CHAPTER 9

Solid Oral ModifiedRelease Dosage Form and Drug Delivery Systems

SOLID ORAL MODIFIED-RELEASE DOSAGE FORMS AND DRUG DELIVERY SYSTEMS

INTRODUCTION


Describes solid oral dosage forms and drug delivery system that virtue of formulation and product design have modified drug release features Modified release products provide either delayed release or extended release of drug Most delayed release products are enteric-coated tablets or capsules designed to pass through the stomach unaltered, later to release their medication within the intestinal tract Enteric coatings are used either to protect a substance from destruction by gastric fluids or to irritating drugs

SOLID ORAL MDIFIED-RELEASE DOSAGE FORMS AND DRUG DELIVERY SYSTEMS Extended release products 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
RATIONAL FOR EXTENDED RELEASE PHARMACEUTICALS


Extended release tablets & capsules = take once or twice daily Conventional forms = 3 to 4 times daily to achieve same TE For non oral rate-controlled DDSs = 24 hours for most transdermal patches to months to years Example: Lovenorgestrel subdermal implants (Norplat System),

MULTIPLE DAILY DOSING

inconvenient for the patient and can result in missed doses, made-up doses, and noncompliance with the regimen  when doses are not administered on schedule, the resulting peaks and valleys reflect the optimum drug therapy


ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS OVER CONVENTIONAL FORMS



Reduction in drug blood levels fluctuation

controlling the rate of release eliminated peaks and valleys of blood levels

Frequency reduction in dosing

extended-release products frequently deliver more than less often than conventional form DepoFoam Drug Delivery System

Enhanced convenience and compliance with less

frequency in dosing, a patient is less apt to neglect taking a dose, also it provides grater convenience with day and night administration

ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS OVER CONVENTIONAL FORMS



Reduction in adverse side effects because of fewer blood level peaks Outside therapeutic range and into toxic range, adverse side effects are less frequent

Reduction in overall health care costs 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 drugs and monitor patients

DISADVANTAGE OF ETENDED-RELEASE DOSAGE FORMS OVER CONVENTIONAL FORMS

loss of flexibility in adjusting the drug dose and/or dosage regimen

risk of sudden and total drug release

dose dumping due to failure in technology

TERMINOLOGY
1. Sustained Release (SR) 2. Sustained Action (SA) 3. Extended Release (ER) 4. Long Acting (LA) 5. Prolong Action (PA) 6. Controlled Release (CR) 7. Timed Release (TR)

TERMS AND ABBREVIATIONS USED FOR EXTENDEDRELEASE DOSAGE FORMS



SR (Sustained Release)

PA (Prolonged Action)

SA (Sustained Action)

CR (Controlled Release)

TERMS AND ABBREVIATIONS USED FOR EXTENDED-RELEASE DOSAGE FORMS



ER (Extended Release)

TR (Time Release)

LA (Long Acting)

TERMS AND ABBREVIATIONS USED FOR EXTENDED-RELEASE DOSAGE FORMS



Products bearing these descriptions differ in design and performance and must be examined individually to ascertain their respective features

Rate-Controlled delivery  applied to certain types of drug delivery systems in

which the rate of delivery is controlled by features of service rather than by physiologic or environmental conditions like gastrointestinal pH or drug transit time through the gastrointestinal tract

TERMS AND ABBREVIATIONS USED FOR EXTENDED-RELEASE DOSAGE FORMS Modified release


has come into general use to describe 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

Extended-release


dosage forms of this type are the ones that allow a reduction in dosing frequency form that necessitated by a conventional dosage forms, such as solution or an immediate-release drug dosage form

TERMS AND ABBREVIATIONS USED FOR EXTENDED-RELEASE DOSAGE FORMS

Delayed release


releases the drug at a time other than promptly after administration. The delay may be time base or base on the influence of environmental conditions such as gastrointestinal pH

Repeat action


two single doses of medication; one for immediate release; another one for modified release

Targeted release


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

Extended Release Oral Dosage Forms (Successful ER Product)

1. Release from dosage forms at a predetermine rate 2. Dissolve in GT 3. Maintain sufficient Gastrointestinal residence time 4. Be absorbed at a rate that will replace the amount of drug being metabolized and excreted

CHARACTERISTICS OF EXTENDED-RELEASE PRODUCTS

1.

