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68 Cards in this Set

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List 4 types of Modified-Release products?
1. Extended release formulations

2. Delayed-release formulations

3. Targeted-release formulations

4. "Controlled release" formulations
Why might drug-release time course or location be altered?
To achieve convenience or therapeutic objectives.
What do Extended-Release formulations allow?
They allow a two-fold or more reduction in dosing frequency.
What terms denote Extended-release formulations?
Drug marketers use terms such as "CD", "ER", "XL", and "SR".
What do Delayed-release formulations allow?
They allow the release of (a) portion(s) of the drug on a non-immediate basis.
What do Targeted-release formulations allow?
They allow the drug release at or near the physiologic site of action.
What do "Controlled-release" formulations allow?
Term previously used for all ORAL extended-release-rate dosage forms.
Name 3 unofficial terms for oral products?
1. Repeat Action

2. Prolonged-Action

3. Sustained-Release
What do repeat-action products do?
One dose is released initially, plus a second dose later on.
What do prolonged-action products do?
Drug is released slowly (not necessarily at a constant rate) to provide a continous supply over time to extend the reaction.
What do sustained-release oral products allow for?
There is an initial loading dose (ORAL), plus a slower constant drug release (maintenance dose calculated such that eliminated drug is replaced with little fluctuation).
List 4 advantages of Modified-Release Formulations?
1. Consistent Cp resulting in consistent clinical response, especially for drugs with short half-lives.

2. Circumvents fluctuation between Cmax (esp. if you don't want too high a Cmax) and Cmin, as occurs in multiple dose regimens.

3. Better patient compliance because of convenience.

4. Economic benefit (may cost less)
List 5 disadvantages of Modified-Release Formulations?
1. Not practical for drugs normally administered in high doses or that have a narrow therapeutic index.

2. Not practical for any drug with a long elimination half-life (unless the XR was very, very long)

3. Errors in drug release arising out of formulation errors can result in toxic Cp

4. Formulation errors can lead to incomplete absorption or drug release at the wrong site.

5. Economic downside (may be more expensive than a generic administered several times throughout the day)
Why are modified-release formulations not practical for drugs normally administered in high doses or with a narrow therapeutic index?
Because if the formulation fails all of the drug could be released.
Why might a modified-release formulation cost more?
Because of technology, marketing, etc.
List 10 means of extending release.
1. Put a tiny pore in a tab

2. Waxy matrix tablet

3. Coated pellets in capsule

4. Pellets in tablet

5. Leaching

6. Coated Ion Exchange

7. Flotation-Diffusion

8. Osmotic Delivery

9. Microencapsulation
How does a waxy matrix tablet formulation extend release?
The matrix is an almost insoluble medium so very little drug is released at a time.
How do coated pellets in a CAPSULE extend release?
Beads of drug have different coatings, so different release times.
How do pellets in TABLETS extend release?
They are lightly held together by a disintegrating agent.
How does leaching extend release?
Only allows slow release of drug from matrix.
How does coated ion exchange extend release?
Only released as it needs to be.
How does an osmotic delivery formulation extend release?
Some excipients (ex. gums) absorb moisture and swell. As the formulation swells it forces/squeezes drug out gradually.
Why are modified-release formulations always a challenge to make?
You have to be sure the rate of release is predictable.
The kinetics of ER dosage forms from a formulation is typically what order?
Zero order
Kinetically what are the goals of an ER product?
1. Smaller ka

2. longer tmax

3. lower Cmax

4. AUC is approx. the same as corresponding immediate release product (B/C we want the same exposure for the patient)
What does the total dose equal? (equation)
Dtot = Di + Dm

Dtot = total dose

Di = dose released initially (don't always have this)

Dm = maintenance dose (amt over time)
What does Dm equal?
Dm = (kr)(td)

kr = zero order rate constant for drug Release

td = Duration of drug release
XR formulations typically have a ? dose.
Typically have a higher dose.
Because of formulation limitation what may happen to Dm? How does this effect need to be taken into consideration?
The Dm (maintenance dose) may start releasing from time 0. The contribution sometimes needs to be subtracted from the Di to avoid "topping": Dtot = Di - (kr)(tp) + (kr)(td)

tp = time needed, following the initial dose, to arrive at peak plasma concentration.
What does R represent in equations?
R = elimination rate
If Dtot is too large it may be impractical to expect what?
For most patients to swallow the dosage form.
The greater the elimination half-life the ? the R should be.
The greater the elimination half-life the smaller the R should be. (so the longer the t1/2 the smaller the elimination rate is)
What is the relationship between k and t1/2?

smaller k = higher t1/2
What is the relationship between t1/2 and R?

higher t1/2 = smaller R
What is the relationshiop between k and R?
Higher k = Higher R

(because, smaller t1/2 = higher k = higher R)
Can an antibiotic be XR.
High t1/2 = ? R = ? total mg drug to achieve duration.
high t1/2 = low R = lower total mg of drug to achieve duration.

