Modified-release drug DDS

Question 1

What are the benefits of modified-released drugs?

Answer 1

-a more constant therapeutic blood concentration of the drug
-reduce the number of administration times

Question 2

Explain the behavior of instant released drugs:

Answer 2

-fast peak but goes down quickly
-many doses needed

Question 3

Explain the behavior of sustained released drugs:
Extended or prolonged release

Answer 3

-extends the therapeutic effect
- first order (rate is dependent on only 1 reactant, elimination rate increases with concentration of the drug)

Question 4

Explain the behavior of controlled released drugs:
Extended or prolonged release

Answer 4

-constant line -> input is equal to the output, with no fluctuation
-often IV administration
- 0 order reaction (constant release regardless of plasma concentration of the drug)

Question 5

Explain the behavior of delayed released drugs:

Answer 5

-IR behavior, just delayed

Question 6

Explain the behavior of Bimodal released drugs:

Answer 6

IR behavior, followed by delayed release

Question 7

Characteristics of extended or prolonged release drugs

Answer 7

Release the drug over a period of time
-includes controlled (0 order) and sustained release (first order)

Question 8

Characteristics of delayed released (DR) drugs:

Answer 8

At least one part of the drug is released at some other time than the IR drug
Example: enteric-coated drug

Question 9

What are repeat action (RA) and targeted release (TR)?

Answer 9

RA: One drug is immediately released followed and an extended released drug -> Bimodal plasma concentration

TR: release the drug at or near the intended site of action

Question 10

Advantages of MRDDS?

Answer 10

-more control, less fluctuation of drug concentration
-reduction in the frequency of dosing
-fewer side effects
-reduction of health care costs: less hospitalization

Question 11

Disadvantages of MRDDS?

Answer 11

-ER drugs are more expensive than IR
-Variability in bioavailability (e.g. pH change in the stomach)
-the risk of toxicity -> wrong usage (crushed tablets) bc one ER tablet has a higher dose or using with alcohol which can dissolve the coating
-bc of the high dose the tablet might be big
-not easy to adjust the dose for a paitent

Question 12

Properties of MRDDS:
When do we want to use MRDDS drugs?

Answer 12

-Rate of absorption and elimination: when a drug is eliminated very quickly or very slowly we don’t need to use MRDDS -_ HALFLIFE of 4-8h is eligible for MRDDS

-Small dose drugs: we do not want to use a high dose drug for MRDDS bc we also need put excipients (there is a limit) and we don´t want a big size tablet

-when the therapeutic index window is big enough: in narrow windows, little change can lead to overdose (crushing of tablets)

-used for chronic diseases

Question 13

What are the modified release technologies used in oral DDS?
A: Coated beats, granules, and microspheres:

Answer 13

-For small doses, the drug is coated on a bead and a polymer coat can be on top to slow down the release

-For high doses, the core is the drug and may be coated with Lipid or some wax to delay the release

-> uncoated is IR and with the coat is delayed release
so a mix of beats can be placed in a capsule

Question 14

What are the commercial examples for coated beats?

Answer 14

-Coreg Carvedilol phosphate Extended-Release Capsules (hypertension): mix of beats with IR drug-layered and some are extra coated with methacrylic acid copolymers for slow release

-Spansule capsule: drug is in the core + coated with lipids

Question 15

Modified release technologies for oral DDS:
B: What is the purpose of multi-tablet systems?

Answer 15

-multiple mini tablets (3-4mm) are put together in one capsule
-tablets with different release paces (coated, uncoated)
-different drugs in one capsule, patients don’t have to take many tablets

Commercial examples: Pancrease MT and Orfiril Long

Question 16

Modified release technologies for oral DDS
C: What are microencapsulated drugs?

Answer 16

Microsized capsuled that contain the drug (solid, liquid, gas), different kinds of coating materials possible -> Gelatin, polyvinyl alcohol, ethyl cellulose,

commercial example: Micro-K Extencaps (potassium chloride -> irritating for the stomach)

Question 17

Modified release technologies for oral DDS
D: Explain embedded drugs in eroding hydrophilic matrix:

Answer 17

-the drug is embedded in a hydrophilic matrix like cellulose HPMC which absorbs water -> swelling and forming a gel layer on the outside -> drug diffuses from the inside to the outer formed gel layer until the drug is gone -> gel layer erodes
some are IR, some are DR
DONT BREAK bc the matrix will be broken

Commercial example: Oromorph (morphine), MS Contin

Question 18

Modified release technologies for oral DDS
E: Embedded drugs in an inert plastic matrix (non-erodible)

Answer 18

-the drug is embedded in a plastic matrix that doesn’t like water, like Polyethylene

-the drug is water soluble and bc of the concentration gradient (less drug outside), the drug will diffuse to the outside

-the plastic matrix will stay and can be found in the stool

Commercial example: OxyContin (oxycodone) - was abused by extracting the API out of the formulation

Question 19

Modified release technologies for oral DDS
F: Complex formation

Answer 19

The drug is mixed with an agent to form a complex that releases the drug on a specific pH

Example: Rynatan

Question 20

Modified release technologies for oral DDS
G: Ion exchange Resin

Answer 20

-a drug is combined with Resin, once it gets to the site where electrolytes (Cl(-) and Na(+)) are present the electrolytes will exchange with the ions (drug and Resin) and thereby separate Resin from the drug, and the drug is released

Examples: Tussionex (hydrocodone), Ionamin

Question 21

Modified release technologies for oral DDS
H: Osmotic tablets OROS system

Answer 21

-We have a tablet with a semi-permeable membrane and a hole and inside we have an osmotically active core = DRUG + osmotic agent like saline

-when the tablet moves to the site, the solvent (saline) concentration will be high outside -> solvent diffuses to the inner core (through the semi-permeable membrane) and dissolves the drug, and pushes the drug outside through the hole

-a slow process that takes time
-0 order (release is constant)
-non-eroded -> may be found in the stool

Question 22

What is an example of an osmotic tablet?

Answer 22

-ADHD patient: 3-layer system with the osmotic solvent on the bottom, and high dose in the middle, and low dose on the top

-on site the solvent diffuses into the matrix and pushes the low dose on top out -> in the morning when the kid is not so active, later the high dose in the middle will be pushed outside, which will be in the afternoon when the kid is more active

Examples: Procardia XL, Ditropan XL

Question 23

What is an important requirement test performed for modified-released drugs?

Answer 23

-Dissolution test, to see if the drug dissolves and is released as expected
-because this system often has an IR and an ER drug -> you have to assess the concentration for at least three time points

Question 24

What are important points to council on in MRDDS?

Answer 24

-switch between IR and XL drugs: bc it can cause overdose and inefficient dosage
-check blood level before changing MRDDS form
-mostly it is not possible to crush
-council about the -matrix that can be found in stool
-cannot be broken bc it destroys the matrix system
-not be taken with alcohol bc it dissolves the enteric coating
-patients undergoing bariatric surgery cant metabolize MRDDS drugs (high dose)
-COREG is the only MRDDS drug taken with food - usually, they are not taken with food bc they are released slowly anyway