[PHA 619 LEC] Chapter 9 - Solid Oral Modified Release Dosage Forms and Drug Delivery System

Most delayed-release products are __________, designed to pass through the stomach unaltered.

Enteric-coated tablets

Coatings used to either protect a substance from destruction by gastric fluids or to reduce stomach distress caused by irritating drugs

Enteric coatings

They are designed to release their medication in a controlled manner, at a predetermined rate, duration, and location to achieve and maintain optimum therapeutic blood levels of drug

Extended-release products

Type of dosing that is inconvenient for the patient and can result in missed doses, made-up doses, and noncompliance with the regimen

Multiple daily dosing

Extended-release tablets and capsules are commonly taken only ________ daily.

Once or twice

What are the advantages of extended-release dosage forms over immediate-release (conventional)?

- Less fluctuation in drug blood levels

- Less frequent administration (taken less often)

- Enhanced convenience and compliance

- Reduction in adverse side effects (fewer blood level peaks)

- Reduction in overall healthcare costs

A disadvantage of extended-release systems wherein there is a risk of sudden and total drug release due to a failure or inappropriate use of technology

Dose dumping

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

Extended-Release

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

Modified Release Dosage Forms

Meaning of SR

Sustained release

Meaning of SA

Sustained action

Meaning of PA

Prolonged action

Meaning of CR

Controlled release

Meaning of ER

Extended release

Meaning of TR

Timed release

Meaning of LA

Long action

Term applied to certain drug delivery systems in which the rate of delivery is controlled by features of the device rather than by physiologic or environmental conditions

Rate-controlled Delivery

Two types of modified-release dosage forms

- Extended-release

- Delayed-release

It is designed to release the drug at a time other than promptly after administration. The delay may be time-based or based on the influence of environmental conditions, like gastrointestinal pH.

Delayed-Release

Dosage form that usually contains two single doses of medication, one for immediate-release and the second for delayed-release

Repeat Action

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

Targeted release

Characteristics of drugs suited for incorporation into an extended-release product

1. Exhibit neither very slow nor very fast rates of absorption and excretion (ex. less than 2 hours are poor candidates for ER)

2. Uniformly absorbed from the gastrointestinal tract

3.Administered in relatively small doses

4. Possess a good margin of safety (therapeutic index

5. Used in the treatment of chronic rather than acute conditions

Drugs with very short half-lives dissolve in?

Less than 2 hours

It is the most widely used measure of the margin of a drug's safety. It is the median toxic dose divided by the median effective dose.

Therapeutic index

For very potent drugs, the therapeutic index may be?

Narrow or very small

(True/False) The smaller the therapeutic index, the safer the drug.

False

- the LARGER the therapeutic index

The rate of drug release from solid dosage forms may be modified by certain technologies, which in general are based on?

- Modifying drug dissolution by controlling access of biologic fluids to the drug through the use of barrier coatings,

- Controlling drug diffusion rates from dosage forms, and

- Chemical reaction or interaction between the drug substance or its pharmaceutical barrier and site-specific biologic fluids

The microcrystalline spheres are considered _____ durable during production than sugar-based cores.

more

Beads made of sugar and starch

Nonpareil seeds

The nonpareil seeds are most often in the range of _______?

425 to 850 mm

Using a conventional pan coating or air suspension coating, asolution of the drug substance is placed on small inert ________ or on __________.

Nonpareil seeds, microcrystalline cellulose spheres

The microcrystalline cellulose spheres range from ________?

170 to 600 mm

They eliminate the hazards and environmental concerns associated with organic solvent-based systems.

Aqueous coating systems

Granules of different ______________ are blended to achieve a mix having the desired drug-release characteristics.

Coating thicknesses

(True/False) The thicker the coat, the more the resistance to penetration and the more delayed will be drug release and dissolution.

True

Coated beads are about __________ in diameter.

1 mm

In a multitablet system, each capsule may contain ____________; some uncoated for IR and others coated for ER.

8-10 minitablets

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

Microencapsulation

Small spheroid compressed tablets may be prepared to have varying drug-release characteristics placed in gelatin capsule shells to provide the desired pattern of drug release.

Multitablet system

In multitablet system, small spheroid compressed tablets are usually _________ in diameter.

3-4 mm

It is a common wall-forming material in microencapsulation.

Gelatin

The wall material for microencapsulated drug usually constitutes _________ of the total particle weight.

2% to 20%

It is usually the additive material that concentrates gelatin (polymer) into tiny liquid droplets during encapsulation.

Acacia

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

Slowly Eroding / Hydrophilic Matrix System

In Hydrophilic Matrix System, the ______ provide the immediate effect.

Uncombined granules

In Hydrophilic Matrix System, the ______ provides the extended action.

Drug-excipient granules

They are commonly used as the excipient base in tablet matrix systems.

