to exert drug effect
Are easier to manufacture compared to syrups
Are not as sweet or viscous (thick) as syrups.
Contain less sugar, and so are less able to mask the unpleasant tastes of medicinal agents
Are capable of solubilizing both water-soluble and alcohol-soluble, components in solution.
use drug that is water soluble and low aqueous solubility– uh okay
what does the Amount of alcohol required to prepare an elixir depend on
The addition of several different drug agents will require what
what are common additives
what are used as substitutes to prepare elixirs containing a high alcohol content
what are elixirs that contain a high amount of alcohol considered
Due to high oil and alcohol content, where should elixirs be stored
what will happen if elixirs are not stored correctly
Amount of alcohol required to prepare an elixir will depend on water solubility of the medicinal agent
The addition of several different drug agents will require specific blending of alcohol and water to achieve the desired solution.
Glycerin, propylene glycol, colorants and flavorants are all commonly used additives
Artificial sweeteners (i.e., saccharin) are used as substitutes to prepare elixirs containing a high alcohol content. This is because sucrose is only partially soluble in alcohol and requires a lot more to achieve the same effect.
Elixirs containing high amounts of alcohol (10% – 12%) are “self-preserving” (not requiring the addition of antimicrobial agents).
Due to high oil and alcohol content, elixirs should be stored in tight, light-resistant containers and protected from excessive heat
–USP monographs provide standards for preparing Elixirs, but NOT formulas. The individual manufacturer can decide on the formula
if not stored correctly, like leaving the cap loose, then the alcohol can evaporate
Preparation of Elixirs
what are alcohol and water soluble drugs dissolved in
which is added to what, the water drug solution or the alcohol solution
why is it done that way
once the two mixtures are mixed, what happens
what often results from the separation
what is done if that happens
The agitation of components in solution (~ simple solution) and/ or admixture of two or more liquid ingredients
Alcohol-soluble drugs are dissolved in alcohol, and then
Water-soluble drugs are dissolved in purified water
The water drug solution is added to the alcohol solution (not the other way around). Why?
—When added In this order the highest alcohol content is maintained
Once the two mixtures have been mixed the desired solvent is added until the desired volume is achieved.
–Cloudy final mixture often results from the separation of flavorant oils in the reduced alcoholic solution.
If this occurs, the mixture sits (typically for a couple of hours) for the globules to coalesce. The formation of large globules makes for easier removal by filtration.
Elixirs
what is used to absorb an excess amount of oils
presence of what can assist with disolution of the solute and enhance ____
what is the downside of adding components
Talc is a frequently used filter which can absorb the excess amount of oils from the solution.
Presence of glycerin, syrup, sorbitol and propylene glycol in elixirs can assist with dissolution of the solute, and enhance stability.
The downside is the additionally added components will slow down rate of filtration due to the increased viscosity resulting from the addition of the 4 different components.
Tinctures
what does the high alcohol content allow for
because of all the alcohol, what must they be kept from
is it preferred by physicians and parents of kids
why is it usually stored in dark bottles
what does it sometimes have for disinfection
Alcoholic or hydroalcoholic solution preparations prepared from vegetable materials or chemical substances”
—Vary in terms of method of preparation, strength of active ingredient, alcoholic content, and intended use in pharmacy
Alcohol content: ranges from 15% to 80%
- The alcohol content protects against microbial growth and keeps alcohol-soluble agents in the solution
Due to high alcohol content, tinctures must be kept away from heat and tightly stopped.
Not preferred by physicians (or by parents of children) for the same reason.
Many of the components are light-sensitive so should be stored in light-resistant containers (protected from light). So usually in dark bottles
Examples, Opium Tincture, USP
highest alcohol content. compared to syrups (0%) and elixirs (10-12%)
sometimes has dye used for disinfection
Example of Tinctures
Vanilla Tincture, USP
*Vanilla, cut into small pieces
100g
*Purified Water
200mL
*Alcohol
207mL
*Sucrose, in coarse granules
200g
*Diluted Alcohol, a sufficient quantity
to make
1000mL
procedure:
Add Purified Water to the comminuted Vanilla in a suitable covered container, and macerate for 12 hours, preferably in a warm place.
Add Alcohol to the mixture, mix, and macerate for about 3 days.
Transfer the mixture to a percolator containing Sucrose, and drain.
Pack the drug firmly, and percolate slowly, using Diluted Alcohol as the menstruum.
Example of Tinctures
what can it be used for
how much iodine does it have
how much alcohol does it have
Iodine Tincture, USP
A tincture of iodine can be used to disinfect the area around an epidural catheter. Marks the area really well
Usually, between 2 and 7% Iodine is used
47% alcohol!
from tutor:
iodine is an inorganic molecule
adding it to a tincture will help it to dissolve because tinctures have a lot of alcohol
Sprays
what kind of solutions are they
what size are the droplets
where is it administered
what can it contain
why were one-way pump sprays developed
Why are one-way pump sprays are important?-
what must meds. for external use read
where must you not put a label
“Aqueous or oleaginous solutions (no alcohol, similar to syrups in regards to alcohol content) in the form of coarse droplets or as finely divided solids to be applied topically, most usually to the nasopharyngeal tract or to the skin.”
Often administered intranasally to relieve nasal congestion and inflammation
Often contain antibiotics, antihistamines
Can administer drugs systemically and quickly
—For example, Insulin, glucagon
One-way pump sprays were developed to deliver drugs to the nose. Used for prescription and non-prescription medications.
Why one-way pump sprays are important?-
Prevents drawback contamination of nasal fluids into the bottle after administration such as viral particles with the common cold.
Medications for external use to read: FOR EXTERNAL USE ONLY and keep out of reach of children make sure to put on be careful in lab
do not put a label on top of a label
Which agent will increase the hardness of a suppository when the incorporated drug lowers the melting temperature of the suppository base?
A
Ascorbic acid
B
Cetyl esters wax
C
Poly-ethylene glycol
D
Suspending agent
E
Emulsifying agent
B
Cetyl esters wax
stiffening agent!
Which of the following could the pharmacist do while filling the following prescription? *Salicylic acid 3g Sulfur 7g Lanolin 10g White petrolatum 10g Note: *Salicyclic acid = drug
A
Reduce the particle size to achieve non-grittiness
B
Place the ingredients on an ointment pill tile and mix with a spatula
C
Use an absorption base to incorporate liquid drug in an oleaginous base
D
All of the above
E
None of the above
- drug agent
** used in derm. prep
D
All of the above
topical application
for B: in the video: use an ointment slab
in oleaginous, there is no water
which of the following solvents is the most viscous
A
ethyl alcohol
B
propylene glycol
C
rubbing alcohol
D
dehydrated alcohol
E
purified water
B
Propylene glycol
CORRECT- GREAT JOB MICHELLE
it is the only one here that is viscous
can be glycerol but it is sweet and do not want for diabetic patients
viscosity
thickness etc
dosage form vs effectiveness
when should you not change the product
Note: If a drug has bioavailability Issues, or if patient has had success with a particular product in the past, product should not be changed without an understanding of behavior of the new product
on graph looks like solutions works a little better
Nonaqueous solutions
liniments
3 types
used for
solvents used
Liniments are nonaqueous solutions that can be alcoholic, oleaginous solutions, or emulsions, intended to be rubbed on skin.
there are two types:
- oleaginous with alcohol
- emulsions
1) Alcoholic-based liniments
—Counter irritant or if penetrating action is needed
2) Oleaginous liniments
- When massage desired; less irritating to the skin compared to alcoholic liniments
- The solvent may be almond oil, peanut oil, sesame oil cottonseed oil, or some volatile substance (i.e., wintergreen) or a combination of oil & volatile substance
3) Emulsion liniments
Emulsions are prepared first, and added to desired solvent
Linaments that are emulsions or contain insoluble matter must bear suitable labels such as
- SHAKE WELL (to distribute disperse phase)
Linaments should bear a label indicating
- for EXTERNAL USE ONLY
Vaginal Solutions
what is used to prepare solutions for vaginal douches - what are these used for
how can the thing used to prepare be packaged
- how are they used by the teaspoonful or tablespoonful
how is it prepared:
A measured amount of ____ is added to ___ _____, stirred, and _____
what is the purpose of vaginal douche’s
Powders are used to prepare solutions for vaginal douche, i.e., for irrigation cleansing of the vagina.
Powders can be prepared and packaged in bulk or as unit packages
—Bulk powders are used by the teaspoonful or tablespoonful to prepare solution
A measured amount of powder is added to warm water, stirred, and dissolved
The purpose is for their hygienic effects.
What do special solutions have?
do you understand why it would be a separate dosage form?
what are the specific sites of application
These solutions possess additional features making them better suited for ophthalmic, nasal, or otic use.
Based on Chapt. 13 (Solutions) and 14 (Suspension) lectures.
