SOLID ORAL MODIFIED-RELEASE DOSAGE FORMS AND DRUG DELIVERY SYSTEM

Modified Release Dosage Forms

• dosage forms having drug-release features based on time, course, and/or location that are designed to accomplish therapeutic or convenience objectives not offered by conventional or immediate-release forms

• may be extended-release and delayed-release

Extended-Release

allows a reduction in dosing frequency from that necessitated by a conventional dosage form, such as a solution or an immediate-release dosage form

Disadvantages of Extended-Release

loss of flexibility, risk of sudden and total drug release or dose dumping

Frequency reduction in dosing

ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS:

• deliver more than a single dose, hence may be taken less often than conventional forms

Enhanced convenience and compliance

ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS:

• patient is less apt to neglect taking a dose

• convenience with day and night administration

Reduction in adverse side effects

ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS:

• because of fewer blood level peaks outside therapeutic range

Reduction in overall health care costs

ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS:

• although initial cost of extended-release dosage forms may be greater than for conventional forms, overall cost of treatment may be less because of enhanced therapeutic benefit, fewer side effects, and reduced time for health care personnel to dispense and administer and monitor drugs

Delayed-Release

• designed to release the drug at a time other than promptly after administration

• delay may be time-based or based on the influence of environmental conditions

Repeat Action

contain two single doses of medication, one for immediate release and the second for delayed release

Targeted Release

describes drug release directed toward isolating or concentrating a drug in a body region, tissue, or site for absorption or for drug action

very slow nor very fast

Extended-Release Oral Dosage Forms Drug Candidates for Extended-Release Products:

1. exhibit neither ___________________ rates of absorption and excretion

2. uniformly absorbed from the __________________

3. administered in relatively _______________

4. possess a ___________________________

5. used in the treatment of ________ rather than acute conditions

1 = ?

gastrointestinal tract

Extended-Release Oral Dosage Forms Drug Candidates for Extended-Release Products:

1. exhibit neither ___________________ rates of absorption and excretion

2. uniformly absorbed from the __________________

3. administered in relatively _______________

4. possess a ___________________________

5. used in the treatment of ________ rather than acute conditions

2 = ?

small doses

Extended-Release Oral Dosage Forms Drug Candidates for Extended-Release Products:

1. exhibit neither ___________________ rates of absorption and excretion

2. uniformly absorbed from the __________________

3. administered in relatively _______________

4. possess a ___________________________

5. used in the treatment of ________ rather than acute conditions

3 = ?

good margin of safety (therapeutic index)

Extended-Release Oral Dosage Forms Drug Candidates for Extended-Release Products:

1. exhibit neither ___________________ rates of absorption and excretion

2. uniformly absorbed from the __________________

3. administered in relatively _______________

4. possess a ___________________________

5. used in the treatment of ________ rather than acute conditions

4 = ?

chronic

Extended-Release Oral Dosage Forms Drug Candidates for Extended-Release Products:

1. exhibit neither ___________________ rates of absorption and excretion

2. uniformly absorbed from the __________________

3. administered in relatively _______________

4. possess a ___________________________

5. used in the treatment of ________ rather than acute conditions

5 = ?

Coated Beads, Granules, and Microspheres

• using conventional pan coating or air suspension coating, a solution of the drug substance is placed on small inert nonpareil seeds (beads made of sugar and starch) or on microcrystalline cellulose spheres

• granules of different coating thicknesses are blended to achieve a mix having the desired drug-release characteristics

Multitablet System

small spheroid compressed tablets (3 to 4mm in diameter) may be prepared to have varying drug-release characteristics placed in gelatin capsule shells to provide the desired pattern of drug release

Microencapsulated Drug

drug can be processed by which solids, liquids, or even gases may be enclosed in microscopic particles by formation of thin coatings of wall material around the substance

Embedding Drug in Slowly Eroding or Hydrophilic Matrix System

drug substance is combined and made into granules with an excipient material that slowly erodes in body fluids, progressively releasing the drug for absorption

Embedding Drug in Inert Plastic Matrix

• drug is granulated with an inert plastic material (polyethylene, polyvinyl acetate, or polymethacrylate) and the granulation is compressed into tablets

• drug is slowly released from the inert plastic matrix by diffusion

Complex Formation

some drug substances, when chemically combined with certain other chemical agents, form complexes that may be only slowly soluble in body fluids, depending on the pH of the environment

Ion-Exchange Resins

a solution of cationic drug is passed through a column with ion-exchange resin, forming a complex by the replacement hydrogen atoms

Osmotic Pump

• system is composed of a core tablet surrounded by a semipermeable membrane having a 0.4-mm-diameter hole produced by laser beam

