CONTROLLED-RELEASE & SUSTAINED-RELEASE DOSAGE FORMS Pharmaceutical Manufacturing-4
The improvement in drug therapy is a consequence of not only the development of new chemical entities but also the combination of active substances and a suitable delivery system. The treatment of an acute disease or chronic illness is mostly accomplished by delivery of one or more drugs to the patient using various pharmaceutical dosage forms. Tablets, pills, capsules, suppositories, creams, ointments, liquids, aerosols, and injections are in use as drug carriers for many decades. These conventional types of drug delivery systems are known to provide a prompt release of the drug. Therefore, to achieve as well as to maintain the drug concentration within the therapeutically effective range needed for treatment, it is often necessary to take this type of drug several times a day, resulting in the significant fluctuation in drug levels
For all categories of treatment, a major challenge is to define the optimal dose, time, rate, and site of delivery. Recent developments in drug delivery techniques make it possible to control the rate of drug delivery to sustain the duration of therapeutic activity and/or target the delivery of drug to a specific organ or tissue.
The basic rationale for controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and/or physiological parameters inherent in a selected route of administration. It is desirable that the duration of drug action become more a design property of a rate-controlled dosage form and less, or not at all, a property of the drug molecules inherent kinetic properties.
The rationale for development and use of controlled dosage forms may include one or more of the following arguments: 1. Decrease the toxicity and occurrence of adverse drug reactions by controlling the level of drug and/or metabolites in the blood at the target sites. 2. Improve drug utilization by applying a smaller drug dose in a controlled release form to produce the same clinical effect as a larger dose in a conventional dosage form. 3. Provide a uniform blood concentration and/or provide a more predictable drug delivery. 4. Provide greater patient convenience and better patient compliance by significantly prolonging the interval between administrations. 5. Control the rate and site of release of a drug that acts locally so that the drug is released where the activity is needed rather than at other sites where it may cause adverse reactions.
A controlled - release drug delivery system serves primarily two functions. First, it involves the transport of the drug to a particular part of the body. This may be accomplished in two ways, parenterally and nonparenterally. Second, the release of active ingredients occurs in a controlled manner, depending on the preparation of dosage forms. This determines the rate at which a drug is made available to the body once it has been delivered. Controlled drug delivery occurs when a biomaterial, either natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner. To be successfully used in controlled drug delivery formulations, a material must be chemically inert and free of leachable impurities.
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 release dosage 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 to ensure safety and to improve efficacy of drugs as well as patient compliance. This is achieved by better control of plasma drug levels and less frequent dosing. For conventional dosage forms, only the dose (D) and dosing interval (τ) can vary above which undesirable or side effects are elicited. As an index of this window, the therapeutic index (TI) can be used. This is often defined as the ratio of lethal dose (LD50) to median effective dose (ED50). Alternatively, it can be defined as the ratio of maximum drug concentration (Cmax) in blood that can be tolerated to the minimum concentration (Cmin) needed to produce an acceptable 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 drug administration because of its convenience, economy, and high patient compliance compared with several other routes. Anatomically, the alimentary canal can be divided into a conduit region and digestive and absorptive regions. The conduit region includes the mouth, pharynx, esophagus, and lower rectum. The digestive and absorptive regions include the stomach, small intestine, and all parts of the large intestine except the very distal region.
Gastrointestinal Tract: Physical Dimensions and Dynamics The role of the stomach in drug and nutrition absorption is very limited, and it acts primarily as a reception area for oral dosage forms. Nonionic, lipophilic molecules of moderate size can be absorbed through the stomach only to a limited extent owing to the small epithelial surface area and the short duration of contact with the stomach epithelium in comparison with the intestine. The transit time in the GI tract varies from one person to another and also depends upon the physical properties of the object ingested and the physiological conditions of the alimentary canal
After passing through the stomach, the next organ that a drug or bioactive compound encounters is the small intestine. The intestinal epithelium is composed of absorptive cells (enterocytes) interspersed with goblet cells (specialized for mucus secretion) and a few enteroendocrine cells (that release hormones). The enterocytes of intestinal epithelium are the most important cells in view of the absorption of drugs and nutrients. Histologically, colonic mucosa resembles the small intestinal mucosa, the absence of villi being the major difference. The microvilli of the large intestine enterocytes are less organized than those of the small intestine. The resulting decrease in the surface area of the colon leads to a low absorption potential in comparison with the small intestine. However, the colonic residence time is longer than that for the small intestine, providing extended periods of time for the slow absorption of drugs and nutrients.
Oral controlled drug delivery is a system that provides the continuous delivery of drugs at predictable and reproducible kinetics for a predetermined period through- out the course of GI transit. Also included are systems that target the delivery of a drug to a specific region within the gastrointestinal tract (GIT) for either local or a systemic action. All the oral controlled drug delivery systems have limited utilization in the GI controlled administration of drugs if the systems cannot remain in the vicinity of the absorption site for the lifetime of the drug delivery.
In the vicinity of the absorption site for the lifetime of the drug delivery. In the exploration of oral controlled-release dosage forms, one encounters three areas of potential challenges: 1. Drug Delivery System: To develop a viable oral controlled-release drug delivery system capable of delivering a drug at a therapeutically effective rate to a desirable site for the duration required for optimal efficacy. 2. Modulation of GI Transit Time: To modulate the GI transit time so that the drug delivery system developed can be transported to a target site or to the vicinity of an absorption site and reside there for a prolonged period of time to maximize the delivery of a drug dose. 3. Minimization of Hepatic First-Pass Elimination: If the drug to be delivered is subjected to extensive hepatic first-pass elimination, preventive measures should be devised to either bypass or minimize the extent of hepatic metabolic effect.
Physical model illustrating various physiological processes during gastrointestinal transit.
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 Profile of drug level in blood: ( a ) traditional dosing of tablets; ( b ) controlled drug delivery dose.
Biological Half-Life The usual goal of an oral controlledrelease dosage form is to maintain therapeutic blood levels, over an extended period of time. A drug must be absorbed and enter the circulation at approximately the same rate at which it is eliminated. The elimination rate is quantitatively described by the half-life (t ). 1/2 Therapeutic compounds with short half-lives are excellent candidates for controlled/sustained-release preparations, since this can reduce dosing frequency.
Gastrointestinal Tract and Absorption: The design of a controlled-release dosage form should be based on a comprehensive picture of drug disposition. Both the pharmacokinetic property and biological response parameter have a useful range for the design of sustainedand controlled-release products. The potential problems inherent in oral controlled-release oral dosage forms generally relate to (i) interactions between the rate, extent, and location that the dosage form releases the drug and (ii) the regional differences in GI physiology.