CONTROLLED-RELEASE &SUSTAINED-RELEASEDOSAGE FORMSPharmaceutical Manufacturing-4

› The improvement in drug therapy is a consequence of not only thedevelopment of new chemical entities but also the combination ofactive substances and a suitable delivery system. The treatment ofan acute disease or chronic illness is mostly accomplished bydelivery of one or more drugs to the patient using variouspharmaceutical dosage forms. Tablets, pills, capsules,suppositories, creams, ointments, liquids, aerosols, and injectionsare in use as drug carriers for many decades.

› These conventional types of drug delivery systems are known toprovide a prompt release of the drug. Therefore, to achieve as wellas to maintain the drug concentration within the therapeuticallyeffective range needed for treatment, it is often necessary to takethis type of drug several times a day, resulting in the significantfluctuation in drug levels

› For all categories of treatment, a major challenge is to definethe optimal dose, time, rate, and site of delivery. Recentdevelopments in drug delivery techniques make it possibleto control the rate of drug delivery to sustain the duration oftherapeutic activity and/or target the delivery of drug to aspecific organ or tissue.

› The basic rationale for controlled drug delivery is to alter thepharmacokinetics and pharmacodynamics ofpharmacologically active moieties by using novel drug deliverysystems or by modifying the molecular structure and/orphysiological parameters inherent in a selected route ofadministration. It is desirable that the duration of drug actionbecome more a design property of a rate-controlled dosageform and less, or not at all, a property of the drug molecules’inherent kinetic properties.

The rationale for development and use of controlled dosage formsmay include one or more of the following arguments:

1. Decrease the toxicity and occurrence of adverse drug reactionsby controlling the level of drug and/or metabolites in the bloodat the target sites.

2. Improve drug utilization by applying a smaller drug dose in acontrolled – release form to produce the same clinical effect asa larger dose in a conventional dosage form.

3. Provide a uniform blood concentration and/or provide a morepredictable drug delivery.

4. Provide greater patient convenience and better patientcompliance by significantly prolonging the interval betweenadministrations.

5. Control the rate and site of release of a drug that acts locally sothat the drug is released where the activity is needed ratherthan at other sites where it may cause adverse reactions.

› A controlled - release drug delivery system serves primarilytwo functions. First, it involves the transport of the drug to aparticular part of the body. This may be accomplished in twoways, parenterally and nonparenterally. Second, the release ofactive ingredients occurs in a controlled manner, dependingon the preparation of dosage forms. This determines the rateat which a drug is made available to the body once it has beendelivered.

› Controlled drug delivery occurs when a biomaterial, eithernatural or synthetic, is judiciously combined with a drug orother active agent in such a way that the active agent isreleased from the material in a predesigned manner. To besuccessfully used in controlled drug delivery formulations, amaterial must be chemically inert and free of leachableimpurities.

Controlled - release systems provide numerous benefits over conventional dosage forms.

› Conventional dosage forms are not able to control either the rate of drug delivery or the target area of administration and provide an immediate or rapid drug release.

› The duration of therapeutic efficacy is dependent upon the frequency of administration, the half – life of the drug, and the release rate of dosage forms. In contrast, controlled – releasedosage forms not only are able to maintain therapeutic levels of drug with narrow fluctuations but also make it possible to reduce the frequency of drug administration.

› The primary objectives of controlled drug delivery are toensure safety and to improve efficacy of drugs as well aspatient compliance. This is achieved by better control ofplasma drug levels and less frequent dosing. Forconventional dosage forms, only the dose (D) and dosinginterval (τ) can vary above which undesirable or side effectsare elicited. As an index of this window, the therapeutic index(TI) can be used. This is often defined as the ratio of lethaldose (LD50) to median effective dose (ED50). Alternatively,it can be defined as the ratio of maximum drugconcentration (Cmax) in blood that can be tolerated to theminimum concentration (Cmin) needed to produce anacceptable therapeutic response.

Different types of modified release systems can be defined

› Sustained release (extended release) that permits a reduction in dosing frequency as compared to the situation in which the drug is presented as a conventional form

› Delayed release when the release of the active ingredient comes sometimes other than promptly after administration

› Pulsatile release when the device actively controls the dosage released following predefined parameters

CONTROLLED - RELEASE ORAL DOSAGE FORMS

› Oral drug delivery is the preferred route for drugadministration because of its convenience, economy, and highpatient compliance compared with several other routes.