• core tablet has two layers, one containing the drug (the active layer) and the other containing a polymeric osmotic agent (the push layer)

Delayed-Release Oral Dosage Forms

• protect a drug destroyed by gastric fluids

• reduce gastric distress caused by drugs particularly irritating to the stomach

• facilitate gastrointestinal transit for drugs that are better absorbed from the intestines

• enteric-coated capsules and tablets (enteric coating may be pH-, time-, or enzyme-dependent)

USP Requirements and FDA Guidance Drug Release

USP test is based on drug dissolution from the dosage unit against elapsed test time

USP Requirements and FDA Guidance Uniformity of Dosage Units

may be demonstrated by either of two methods (weight variation or content uniformity)

USP Requirements and FDA Guidance In Vitro–In Vivo Correlations (IVIVCs)

critical to the development of oral extended-release products

Level A

3 categories of IVIVCs:

• relationship between the entire in vitro dissolution and release time course and the entire in vivo response time course

Level B

3 categories of IVIVCs:

• relationship between summary parameters that characterize the in vitro and in vivo time courses

Level C

3 categories of IVIVCs:

• relationship between the amount dissolved in vitro at a particular time and a summary parameter that characterizes the in vivo time course

release rates or a single-release rate

most common process for developing an IVIVC model (level A) is to:

a) develop formulations with different _______________________________ if dissolution is independent of condition

b) obtain _________________________________________________ profiles for these formulations

c) estimate the ________________________________ for each formulation and subject using appropriate mathematical approaches

a = ?

in vitro dissolution profiles and in vivo plasma concentration

most common process for developing an IVIVC model (level A) is to:

a) develop formulations with different _______________________________ if dissolution is independent of condition

b) obtain _________________________________________________ profiles for these formulations

c) estimate the ________________________________ for each formulation and subject using appropriate mathematical approaches

b = ?

in vivo absorption or dissolution time course

most common process for developing an IVIVC model (level A) is to:

a) develop formulations with different _______________________________ if dissolution is independent of condition

b) obtain _________________________________________________ profiles for these formulations

c) estimate the ________________________________ for each formulation and subject using appropriate mathematical approaches

c = ?

dissolution apparatus

criteria (development of IVIVCs):

1. USP ____________________, type I (basket) or type II (paddle), is preferred

2. _____________________ with a pH not exceeding 6.8 is preferred as the medium for dissolution studies

3. of at least _________________ from each lot

4. for in vivo studies, human subjects are used in the _________ state unless the drug is not well tolerated; use of 6 to 36 human subjects

5. __________ studies are preferred

1 = ?

aqueous medium

criteria (development of IVIVCs):

1. USP ____________________, type I (basket) or type II (paddle), is preferred

2. _____________________ with a pH not exceeding 6.8 is preferred as the medium for dissolution studies

3. of at least _________________ from each lot

4. for in vivo studies, human subjects are used in the _________ state unless the drug is not well tolerated; use of 6 to 36 human subjects

5. __________ studies are preferred

2 = ?

dissolution profiles of 12 individual dosage units

criteria (development of IVIVCs):

1. USP ____________________, type I (basket) or type II (paddle), is preferred

2. _____________________ with a pH not exceeding 6.8 is preferred as the medium for dissolution studies

3. _________________ from each lot

4. for in vivo studies, human subjects are used in the _________ state unless the drug is not well tolerated; use of 6 to 36 human subjects

5. __________ studies are preferred

3 = ?

fasted

criteria (development of IVIVCs):

1. USP ____________________, type I (basket) or type II (paddle), is preferred

2. _____________________ with a pH not exceeding 6.8 is preferred as the medium for dissolution studies

3. of at least _________________ from each lot

4. for in vivo studies, human subjects are used in the _________ state unless the drug is not well tolerated; use of 6 to 36 human subjects

5. __________ studies are preferred

4 = ?

crossover

criteria (development of IVIVCs):

1. USP ____________________, type I (basket) or type II (paddle), is preferred

2. _____________________ with a pH not exceeding 6.8 is preferred as the medium for dissolution studies

3. of at least _________________ from each lot

4. for in vivo studies, human subjects are used in the _________ state unless the drug is not well tolerated; use of 6 to 36 human subjects

5. __________ studies are preferred

5 = ?

Repeat-Action Tablets

• prepared so that an initial dose of drug is released immediately and a second dose follows later

• The tablets may be prepared with the immediate-release dose in the tablet's outer shell or coating and the second dose in the tablet's inner core, separated by a slowly permeable barrier coating.