So a drug with an long half-life requires less of the drug to form an XR product then one with a smaller half-life.
What is the equation for Clt?
Clt = (k)(Vd)
What does k equal?
k = 0.693/(t1/2)
Do most XR products have an initial loading dose?
No, most do not. So Dm = Do and Dm = Dtot
What is "biotechnology" a reference to?
It is a reference to the use of biological material to create specific drug products (called biologic drugs or biopharmaceuticals).
What is required of a biopharmaceutical drug's structure?
It has to be accurate, reproducible (can be difficult to attain), and stable during manufacture, storage, and administration.
Most biopharmaceutical drugs are too unstable for what?
Oral delivery. (this is a challenge because the oral route is the most convenient)
Biopharmaceuticals are a ? ? class of drug.
Rapidly expanding class of drugs.
What are some examples of a biopharmaceutical?
Insulin, vaccines
What is recombinant technology?
An example of how biopharmaceuticals may be obtained.

1. A human gene is introduced into bacterium

2. Bacterium (ex. E. coli) expresses it

3. Then we take it and use it.
What category are protein drugs included under?
What do protein drugs include?
Certain hormones and interferons.
What are monoclonal antibodies?
Related to protein drugs. Their appeal lies in their highly specific binding to specific antigens. They can be used as a delivery system for biopharmaceutical drugs. Can be used for diagnostics or as therapeutic agents (to neutralize unwanted molecules or cells).
Why are biopharmaceuticals so large?
Because they need to be delivered with their biological 'machinery'.
What is gene therapy?
A type of biopharmaceutical. A biopharmaceutical delivers a recombinant gene to somatic cells in vivo to help restore a defective biological function.
What are some disadvantages of gene therapy?
1. Because promoter and other regions have to be included, the actual recombinant DNA (rDNA) delivered can be large (up to 20kb)

2. The need for sufficient and stable expression of the therapeutic protein for long enough

3. Safety
What can be used as a vector in biopharmaceuticals?
Plasmids can be used as vectors. They insert genes into plasmids and it will divide and express it.
What is a retrovirus?
RNA virus that inserts RNA into chromosome.
List 3 delivery systems for biopharmaceuticals?
(use vectors)

1. Viral

2. Non-viral

3. Ex-vivo administration
How does a viral delivery system work?
Viral replicative genes are replaced with the transgene in the viral particle.
How do non-viral delivery systems work?
Vectors such as plamids may be used.
How do Ex-vivo administration delivery systems work?
Consist of ex vivo administration, followed by a return of the cells back into the patient.
What are the reqts of delivery systems for biopharmaceuticals?
1. Vector must effectively enter target cell

2. Gene should be stably expressed in cells

3. The vector as well as the protein should not cause immune rxns (should not be rejected)
What are some disadvantages of biopharmaceutical delivery systems?
1. Difficult to control amt

2. Physicochemical properties and stability of DNA and RNA

3. Rapid degradation from body

4. Bioavailability, distribution and uptake may present problems.
What are antisense drugs?
(a biopharmaceutical)

Oligonucleotides (strand of nucleotides, ex. ACTG) that bind complementary mRNA sequences to block translation. Chemical modifications are made to enhance the stability of the drug.
What are two disadvantages of Antisense drugs?
1. Disease etiology has to be well understood

2. Uptake is low enough to require the use of delivery agents

(there are not many of these drugs yet)
List 4 delivery agents of biopharmaceuticals?
1. Polymeric carriers and conjugates

2. Albumin

3. Lipoproteins

4. Liposomes
What are liposomes?
A delivery agent that has a aqueous interior and a lipid bilayer exterior. The interior contains the drug. You can determine where in the body it goes by the lipid you choose to use.
What two different things can be done with monoclonal antibodies?
1. Can be incorporated into liposomes to target a specific target

2. Can stand on their own as a vector
What are used to improve the delivery of biopharmaceuticals?
Conjugates, nanoparticles, viral vectors, and liposomes.
Why are the kinetics of viral gene delivery systems difficult to measure?
Because of low doses and inefficient transgene expression. (we are not sure about doses and efficiency of expression once a vector is introduced)
Why would polyethylene glycol (PEG) be incorporated into liposomes?
To help evade phagocyte detection. It can reduce the Vd and increase the half-life or certain drugs. In other words, you keep it in the blood stream longer and it is not absorbed into tissues (thus lower Vd) and it takes longer to get rid of (thus longer t1/2)