Oral Delivery of Modified Release solid dosage forms

Question 1

Overall purpose of a drug delivery system

Answer 1

To provide a therapeutically effective amount of drug to the appropriate site in the body for a desired duration of action

Question 2

Modified release (MR)

Answer 2

is a general term referring to any formulation that

releases drug other than immediately (IR – Immediate release)

Question 3

Magnitude of drug response is related to concentration at site of action

Answer 3

– Dependent upon dosage
– Extent of absorption
– Distribution to the site of action
– Rate and extent of its elimination and clearance from the body

Question 4

Purpose of modified drug delivery technologies

Answer 4

Try to optimize drug
performance and enhance patient compliance by reducing side effects
-Through development of new chemical entities (NCEs)
– Through reformulation of marketed products
❖For better patient acceptance
❖Enables pharmaceutical companies to extend the patent life of their product and
protect the company’s intellectual property (IP)

Question 5

Modified release

Answer 5

Dosage forms having drug release features based on time, course, and/or location that are designed to accomplish therapeutic
or convenience objectives not accomplished by conventional or immediate
release dosage forms.
A general term

Question 6

Extended release

Answer 6

Dosage forms that allow a reduction in dosing

frequency compared to that presented by a conventional dosage form, i.e., allows for less frequent dosing.

Question 7

Delayed release

Answer 7

• Dosage forms designed to release drug at a time other than soon after administration
• Demonstrates a lag time that is designed
  into the formulation based upon GI environmental conditions

Question 8

Repeat action

Answer 8

A dosage form that usually contains two single doses (or more) of medication.
- One dose is for immediate release and the second is for delayed or extended release

Question 9

Targeted release

Answer 9

A dosage that is directed towards isolating or
concentrating a drug in a body region, tissue or site for absorption or for
drug action. Site specific delivery, i.e., colon-targeted oral drug delivery
systems.

Question 10

Routes of Administration

Answer 10

Parenteral
o From the Greek: Para (beside) + enteron (intestine)
o IV, IM, SC, ID, vaginal, nasal/inhalation
– Non-parenteral (AKA – Enteral)
o Via intestine
o Most commonly oral, rectal and nasogastric

Question 11

Oral route is the preferred route of administering medication due to

Answer 11

• patient acceptance
• ease of administration
• dosing accuracy
• ‘easy’ manufacturing
  methods
  -generally improved product shelf-life

Question 12

The ultimate goal of drug delivery is to

Answer 12

deliver the right amount of drug, to the right tissue, for the right duration while minimizing adverse side
effects;
- modified drug delivery assists in meeting these goals, often when
conventional methods are unsuccessfu

Question 13

Rationale: Immediate release

Answer 13

Formulated to rapidly release drug immediately after administration and
subsequently absorbed into the body
- Generally results in relatively rapid absorption in GI
-Short duration of action may be observed

Question 14

Immediate release (IR)

Answer 14

Does not maintain plasma levels of drug within the therapeutic range for an extended
period of time
– Blood levels (concentration) peaks shortly after administration as drug absorption
dominates
– Blood levels decrease over time as metabolism and/or excretion processes dominate
- conventional form

Question 15

Rationale: IR – Multiple dosing

Answer 15

Since conventional IR dosage forms do not maintain plasma levels, multiple dosing may be needed to give good clinical performance with an appropriate
balance of efficacy and safety
-may be tolerated for short-term treatment; not desirable for
chronic conditions

Question 16

Examples of modified release oral product types

Answer 16

• Extended release
  – Delayed release
  – Targeted release
  – Orally disintegrating tablets

-Describes products that alter the timing and/or release of drug

Question 17

Goals and advantages of MR delivery systems

Answer 17

• Enhance the drug’s therapeutic benefits by releasing drug in a controlled manner
  – Improve overall management of the disease
  – Improved therapeutic effect
  -Maintaining drug at the active site minimizes the troughs of traditional dosing
• Improves bioavailability by protecting against degradation; helping to direct drug to site
  of absorption
• Fewer relapses may result in fewer hospitalizations in chronic disease treatment
  -Potentially fewer side effects vs. traditional dosing due to less fluctuation in drug
  levels
  – Convenient for the patient – Reduced dosing frequency improves compliance