Hydrophilic cellulose polymers

It is a free-flowing powder commonly used to provide the hydrophilic matrix.

Hydroxypropyl methylcellulose (HPMC)

In hydrophilic matrix, the rate of drug release is controlled by?

Diffusion and tablet erosion

Matrix wherein the drug is granulated with an inert plastic material (polyethylene, polyvinyl acetate, or polymethacrylate) and the granulation is compressed into tablets. Drug is slowly released by diffusion.

Inert Plastic Matrix

Some drug substances, when chemically combined with certain other chemical agents, form complexes that may be only soluble in body fluids, depending on the pH of the environment. The slow dissolution rate provides the ER of the drug.

Complex Formation

A solution of a cationic drug may be passed through a column, forming a complex by the replacement of hydrogen atoms.

Ion-Exchange Resins

In ion-exchange resins, the release of the drug depends on the?

pH and electrolyte concentration in the GI tract

The coating does not dissolve, and release is extended over _______ by ionic exchange.

12 hours

OROS stands for?

Oral release osmotic system

(True/False) In ion-exchange resins, the release is greater in the acidity of the stomach than in the less acidic environment of the small intestine.

True

What are the two layers of the core tablet in osmotic pump?

- Active layer contains the drug

- Push layer contains a polymeric osmotic agent

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

Osmotic Pump

Enteric coating may be dependent on?

- pH (breaks down is less acidic intestine)

- Time (eroding by moisture over time)

- Enzyme (deterioration due to hydrolysis-catalyzing action)

Type of osmotic system in which the initial drug is released 4-5 hours after tablet ingestion.

Controlled-onset extended release (COER)

Tablets prepared so that an initial dose of drug is released immediately and a second dose follows after. They are best suited for treatment of chronic conditions requiring repeated dosing.

Repeat-action tablets

These are critical to the development of oral extended-release products

In vitro-in vivo correlations (IVIVCs) or relationships

Dosage forms that aim to protect a drug destroyed by gastric fluids, reduce gastric distress caused by drugs particularly irritating to the stomach, and

facilitate GI transit for drugs that are better absorbed from the intestines.

Delayed-Release Oral Dosage Forms

USP test for drug release for ER and delayed-release articles is based on?

Drug dissolution against elapsed test time

What USP Chapter contains descriptions of the various test apparatus and procedures?

Chapter 724

How many percent of aspirin dose dissolved must be met over an hour?

15%-40%

How many percent of aspirin dose dissolved must be met over two hours?

25%-60%

How many percent of dose dissolved must be met over four hours?

35%-75%

How many percent of dose dissolved must be met over eight hours?

Not less than 70%

What are the two methods performed to demonstrate uniformity of dosage units?

As described in Chapter 905:

- Weight variation

- Content uniformity

It is the most common process for developing an IVIVC model.

Level A

A predictive mathematical model for the relationship between the entire in vitro dissolution and release time course and the entire in vivo response time course

Level A

A predictive mathematical model of the relationship between summary parameters that characterize the in vitro and in vivo time courses

Level B

A predictive mathematical model of the relationship between the amount dissolved in vitro at a particular time and a summary parameter that characterizes the in vivo time course

Level C

What is the step-by=step process for developing an IVIVC model?

1. Develop formulations with different release rates or a single-release rate if dissolution is independent of condition,

2. Obtain in vitro dissolution profiles and in vivo plasma concentration profiles for these formulations

3. Estimate the in vivo absorption or dissolution time course for each formulation and subject using appropriate mathematical approaches.

What is the preferred aqueous medium for dissolution studies?

pH not exceeding 6.8

In determining in vitro dissolution, what is type I USP appartus used?

Basket

In determining in vitro dissolution, what is type II USP appartus used?

Paddle

In determining in vitro dissolution, what USP appartus are preferred?

Type I and II

In determining in vitro dissolution, what is type III USP appartus used?

Reciprocating cylinder

In determining in vitro dissolution, what is type IV USP appartus used?

Flow-through cell

The dissolution profiles of at least ______ individual dosage units from each lot should be determined.

12

For in vivo studies, human subjects are used in the __________ state unless the drug is not well tolerated, in which case the studies may be conducted in the ________.

Fasted, fed

Acceptable data sets have been shown to be generated with the use of _______ human subjects.

6-36

What type of studies are preferred in IVIVCs?

Crossover studies

Patients should be advised that modified-release tablets and capsules should not be _____________.

Crushed or chewed

Release mechanism of hydrophilic matrix

Dissolution/diffusion

Release mechanism of inert matrix

Diffusion

Release mechanism of microparticulate reservoir

Diffusion

Release mechanism of hybrid microparticulate reservoir in matrix

Diffusion

Release mechanism of single reservoir

Diffusion

Release mechanism of osmotic tablets

Osmotic pressure

Release mechanism of ion exchange

ph or ion displacement