Oral Delivery of Modified Release solid dosage forms Flashcards
Overall purpose of a drug delivery system
To provide a therapeutically effective amount of drug to the appropriate site in the body for a desired duration of action
Modified release (MR)
is a general term referring to any formulation that
releases drug other than immediately (IR – Immediate release)
Magnitude of drug response is related to concentration at site of action
– Dependent upon dosage
– Extent of absorption
– Distribution to the site of action
– Rate and extent of its elimination and clearance from the body
Purpose of modified drug delivery technologies
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)
Modified release
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
Extended release
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.
Delayed release
- 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
Repeat action
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
Targeted release
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.
Routes of Administration
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
Oral route is the preferred route of administering medication due to
- patient acceptance
- ease of administration
- dosing accuracy
- ‘easy’ manufacturing
methods
-generally improved product shelf-life
The ultimate goal of drug delivery is to
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
Rationale: Immediate release
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
Immediate release (IR)
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
Rationale: IR – Multiple dosing
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
Examples of modified release oral product types
- Extended release
– Delayed release
– Targeted release
– Orally disintegrating tablets
-Describes products that alter the timing and/or release of drug
Goals and advantages of MR delivery systems
- 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
Drug properties that influence MR
dosage solids
- Solubility
- Permeability
- Absorption
Solubility
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
Permeability
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
Absorption
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
maximum swallowable dose is generally considered to be between
500-1000 mg
Delayed release characteristics
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
Common polymers used in oral delayed release dosage forms
Classified based on the chemical backbone (celluloses, vinyls, acrylics))
-Some natural polymers have also been used (e.g., shellac, rosin)
Enteric coats
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
Natural polymers
shellac, rosin
Other approaches to delayed release
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.
Extended release
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)
Sustained Release
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
Controlled Release
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
Bimodal release
Part is released in
an immediate fashion and part is released in a delayed or extended fashion
- type of extended release
Goals of ER systems
- 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
MR dosage forms control the rate of absorption by design
; drug is released more
slowly in the small intestine than it will be absorbed
Slowing the absorption rate can mean that the time to peak is quite long
in addition, the onset of the therapeutic effect after the first dose will be slow when
compared to an immediate release product
Extended release dosage forms ideally release drug in a constant fashion
to provide therapeutic concentrations over a convenient time frame
Drug is released from the MR dosage forms by
dissolution and diffusion or a
combination of the two
Other ER key points
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
Controlled Delivery
CD
Controlled Release
CR
Delayed Release
DR
Extended Release
ER, XL, XR, XT
Long Acting
LA
Modified Release
MR
Sustained Action
SA
Timed Release
TR
Sustained Release
SR
Biological considerations
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
Which factors may influence drug absorption
GI conditions
Transit times
Presence/Absence/ types of food
- Age, gender as well as health status
(e. g., gastric acidity, diarrhea, colitis) and diet
Earliest ER design
- drug granules were covered with varying thicknesses of lipophilic coating; the coated granules were then pressed into tablets or placed into capsules
Common design today
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
Drug release is determined by
the thickness and dissolution rate of the coating surrounding the drug core
Diffusion-dissolution controlled
- 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
Use of a water permeable coating may be added to hydrophilic matrix to
reduce burst effect; swelling tablet breaks coating allowing drug release
Diffusion controlled reservoir systems
– 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
Alternative reservoir designs
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
Hybrid system
Membrane coated drug pellets imbedded in a tablet matrix
Repeat action tablets
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
Complex Formation
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
Cyclodextrins are
- Hydrophobic inside and hydrophilic outside
- Hydrophobic drug complexes within the molecule
Ex of complex formation
Osmotic controlled systems
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
For an osmotic controlled system release rate is
independent of GI pH, fed/fasted conditions or gastric motility
Oral osmotic controlled systems advantages over conventional tablets
- 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
Oral osmotic controlled systems: Disadvantages over conventional tablets
More expensive
– Quality control is more extensive
– Does not dissolve and is excreted as an insoluble shell
Ion exchange resins
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
As the pH or ion concentration changes during drug complex moves through
the GI
the resin will release the drug
Resins
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
Gastric retentive systems
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
Gastric retentive dugs are used to
treat stomach conditions such as H. pylori infections
Three promising designs
– 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
Bioavailability and bioequivalence
Dosing intervals for ER formulations is determined by
the dose size and release rate (IR dosing interval is determined by half-life)
Important note
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
dose
dumping
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
Most ER formulations are intended
to be used/administered whole
Alcohol is a good solvent for many coating materials
alcoholic beverages may dissolve
or weaken the rate controlling mechanism, potentially resulting in dose dumping in the
stomach
Advantages of modified delivery
Advantages
Disadvantages of modified delivery
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
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
A. Blood and plasma levels peak shortly after administration and decrease over
time as clearance dominates
In the attached image, curves B and C describe which release profile? A. Immediate release B. Repeat action C. Extended release D. Delayed release
D. Delayed release
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
B. Concentration held within the therapeutic window
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
B. pKa = 4.5-7
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
D. Minimize cost of production of oral dose
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
D. It releases drug through a laser-drilled orifice at a zero-order rate
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
B. They have a hydrophobic core and hydrophilic external environment
