pharmaceutics final exam - clinical Flashcards
Regarding the lecture on Liver Metastases from Colorectal Cancer: Drug Delivery with liposome-encapsulated doxorubicin
Liposome Composition used:
What composition should have been used in the liposomal doxorubicin, and Why?
Liposome Composition used:
-Dox-SL
DSPC/Chol/PEG (45% DSPC/50% Chol/5% PEG )+Dox
DSPC/Chol/PEG = composition
(45% DSPC/50% Chol/5% PEG ) = ratio
- what is the best component to use, and in what ratio to achieve the greatest targeting
chart of lipid type, charge, degree of saturation, uptake, and toxicity
DMPC - electroneutral (due to zwitterion, have a positive and negative portion), saturated, uptake: +, toxicity: +
DPPC - electroneutral (due to zwitterion, have a positive and negative portion), saturated, uptake: +, toxicity: +
DSPC - electroneutral (due to zwitterion, have a positive and negative portion), saturated, uptake: +, toxicity: +
DOPC - electroneutral (due to zwitterion, have a positive and negative portion), unsaturated, uptake: +, toxicity: +
DOPG - anionic, unsaturated, uptake: +, toxicity: +
DOTAP - cationic, unsaturated, uptake: ++, toxicity: ++
DOTMA - cationic, unsaturated, uptake: +++, toxicity: +++
uptake: intended target cell population
1 + = uptake not that high
2 + = more uptake
increase uptake, increase toxicity too :(
need to balance uptake with toxicity
cholesterol: make more stable etc (go over)
cholesterol: the # is the MW
PEG-2000
PEG-5000
PEG-1000
higher the MW = longer circulation half-life
want longer extended circulation si can use more PEG. 5000 ciruclates longer, so can use less ~ this is beyond the exam tho :)
figure of the percentage of polyethylene glycols remaining in the circulation as a function of their size
you have a drug agent
can conjugate PEG of those drugs to PEG
170 is the highest
170 has the highest amount in the blood over time
6 has the lowest amount in the blood
no PEG means the drug will clear much sooner, more PEG will allow you to circulate the drug for longer
PEG does not affect the intrinsic properties of the protein or drug, will increase or enhance the circulation half-life
reducing and conjugating drug to PEG, then less is taken up by some organs like the liver, lung, and spleen (RES system)
prevent the protein from absorbing to the drug, PEG puts a barrier between protein (the receptors of the RES system that will allow the PEG to be taken up) and the drug
Generic Medicines:
how should the generic drug compare to the brand name?
A generic drug should be identical or bioequivalent to the brand name in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. Anything else????
Chemical equivalence -vs- therapeutic equivalence?
Generics: A question of quality
Equivalence of generics may be thought of at two different levels
what are these two levels
Equivalence of generics may be thought of at two different levels
Chemical equivalence
- Dosage forms containing the same amount of the same drug in similar dose forms
Therapeutic equivalence
- Medicines having the same bioavailability and same clinical effects
- bioavailability: area under the curve, you are looking to see the % of drug that remains after time like 1 hour, 24 hr, 48 hr, etc. What is the amount that is left after 24 hours of the generic and the brand, are they the same or different
- we also look at absorption, and one could absorb faster after 15 minutes than another but then level off after 24 hours, and this difference is important!
similar within a range,
generic is compared to the brand leader and not generic compared to other generics
Regulatory statements on generic products
All generics should,
- Contain same active ingredients as innovator drug (inactive drug, like excipients, may vary)
- Be identical in strength, dosage form, and route of administration
- Have the same use indication
- Meet the same batch requirements for identity, strength, purity, and quality
- Be manufactured under the same cGMP requirements
What is an early indicator that the dilution of a parenteral intended for IV administration is unsafe to administer?
what may you consider that it may be unsafe
Considerations
- What is the solubility of the drug? In what?
- Is pH required to achieve solubility?
- Any electrostatic interactions?
- Under what conditions could precipitation occur?
- Some knowledge of the solubility of acidic and basic drugs could help
the drug may be fine in a syringe or bag but may not be in the body so need to make sure they are similar at physiological pH and at the bench. Just change the pH in the test tube – this is an early formulation to work out
We know that excipients are beneficial, but is it right to assume that they are always inert?
- We should note that the formulations of some branded products differ depending on the country of source.
- Clinical papers are not always specific about the formulation of drugs used thus making the interpretation of literature somewhat difficult
- Are there clinical situations where patient populations have been affected by the excipients used in the finished formulation?
- yes :(
Adverse effect of Dyes and Colorants
Tartrazine
E 102; or FD&C Yellow 5
Synthetic yellow azo dye found in soft drinks, chips, popcorn and cereals
One of the most widely used food and cosmetic colorant
Most allergic and intolerance reactions of all dyes
Adverse effect of Dyes and Colorants
Brilliant Blue
E133; FD&C Blue No. 1
Commonly in food, shampoos cosmetics
Used in popsicles, soft drinks, jell-o,
canned peas and in combination with other food colors/dyes
FDA issued a public health advisory because of side effects- blue-tinged skin, urine, and feces, hypotension and death in some situations. FOX NEWS-”New Fears about Food Dyes”
Should the formation of eutectic mixtures always be avoided?