Question 18

Drug properties that influence MR

dosage solids

Answer 18

1. Solubility
2. Permeability
3. Absorption

Question 19

Solubility

Answer 19

For drugs with good solubility, many formulation options for ER product design
– Drugs with very low solubility (e.g., <0.1 mg/mL; 0.01%), may be inherently sustained
release due to its slow dissolution rate

Question 20

Permeability

Answer 20

Drug must be sufficiently permeable (log P of 1-5) to provide an absorption rate that is faster
than the release rate from the dosage form

Question 21

Absorption

Answer 21

Drugs absorbed via carrier mediated transport
– Likely to have too narrow an absorption window to allow 12-24 h medication delivery in one
portion
– Most active transport carriers operate in only one portion of the small intestine

Question 22

maximum swallowable dose is generally considered to be between

Answer 22

500-1000 mg

Question 23

Delayed release characteristics

Answer 23

Delayed release technology exhibits a lag time in drug release
- Designed to pass through the stomach unaltered and disintegrate in a site specific location
- Delay in release is usually the result of the oral dosage form being coated by a polymeric
film
- No immediate release of the drug
– Bioavailability is not normally significantly affected by food

Question 24

Common polymers used in oral delayed release dosage forms

Answer 24

Classified based on the chemical backbone (celluloses, vinyls, acrylics))
-Some natural polymers have also been used (e.g., shellac, rosin)

Question 25

Enteric coats

Answer 25

are acidic polymers that dissolve as the intestinal pH increases -Methacrylic acid copolymers are widely used to deliver an intact dosage to small or large intestines • Soluble pH sensitive coatings control site disintegration • Protect acid labile drugs from harmful effects in gastric environment (acidic or enzymatic). • Protect stomach from drugs that can irritate mucosal lining (ex., NSAIDs) • Deliver drug to the intestine for local effects as well as for systemic absorption • May be designed to remain intact through the small intestine to release drug in the colon

Question 26

Natural polymers

Answer 26

shellac, rosin

Question 27

Other approaches to delayed release

Answer 27

Using coatings, build a lag time into the dosage form - The coatings slowly erode to release drug at the time ‘typical gastrointestinal transit’ would carry it to the targeted location.

Question 28

Extended release

Answer 28

Maintains therapeutic blood levels of a drug for a prolonged period – Reduce blood level fluctuations - ER dosage forms may release drug in a Sustained fashion or a Controlled (constant) fashion - Dependent upon whether the release is concentration dependent (first order) or concentration independent (zero order)

Question 29

Sustained Release

Answer 29

o First order drug release: First order rate equation: dc/dt = kC o Characterized by a slow rise to an initial peak and a slower decline in release rate – drug clearance/elimination o The rate slows as the amount of drug in the dosage form declines

Question 30

Controlled Release

Answer 30

Provides a constant rate of release for a predictable period of time; delivery of drug at a predetermined rate for a defined period – Referred to as zero order because the rate of drug release is independent of the concentration of drug in the dosage form (Zero order rate equation: dc/dt = k

Question 31

Bimodal release

Answer 31

Part is released in an immediate fashion and part is released in a delayed or extended fashion - type of extended release

Question 32

Goals of ER systems

Answer 32

- To allow at least a two-fold reduction in dosing frequency as compared to the IR form – To release drug in a controlled manner – To reduce fluctuations in drug levels in the blood – Since dosing is less frequent, patient compliance is better

Question 33

MR dosage forms control the rate of absorption by design

Answer 33

; drug is released more | slowly in the small intestine than it will be absorbed

Question 34

Slowing the absorption rate can mean that the time to peak is quite long

Answer 34

in addition, the onset of the therapeutic effect after the first dose will be slow when compared to an immediate release product

Question 35

Extended release dosage forms ideally release drug in a constant fashion

Answer 35

to provide therapeutic concentrations over a convenient time frame

Question 36

Drug is released from the MR dosage forms by

Answer 36

dissolution and diffusion or a | combination of the two

Question 37

Other ER key points

Answer 37

In most cases, rate and extent of drug release and absorption are clinically unaffected by food • Commercially available extended release products are known by various abbreviations essentially describing the same issue

