PDD 14 and 15: Solid Oral Modified Dosage Forms Flashcards
What are the types of oral modified-release forms?
- delayed release
- extended release
What is delayed release?
dosage form allows a reduction in dosing frequency
- enteric coating to prevent drug release in stomach
What is extended release?
dosage form designed to release the drug at a time other than promptly after administration
- maintain optimal drug concentration in blood over a period of time
What are the advantages of extended-release pharmaceuticals? (2)
- reduce dosing frequency
- eliminate the need for night dosing
What are the disadvantages of extended-release pharmaceuticals? (2)
- loss of flexibility in adjusting the dose
- risk of dose dumping
What is repeat action?
tablet contains the immediate-release dose in the shell or coating, and the second dose in the inner core, separated by a slowly permeable barrier coating
What is targeted release?
dosage form releases the drug at a specified site (ie. pH sensitive and microflora sensitive)
What are the characteristics of drug candidates for extended-release products? (6)
- do not exhibit very slow rates of absorption
- do not exhibit very fast nor very slow rates of excretion (t1/2 need to be > 2h, but < 8 h)
- uniformly absorbed from the gastrointestinal tract
- administered in relatively small doses
- possess a good margin of safety
- used in the treatment of chronic conditions
How are extended-release technologies generally achieved?
by modifying the drug release rate or slowing the transit time of the dosage forms thorough the GI tract
What are the 3 major mechanisms of extended-release technologies?
- modify drug dissolution by using barrier coatings
- control drug diffusion rates from dosage forms
- chemical reaction or interaction between the drug substance or its pharmaceutical barrier and site-specific biological fluids
Case Study 1: Coated Beads, Granules, and Microspheres
What are granules coated with?
materials like beewax, glyceryl monostearate, cetyl alcohol or ethylcellulose with different thicknesses
Case Study 1: Coated Beads, Granules, and Microspheres
What are granules formulated into?
blended and formulated into a capsule or tablet
Case Study 1: Coated Beads, Granules, and Microspheres
What does the coating thickness of granules determine?
the fluid penetration rate into the granules, and ultimately the drug dissolution rate
Case Study 2: Multitablet System
What is a multitablet system?
- each capsule contains 8-10 minitablets (3-4 mm)
- some minitablets are coated for extended release, and some are uncoated for immediate release
Case Study 3: Microencapsulated Drug
- drug is encapsulated in gelatin-acacia droplets, followed by drying and filling into a capsule
- drug release rate is determined by the ratio of core to wall, and the polymer used for microencapsulation
- other polymers: polyvunyl alcohol, ethylcellulose, polyvinyl chloride
Case Study 4: Embedding Drug in Slowly Eroding or Hydrophilic Matrix System
- drug is mixed with hydroxymethylcellulose (HPMC) (generally 20%) and made into a tablet
- after ingestion, the tablet is wetted by fluid, and HPMC begins to hydrate, forming a gel layer for soluble drug to release (diffusion dependent) – polymer must form a gel layer rapidly to protect the tablet from rapid disintegration
- the gel layer will erode overtime allowing insoluble drug to release (erosion dependent)
Tablet Disintegration vs. Tablet Erosion
- disintegration: immediate release
- erosion: extended release
Case Study 5: Embedding Drug in Inert Plastic Matrix
- drug is granulated with an inert plastic material such as polyethylene, polyvinyl acetate, or polymethacrylate, and the granulation is compressed into tablets
- drug is slowly released from the inert plastic matrix by diffusion
- inert tablet matrix, expended of drug, is excreted with the feces
Case Study 6: Complex Formation
- certain drugs form chemical complexes with other agents, resulting in reduced dissolution in body fluids
- salts of tannic acid (tannates) provide this quality in a variety of proprietary produces by the trade name Rynatan
- tannic acid can complex with positively charged drugs (weak base) such as brompheniramine maleate (antihistamine)
- complex formation reduces the solubility and therefore, sustains the drug release
Case Study 7: Ion-Exchange Resin
- resin-drug complex may be tableted, encapsulated, or suspended in an aqueous vehicle
- drug release is dependent on the pH and the electrolyte concentration in the gastrointestinal tract
Case Study 8: Osmotic Pump
What is the OROS system (Alza)?
core tablet surrounded by a semipermeable membrane coating having a 0.4-mm-diameter hole
- core tablet contains a drug reservoir layer and a polymeric osmotic layer
- after swallowed, water enters into the core tablet, dissolving or suspending the drug
- as the pressure increases in the osmotic layer, it expands and pushes drug solution out
- release is driven by the osmotic gradient
Case Study 9: Repeat-Action Tablet
tablet contains the immediate-release dose in the shell or coating, and the second dose in the inner core, separated by a slowly permeable barrier coating
- design will generally allow the drug release from the inner core 4-6 h after the administration
Why might the release of a drug from an oral dosage form be intentionally delayed until it reaches the intestines? (3)
- to protect a drug from being destroyed by gastric fluids
- to reduce gastric distress caused by drugs particularly irritating to the stomach
- to facilitate GI transit for drugs which are better absorbed from the intestines
What are enteric coated capsules and tablets?
specially coated to remain intact in the stomach and to yield their ingredients in the intestines
What might enteric coating be dependent on?
- pH dependent, breaking down in the less acidic environment of the intestine
- time dependent, eroding by moisture over time during gastrointestinal transit
- enzyme dependent, deteriorating as a result of the hydrolysis-catalyzing action of intestinal enzymes
What agents may be used for enteric coating of tablets and capsules?
fats, fatty acids, waxes, shellac, and cellulose acetate phthalate
What are the advantages of extended-release dosage forms over conventional forms?
- reduction in drug blood level fluctuations
- frequency reduction in dosing
- enhanced patient convenience and compliance
- reduction in adverse side effects
- reduction in overall health care costs
What are the features of the OROS?
- drug release rate is constant as long as the osmotic gradient remains constant
- drug release rate can be altered by changing the surface area, thickness and composition of the semipermeable membrane, and the diameter of the drug-release orifice
- drug release rate is not affected by pH and fed conditions
- tablet is eliminated in the feces as an insoluble shel
Describe the specifics of labelling modified-release pharmaceuticals.
- label of aspirin delayed-release tablets must state that the tablets are enteric coated
- label for theophylline extended-release capsules must indicate whether the product is intended for dosing every 12-14 h and state with which in vitro drug release test the product complies
What are some clinical considerations in the use of oral modified-release dosage forms?
- patients should be advised of the dose and dosing frequency of modified drug release products and instructed not to use them interchangeably or concomitantly with immediate-release forms of the same drug
- patients stabilized on a modified-release product should not be changed to an immediate-release product without considering any existing drug in the blood – they should not be changed to another extended-release product unless there is assurance of equivalent bioavailability
- patients should be advised that modified-release tablets and capsules should not be crushed or chewed since such action would compromise their drug release features
- patients and caregivers should be advised that non-erodible plastic matrix shells and osmotic tablets remain intact throughout GI transit and the empty shells from osmotic tablets may be seen in the stool