The specific sites of application are,
Ophthalmic Drugs
Nasal Preparations
Otic Preparations
Ophthalmic Drug Delivery
The normal volume of tear fluid in the cul-de-sac of the human eye is ~7 to 8 μl.
When an eye does not blink, it accommodates a maximum of 30 μl of fluid. When blinking it can retain ~10 μl.
Whether externally added or naturally produced, excessive liquids rapidly drain from the eye. Can only have so much there, issue: hard to deliver a good amount of drug to the eye
A single drop of an ophthalmic solution or suspension measures about 50 μl, so the majority of it gets drained.
The optimal volume to add is 5 to 10 μl.
—Unfortunately, the average dropper delivers ~25 to 50 μl/ drop, and other microliter dosing droppers do not exist
cannot be too small otherwise will poke eye
retention of solution
is the retention time for ophthalmic solutions long or short
how much of the dose administered is absorbed into the eye
example: how much of pilocarpine is flushed out of the eye
because of this, what needs to be done
what will improve the duration that the drug is exposed to the eye
what solution can be used and why
The retention time of ophthalmic solution on the eye surface is short.
The amount of ophthalmic solution absorbed is thus a small fraction of the dose administered.
For example,
- When pilocarpine ophthalmic solution is flushed from the eye within 1 to 2 minutes, the amount absorbed is <1%.
Due to the small fraction of absorbed drugs, repeated administration of solutions is required to achieve the maximum benefit of the therapy.
Increasing the viscosity of the solution will improve the duration that the eye is exposed to the drug, compared to when a less viscous substance is employed.
because methyl cellulose is tasteless and can be used in opth. solutions too
anatomy of eye
To minimize systemic absorption of active agents,what must you do
lacrimal gland
lacrimal sac
To minimize systemic absorption of active agents apply pressure to the lacrimal sac for 3 to 5 minutes following administration.
A recommendation to pharmacists: May be useful to inform patients using eye drops
Categories of Ophthalmic drugs
1) Anesthetics
2) Antibiotic and Antimicrobial agents
3) Antifungal agents
4) Anti-inflammatory agents
5) Antiviral agents
6) Astringents
7) Beta-adrenergic blocking agents
8) Miotics and other glaucoma agents
9) Mydriatics
10) Protectants and artificial tears
11) Vasoconstrictors
Sterility and preservation
which prep. must be sure to be sterilized
how is the sterilization don e
what is the benefit of filtration
what needs to be done if antimicrobial preservatives are to be added
how are they packaged if antimicrobial preservatives are not added
Ophthalmic preparations must be sterilized
Sterilization by bacterial filtration or by autoclave has been used.
The benefit of filtration is the removal of all particulate matter (microbial, dust, fibers) from preparation.
If antimicrobial preservatives are to be added, formulation stability, chemical and physical compatibility with other formulation components, and effectiveness must be determined.
–This is generally done at the preformulation stage
If antimicrobial preservatives are not added they are generally packaged in single-use containers.
Antimicrobial preservatives used,
are they always used or are there some limitations
can you autoclave chlorobutanol why or why not
Benzalkonium chloride, 0.004% to 0.01%
Benzethonium chloride, 0.01%
Chlorobutanol, 0.5%*
Phenylmercuric acetate, 0.004%
Phenyl mercuric nitrite, 0.004%
Thimerosal, 0.005% to 0.01%
There are limitations to their use,
For example,
It is not possible to autoclave chlorobutanol* due to instability when exposed to even moderate heat because the heat decomposes it to HCL
Review of Colligative Properties
what are they
what do the properties depend on
what do the properties not depend on
what happens when you increase solute
Physical changes that result when adding solute to solvent ( the properties will always change when solute is added to solvent)
- The properties depend on how many solute particles are present, and the solvent amount
- The properties do not depend on the type of solute, but rather the solvent type employed
increase solute: more and more changes
Colligative properties are,
Vapor pressure lowering
Boiling point elevation to a certain point
Freezing point depression, usually much greater
Osmotic pressure
Colligative properties continued: osmotic pressure
where does water flow
this happens until what
“Water flows through the semipermeable membrane to dilute the alcohol solution
until the force of gravity pulling down on the column of this solution balances the osmotic pressure, pushing the water through the membrane. “
Isotonicity Value
what is osmosis
what is osmotic pressure
the [ solution ] with respect to osmotic pressure is concerned with what
what is the concentration if the solute is not an electrolyte
what is critical for electrolytes
what do highly ionized substances do to particles
how does the number of particles effect pressure
Osmosis: The movement of water across a selectively permeable membrane from an area of high water potential (low solute concentration) to an area of low water potential (high solute concentration).
Osmotic pressure: the minimal pressure applied by a solution to prevent the inward flow of water across a semi-permeable membrane.
—The concentration of a solution with respect to osmotic pressure is concerned with the # of particles of solute in a solution.
If the solute is not an electrolyte, the concentration of the solution depends on the number of particles.
- For electrolytes, such as sodium chloride, the number of particles and degree of ionization are both critical.
- Highly ionized substances contribute a greater number of particles to the solution, compared to the same amount of poorly ionized particles- if more ionized then there will be higher pressure
So What?? The greater the number of ionized particles the greater the pressure
isotonicity and RBCs
body fluids like ___, have how much osmotic pressure corresonding to ___ of NaCl
what can the solution be considered because of this
what are hypotonic solutions defined as, what is the result
what are pertonic solutions defined as, what is the result
what is the range of isotonicity for ophthalmic solutions adn. without doing what
Body Fluids (blood and tears) have an osmotic pressure corresponding to that of 0.9% solution of sodium chloride.
–Therefore, the solution is ‘isosmotic’ (or having an osmotic pressure equal to physiologic fluids).
Solutions with lower osmotic pressure than body fluids (or 0.9% sodium chloride) are called hypotonic solutions. so less than 0.9%
–Hypotonic solutions may cause hemolysis of red cells
Solutions with higher osmotic pressure than body fluids are hypertonic.
–Hypertonic solution added to the body can draw water from cells toward the site of topical application, causing blood cells to shrink (crenate- crenation).
Isotonicity limits of an ophthalmic solution (in terms of sodium chloride) may range from 0.6% to 2.0%, that is without causing any discomfort.
Buffering
Why does a solution have to be buffered?
To achieve greater comfort to the eye
To render the formulation more stable
To enhance aqueous solubility
To enhance the drug’s bioavailability
To maximize preservative efficacy
do not want too acidic
pH and ophthalmic
what is the pH of normal tears
what can tears neutralize
what can tear prevent
when a drug is too acidic, what may happen
pH of normal tears is 7.4. Tears have a buffering capacity.
Tears can neutralize any excess hydrogen and hydroxyl ions introduced with the medicated solution.
Tears can prevent any discomfort associated with the use of medicines; most agents are weakly acidic (and have a weak buffering capacity).
When a drug is very acidic (i.e., pilocarpine hydrochloride, epinephrine bitartrate) it can overwhelm the natural buffering capacity of tears.
Viscosity and Thickening Agents
Viscosity: The force required to move one plane surface past another when the space between the surfaces is a liquid.
– Viscosity of water is given as 1 centipoise (1.0087cP).
A liquid material that is 10 times as viscous as water (at the same temperature) has a viscosity of 10 cP.
– The optimal range for ophthalmic use is between 15 to 25 cP.
Viscosity generally decreases with increasing temperature, so important to note temperature.
Methylcellulose
what does it do and for what kind of solution
what are hydroxypropyl methylcellulose and polyvinyl alcohol used for
Why is increasing viscosity important?
Methylcellulose is added to increase viscosity during the preparation of ophthalmic solutions.
–Hydroxypropyl methylcellulose and polyvinyl alcohol are often used as thickeners in ophthalmic solutions as well.
Why is increasing viscosity important?
- This helps to retain the drug in contact with the tissues to enhance therapeutic effectiveness.
- enhance duration of drug exposure
Packaging of ophthalmic solns
how are most packaged
what are the volumes of the containers that they usually are packaged with
what should patients protect ophthalmic solutions from and how will they do that
what are ophthalmic solutions that are packaged as eyewashes also packaged with
Most are packaged in small plastic containers with a fixed built-in dropper.
Ophthalmic solutions are commonly packaged in containers holding 2, 2.5,5,10, 15, and 30 mL of product.
Patients should protect ophthalmic solutions or suspensions from external contamination.
—Avoid the tip of the dropper from touching eyes or eyelids
Ophthalmic solutions used as eyewashes are packaged with eye cup, it must be washed and dried before use, and following each use.
what is a parenteral used for
what must the finished product be
what are pyrogens
To minimize systemic absorption of active agents as opposed to oral system which uses the systemic system to treat the illness - so parenteral will cause more localized absorption
A finished product must be
- Sterile,
- Non-pyrogenic*
- Free from insoluble materials
Pyrogens: “fever-producing organic substances from microbial
contamination”
Sterile conditions
what is used to administer sterile preparations via intravenous push or infusion systems and in what environment
where is this done
The syringe is used to administer sterile preparations via intravenous push or infusion systems
Positive
Flow hood
Intravenous route
what did Sir Christopher Wren do
Intravenous injection (I.V.) of drugs had its scientific origin in 1656 of Sir Christopher Wren who was an amateur scientist.