Question 38

Controlled Delivery

Answer 38

CD

Question 39

Controlled Release

Answer 39

CR

Question 40

Delayed Release

Answer 40

DR

Question 41

Extended Release

Answer 41

ER, XL, XR, XT

Question 42

Long Acting

Answer 42

LA

Question 43

Modified Release

Answer 43

MR

Question 44

Sustained Action

Answer 44

SA

Question 45

Timed Release

Answer 45

TR

Question 46

Sustained Release

Answer 46

SR

Question 47

Biological considerations

Answer 47

Drug must first be released from dosage form, then dissolve in the GI media before being absorbed through GI membranes - Drug must be soluble in GI media for absorption to occur - Drug absorption process is therefore described by diffusion and Fick’s Law

Question 48

Which factors may influence drug absorption

Answer 48

GI conditions Transit times Presence/Absence/ types of food - Age, gender as well as health status (e. g., gastric acidity, diarrhea, colitis) and diet

Question 49

Earliest ER design

Answer 49

- drug granules were covered with varying thicknesses of lipophilic coating; the coated granules were then pressed into tablets or placed into capsules

Question 50

Common design today

Answer 50

Drug is dispersed in a matrix of water-insoluble polymers or waxes; drug release occurs as GI fluids permeate the matrix and dissolves the drug

Question 51

Drug release is determined by

Answer 51

the thickness and dissolution rate of the coating surrounding the drug core

Question 52

Diffusion-dissolution controlled

Answer 52

- Most common extended release design – Drug is homogeneously dispersed within water soluble polymer and compressed into a tablet – Polymer rapidly hydrates and swells upon contact with GI fluids – It forms a gel-like network through which drug must diffuse to be released – Water continues to penetrate towards the tablet core

Question 53

Use of a water permeable coating may be added to hydrophilic matrix to

Answer 53

reduce burst effect; swelling tablet breaks coating allowing drug release

Question 54

Diffusion controlled reservoir systems

Answer 54

– Dosage form enclosed by a flexible membrane – Contains core of drug enclosed by an insoluble polymer coat that allows water into the dosage form – Once the drug has dissolved, it can diffuse out through the membrane coating

Question 55

Alternative reservoir designs

Answer 55

The membrane may be composed of an insoluble polymer blended with soluble polymers; these soluble polymers dissolve in the GI fluids producing tiny pores to allow entry of water and exit of soluble drug -Use of insoluble, but permeable membranes that allow water in and dissolved drug out, but do not disintegrate; these tablets will appear in the patient’s stoo

Question 56

Hybrid system

Answer 56

Membrane coated drug pellets imbedded in a tablet matrix

Question 57

Repeat action tablets

Answer 57

Biphasic release; bimodal release – Usually contain two single doses of medication o One for immediate release o Second for delayed release -– Example two layered tablets with one of the layers in an extended release matrix

Question 58

Complex Formation

Answer 58

Some drugs are able to combine chemically to form complexes that may be slowly soluble or slowly release drug in situ - Slowly soluble in body fluids dependent upon pH of the environment o Extended release results from this slow dissolution rate o Cyclodextrins ❖ Hydrophobic inside and hydrophilic outside ❖ Hydrophobic drug complexes within the molecule

Question 59

Cyclodextrins are

Answer 59

- Hydrophobic inside and hydrophilic outside - Hydrophobic drug complexes within the molecule Ex of complex formation

Question 60

Osmotic controlled systems

Answer 60

System utilizes osmotic pressure as the driving force for the delivery of drugs -After taking orally, as soon as the tablet comes into contact with water in the GI, water will slowly imbibe through the membrane due to the resultant osmotic pressure at a controlled rate; the drug will then be released through the orifice at a controlled, zero order rate

Question 61

For an osmotic controlled system release rate is

Answer 61

independent of GI pH, fed/fasted conditions or gastric motility

Question 62

Oral osmotic controlled systems advantages over conventional tablets

Answer 62

- Drug release is independent of the environment of the system – Can control the release of poorly soluble drugs – GI exposure is reduced – Zero order release is possible

Question 63

Oral osmotic controlled systems: Disadvantages over conventional tablets

Answer 63

More expensive – Quality control is more extensive – Does not dissolve and is excreted as an insoluble shell

Question 64

Ion exchange resins

Answer 64

are insoluble polymeric particles or gels that contain basic or acidic groups that can form ionic complexes with oppositely charged drugs -can be suspended, compressed into tablets or encapsulated