They exhibit very slow nor very fast rates of absorption and excretion drugs with slow rates of absorption and excretion are usually inherently long-acting, and it is not necessary to prepare them in extended-release forms drug with very short half-lives, less than 2 hours, are poor candidates for extended release drugs that act by affecting enzyme systems may be loner acting than indicated by their quantitative half-lives because of their residual effects and recovery of the diminished biosystem

CHARACTERISTICS OF EXTENDED-RELEASE PRODUCTS

2. They are uniformly absorbed from the gastrointestinal tract


they must have good aqueous solubility and maintain adequate residence time in the gastrointestinal tract drugs absorbed poorly or at varying and unpredictable rates are not good candidates for extended-release products

3. They are administered in relatively small doses



drugs with large single doses frequently are not suitable for extended release because the tablet or capsule needed to maintain a sustained therapeutic blood level of the drug would be too large for the patient to swallow easily

CHARACTERISTICS OF EXTENDED-RELEASE PRODUCTS

4.


They possess a good margin of safety the most widely used measure of the margin of a drugs safety is its therapeutic index, that is, the median toxic dose divided by the median affective dose the larger the therapeutic index, the safer the drug drugs that are administered in very small doses or possess very narrow therapeutic indices are poor candidates for formulations because of technologic limitations of precise control over release rates and the risk of dose dumping due to a product defect

 

CHARACTERISTICS OF EXTENDED-RELEASE PRODUCTS

5. They are used in the treatment of chronic rather than acute conditions


drugs for acute conditions require greater adjustment of the dosage by the physician than that provided by extended-release products

BASIS OF DRUG RELEASE



modifying drug dissolution by controlling excess of biologic fluids to the drug through the use of barrier coatings controlling drug diffusion rate from dosage forms chemical reaction or interaction between the drug substance or its pharmaceutical barrier and site-specific biologic fluids

COATED BEADS, GRANULES AND MICROSPHERES



using conventional pan coating or air suspension coating, a solution of the drug substance is placed on small intact nonparent seeds or beads made of sugar and stand or on microcrystalline cellulose sphere

Nonpareil seeds  425-850 m

COATED BEADS, GRANULES AND MICROSPHERES

Microcrystalline cellulose  More durable during production than sugar-based cores  170-600 m

Lipid materials used to coat granules



Beeswax

Carnauba wax

Glyceryl monostearate

Cetyl alcohol

Cellulosic material (ethyl cellulose)

Lipid materials used to coat granules



Aqueous coating system eliminate the hazards and environmental concerns associated with organic based solvent systems The thicker the coat, the more resistant to penetration and the more delayed will be the drug release and dissolution Spansule

MULTITABLET SYSTEMS


small spheroidal compressed tablets 3 to 4 mm in diameter may be prepared each capsule contain 8 to 10 minitablets some uncoated for immediate release and others coated for extended drug release

MICROENCAPSULATED DRUG
Microencapsulation


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

Gelatin


A common wall forming material and synthetic polymers, such as polyvinyl alcohol, ethyl cellulose, polyvinyl chloride and other materials may be used

ENCAPSULATION PROCESS


dissolving the wall material encapsulated material is added to the mixture and the thoroughly stirred a solution to second material is added, example of acacia the final dry microcapsules are free-flowing discrete particles of coated material wall material constitute into 20% of the total particle weigh

ADVANTAGE OF MICROENCAPSULATION
administered dose of a drug is subdivided into small units that are spread over a large area of the gastrointestinal tracts, which may enhance absorption by diminishing local drug concentration

Micro-K ExtenCaps

Encapsulation. All of the single and combination capsules are produced here. The empty gelatin capsules are placed in hoppers and free-flowing to the machine. The bottom portion of the capsule is filled, which is gravity-fed from a stainless steel bin into the machines hopper. An average of 6 million capsules a day can be produced.

EMBEDDING DRUG 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

Hydrophilic cellulose polymers  commonly used as the excipient base in tablet matrix systems

EFFECTIVENESS OF THE HYDROPHILIC MATRIX IS BASED ON:



successive process of hydration on the polymers surface

gel formation on the polymers surface

tablet erosion

subsequent and continuous release of drug

Hydroxypropyl Methyl Cellulose (HPMC)



a free flowing powder; commonly used to provide the hydrophilic matrix

A successful hydrophilic matrix system must contain the following:

polymer must form a gelatinous layer rapidly enough to protect the inner core of the tablet from disintegrating too rapidly after ingestion 20% of HPMC results in satisfactory rates of release for an extended-release tablet formation e.g Oramorph SR Tablet

manufacturers may prepare two-layer tablets



one layer containing the uncombined drug for immediate release the other layer having the drug encoded in a hydrophilic matrix for extended release

they may also prepare a three-layer tablets

 

outer layers containing the drug for immediate release some commercial tablets are prepared with an inner core containing the extended-release portion of the drug and an outer shell containing drug for immediate release