Injected wine, opium and other substances into dog veins and studied their effects
Drugs were administered to humans in 1662 but for some time were not used due to the occurrence of thrombosis and embolism in treated patients
Potential Problems
what do thrombus and embolus mean and what do they have to do with intravenous administration
when was the hypodermic needle introduced
Thrombus (blood clot)
embolus (traveling blood clot)
thrombus and embolus formation may be induced by intravenous administration.
These clots can lodge in a blood vessel and obstruct flow, and this happens when the needle comes in direct contact with the vessel wall
The Hypodermic needle was later introduced for injection of sodium chloride and glucose
Injections
what must injections be
what kind of drug action do we use it for
when do we use it for patients?
Should be sterile, pyrogen-free preparations
Used when rapid drug action is desired & when drug is ineffective by other routes
Used when patients are uncooperative or unconscious and when patients cannot tolerate medicine
Intravenous route
advantage
disadvantage
Advantage:
- Rapid action due to direct injection into the blood
Disadvantage:
- Once a dose has been administered it cannot be retrieved
what veins can be used to administer venipuncture?
what precautions must be taken at all times while giving venipuncture?
what volume of drugs may be administered intravenously?
what mL containers are used for IV infusion
what are the flow rates
superficial veins can be used for venipuncture
basilic and cephalic veins on the back of the hand and dorsal forearm are best for peripheral veins for IV therapy
Aseptic precautions must be taken at all times to avoid the risk of infection
Small and large volumes of drug solutions may be administered intravenously.
- 23 gauge size (for bolus injections)
- 18 gauge size (for continuous IV infusions)
1000 ml containers of solutions for IV infusion used frequently
Flow rates: 42-150 mL/hour and lower flow rates are used to maintain open infusion lines.
what sites are used for IVs
cephalic vein (on hand)
median cubital vein (on arm)
Intramuscular Route
how fast are the drug effects compared to IV
are drugs in suspension or solution more or less likely to be absorbed?
are drugs in aqueous or oleaginous more or less likely to be absorbed?
the physical type of preparation employed is based on what
Provides drug effects that are less rapid than intravenously administered substances, but generally longer lasting.
Drugs in solution are more likely to be absorbed than those in suspension.
Drugs in aqueous preparations are more rapidly absorbed than drugs in oleaginous preparations.
The physical type of preparation employed is based mainly on drug properties and therapeutic goals
Intramuscular Route
where should the point of injection be
what are injures related to
in adults, what site of injection is also used
what about for child, is that the same site of injection?
The point of injection should enter deep into the skeletal muscles, and must NOT come in contact with major nerves and blood vessels
Injuries are usually related to point of injection and where medication is deposited
(i.e., paralysis resulting from neural damage, scarring, abscess cysts)
In adults, the upper outer quadrant of the gluteus maximus is used for injection purposes
In children, the gluteus maximus
is composed primarily of fat (NOT muscle).
So……there is a chance of hitting the sciatic nerve, especially if the child is not cooperating. In these cases an injection of drug in the deltoid would be a suitable alternative
Intramuscular Route
is the dose limited or abundant?
how many mL can be administered in the gluteus vs the deltoid
injections are how deep
The dose administered is limited
5 ml is the maximum administered normally to the gluteus
2 ml is the maximum administered to the deltoid
Injections are 2 to 3 inches deep and a 20 to 22 guage needle is utilized.
Subcutaneous Route
what is this route suitable for
where are the injections applied?
This route may be suitable for small amounts of medication
Injections are to the…
- Loose interstitial tissue areas of the outer surface of the upper arm
- Anterior surface of the thigh
- The lower portion of the abdomen
- Site of injection rotates when the drug is administered daily as with daily insulin injections
Subcutaneous Route
the skin should be what
what the maximum injected volume
what size syringes are used
when should a new site be selected?
what substances are not suitable for injections
The skin should be thoroughly cleansed
The maximum volume injected comfortably is approximately 1.3 ml and slightly above.
2 ml is enough to cause painful pressure
Syringes with up to 3 ml capacities [24 to 26] gauges are used for this purpose
Insulin is administered using 25 to 30 gauge needles
Upon insertion of the needle if blood appears in the syringe a new site should be selected
Make NOTE: Irritating drugs and thick suspensions may be painful and so are not considered suitable for SC injections
Intradermal Route
where are the substances injected?
what substances are included
where is the usual site of injection
when is the injection made?
what needle size is used and what volume is best
Substances are injected into the corium (dermis). This is the more vascular layer of the skin located just beneath the epidermis
Substances include diagnostics agents and for purposes of immunization
The usual site for intradermal injection is the anterior surface of the forearm
The injection is made when the bevel just disappears into the corium
Needle size: 23 to 26 gauge
The volume injected: approximately 0.1 ml is the limit
Vaccines can be administered via the intradermal route, i.e. injection in the dermis,
Solvent and Vehicles
what solutions can be used as solvents and vehicles for injections?
Water for injection, USP
Sterile water for injection, USP
Bacteriostatic water for injection, USP
Ringer’s injection, USP
Small volume parenteral
what does a small-volume injection apply
are premixed IV delivery systems a thing, what is an example if it is
advantages of small volume parenterals
disadvantages of small volume parenterals
USP designation small volume injection applies to an injection packaged in containers labeled as containing 100 ml or less liquid.
–Premixed IV delivery systems are available for product administration
—Ex. of solutions, Digoxin (cardiotoxin) given IM or IV with carefully monitored dosage- “ready-to-use systems”
Advantages:
Require very little manipulation to make patient-specific
pH can range between 4 to 10
Disadvantages:
No flexibility in changing the volume or concentration
Thawing of the frozen drug product
High-energy microwave — water bath—- room temperature
Large volume parenteral
what are large-volume parenteral used for and what is the volume
What are examples of large-volume parenterals
when are these generally used?
what must you be aware of
USP designation for large volume parenteral applies to a single dose injection intended for IV use and packaged in containers labeled as containing more than 100 ml of liquid
Ex. Of solutions are,
Ringer’s injection, USP
Lactated Ringers injection, USP
Sodium chloride injection, USP
These are generally used for IV infusion to replenish body fluids or electrolytes or nutrition, and 100 ml to 1L is typically used.
Be aware of different issues with compatibilities.
–During compounding procedures
–During multiple infusions
Official types of Injections
According to the USP, all injectable materials are separated into 5 general categories
what are they
Injection
For Injection
Injectable emulsion
Injectable suspension
For injectable suspension
for injection, USP
what is it the most frequently used solvent for
how is the water treated
is it required to be sterile
what must it be free of at time of use
once product is prepared, what must be done to it
how should the water be collected and what are usually the containers
Most frequently used solvent in the large scale manufacturer of injections
Water used for injection is usually purified by distillation or reverse osmosis, and should be used within 24 hrs after collection
Not required to be sterile (free from all live bacteria and microorganisms)
Must be pyrogen-free (whatever organisms are present should not result in an infection or fever) at time of use.
Once product is prepared is must be sterilized.
Water should be collected in sterile and pyrogen-free containers, and the containers are usually glass or glass lined
Sterile water for injection, USP
how is the water treated and how is it packaged
what must it be and what must it not contain
what is water intended to be used as
what cannot be adminstered intravenously
what is suitable injection
what is tonicity
Water that is sterilized and packaged in single-dose containers of not more than 1-liter size.
Must be pyrogen-free and may not contain antimicrobial agents or any other added substances
Water is intended to be used as a solvent, vehicle or diluent for already sterilized and packaged injectable medications
One-liter bottles cannot be administered intravenously because they lack tonicity. These are used to reconstitute antibiotics.
—–Suitable injection: water is added directly to the medicinal substance such as with dry powders or granular substances
*******************
Tonicity: For our purposes, it is the osmotic pressure or tension of a solution, usually relative to that of blood
Bacteriostatic water for injection, USP
what kind of water is it and what does it contain
how is it packaged
what must the label state
in theory, the presence of bacteriostatic agent should allow what
what should not be a problem (in theory)
Sterile water for injection containing one or more suitable antimicrobial agents
Packaged in pre-filled syringes or in vials containing not more than 30 ml of water
Label must state proportion of antimicrobial agent to water used to prepare vial
In theory, the presence of bacteriostatic agent should allow for multiple-dose vials (use a single vial for multiple purposes)
—-Inadvertent contamination of vial during use should not be a problem (in theory).
Bacteriostatic water for injection, USP
what flexibility does it give
what causes it to be limited
how is it packaged
Large injected volumes of antimicrobial agents are what
when is bacteriostatic water for injection not preferred
what should you always think of
Gives the flexibility of multiple-dose vials because of presence of antimicrobial agents
The presence of antimicrobial agents in this water limits use of these vials to parenterals that are administered in small volumes only.