EMLA
- Contains 50/50 (Lidocaine/ Prilocaine)
- Used to prevent pain of injection or catheter insertion
Lidocain base (66 -69 ºC)
Prilocaine base (36 - 30ºC)
Lidocain base + Prilocain base (16 ºC) - like a liquid at room temp. Lower melting temp. compared to using each of the drugs individually
lowering of the melting when you place the drug together is quite helpful
Result:
- An oil-in-water (o/w) emulsion where the dispersed phase is the drug can be formulated as a cream, or as a patch
Excipients found in EMLA
Each gram of cream contains:
Lidocaine 2.5% w/w (25 mg)
Prilocaine 2.5% w/w (25 mg)
Excipients:
Polyoxyethylene hydrogenated castor oil (19 mg).
*Carbomer 974P (emulsion stabilizer)
Sodium hydroxide (for pH adjustment)
Purified water - the continuous phase
*any of a variety of polymers of acrylic acid
Adverse reactions reported for excipient use
Preservatives
Sweeteners and Flavorings
Dyes and colorants
Preservatives in pediatric medicines
Antimicrobials and antioxidants
Commonly used antimicrobial agents are:
- Chorbutol, benzyl alcohol, sodium benzoate, sorbic acid, parabens, benzalkonium chloride
Commonly used antioxidants are:
- Butylated hydroxytoluene, propyl gallate and sulfites
Benzalkonium Chloride
Benzalkonium Chloride is/was used in many nasal sprays and metered dose inhalers
In some asthmatic patients, the excipient has caused significant bronchoconstriction.
Zhang and colleagues studied 28 asthmatic patients and reported a significant decrease in pulmonary function tests after benzalkonium chloride administration.
The most significant effect on pulmonary function was observed 1 minute following administration lasting up to 60 minutes.
Concomitant administration of cromolyn blocked the effect, suggesting an allergic mechanism.
Sweeteners and Flavorings
In a study conducted by Kumar et al., more than 90% of products evaluated contain both sweeteners and flavorings
The high number reflects society’s need for medications to look and taste appealing.
Clinicians and pharmacists should note that taste perception changes with age - patient compliance
For i.e., a sweet taste is preferred by infants.
- However, individual differences in tastes develop throughout life and are influenced by such factors as feeding experiences and genetics
What are the implications for therapy?
Teens who are unable to swallow tablets and capsules may prefer to Take medications in a liquid dosage form.
This is problematic if liquids containing large amounts of Artificial
Sweeteners can leave bitter aftertastes resulting in decreased patient Compliance.
Long-term use of oral medications containing large amounts of Sweeteners has been linked to dental caries in children. For i.e., Sugars (-sucrose) can cause a decrease in dental plaque pH, dissolving tooth enamel and promoting dental carcinogenesis. If used, parents should instruct children to rinse mouth with water after each dose
Dyes and colorants
Dyes and other coloring agents are used to improve a product’s appearance and provide unique identity
Most oral liquid dosage forms contain between one and three different dyes
Some parents and clinicians have suggested a link between dyes and hyperactivity and aggressive behavior in children.
Confirmed adverse reactions include, anaphylaxis, bronchoconstriction, angioedema, abdominal pain and vomiting.
Sensitive patients should be advised to use dye-free preparations when purchasing non-prescription medications
The Bottom Line-
“There are six artificial food dyes that are approved by both the FDA and the *EFSA. Red 40, Yellow 5, and Yellow 6 are the most common.”
*EFSA= European Food Safety Authority
“Some artificial food dyes, particularly Blue 1, Red 40, Yellow 5 and Yellow 6, may cause allergic reactions in sensitive individuals.”
“Food dyes are likely not dangerous for most people, but avoiding processed foods that contain dyes can improve your overall health.”
“Most whole foods are highly nutritious and naturally free of artificial dyes.”
Take Home message: USE YOUR BEST JUDGEMENT! :)
Which of the following was the most ineffective route for the administration and delivery of liposomal doxorubicin, as reported in the Liver metastases study performed by Osman Cay, MD, and colleagues?
A
Intravenous
B
Intra-portal
C
Intra-arterial
D
Intradermal
A
Intravenous
As reported in the same study, what organ tissue environment are CX-1 cells derived from?
A
Lung
B
Spleen
C
Liver
D
Colon
D
Colon
colorectal cells are injected into the spleen and metastasized to the liver
solubility considerations
a query raised by a nurse on Levaquin (levofloxacin) and lasix (furosemide)
will the drug be ionized or unionized with physiological pH
if unionized then it will most likely precipitate and not be absorbed
if it does this then it forms needles
for IV Push - it will not work so they use filters to catch this
electrostatic
