Kinetics: Lecture 13: Kinetics Of Modified Release Products And Biopharmaceuticals

Front 1

List 4 types of Modified-Release products?

Back 1

1. Extended release formulations

2. Delayed-release formulations

3. Targeted-release formulations

4. "Controlled release" formulations

Front 2

Why might drug-release time course or location be altered?

Back 2

To achieve convenience or therapeutic objectives.

Front 3

What do Extended-Release formulations allow?

Back 3

They allow a two-fold or more reduction in dosing frequency.

Front 4

What terms denote Extended-release formulations?

Back 4

Drug marketers use terms such as "CD", "ER", "XL", and "SR".

Front 5

What do Delayed-release formulations allow?

Back 5

They allow the release of (a) portion(s) of the drug on a non-immediate basis.

Front 6

What do Targeted-release formulations allow?

Back 6

They allow the drug release at or near the physiologic site of action.

Front 7

What do "Controlled-release" formulations allow?

Back 7

Term previously used for all ORAL extended-release-rate dosage forms.

Front 8

Name 3 unofficial terms for oral products?

Back 8

1. Repeat Action

2. Prolonged-Action

3. Sustained-Release

Front 9

What do repeat-action products do?

Back 9

One dose is released initially, plus a second dose later on.

Front 10

What do prolonged-action products do?

Back 10

Drug is released slowly (not necessarily at a constant rate) to provide a continous supply over time to extend the reaction.

Front 11

What do sustained-release oral products allow for?

Back 11

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).

Front 12

List 4 advantages of Modified-Release Formulations?

Back 12

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)

Front 13

List 5 disadvantages of Modified-Release Formulations?

Back 13

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)

Front 14

Why are modified-release formulations not practical for drugs normally administered in high doses or with a narrow therapeutic index?

Back 14

Because if the formulation fails all of the drug could be released.

Front 15

Why might a modified-release formulation cost more?

Back 15

Because of technology, marketing, etc.

Front 16

List 10 means of extending release.

Back 16

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

Front 17

How does a waxy matrix tablet formulation extend release?

Back 17

The matrix is an almost insoluble medium so very little drug is released at a time.

Front 18

How do coated pellets in a CAPSULE extend release?

Back 18

Beads of drug have different coatings, so different release times.

Front 19

How do pellets in TABLETS extend release?

Back 19

They are lightly held together by a disintegrating agent.

Front 20

How does leaching extend release?

Back 20

Only allows slow release of drug from matrix.

Front 21

How does coated ion exchange extend release?

Back 21

Only released as it needs to be.

Front 22

How does an osmotic delivery formulation extend release?

Back 22

Some excipients (ex. gums) absorb moisture and swell. As the formulation swells it forces/squeezes drug out gradually.

Front 23

Why are modified-release formulations always a challenge to make?

Back 23

You have to be sure the rate of release is predictable.

Front 24

The kinetics of ER dosage forms from a formulation is typically what order?

Back 24

Zero order

Front 25

Kinetically what are the goals of an ER product?

Back 25

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)

Front 26

What does the total dose equal? (equation)

Back 26

Dtot = Di + Dm

Dtot = total dose

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

Dm = maintenance dose (amt over time)

Front 27

What does Dm equal?

Back 27

Dm = (kr)(td)

kr = zero order rate constant for drug Release

td = Duration of drug release

Front 28

XR formulations typically have a ? dose.

Back 28

Typically have a higher dose.

Front 29

Because of formulation limitation what may happen to Dm? How does this effect need to be taken into consideration?

Back 29

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.

Front 30

What does R represent in equations?

Back 30

R = elimination rate

Front 31

If Dtot is too large it may be impractical to expect what?

Back 31

For most patients to swallow the dosage form.

Front 32

The greater the elimination half-life the ? the R should be.

Back 32

The greater the elimination half-life the smaller the R should be. (so the longer the t1/2 the smaller the elimination rate is)

Front 33

What is the relationship between k and t1/2?