Question 65

As the pH or ion concentration changes during drug complex moves through the GI

Answer 65

the resin will release the drug

Question 66

Resins

Answer 66

are not absorbed by the body • The resins can mask taste and reduce upper GI side effects due to limited release in mouth and stomach

Question 67

Gastric retentive systems

Answer 67

Dosage forms designed to be retained in the stomach - Provide longer exposure to upper small intestine, especially important for drugs whose absorption depends upon carrier-mediated transport -must be acid-stable and the dosage form must be able to withstand the mechanical grinding activity of the stomach

Question 68

Gastric retentive dugs are used to

Answer 68

treat stomach conditions such as H. pylori infections

Question 69

Three promising designs

Answer 69

``` – Floating dosage forms – Bioadhesive multiparticulates – Swelling, single-unit systems Most promising o Dosage forms are polymers that swell in the stomach becoming larger than the pyloric opening o Have shown to increase bioavailability of carrier–mediated drugs being retained in stomach for up to 16 h ```

Question 70

Bioavailability and bioequivalence

Answer 70

Cmax for modified release dosage forms will generally be lower than the immediate release product – Side effects are less likely to occur -

Question 71

Dosing intervals for ER formulations is determined by

Answer 71

``` the dose size and release rate (IR dosing interval is determined by half-life) ```

Question 72

Important note

Answer 72

Bioequivalence of modified release dosage forms does not imply that the release mechanisms are the same; for example, a hydrophilic matrix tablet may be bioequivalent to an osmotic tablet

Question 73

dose | dumping

Answer 73

A formulation that fails to sustain drug release and abruptly release the drug in an IR fashion is potentially dangerous -key reasons reported for dose dumping is related to food compounded by a ‘weak’ formulation – For examples, low levels of pH coatings; defects in the membrane of a membrane controlled ER design

Question 74

Most ER formulations are intended

Answer 74

to be used/administered whole

Question 75

Alcohol is a good solvent for many coating materials

Answer 75

alcoholic beverages may dissolve or weaken the rate controlling mechanism, potentially resulting in dose dumping in the stomach

Question 76

Advantages of modified delivery

Answer 76

Advantages

Question 77

Disadvantages of modified delivery

Answer 77

Potential for dose dumping if a possible failure occurs in the delivery system – More complex manufacturing processes – More sophisticated technology and higher cost – This higher cost to passed on to the consumer (and insurer) – Biocompatibility of materials needs to be assured

Question 78

Which of the following describes a conventional oral dosage form? A. Blood and plasma levels peak shortly after administration and decrease over time as clearance dominates B. Typically result in a slow onset of pharmacodynamic effects C. Drug is released slowly and available for absorption within the GI D. Almost never administered with multiple dosing

Answer 78

A. Blood and plasma levels peak shortly after administration and decrease over time as clearance dominates

Question 79

``` In the attached image, curves B and C describe which release profile? A. Immediate release B. Repeat action C. Extended release D. Delayed release ```

Answer 79

D. Delayed release

Question 80

Which of the following is an advantage of modified drug delivery? A. Dose dumping B. Concentration held within the therapeutic window C. Low cost to produce

Answer 80

B. Concentration held within the therapeutic window

Question 81

``` What is the ideal pKa range for a polymer coating on an enteric tablet? A. pKa = 1-4.5 B. pKa = 4.5-7 C. pKa = 7-10.5 D. pKa = 10.5-13 ```

Answer 81

B. pKa = 4.5-7

Question 82

Which of the following is NOT a goal of an ER system? A. Release drug in a controlled manner B. Improve patient compliance C. Reduce fluctuations in drug levels in the blood D. Minimize cost of production of oral dose

Answer 82

D. Minimize cost of production of oral dose

Question 83

Which of the following statements about an oral osmotic controlled drug delivery system is true? A. It dissolves easily B. It is typically cheaper to produce than conventional forms of tablets C. It shows a release rate that is dependent on the environment of the system D. It releases drug through a laser-drilled orifice at a zero-order rate

Answer 83

D. It releases drug through a laser-drilled orifice at a zero-order rate

Question 84

Why are cyclodextrins good for complex formation and modified release of lipophilic drugs? A. They have a hydrophilic core and a hydrophobic external environment B. They have a hydrophobic core and hydrophilic external environment C. They result in rapid drug dissolution D. They are not good for formation and modified release of lipophilic drugs

Answer 84

B. They have a hydrophobic core and hydrophilic external environment