—-Packaged in prefilled syringes or vials containing ≤30 ml of the water
Large injected volumes of antimicrobial agents are toxic. For this reason, if volumes more than 5 ml of solvent is required, sterile water for injection is preferred over bacteriostatic water
You should also think about the compatibility issues regarding the interaction(s) of bacteriostatic agents and the medicinal drug substance
USP labeling requirementsfor use of bacteriostatic water**
what must labels state
what problems did it cause?
does it affect older infants, children or adults
Demands that labels must state the following,
“Not for use in newborns”
- Due to problems resulting from benzyl alcohol - which caused gasping syndrome which resulted in death :(.
- This caused problems to the liver when administered in mg/kg quantities; the limited detoxification capacity of liver in newborn infants was not sufficient to avoid toxicity
- The solution was/has not been reported to have such effects in older infants, children or in adults.
Benzyl Alcohol Poisoning
what is it also known as
how many premature infants developed this
what is the typical clinical course
how did the FDA respond to this
Benzyl alcohol poisoning (“gasping syndrome”)
One study reported that 10 premature infants developed this clinical syndrome characterized by multi-organ failure and eventually death
Typical clinical course:
Metabolic acidosis (decrease pH and bicarbonate conc. of body fluids), respiratory distress requiring mechanical ventilation, CNS dysfunction, apnea, seizure, coma and …… cardiovascular collapse and death.
In 1980 FDA said , stop the use of fluids preserved with benzyl alcohol for use in neonates for any purpose.
Ringer’s injection, USP
what is composed of
what are the ratios consistent with
what is it used as a vehicle for
what is lactate ringer’s injection, USP
- what is it used for
A sterile solution of sodium chloride, potassium chloride and calcium chloride in water for injection.
Ratios are consistent with physiological fluids.
Used as a vehicle for other drugs, alone, as an electrolyte replenisher and plasma volume expander.
Lactate Ringer’s Injection, USP:
—-Different quantities of the same salts used for Ringer’s injection + sodium lactate (used as an electrolyte replenisher and/or systemic alkalizer).
Nonaqueous vehicles
aqueous vehicles are preferred for what
when are non-aqueous vehicles preferred?
what must it not do
what are some examples
Aqueous vehicles are preferred for injection
nonaqueous vehicle is perferred for poor drug solubility in water (or drug is susceptible to hydrolysis)
Like water, must not exert pharmacological activity nor adversely affect activity of drug substance.
What are some examples,
Vegetable oil, glycerin, polyethylene glycols etc…….
Non-aqueous solutions
No single solvent is free from all what
what must the disadvantages and advantages be noted for
what is the fluidity of vegetable oil?
how are oleaginous injections administered, what if by another route what would happen
No single solvent is free from all limitations
Disadvantages and advantages should be noted to match the appropriate drug with the most appropriate non-aqueous solutions
Fluidity of vegetable oil: Proportion of vegetable oil, degree of unsaturated fatty acids to saturated variety
Oleaginous injections are administered intramuscularly, and must not be administered intravenously as the oil globules will occlude the pulmonary microcirculation
Methods of sterilization
what are the 3 main ones?
what are the 2 less common ones?
Steam
Dry Heat
Filtration
Others include sterilization by gas and ionizing radiation
Steam Sterilization
what does this method use
what is the temp. responsible for and not pressure
what is the pressure responsible for
how long will it take to sterilize
10 Ibs
15 lbs
20 lbs
what is the temp. that most autoclaves operate at
what can this be used to sterilize
what is it not useful for
This sterilization method uses steam under pressure.
Temperature is responsible for sterilization and not the pressure. The pressure is only responsible for increasing the temperature
10 lbs of pressure (115.5 ˚ C)-30 minutes
15 lbs of pressure (121.5 ˚C)-20 minutes
20 lbs of pressure (126.5 ˚C)-15 minutes
Most autoclaves operate at: 121 ˚C
May be used to sterilize bulk solutions, glassware, surgical dressings and instruments.
Not useful for oils, fats and oleaginous preparations
Dry Heat Sterilization
where can it be done?
how are the temps and sterilization times
how are the ovens heated?
what is it used for
Sterilization by this method is carried out in ovens
Higher temperatures and longer sterilization times
- 150 to 170 ˚C and not for less than 2 hrs.
Ovens are heated by gas or electricity
Used for sterilizing glassware, surgical instruments, oils, glycerin, mineral oil and heat-stable powders; for steam sterilization, cannot use oils, oleaginous or fats
I would rather use the autoclave which is usually used for 15 lbs items at 121* C for 20 minutes! which is much better than 2 hours for dry heat!
Sterilization by Filtration
- what does it involved
- what is used
- what are the advantages
- what are the disadvantages
is this system always perfect
This method involves the removal of all bacteria and spores with use of a 0.22 µm filter
Millipore Filter: plastic membrane with millions of uniform pores made of cellulosic esters
Advantage of filter units: Speed in filtration, relatively inexpensive and complete removal of living and dead microorganisms
Disadvantage of filter units: Proper inspection of filter unit is necessary to avoid using systems that are ruptured or faulty in some other way.
Systems can be flawed during assembly
Adsorption of drugs
where does this happen
what are example
what can an RPh do to prevent this from happenng
what does PVC stand for
This happens when drugs adsorb to inner lining of intravenous containers and tubing sets
Ex: [Diazapam, Insulin, Nitroglycerin, Warfarin sodium]
Ex: Nitroglycerin loss as much as 40 - 80% of dose to PVC
Pharmacists must prevent this from occurring
How? Administer infusions through short lengths of small-diameter tubing made of inert plastic
—for Nitroglycerin: use non-PVC tubing results in <5% loss
PVC = Polyvinyl chloride
Adsorption of drugs
Insulin adsorption
what factors effect the adsoprtion
how much insulin is lost
what is percent loss inversely proportional to and how long does it take
what is recommended concerning the patient
factors that effect it:
- Concentration of insulin
- Contact time of insulin with glass & tubing
- Flow rate of infusion
- Charged protein interactions
Up to 80% loss of dose, usually between 20-30%
Percent loss is inversely proportional to concentration and takes between 30-60 minutes
It is recommended that patient be monitored due to unpredictable nature of clinical situation
Handling and Disposal of Chemotherapeutic agents
what is needed
what is minimized with proper training
what kind of hood is used and what kind of glove is used
what must you wear on your face
how must you dispose of waste
what do personnel. who handle. cytotoxic drugs have to go through
what is put on labels and for what reason
Training and quality assurance programs needed
Minimize unnecessary exposure with these steps
Use laminar flow hoods or bacteriologic glove boxes for preparing reconstitution of cytotoxic drugs
Wear mask during preparation
Use special waste containers
Periodic monitoring of personnel who handle cytotoxic drugs
Informing personnel handling cytotoxic drugs of risk to health
Specialized labeling of containers to ensure proper handling and disposal of cytotoxic drug agent
Patient counseling tips for pharmacists
- maintain
- expiration and BUD
- disposal
- children
Instruct patient on proper storage and use of parenterals
Explain proper method of maintaining a sterile administration
site, and proper handling of any equipment.
3) Explain importance of expiration date and beyond-use
date of the dispensed parenteral product
4) Discuss correct disposal of parenteral preparations, needles,
syringes, tubing etc…
5) Explain importance of keeping the medication and supplies
such as needles/syringes out of the reach of children
flow of drugs- very systemic
what are the components of liver cells?
lungs
heart
tissues
some go to the gut then to liver
some go back to the heart directly from tissues
the flow that went to the liver meets up with the flow that went directly to the heart
liver cells have and what the function of each
- Kupffer cell - liver macrophages, remove foreign debris
- sinusoid - space between epithelial cells
- hepatocytes - liver cell
- basement membrane - membrane below
- fenestrations - pores
- tight junctions - junctions between cells
- lumen - space within
biologics cabinets
I
II
- A1
- A2
- B1
- B2
(I think)
III
What are Biologics?
what does it include
how does the code of federal regulations define
is it administered IV
HOW ARE THEY PREPARED AND WHAT MAKES BACTERIAL ONE DIFFERENT THEN THE VIRAL ONE
Defined as:
– Any substance produced by a living source.
– Biologics include antibiotics, hormones, vitamins, etc… Also known as immunobiology
- Code of Federal Regulations defines Biologics as:
“any virus, therapeutic serum, toxin, antitoxic, or analogous product employed for the prevention, treatment, or cure of disease in humans.” - kill living system and weaken them so they will not cause harm
Not administered IV
sterility is still important
Any proven benefits of using biologics?
what virus was first used
did the vaccine work and reduce the infection rates
During the 1950s, # of polioviruses ~20,000 cases
– Inactivated Polio vaccine- introduced in 1955 – Oral Poliovirus (OPV)- introduced in the 1960s
By the 1960s the # of polioviruses was ~3,000.