Back 33

Inverse,

smaller k = higher t1/2

Front 34

What is the relationship between t1/2 and R?

Back 34

Inverse,

higher t1/2 = smaller R

Front 35

What is the relationshiop between k and R?

Back 35

Higher k = Higher R

(because, smaller t1/2 = higher k = higher R)

Front 36

Can an antibiotic be XR.

Back 36

Yes

Front 37

High t1/2 = ? R = ? total mg drug to achieve duration.

Back 37

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.

Front 38

What is the equation for Clt?

Back 38

Clt = (k)(Vd)

Front 39

What does k equal?

Back 39

k = 0.693/(t1/2)

Front 40

Do most XR products have an initial loading dose?

Back 40

No, most do not. So Dm = Do and Dm = Dtot

Front 41

What is "biotechnology" a reference to?

Back 41

It is a reference to the use of biological material to create specific drug products (called biologic drugs or biopharmaceuticals).

Front 42

What is required of a biopharmaceutical drug's structure?

Back 42

It has to be accurate, reproducible (can be difficult to attain), and stable during manufacture, storage, and administration.

Front 43

Most biopharmaceutical drugs are too unstable for what?

Back 43

Oral delivery. (this is a challenge because the oral route is the most convenient)

Front 44

Biopharmaceuticals are a ? ? class of drug.

Back 44

Rapidly expanding class of drugs.

Front 45

What are some examples of a biopharmaceutical?

Back 45

Insulin, vaccines

Front 46

What is recombinant technology?

Back 46

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.

Front 47

What category are protein drugs included under?

Back 47

Biopharmaceuticals

Front 48

What do protein drugs include?

Back 48

Certain hormones and interferons.

Front 49

What are monoclonal antibodies?

Back 49

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).

Front 50

Why are biopharmaceuticals so large?

Back 50

Because they need to be delivered with their biological 'machinery'.

Front 51

What is gene therapy?

Back 51

A type of biopharmaceutical. A biopharmaceutical delivers a recombinant gene to somatic cells in vivo to help restore a defective biological function.

Front 52

What are some disadvantages of gene therapy?

Back 52

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

Front 53

What can be used as a vector in biopharmaceuticals?

Back 53

Plasmids can be used as vectors. They insert genes into plasmids and it will divide and express it.

Front 54

What is a retrovirus?

Back 54

RNA virus that inserts RNA into chromosome.

Front 55

List 3 delivery systems for biopharmaceuticals?

Back 55

(use vectors)

1. Viral

2. Non-viral

3. Ex-vivo administration

Front 56

How does a viral delivery system work?

Back 56

Viral replicative genes are replaced with the transgene in the viral particle.

Front 57

How do non-viral delivery systems work?

Back 57

Vectors such as plamids may be used.

Front 58

How do Ex-vivo administration delivery systems work?

Back 58

Consist of ex vivo administration, followed by a return of the cells back into the patient.

Front 59

What are the reqts of delivery systems for biopharmaceuticals?

Back 59

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)

Front 60

What are some disadvantages of biopharmaceutical delivery systems?

Back 60

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.

Front 61

What are antisense drugs?

Back 61

(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.

Front 62

What are two disadvantages of Antisense drugs?

Back 62

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)

Front 63

List 4 delivery agents of biopharmaceuticals?

Back 63

1. Polymeric carriers and conjugates

2. Albumin

3. Lipoproteins

4. Liposomes

Front 64

What are liposomes?

Back 64

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.

Front 65

What two different things can be done with monoclonal antibodies?

Back 65

1. Can be incorporated into liposomes to target a specific target

2. Can stand on their own as a vector

Front 66

What are used to improve the delivery of biopharmaceuticals?

Back 66

Conjugates, nanoparticles, viral vectors, and liposomes.

Front 67

Why are the kinetics of viral gene delivery systems difficult to measure?

Back 67

Because of low doses and inefficient transgene expression. (we are not sure about doses and efficiency of expression once a vector is introduced)

Front 68

Why would polyethylene glycol (PEG) be incorporated into liposomes?

Back 68

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)