Time-Release Product Concepts

June 26, 2001

7 Min Read
Time-Release Product Concepts

Time-Release Product Concepts

by Dimitri Papadimitriou, Ph.D.

The concept of dosage form development is defined as the delivery ofspecific and reproducible amounts of pharmacologically active compounds to thebody in the maximum amount possible. Today's most frequently utilized dosageforms are orally administered solids formulated as tablets, capsules or powders.The emergence of such delivery forms in the nutritional arena was not for doseaccuracy, other than addressing considerations dealing with taste, amount andpracticality of administration of herbs. However, current developments emergingout of standardization of plant extracts to specific compounds and theirsubsequent incorporation into products that meet drug-like quality criteriaprovide the impetus of dosage form implementation. This raises two fundamentalconcerns: product bioavailability and accuracy of product delivery. Althoughboth are intricately connected, the discussion remains focused on the deliveryaspect at an introductory level for solid products, specifically those thatdemonstrate an attribute of time release of actives.

Time-release products intend to improve delivery efficacy and/oreffectiveness; for instance, the frequency of dosing can be reduced and, incertain cases, the actual daily dose can be reduced, offering the manufacturer afinancial benefit. A variety of techniques have been used to prepare oraltime-release delivery systems, and combining them is often done to maximizetheir advantages. One of the goals behind developing time-release products wasto maintain a steady level of concentration of actives in the blood. Atime-release product essentially controls the rate at which a compound isavailable for absorption. In doing so, a balance can be achieved between theamount absorbed and that being excreted. This balance can smooth the peaks andvalleys (fluctuations) of the concentration of the active in the blood,maintaining a steady level. This significantly improves the product's efficacysince the effective concentration range that a compound needs to be at any giventime can be monitored. An effective range (therapeutic or pharmacologicalwindow) is determined by the body's tolerance for the compound of interest.Going over the high end of this range, one may experience toxic effects whileconcentrations below the lower end of the range render the product ineffective.This is achieved by most time-release delivery systems that release smallamounts of active at frequent intervals.

Orally administered time-release delivery systems are preferred because theyoffer flexibility in dosage-form design and are relatively safe in spite of thedifficulties of releasing actives due to the variable gastrointestinalenvironment. Still, such systems are not suitable for all nutritionalsupplements and the rationale for their development depends on certainconsiderations.

  • If the active compound has a long half-life (over six hours), it issustained on its own.

  • If the pharmacological activity of the active is not related to its bloodlevels, time releasing then has no purpose.

  • If the absorption of the active involves an active transport, thedevelopment of a time-release product may be problematic.

  • Finally, if the active has a short half-life, it would require a largeamount to maintain a prolonged effective dose. In this case, a broad therapeuticwindow is necessary to avoid toxicity; otherwise, the risk is unworthy to takeand another mode of administration would be recommended.

Beyond these considerations, there are certain limitations associated withtime-release product development.

  • The most one can hope for in an oral time-release delivery system is 12hours due to its effective transit in the gastrointestinal tract.

  • There is a significant time span recognition between desired activity andadverse effect.

  • Poor formulation design could result in dose dumping or poor dispersion ofthe actives, creating a "reservoir" effect that could allow largeconcentrations of the active to come in contact with the GI mucous and enhancelocal toxic effects of a potentially irritant active.

  • Reduction of absorption rate to reduce side effects of actives might resultin reduced absorption.

  • Inappropriate dosing intervals that result in a significant residual amountof active in relation to the dose could push the steady level into the toxicrange.

There have been many techniques developed for producing the variety oftime-release products. Therefore, there is also a plethora of terms thatessentially describe the release mode, duration and rate a product exhibits.Based on such techniques, time-release products can be categorized in fourgroups.

Delayed Release

This mode of action was the first type of time-released products, developedin the 1950s with the intention of providing patient comfort and thus improvedcompliance. In this instance, the action is delayed post product administration,with the intention of reducing the side effects stemming from irritation fromactives on the stomach or reducing active degradation due to gastric acidity.One technique employed to achieve this is enteric coating procedures via pHsensitive coating materials. Another is use of materials that will erode withtime and when the coating is dissolved, the actives are released in one burstthat delivers the full dose rather than continuously releasing. Tablets,capsules and beads are used for this purpose. In the case of beads, these can becovered with the coating material of increasing thickness to achieve acontinuous release of active as controlled by the thickness or permeability ofthe coating film. The technique is easy to use for modifying time release andmore than one active can be incorporated in the dosage form as a mixture ofbeads. Another technique used for this mode of action involves microencapsulation. In this instance, the coating remains intact and the activediffuses through it, usually in a first-order release rate. This technique isnormally used on very small particles (granules or crystals). Examples ofdelayed release are fish oils in enteric-coated soft gels, enteric-coated garlictablets or enteric-coated probiotics.

Repeat Action

This mode combines two mechanisms of release, an immediate and a delayed, inone unit dose. One part readily delivers the active, supplying the dose requiredto achieve efficacy as rapidly as possible, while the other part supplies theactive as a time release. A two-layer tablet best exemplifies this release mode.Other examples include time-release tablets that are coated with the active forimmediate release, or capsules containing beadlets that release the actives atdifferent time intervals. This time-release mode is particularly suitable whenthe absorption of the active occurs at specific sites or when the activity ofthe immediate release component is to be altered by the second portion when itreaches a certain concentration level.

Sustained Release

This mode of release delivers the active continuously slowly. The releaseprofile can follow first-order kinetics, meaning upon onset the release rate isfast and then slows down with time. This is typical when the active is embeddedin a tablet matrix and the release rate is governed by diffusion. The matrixitself can be errodable or not during this process. Materials that gel when incontact with water represent eroding matrices, while non-eroding ones are madeof silica or waxes. It is possible to achieve a zero order release by properlycontrolling the matrix erosion and the diffusion of the active. In thisinstance, the release rate remains constant for most of the time it takes theactive to be released in its entirety from the matrix. This mode of release ispopular because it utilizes conventional equipment and normal processing usedfor tablet manufacturing. The key to the success of these types of time-releaseproducts depends on how physiological factors (pH, gastric emptying, ionicenvironment and concentration of bile acids) interact with the matrix and affectthe release rate of the active.

Controlled Release

All preceding modes of release are "active programmed," meaningthat some biological signal is required to initiate the release. This last modeof action is "passive programmed," where the release is constant andindependent of the physiological environment. The release is predictable andsteady. This mode is best exemplified with implants, subcutaneous injections orby an IV constant drip. In the case of tablets, the "osmotic pump"demonstrates this type of release pattern, zero order thus being linear withtime. The product is a tablet coated with a semi-permeable membrane that allowsbody fluids to enter and build up pressure in the tablet core, forcing theactive to be expelled from an orifice drilled on top of the tablet surface via alaser beam. Although such release patterns are desirable due to the constantrate of release, the manufacture of this type of dosage form requiressophisticated equipment and specialized handling procedures. Only a fewenterprises can afford the technology, particularly because this technology isextensively patent protected.

Cost, availability of technology, and lack of creativity are the limitingfactors for further developing time-release products. The field remains open fordevelopment as long as new materials become available that can be implementedfor this purpose.

Dimitri Papadimitriou, Ph.D., is with Arevno Consultants. He may be contactedat [email protected].

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