By 1979 the # of polio cases was ~10 in the U.S.
German measles (an acute viral disease) ~58,000 cases
– Rubella vaccine- introduced in 1969
By 1992 the # of infected individuals dropped to less than 500 per year
biologics can address a clinical unmet need
Natural Immunity
what are the three types?
what does each mean
Species Immunity
– Some diseases naturally occur in humans,
some in animals
- Racial Immunity
– Human races differ in general susceptibility to common infections
– not the same as environmental immunity which means a pop. recent to a place may be more susceptible to diseases - Individual Immunity
– Differences in capacity to resist familiar
diseases (i.e., common cold, skin disorders) - factors: smoker, alcohol, food, exercise –these can play a role
- person to person
Acquired Immunity Can Be Active or Passive?
what is active immunity?
what is passive immunity?
how to do T-Lymphocytes effect B-lymphocytes
Active immunity- body builds up its own defense against the antigen
- Passive immunity- introduction of antibodies produced in another individual (human or animal) into the host, who was not involved in the antibody production
- During this event T-lymphocytes augment the activity of B lymphocytes primarily involved in humoral immunity and antibody production, which helps individuals to resist infections the next time they are exposed.
Human antibody production
- B cell activation
Production of Biologics
what standards must be met?
which is important
if contaminated, what will happen
All biologics must meet standards as set by Center
for Biologics Evaluation and Research of the FDA.
* Tests must be performed to establish product, – Potency
– General safety
– Sterility
– Purity
– Water (residual moisture) – Pyrogens
– Identity
– Constituent materials -
important: potency and general safety
if contaminated: see color change, and bubbling but they take time to show themselves so we use BSC. Maintain stability and safety level
Production of Biologics
what do the packing include
what should be avoided?
Packaging and labeling requirements are similar to all other injectables
* Other packaging requirements include,
– Title or proper name (name under which the product is licensed under
Public Health Service Act)
– Name, address, license number of manufacturer
– Lot number and expiration date
– Recommended individual dose for multiple-dose containers
– Preservative type and amount
– Amount of product in the container
– Recommended storage conditions
– Statement that freezing is to be avoided (if necessary)
And, anything else the FDA believes to be important to ensure the safe and effective use of the product.
sometimes no preservatives
production of biologics
what is the range of freezer?
what does no freezing protect
when is the expiration date?
what is the exception
Majority of biologics are stored in refrigerator (2°C to 8°C)
– Generally no freezing of biologics which protects
* The active biologic material
* Expansion of aqueous material (because When water freezes, it expands and takes up more space) could result in expansion of glass and breakage and loss of product
Expiration dates are usually one year following the date of manufacture
- Exception: Some COVID-19 vaccines require freezing, exp. dates are also less than one year. See supplemental COVID-19 manufacturing details for this lecture
Storage, Handling, and Shipping of Biologics
what are they senstive to
what are the real potential dangers
what should pharmacist maintain
what should fridge not be and why
what is recommended as a result
Biologics are sensitive to extreme temperatures
– Heating or freezing can decrease potency and effectiveness
Real Potential Dangers:
– Patient gets little or no intended benefit.
- The patient does not build up immunity and is now exposed
Pharmacists should maintain the “cold chain”
– If you receive it from the manufacturer cold, keep it cold:
- Refrigerators should not be overstocked with products; cool air must have room to circulate
- A separate refrigerator for biologics is advisable, this will cut down on the number of times the refrigerator is opened and closed
What does World Health Organization say about refrigeration of Biologics?
how often should door be opened and how fast should doors be closed
where should pharmacists not store biologics
what should you out inside of door
where should vaccines be stored
where should coolant be stored and for what
National Immunization Program recommend for temp. monitoring
how long should you keep these logs
The door should not be opened frequently, no more than 4 times per day
- Doors should be closed as quickly as possible after securing the product
- Pharmacists should not use the inside of the door to store biologics, this contributes to temperature variations
– Inside of the door can be used to store diluents or bottles of water for better insulation - Vaccines should be stored in top or bottom shelves of the refrigerator due to temperature variations. Not floor
- Coolant packs should be kept in freezer and ready for use in shipping. They are handy to have if there are interruptions in freezing.
National Immunization Program recommends twice daily temperature monitoring and recording
– Logs of these temperature should be kept for 3 years
Storage, Handling, and Shipping (continued)
who should be trained?
what should be stored together and what does this reduce
what are look-alike and sound-alike packaging and should you be careful
for center for disease control, what are the issues
Pharmacists should educate and train every person who will handle biologics in good storage and handling procedures
Always store bottles containing the same vaccine material together. This will reduce chances of selecting the wrong product.
– “Look-alike packaging and sound-alike names can confuse even most conscientious practitioner”
* Center for Disease control issues on line publication describing storage and handling requirements for vaccines
Biologics for Active Immunity
what are the 3 types
What is the purpose of a vaccine?
does this happen immediatly
types:
Bacterial Vaccines
* Viral Vaccines
* Cancer Vaccines
purpose:
- A vaccine tricks the body into thinking an infection has occurred.
- A vaccinated person’s immune system attacks the harmless injected vaccine and then prepares for invasions against the same microbe the vaccine contained
needs time for production to occur
Bacterial Vaccines
what is it
is it a suspension (particles suspending throughout) or solution (no particles)
how it grown
what is it sensitive to
what do the ingredients need to be
after the bacteria is grown what happens next
how is inactivated vaccine produced
why centrifuge
what do you use when furthur purification is required
“A suspension (if not can lose potency) of attenuated (living) or inactivated (killed) microorganisms or fractions administered to induce immunity and prevent disease”
- Organism is grown in broth medium (amino acids, glucose etc)
- Temperature, pH and Oxygen tension-sensitive
- Chemically defined ingredients used to prepare broth medium
- Following bacteria growth the culture is processed in 2 steps: inactivated and live attenuated
Inactivated Vaccines:
– Produced by exposure to phenol or formaldehyde. For e.g.,
heat + phenol employed for typhoid fever vaccine.
– Next, organisms are separated from the medium through centrifugation (get rid of formaldehyde and phenol) and suspended (in sterile water or 0.9% sodium chloride) for injection.
– If further purification is required dialysis and special centrifugation methods can be used.
Bacterial Vaccines
how is live attenuated vaccine produced
what is done to DNA
what happens to the organism now
Live attenuated vaccine:
Produced by genetic alteration of pathogenic organisms
– Several base pairs of DNA are deleted (or altered).
– Organism is now incapable of reverting to pathogenic form
- Other methods to create vaccines do exist
Regardless of the method the vaccine may be
expressed as
– Total # of organisms,
– Total protective units per milliliter or dose, or
– Micrograms of immunogen in each milliliter, or in each dose of vaccine.
Viral Vaccine
do they grow like bacteria?
- What growth conditions have been used for viral propagation?- are all of them living
what is required
what must the final viral product contain?
Viruses grow differently from bacteria and thus require different media
- What growth conditions have been used for viral propagation?
– Embryonic egg,
– Cell cultures of chick embryo, – Monkey cell culture,
– Skin of living calves and
– Intact mice - Separation of the virus from the host cell is required
- Purification step required to reduce the incidence of hypersensitivity reactions to media or host cells
- The final viral product may contain a single or multiple immunogen(s) to elicit immunity against the disease
viral vaccine
what can they contain?
what is an example of it?
what is the standard practice?
what does that provide
what can communities have
The vaccine may remain as the entire virion or split into a subvirion vaccine:
The influenza virus vaccine is a subvirion vaccine and since 1977 it is prepared yearly using three different strains
– 1) HINI (Influenza A)
– 2) H3N2 (Influenza A)
– 3) Influenza B
- Vaccination with all three (trivalent influenza) is the standard practice.
– This provides partial protection against related strains, reducing risk of influenza-related complications & deaths
– Communities can have an outbreak of more than one strain of influenza
WHO changes 2 strains- since 2018-19 flu vaccine
The WHO recommends the following for the Northern Hemisphere’s quadrivalent (four-strain) vaccines:
- For H1N1, an A/Michigan/45/2015-like virus
- For H3N2, an A/Singapore/INFIMH/2016-like virus
*For B Victoria, a B/Colorado/06/2017-like virus
B Yamagata, a B/Phuket/3073/2013
- - For trivalent (three-strain) vaccine formulations, the group recommended including the Victoria lineage influenza B vaccine strain
Cancer Vaccines
what is the goal
how does it work
what does the vaccine increase
what immune cells have natural antitumor activity
what do cancer vaccines do to those cells and how
what are the two types of tumor vaccines (there’s a 3rd one but we really only focus on 2)
The goal is to increase the recognition of cancer cells by the immune system
An additional treatment modality
How do they work?
– Immune cells recognize foreign antigens on the tumor cells, and receive co-stimulatory signals as foreign to the body. Otherwise, tumor cells go undetected and proliferate.