EMBEDDING DRUG IN INERT PLASTIC MATRIX



Drug is granulated with an inert plastic material such as polyethylene, polyvinyl acetate, o polymethacrylate and the granulation is compressed into tablets released from the inert plastic matrix by diffusion retains its shape during leaching of he drug and during its passage through the alimentary tract Example: Gradumet

COMPLEX FORMATION
form complexes that may be slowly soluble in body fluids, depending on the pH of the environment  slow dissolution rate


Example: Rynatan


salts of tannic acid, tannates, provide this quality in a variety of proprietary products

ION EXCHANGE RESINS



solution of a cationic drug may be passed through a column containing an ion exchange resin, forming a complex by the replacement of hydrogen atoms release of the drug depends on the pH and electrolyte concentration in the gastrointestinal tract release is greater in the acidity of the stomach than in the less acidic environment of the small intestine hydrocodone polistirex (Tussionex) and chlorpheniramine polistirex suspension and phentermine resin capsules

Mechanism of ion exchange resins:

In the stomach 1. drug resinate + HCl 2. resin salt + HCl acidic resin + drug hydrochloride

resin chloride + acidic drug

In the intestine 1. drug resinate + NaCl 2. resin salt + NaCl sodium resinate + drug hydrochloride

resin chloride + sodium salt of drug

release is extended over 12 hours by ionic exchange

Drug suspension or solution Osmotic drug core Deliver orifices

Delivery orifice

Water

Water

Rate controlling Semipermeable membrane Osmotic core containing drug membrane

Polymeric osmotic push compartment

A. Elementary OROS osmotic pump drug delivery system

B. OROS Push-Pull Osmotic System

OSMOTIC PUMP


the pioneer oral osmotic pump drug delivery system is the Oros system developed by Alza composed of a core tablet surrounded by a semipermeable membrane coating having a 0.4mm diameter hole produced by laser beam. Example: Acutrim core tablet has two layers, one containing the drug and the other containing a polymeric osmotic agent the system is designed such that only a few drops of water are drawn into the tablet each hour function of the tablet depends on the osmotic gradient between the contents of the two-layer core and the fluid in the gastrointestinal tract

Drug release rate may be altered by :



changing the surface area

thickness

composition of the membrane and/or diameter of the drug release orifice

Release rate is not affected by:



gastrointestinal acidity or alkalinity fed conditions gastrointestinal motility

Gastrointestinal therapeutic system (GIT systems)  is employed in the manufacture of Glucotrol XL Extended release tablets, and Procardia XL release tablets


the initial drug is released 4 to 5 hours after tablet ingestion

REPEAT-ACTION TABLETS


the initial dose of drug is released immediately and a second dose follows later released 4 to 6 hours after administration Example: Repetabs they are best suited for treatment of chronic conditions requiring repeated dosing low dosage and fairly rapid rates of absorption and excretion

 

DELAYED-RELEASE ORAL DOSAGE FORMS



release of a drug that may be intentionally delayed until it reaches the intestines for several reasons protect a drug destroyed by gastric fluids reduce gastric distress caused by drugs of particularly irritating to the stomach to facilitate gastrointestinal transit for drugs that are absorbed from the intestines Examples: Enteric Coated Enseals Lilly; Ecotrin SmithKline

PROPERTIES OF AN ENTERIC COATING TABLETS/CAPSULES

     

pH dependent breaks down in the less acidic environment of the intestine time dependent erodes by moisture over time during gastrointestinal transit enzyme dependent deteriorating as a result of hydrolysis-catalyzing action of intestinal enzyme

AGENTS USED FOR ENTERIC COATING OF CAPSULES AND TABLETS

fats

fatty acids

waxes

shellac

cellulose acetate phthalate

EXAMPLES OF MODIFIED-RELEASE TABLETS AND CAPSULES OFFICIAL IN THE USP

Delayed release
Aspirin delayed-release tablets Dirithromycin delayed-release tablets Doxycycline hyclate delayed-release capsules Erythromycin delayed-release capsules Oxtriphylline delayed-release tablets

Extended release
Diltiazem extended-release capsules Disopyramide phosphate extended-release capsules Isosorbide dinitrate extended-release tablets and capsules Propanolol hydrochloride extended-release capsules Theophylline extended-release capsules

USP Requirements and FDA Guidelines for Modified Release Dosage Forms 1. DRUG RELEASE


based on drug dissolution from the dosage unit against elapsed test time Example: Aspirin Extended-release Tablets Aspirin dissolution rate: Time (hours) 1.0 2.0 4.0 8.0

Amount dissolved 15 40% 25 60% 35 75% Not less than 70%

2. UNIFORMITY OF DOSAGE UNITS



uniformity of dosage units may be demonstrated by either of two methods, weight variations or content uniformity

3.

