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