The cancer vaccine increases
- antigen awareness of your immune cells, or increase co-stimulatory signals that induce an immune response
- so they increase the recognition that your immune system has for tumor cells; makes immune system recognize tumor cells more
Immune cells having natural antitumor activity are
- T cells
- Lymphokine-activated killer cells
- Natural killer cells.
Cancer vaccines stimulate these immune cells.
* Tumor-killing cells recognize tumor-associated antigens (TAA) on tumor cell surface.
Tumor Vaccines: Autologous, Allogeneic, Gene Therapy
Tumor Vaccines:
what is autologous
- where is the vaccine from
- can be shared between patients
- what is the disadvantage
- how are cells treated
what is allogenic
- what is injected and how
which one can more patients benefit from
Autologous –vs- Allogeneic
- autologous vaccines
- Derived from a tumor removed from a patient
– Biopsy, Surgery - Cells are killed or attenuated and reinjected into the patient
- has tumor antigen (TAA)
- Disadvantage:
– Cost
– No antigenic expression - so do not have immune system address tumor - patient-specific and the TAA will be raised against that tumor from that patient
allogenic vaccines
* Derived from cell lines that express tumor-specific or shared TAAs.
- To induce immune response- a fragment, or whole (attenuated) cell so admin. IM route
is injected into the patient. - Benefit is wider
population of patients
Administration and Toxicity Associated With Biologic Products
what can cause unwanted side effects?
what can demonstrate fewer side effects?
what are OTC meds used for
is there IV?
Traditional vaccines constituted by inactivated whole cells can cause unwanted side effects
- Use of selected antigens demonstrates fewer side effects
- Over-the-counter analgesic agents are often used to control,
– Itching, pain, and tenderness around the injection site (in connection with SubQ, IM, ID administration
– Analgesics are used only if they agree with the patient’s health status and other drug therapy
NO IV!
Administration and Toxicity Associated With Biologic Products
Hypersensitivity-anaphylaxis is a major concern, What can happen
are they common
Hypersensitivity-anaphylaxis is a major concern
– Bronchospasm
– Respiratory distress – Laryngeal edema
– Circulatory collapse – Death
1 in every 600,000 to 6.4 million doses of vaccine distributed
Because hypersensitivity reactions are so rare it’s not clear whether patients are allergic to proteins that make up the active antigenic portion of the vaccine, or the excipients (i.e., neomycin, gelatin, aluminum gels).
Thimerosol toxicity
what is it
what is it used for
who experienced a bad reaction to thimerosol and what was it
in what did the American Academy of Pediatrics (AAP) Committee on Environmental Health encourage pharmaceutical industry and government agencies to do
since 2001, is thimerosol used
what other guidelines were put in place
Thimerosal: A preservative used in many vaccines; vaccine perservative
Since 1930s, Thimerosol (49.6 w/v%) has been used in multidose vials
What went wrong and why?
* In children, metabolism of Thimerosol produced methyl
mercury and ethyl mercury resulting in neurotoxicity
- 1999, American Academy of Pediatrics (AAP) Committee on Environmental Health encouraged pharmaceutical industry and government agencies to reduce child exposure to mercury.
- Since 2001, very little (98% less) if any Thimerosol is used.
- Structure
- Issued guidelines for women of childbearing age to amounts of mercury that could be toxic
Biologics for Passive Immunity
what is passive immunity?
What are the two types
passive: injected
Human Immune Sera and Globulins (Homologous Sera)
* Antibodies derived from human blood.
* Produced as a result of having disease, or immunized against it with a specific biologic product
* Source is from pooled plasma of adults
* Must be free of hepatitis B antigen and antibodies to HIV
Animal Immune Sera (Heterologous Sera)
* Prepared by immunization of horses against specific immunogen (e.g., toxin, venom).
* After several injections over weeks/months horse is bled. Contamination must be avoided, and plasma harvested
* Precautions must be taken to ensure safety of patients sensitive to horse protein
Varicella Zoster
how many U.S citizens are immune
what is varicella virus vaccine intended for
what can those receiving vaccine do
when should you avoid it
when is it contraindicated
More than 95% of U.S. Citizens are immune to VZV.
- The varicella virus vaccine for adults is intended to cover those who have not had chickenpox, or those without a reliable clinical history of varicella infection
- Those receiving the vaccine may transmit the vaccine virus to close contacts
– Recipients should avoid close contact with high-risk individuals (Such as pregnant women, newborns, and immunocompromised individuals) - Avoid vaccination during pregnancy
– Women contemplating pregnancy should be counseled to avoid pregnancy within 4 weeks of vaccination - Varicella vaccination is contraindicated for use in patients with immunocompromising conditions
– (For i.e., HIV infections with CD4+ T lymphocyte count of 200 cells/μl)
toxins
what are the three types?
Botulinum Toxin Type A
- how is available and what must be done to it
- after then, within how many hours must it be used
- what should the final form look like
- how long can you store the open vials
Botulinum Toxin Type A
- what is it used for
- what is this toxin
Botulinum Toxin Type A
- what is it used for and for what age group
- what size needle used and to draw up how much material
- what is this toxin
(they all have the same name but do different things…lol
do you shake it up and down
Botulinum Toxin Type A
– Available as a powder for injection; reconstituted with sterile 0.9% sterile saline
– Must be used within 4 hrs following reconstitution
– Should be clear, colorless and free from particulate matter
– Unopened vials can store in refrigerator for up to 24 months.
Botulinum Toxin Type A (i.e, Botox)
– Used to decrease severity of pain associated with abnormal head position and neck pain associated cervical dystonia (CD).
- this toxin is botox
Botulinum Toxin Type A (i.e, Botox cosmetic)
– Used for temporary improvement in the appearance of moderate to severe facial frown lines in adult patients ≤65 year of age.
– 21 guage needle to draw up 0.5 to 2.5 ml of saline containing reconstituted material.
- this toxin is botox cosmetic
do not shake up and down
oooh…BOtulinum TOXin = BOTOX
Vaccination Advocacy From Pharmacists
How can pharmacists protect the public?
How can pharmacists protect the public?
Pharmacists can encourage,
– Formulary management
– Participate on infection committees, policy and procedure development
– Participation in administrative programs
– Patient history and screening
– Counseling and documentation
– Public administration and advocacy
All may not be possible but do what you can
alcohol
(Ethyl alcohol, ethanol, C2H5OH
a solvent
USP
Composition
94.9% to 96.9% ethanol
internal/external
- can be for external or internal
primary purpose
- primary solvent for organic compounds
- used for drugs not soluble in water (for its miscibility in water)
- help dissolve organic compounds to be mixed in water
diluted alcohol
solvent
NF
composition
- 50% alcohol
- 50% purified water
internal/external
- can be for external or internal
primary purpose
- useful hydroalcoholic solvent
- help to dissolve organic compounds
rubbing alcohol
USP
comp.
70% ethyl alcohol by volume
30% water, stabilizers, perfume oils, color additives, denaturants
intern/external
external
(educated guess, discourage oral by adding sucrose octa-acetate)
disinfectant (educated guess)
glycerin
USP
comp/
glycerin
Internal but can be for external too
- preservative
-stabilizer
isopropyl (rubbing?)
alcohol
USP
~70% isopropyl alcohol
the remaining amount is water, stabilizers, perfumes
internal/external
externally
but 91% can be internal
purpose
- To prepare diabetic needles and syringes for hypodermic injections of insulin, a commercially available ~91% isopropyl rubbing alcohol is used also.
- as *rubefacient and soothing rub vehicle for topical purposes.
propylene glycol
USP
comp:
propylene glycol
internal or external
purpose:
- Used as a solvent for flavors, extracts, drugs, and food antioxidants as well as a heat transfer medium
- Can substitute for glycerin in pharmaceutical formulations
purified water
USP
pure water
Internal or external
Used in the preparation of aqueous dosage forms (except for IV administered drug substances)
Class I: When do you use this type?
- personnel & environmental protection
- uses uncirculated inward air flow away from operator
Class II: When do you use this type?
- for personnel, product & environmental protection
- open front, inward air flow for personnel protection
- hepa flow downward air into work area for product protection
-hepa filter exhaust air for environmental protection
Class II Type A1: When do you use? How much air flow?
minimum in flow velocity of 75 ft per minute through work area access opening
- no suitable for work with volatile toxic chemicals and volatile radionuclides
Class II Type A2: When do you use? How much air flow?
– minimum in flow velocity of 100 ft per minute through work area access opening
- used for work with minute quantities of volatile toxic chemicals and tracer amounts of radionuclides required as an adjunct to microbio. studies
Class II Type B2: When do you use? How much air flow?
- minimum in flow velocity of 100 ft per minute through work area access opening
- work with for work treated with volatile toxic volatile toxic chemicals and tracer amounts of radionuclides required as an adjunct to microbio. studies
Class II Type B1: When do you use? How much air flow?
