PDD: L9 Solid Oral Modified-Release Dosage Forms

Oral modified-release include:

• … release

  • … coating to prevent drug release in stomach

• … release

  • Maintain optimal drug concentration in … over time

Delayed, Enteric, Extended, blood

Advantages of extended-release pharmaceuticals:

• Reduce dosing …

• Eliminate the need for … dosing

frequency, night

Disadvantages of extended-release pharmaceuticals:

• Loss of … in adjusting the dose

• Risk of dose …

flexibility, dumping

Modified-release forms:

• … release: a dosage form allows a reduction in dosing frequency (FDA)

• … release: a dosage form designed to release the drug at a time other than promptly after administration

• … action: a 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

• … release: a dosage form releases the drug at a specified site (e.g. pH sensitive and microflora sensitive)

Extended, Delayed, Repeat, Targeted

What types of modified-release form produce prolonged pharmacological effect? Select ALL that apply.

a. Extended release

b. Delayed release

c. Repeat action

d. Targeted release

a, c

Drug candidates for extended-release products:

• Do not exhibit very slow rates of …

• Do not exhibit very fast nor very slow rates of … (t1/2 need to be > … h, but < … h)

• … absorbed from the gastrointestinal tract

• Administered in relatively … doses

• Possess a good … of safety

• Used in the treatment of … conditions

absorption, excretion, 2, 8, Uniformly, small, margin, chronic

Extended-release technologies:

• Generally achieved by modifying the drug release … or slowing the transit time of the dosage forms thorough the GI tract

• Include three major mechanisms:

  • Modify drug dissolution by using … coatings;

  • Control drug … rates from dosage forms;

  • … reaction or interaction between the drug substance or its pharmaceutical barrier and site-specific biological fluids

rate, barrier, diffusion, Chemical

Coated beads, granules, and microspheres

• Drug is formulated in particulate systems such as beads and granules

• Granules are coated with materials like …, glyceryl monostearate, cetyl alcohol or ethylcellulose with different …

• The granules are blended and formulated into a capsule or tablet

• Coating thickness determines the fluid … rate into the granules, and ultimately the drug … rate

beewax, thicknesses, penetration, dissolution

Multitablet system:

• Each capsule contains … minitablets (3-4 mm)

• Some minitablets are coated for extended release, and some are uncoated for … release

8-10, immediate

Microencapsulated drug:

• Drug is encapsulated in gelatin-acacia …, followed by … and filling into a capsule

• Drug release rate is determined by the ratio of … to …, and the polymer used for microencapsulation

• Other polymers: polyvunyl alcohol, ethylcellulose, polyvinyl chloride

droplets, drying, core, wall

Embedding drug in slowly eroding or hydrophilic matrix system:

• Drug is mixed with … (HPMC) (generally 20%) and made into a tablet

• After ingestion, the tablet is wetted by fluid, and HPMC begins to hydrate, forming a … layer for soluble drug to release (diffusion dependent)

• The gel layer will … overtime allowing insoluble drug to release (erosion dependent)

• The polymer must form a gel layer rapidly to protect the tablet from rapid …

hydroxymethylcellulose, gel, erode, disintegration

• Tablet disintegration: … release

• Tablet erosion: … release

immediate, extended

Embedding drug in inert plastic matrix:

• Drug is granulated with an inert … material such as polyethylene, polyvinyl acetate, or polymethacrylate, and the granulation is compressed into …

• The drug is slowly released from the inert plastic matrix by …

• The inert tablet matrix, expended of drug, is excreted with the …

plastic, tablets, diffusion, feces

Complex formation:

• Certain drugs form chemical … with other agents, resulting in reduced … in body fluids

• Salts of … acid (tannates) provide this quality in a variety of proprietary produces by the trade name Rynatan

complexes, dissolution, tannic

• Tannic acid can complex with … charged drugs (weak base) such as brompheniramine maleate (antihistamine)

• Complex formation … the solubility and therefore, sustains the drug release

positively, reduces

Ion-exchange resin:

• The resin-drug complex may be …, …, or suspended in an aqueous vehicle

• The drug release is dependent on the … and the … concentration in the gastrointestinal tract

tableted, encapsulated, pH, electrolyte

Osmotic pump:

• OROS system (Alza): a core tablet surrounded by a … membrane coating having a 0.4-mm-diameter …

• The core tablet contains a drug … layer and a … osmotic layer

• After swallowed, water … into the core tablet, dissolving or suspending the drug

• As the … increases in the osmotic layer, it expands and pushes drug solution out

• Release is driven by the … gradient

semipermeable, hole, reservoir, polymeric, enters, pressure, osmotic

Repeat-action tablet:

• A tablet contains the immediate-release dose in the shell or coating, and the second dose in the inner …, separated by a slowly permeable barrier coating

• The design will generally allow the drug release from the inner core … h after the administration

core, 4-6

Which modified-release dosage form may be seen in the stool even if well-absorbed?

a. Multitablet system

b. Coated beads system

c. HPMC hydrophilic matrix system

d. Osmotic pump system

d

Which modified-release dosage form can be chewed or crushed?

a. Inert matrix system

b. Coated beads system

c. Osmotic pump system

d. Tannic acid complex system

d

Drug properties desirable for extended-release dosage forms include:

a. Absorbed only through intestines

b. Given at a high dose

c. A broad therapeutic window

d. Used for treating acute conditions

c

Features of extended-release medications include:

a. More frequent administration

b. Therapeutic effect overnight

c. Better flexibility in dose adjustment

d. More variation in plasma concentration

b

Delayed-release oral dosage forms:

• The release of a drug from an oral dosage form may be intentionally delayed until it reaches the intestines for several reasons:

  • To … a drug from being destroyed by gastric fluids

  • To … gastric distress caused by drugs particularly irritating to the stomach

  • To facilitate GI … for drugs which are better absorbed from the intestines

protect, reduce, transit

Enteric coating:

• Capsules and tablets specially coated to remain … in the stomach and to yield their ingredients in the intestines are termed enteric coated

• The enteric coating may be:

  • … dependent, breaking down in the less acidic environment of the intestine

  • … dependent, eroding by moisture over time during gastrointestinal transit

  • … dependent, deteriorating as a result of the hydrolysis-catalyzing action of intestinal enzymes

  • Among the many agents used for enteric coating of tablets and capsules are fats, fatty acids, waxes, shellac, and cellulose acetate phthalate

intact, pH, Time, Enzyme

Features of the OROS:

• The drug release rate is … as long as the osmotic gradient remains constant

• The drug release rate can be altered by changing the surface …, … and composition of the semipermeable membrane, and the … of the drug-release orifice

• The drug release rate is not affected by … and fed conditions

• The tablet is eliminated in the feces as an … shell

constant, area, thickness, diameter, pH, insoluble

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 … or concomitantly with immediate-release forms of the same drug.

• Patients stabilized on a modified-release product should not be changed to an …-release product without considering any existing drug in the blood. They should not be changed to another …-release product unless there is assurance of equivalent bioavailability.

• Patients should be advised that modified-release tablets and capsules should not be … 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 … throughout GI transit and the empty shells from osmotic tablets may be seen in the stool.

interchangeably, immediate, extended, crushed, intact

Labelling of modified-release pharmaceuticals:

• The USP requires labelling in the … article

  • The label of aspirin delayed-release tablets must state that the tablets are … coated

  • The label for theophylline extended-release capsules must indicate whether the product is intended for dosing every … h and state with which in vitro drug release test the product complies

monograph, enteric, 12-14