› Anatomically, the alimentary canal can be divided into aconduit region and digestive and absorptive regions. Theconduit region includes the mouth, pharynx, esophagus, andlower rectum. The digestive and absorptive regions includethe stomach, small intestine, and all parts of the largeintestine except the very distal region.

› Gastrointestinal Tract: Physical Dimensions and Dynamics

› The role of the stomach in drug and nutrition absorption is verylimited, and it acts primarily as a reception area for oral dosageforms. Nonionic, lipophilic molecules of moderate size can beabsorbed through the stomach only to a limited extent owing tothe small epithelial surface area and the short duration of contactwith the stomach epithelium in comparison with the intestine. Thetransit time in the GI tract varies from one person to another andalso depends upon the physical properties of the object ingestedand the physiological conditions of the alimentary canal

› After passing through the stomach, the next organ that a drug orbioactive compound encounters is the small intestine. Theintestinal epithelium is composed of absorptive cells (enterocytes)interspersed with goblet cells (specialized for mucus secretion) anda few enteroendocrine cells (that release hormones). Theenterocytes of intestinal epithelium are the most important cells inview of the absorption of drugs and nutrients. Histologically,colonic mucosa resembles the small intestinal mucosa, the absenceof villi being the major difference. The microvilli of the largeintestine enterocytes are less organized than those of the smallintestine. The resulting decrease in the surface area of the colonleads to a low absorption potential in comparison with the smallintestine. However, the colonic residence time is longer than thatfor the small intestine, providing extended periods of time for theslow absorption of drugs and nutrients.

› Oral controlled drug delivery is a system that provides thecontinuous delivery of drugs at predictable and reproduciblekinetics for a predetermined period through- out the courseof GI transit. Also included are systems that target thedelivery of a drug to a specific region within thegastrointestinal tract (GIT) for either local or a systemicaction. All the oral controlled drug delivery systems havelimited utilization in the GI controlled administration of drugsif the systems cannot remain in the vicinity of the absorptionsite for the lifetime of the drug delivery.

› In the vicinity of the absorption site for the lifetime of the drugdelivery. In the exploration of oral controlled-release dosageforms, one encounters three areas of potential challenges:

1. Drug Delivery System: To develop a viable oral controlled-releasedrug delivery system capable of delivering a drug at atherapeutically effective rate to a desirable site for the durationrequired for optimal efficacy.

2. Modulation of GI Transit Time: To modulate the GI transit time sothat the drug delivery system developed can be transported to atarget site or to the vicinity of an absorption site and reside therefor a prolonged period of time to maximize the delivery of a drugdose.

3. Minimization of Hepatic First-Pass Elimination: If the drug to bedelivered is subjected to extensive hepatic first-pass elimination,preventive measures should be devised to either bypass or minimizethe extent of hepatic metabolic effect.

Physical model illustrating various

physiological processes during gastrointestinal

transit.

Profile of drug level in blood: ( a ) traditional dosing of tablets;

( b ) controlled drug delivery dose.

The degree to which a delivery system can

achieve standard release profiles for

a variety of chemically and physically diverse,

pharmaceutically active molecules is

a measure of a delivery system’s efficacy and

flexibility

› Biological Half-Life The usual goal of an oral controlled-release dosage form is to maintain therapeutic blood levels,over an extended period of time. A drug must be absorbedand enter the circulation at approximately the same rate atwhich it is eliminated. The elimination rate is quantitativelydescribed by the half-life (t1/2

).

› Therapeutic compounds with short half-lives are excellentcandidates for controlled/sustained-release preparations,since this can reduce dosing frequency.

› Gastrointestinal Tract and Absorption:

› The design of a controlled-release dosage form should bebased on a comprehensive picture of drug disposition. Boththe pharmacokinetic property and biological responseparameter have a useful range for the design of sustained-and controlled-release products. The potential problemsinherent in oral controlled-release oral dosage forms generallyrelate to (i) interactions between the rate, extent, andlocation that the dosage form releases the drug and (ii) theregional differences in GI physiology.