– minimum in flow velocity of 100 ft per minute through work area access opening
- for work treated with minute quantities of volatile toxic volatile toxic chemicals and tracer amounts of radionuclides required as an adjunct to microbio. studies if work is done in the direct exhaustive portion of the cabinet or if chemicals and radionuclides will not interfere with the work when recirculated in down flow air
What makes the class III type cabinet different from the rest?
It uses a totally inclosed ventilated cabinet with gas tight construction
- operations in the cabinet are conducted through attached rubber gloves
biologics or biosimilar
what is a biosimilar
are they more expensive
what does it facilitate
what are teh rgeulations
are they the same as biologics
are they identical
biosimilar is a biological product that is approved based on demonstrating that is it highly similar to the FDA-approved biological product, with no clinically meaningful differences in terms of safety and effectiveness from the original biological product
less expensive
facilitates access
state-by-state regulations
biosimilar is not the same as biologics
not identical but are similar
Human antibody production’
- B cell activation
where do B cells come from
how many B cells are there
what do they go through
B cells come from bone marrow
there are 3 types B cells but there are 10 billion different combinations
goes through:
- replication
- differentiation
- and turns to either memory cells or effector cells
one of the 10,000 will find the antigen and be a good fit for it and sends a signal that it is the one that fits best and then:
goes through:
- replication
- differentiation
- and turns to either memory cells or effector cells
memory cells: next time you have the infection it will recognize
effector cells are made 2000 per second
increase size of antigen and so macrophase can engulf them
1- foriegn antigen
2- B cell
3- replaicaion
6-
John was exposed to a foreign antigen for the second time, which cell type will accelerate the activation process this time around
A
Opsonins
B
Effector cells
C
Phagocytes
D
Epitopes
E
Memory cells
E
Memory cells
key: second time
refrigerator ina combination unit
what must you do
what must you not do
do
- place vaccine in breathable plastic
- spearate adult and child vaccines; group vaccines by age group
- spearate the VFC (vax for children) vaccine supply from privately purchase vaccine
- keep baskets 2-3 inches from walls and other baskets
- keep vaccines in their original boxes until you are ready to use them
- store only vaccine and other med invaccne storage
do not
- store on the floor
what are the 3 types of COVID?
Pfizer Vaccine
Moderna Vaccine
Janssen COVID-19 Vaccine:
Pfizer vaccine?
mRNA
lipids ((4-hydroxybutyl) azanediyl)bis(hexane-6,1-diyl) bis(2-hexyldecanoate)
2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide for mRNA stablity
1,2-Distearoyl-sn-glycero-3- phosphocholine, and cholesterol)
potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate - stable
sucrose for cryo protection and because it is frozen
very concerned with stability
acetic acid, maintain stability
Janssen COVID-19 Vaccine
sucrose not need because not frozen
Recombinant, replication-incompetent adenovirus type 26 expressing the SARS-CoV-2 spike protein, citric acid monohydrate, trisodium citrate dihydrate, ethanol, 2- hydroxypropyl-β-cyclodextrin (HBCD), polysorbate-80, sodium chloride.
Moderna Vaccine
mRNA
lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG]
cholesterol
1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate trihydrate, and sucrose.
is covid vaccine. safe?
no eggs
not latex
no preservatives
nothing in here that is a problem and is very safe, safer than all vaccines that we have known
how are the Pfizer, Moderna and Janssen covid vaccines stored
(1) Pfizer must be maintained at -70 degrees Celsius.
(2) Moderna can be shipped at -20 degrees Celsius, and can be comfortably stored in refrigerator units for up to 30 days after that.
(3) Jansen Covid-19 vaccine. Store unpunctured multi-dose vials of Janssen COVID-19
Vaccine between 2°C to 8°C. Protect from light. Do not store frozen. Vaccine is initially stored frozen by manufacturer, then shipped at 2°C to 8°C. If vaccine is still frozen upon receipt, thaw at 2°C to 8°C. Do not re-freeze once thawed.
for steam sterilization
- what are the 3 weights
- what are the temps
- what is the amount of time
weights (lbs), temps + time
- 10, 115.5*C , 30 min
- 15, 121.5 *C, 20 min
- 20, 126.5*C, 15 min
intravenous
anatomical site
needle gauge/volume used
purpose of the injection type
- cephalic vein on hand
- median cubital vein on arm
23 guage size (for bolus injections)
18 guage size (for continuous IV infusions)
- 100% bioavailability of med.
- rapid action due to direct injection into blood
intramuscular
- adults: gluteus maximus
- child: deltoid in arm
- 5mL for gluteus
- 3mL for deltoid
- injections are 2 - 3 inches
- 20-22 gauge needle is used
- less rapid but long lasting
subcutaneous
- upper arm
- thigh
- abdomen
- 1.3mL (not more the 2mL)
- 3mL syringe
- 24 - 26 gauge needle
- 25 - 30 gauge for insulin
for drugs administered daily like insulin
intradermal
- anterior surface of forearm
23 - 26 gauge needle
0.1mL volume
immunizations
Therapeutic benefits of NDDSs
Optimization of duration of action of the drug
- increase viscosity; for ophthalmic - importance for contact time
- absorb to the site and keep on-site; develop delivery system with high affinity for site for drug to stay there
- have more time of absorption
Decreasing dosing frequency
Controlling the site of release
Maintaining constant drug levels
on exam: think of why you want to use it
Improving drug efficacy
how can you design a system that will improve the Therapeutic benefits of NDDSs
Degradable bonds- bond that degrades in response to physio. system. Under pH 7.4, the complex stays in tact but at pH 6 (tumor of pH) then bond breaks and allows release of drug substance. Can get rapid or controlled release
Implantable drugs
- put drug in body and surgically close
- with timelike 3 months, the system will continously release the durg in resposne to either pH, osmotic pressure, time-release capsule
- after time, drug is released
- long polymers or shorter chains will impact the time in which is releases
- short chain: release faster
What are some potential problems associated with polymer use?
High molecular weight
- Slow permeability
- Delay excretion
Unfavorable Immunologic or toxic reactions
Expense associated with preparation
Long-Acting Parenteral Systems
Why have long-acting parenteral systems?
how is this accomplished
Why have long-acting parenteral systems?
- To extend rates of drug action following injection of the final product
- conjugate polymer to drug and administer it to patient: will extend circulation half-life, % of
blood will go up
In what ways is this accomplished?
- Slowly dissolving chemical complexes of drug entity
- Slow erosion of drugs encapsulated in microspheres
- Mechanically controlled-rate drug infusion pumps
Spinal Cord Stimulation therapy
For spinal cord stimulation (SCS)
(Implantable system
Interferes with pain signaling to the brain gets interrupted
- implant pulse generator by surgical op.
- signal pulses are released
- interfere with the pain signals to the brain
- last resort for pain (have even tried morphine)
- for chronic pain
- 50-75% of the pain pop. say they feel better
- no drugs released
For SCS therapy
(External system)
Patient can expect 50—75% pain relief
Intraspinal drug infusion therapy
how many doses can you give over time
how much does it weigh
how can drug be injected
what amount of doses does it require
what do patients report
what kind of flexibility does it offer
is it systemic, it is effective, how many side effects
are there electrical signals
what is implanted and what is released
- Can administer small doses over an extended period
- Weighs ~6 ounces
Drug can be injected into device from outside of the body - Requires smaller doses than with pills or IV
- Patients report fewer side effects and better pain relief
- Offers greater flexibility with matching dose with patient needs
- localized, more effective and little side effects
- no electrical signals
- implant a pump with a catheter and release small doses over time to area with pain
- not like a pill, very effective
- patients have tried other things
Gliadel Wafer Implant
- Sterile off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick.
- The wafers contain 192.3 mg of a biodegradable polyanhydride copolymer and 7.7 mg of carmustine.
- Designed to deliver carmustine directly into the surgical cavity created when a brain tumor is resected (cut out)
- Within 3 weeks more than 70% of the copolymer degrades not the drug. The polymer relases the drug in a controlled way over 3 weeks. Take away copolymer, just have carmustine - release quickly/immediate release
- if drug released right away, it is a issue because the residual cells have a doubling time and want drug to be there for doubling time, only works if cell is dividing. In G0 cell is resting and not dividing and spared the effects of the therapeutic drug. So any residual cells will be eradicating
- targets DNA replication in dividing cells
- brain tumor removed first
- this implant is for residual cancer cells that could still be dividing
Gliadel Wafer Implant
Overall patient survival:
- Median survival was 13.5 months with 20% survival at 2 years for Grade IV gliomas (more severe),
and …
- 57 months with 66% survival at 2 years for Grade III gliomas
- higher success rate for patients with less severe disease
more survived when condition was less severe than if condition was severe. Grade III survived more than Grade IV
Gliadel: Packaging, storage, handling
- Wafers designed as a single-dose treatment box as opposed to what…
- Each box contains 8 individually pouched wafers, all 8 is a single dose. Just 6 if you need 6
- Each wafer is double-pouched in foil, Inner pouch is sterile WHY make sure to stay sterile inside
- Must be stored at or below -20ºC, -20 is always
Introduction to Micelles
“Small clusters of molecules in which the nonpolar hydrocarbon groups are in the center, and the hydrophilic polar groups are on the outside.”