IN VITRO-IN VIVO CORRELATIONS

critical to the development of oral extended-release products important throughout product development, clinical evaluation submission of an application for FDA approval for marketing, and during post approval for any proposed formulation or manufacturing changes it provides guidance to sponsors of new drug applications and abbreviated new drug applications and abbreviated new drug applications for extended release of oral products

IVIVC provides methods of:



developing an IVIVC and evaluating its predictability using an IVIVC to establish dissolution specifications applying an IVIVC as a surrogate for in vitro-in vivo bioequivalence during the approval process or during post approval for certain formulation or manufacturing changes

3 Categories of IVIVCs include in the document

Level A


the relationship between the entire in vitro dissolution and release time course and the entire in vivo response time course Example: the time course of plasma drug concentration or amount of drug absorbed

Level B


predictive mathematical model of the relationship between summary parameters that characterize in vitro and in vivo time courses Example: models that relate the mean in vivo dissolution time to the mean in vitro dissolution time

Three Categories of IVIVCs are include in the document:

Level C


a predictive mathematical model of the relationship between the amount dissolved in vitro at a particular time and a summary parameter that characterizes the time in vivo time course or area under the curve the level of IVIVCs may be useful in the early stages of formulation development when pilot formulations are being selected

MOST COMMON PROCESS FOR DEVELOPING IVIVC MODEL (LEVEL A)



develop formulations with different release rates or a single release rate if dissolution is independent of condition obtain in vitro dissolution profiles and in vivo plasma concentration profiles for these formulations estimate the in vivo absorption or dissolution time course for each formulation and subject using appropriate mathematical approaches

CRITERIA IN DEVELOPMENT APPLICABLE TO THE DEVELOPMENT OF IVIVCS ARE THE FOLLOWING

in determining in vitro dissolution, USP dissolution apparatus; type I (basket) or type II (paddle) is preferred, although type III (reciprocating cylinder) or type IV (flow-through cell) may be applicable in some substances

aqueous medium with a pH not exceeding 6.8 is preferred as the medium for dissolution studies. For poorly soluble drugs, a surfactant may be added

the dissolution profiles of at least 12 individual dosage units from each lot should be determined

CRITERIA IN DEVELOPMENT APPLICABLE TO THE DEVELOPMENT OF IVIVCS ARE THE FOLLOWING

for vivo studies, human subjects are used in the fasted state unless the drug is not well tolerated, in which case the studies may be conducted in the fed state. Acceptable data sets have been shown to be generated with use of 6 to 36 human subjects

crossover studies are preferred, but parallel studies or crossstudy analysis may be acceptable using a common reference treatment product, such as an intravenous solution, an aqueous oral solution, or an immediate-release product

LABELING


they must be specific for the monograph article aspirin delayed-release tablets must state that the tablets are enteric coated capsules must indicate whether the product is intended for dosage every 12 to 24 hours and state which in vitro drug release test the product complies

CLINICAL CONSIDERATIONS


not to be used interchangeably or concomitantly with immediate-release forms of the same drug patients using a modified release product should not be changed into immediate release without consideration to the blood concentration patients should not be changed to another extended-release product unless there is assurance of equivalent bioavailability

CLINICAL CONSIDERATIONS


different product can result in a marketed shift in the patients drug blood level because of differences in drug release characteristics modified release tablets and capsules should not be crushed or chewed patients if fed through the nasogastric tube may receive modified-release medications nonerodible plastic matrix shells and osmotic tablets remain intact throughout gastrointestinal transit and the empty shells or ghosts from osmotic tablets may be seen in the stool

Propriety Modified-Release Oral Dosage Forms

Delayed Release

Propriety Modified-Release Oral Dosage Forms

ExtendedRelease Coated Particles and Breads

Propriety Modified-Release Oral Dosage Forms

Extended-Release Inert Matrix

Propriety Modified-Release Oral Dosage Forms

Extended Release Hydrophilic/ Eroding Matrix

Propriety Modified-Release Oral Dosage Forms

Extended-Release Microencapsulated Drug

Extended-Release Osmotic