- not implantable, using detergents and lipids and polymers
Micelles
what do detergents in low concentration form
what do detergents in high concentration form
- Detergents at low concentration
in aqueous solution form a monolayer at the air-liquid interface. - no longer a monomer
- At higher concentrations,
detergent monomers aggregate
into structures called micelles
inside is sheilded in water
chemotherapy will be lipophilic feature
is a sphere
can make using skin
Introduction to Liposomes
- Spontaneously forming microparticulates used to deliver drugs, genes, proteins etc.. to target cells
- one of the very first drug delivery systems
- many other drug deliveries are modeled after this system
Liposomes are composed of small vesicles of a bilayer of phospholipids encapsulating an aqueous space
Both aqueous and bilayer compartments are capable of incorporating drug substances
Lipid structure and assembly
- Liposomes mimic the structure of biological membranes so biocompatiable
- In aqueous solutions lipids form organized structures by hydrophobic and hydrophilic interactions
- in membrane there is protein, lipids
lipids
what are the 4 types and their # of carbons and double bonds
what do double bonds effect
what two phases do double bonds result in
Myristoyl 14:0 (no kink)
Palmityol 16:0 (2 more carbons than myristoyl)
Stearyl 18:0 (2 more carbons than Palmityol)
Oleoyl 18:1 (one double bond)
polar head group - phosphate, glycerol backbone
hydrophobic tails - satrurated (straight) and unsaturated fatty acid (kink)
double bonds affect melting temp.
- has two phases of equal amounts,
- 50% gel phase
- 50% lipocrystaline phase
want more drug into bilayer portion of liposome, put into the. things that look like fingers lol
DPPC on right - larger so use to incorporate more drugs
DMPC on left
Influence of cholesterol in Liposomes
1) Adds firmness and integrity and stability
- retain drugs in the liposome better
2) Helps separate the phospholipids-
- orients into the bilayer
- if too high or too low then unfavorable
Orients similar to Sucrose
sucrose is a cryoprotetcant in vaccines
- sucrose also prevents mobility of chains by also going in between
- if you are freezing the vaccine then you do not want them moving around
- helps to protect
- not in Janssen because you do not freeze that one
REVIEW: Introduction to Liposomes
what is the nature of the phospholipids used to make liposomes
what is the tail composed of and how many carbons atoms make it up what end does it have
The phospholipids used to make liposomes are amphipathic, possessing both a hydrophilic (or polar) and a hydrophobic (non-polar) tail.
The tail is composed of fatty-acids containing generally 10 to 24 carbon atoms and a polar end that can interact with the aqueous environment
Quick REVIEW
Phospholipid chain length and head group, Why are both important?
Chain
14:0 (Myristoyl) 20 °C [saturated]
16:0. (Palmitoyl) 41 °C [saturated]
18:0 (Stearyl) 55 °C [saturated]
18:1 (Oleoyl) -20*C [unsaturated]
one double bond, then temp. goes to negative
-20*C with DOPC, there is still 50% gel and 50% lipocyrstalline phase
ex:
14:0, 14 is # of carbons, 0 is the # of double bonds
Phospholipid head groups: PC, PG, PE, PS etc….
Liposomal Therapeutics
what are the 2 goals
what substances are usually the most toxic
how much of the drug accumulates at the target site
goal: To reduce toxic side effects of agents in sensitive organs such as heart and kidneys, and to target diseased tissues.
Potent medicinal substances are usually the most toxic and so there is an urgent need for effective drug delivery systems.
Less than 5% of the injected drug accumulates at the target site, the remaining drug interacts with healthy host tissues.
Can you discuss major differences between liposomes and micelles?
they are pretty much the same thing except the liposome has a hollow pore that be used to put in drugs like Doxirubicin
liposome has an aqeuous internal compartment
micelle is closed
Liposomes are composed of a lipid bilayer separating an aqueous internal compartment from the bulk aqueous phase.
Micelles are closed lipid monolayers with a fatty acid core and polar surface, or polar core with fatty acids on the surface (inverted micelle).
Specific Application #1
lipoceutical vs. conventional vehicle with free active
how does lipoceutical compare with conventional vehicle with free active
lipoceutical
- better penetration
- permeation is greater with liposomal encapsulation
- eliminates irritation and optimizes dosage
- greater concentration and residue time in the epidermis and dermis for prolonged release
- protects encapsulated material from metobolic degradation
- reduces systemic absorption
conventional vehicle with free active
- less permeation
- has higher systemic adsorptio
How are novel drug delivery systems administered?
Parenterally
topically
inhalation methods
orally or possibly by other routes.
Intravenously
(chemotherapy)
Aerosol
particles
Cream
How are liposomes prepared?
what needs to be done to the cholorform that is in it
how is the solvent removed
how is the film then hydrated and what is the tem. of the buffer usually
what next has to be done to it
how is the size of the liposome controlled
- In general, a required amount of lipid is dissolved in chloroform [selection of lipid type is important]. Remove chloroform
- Solvent is removed usually with a rotary evaporator to form a thin film on the wall of a flask [selection of buffer is important]
- Film is then hydrated with a buffer of choice. The temperature of the buffer to be added to the lipid film is usually above the melting temperature of the dominant phospholipid used to prepare film.
- Vortex and heat and repeat sequence until lipid film has completely dissolved in the aqueous solution.
- Control liposome size using mini-extruder [their size is important]
Hyperthermia: Enhancing permeability of tumor vessels with heat
blood vessels in tumor become more permeable
the particle extravasate (flow out from the vessel that naturally contains it into the surrounding area - so leaves?) and move from intracellular to extracellulae space
heat
- make blood vessles more permeable
what Physiological barriers limit optimal delivery of drugs to solid tumors/slow down drug delivery to tumor
Wide range of vascular pore sizes - gap junctions are much wider in tumors
- tumor are quite permeable
Heterogeneous blood supply
- blood supply in tumor is irregular
some might be flowing, some flowing and some not
Irregular blood flow velocities (same as heterogenous)
- hard to depend upon
Elevated interstitial pressures - inside of tumor
- high pressure inside due to cells dividing inside
Long interstitial transport distances
- once drug in the tumor, takes a long time to get access to all of the cancer cells – a problem
elevated or high collagen content
- lots of collagen
- helps to impede the delivery and transport of drug once they get into the tumor
- blood vessles extravascate
targeting tumor vessels is an effective alternative to targeting cancer cells in tissue
what method is used to do this
liposomal therapeutics
Searching for the ‘magic bullet’.?
Conventional Liposome
- bilayer
- aqueous core
Stealth Liposome
- longer circulating in tumor due to PEG on surface
- Doxorubicin inside
- PEG absorbs water and protects contents of drug on the inside. Proteins do not come into contact with proteins in the blood and some into contact with PEG and circulate longer and will not be eliminated
- drug encounter blood, and the absorption allows for premature release
- stay in system for 3 days
carmustine - want drug to be present during doubling time
doxil - shows on NAPLEX
- PEG
- cholesterol
PEG (Stealth) liposomes (continued)
PEG on the outside
protecting liposome bilayer
doxorubicinn in the core (is this part of the long-acting release therapeutic like Gliadel wafer?)
Physicochemical Properties
what influences membrane fluidity
what is the cause of surface charge
what is the cause of steric stabilization
Lipid composition
Liposomal size
Membrane fluidity
- cholesterol
- degree of saturation
- have to do with tails; kink
Surface charge
- head group
Steric stabilization
(or stealth liposome technology)
- PEG
- liver, and spleen cannot eliminate it
DOXIL
Formulations incorporating doxorubicin have been developed to decrease the incidence of severe toxicity seen with the conventional formulation of doxorubicin, while taking advantage of the unique delivery properties of liposomes and the cytotoxic effects of doxorubicin.
Approved for treatment of
Aids-related Kaposi Sarcoma,
Ovarian cancer and many other
Solid tumor varieties
Liposomal Amphotericin B
what is this
why were lipid-based formulations developed
what form does it come and what is it for
Amphotericin B is an antifungal antibiotic.
Because of the many well-known side effects and certain dose-limiting toxicities associated with conventional amphotericin B,
lipid-based formulations were developed to increase the tolerability (e.g., decrease nephrotoxicity) of the drug without compromising its antifungal effects.
Ambisome powder for injection
which of the following should be altered to increase drug loading in liposomes
B - phospholipid hydrocarbon chain length (so more space to input drug because more carbons)
magic bullet
need time for healthy tissue to repair but also tumor is also repairing
we want more target and selective delivery that only selects for the tumor and not the health cells
how close are we to getting a magic bullet
