Controlled drug delivery

Controlled drug delivery occurs when a polymer, whether 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 pre designed manner. The release of the active agent may be constant over a long period, it may be cyclic over a long period, or it may be triggered by the environment or other external events. In any case, the purpose behind controlling the drug delivery is to achieve more effective therapies while eliminating the potential for both under- and over-dosing. Other advantages of using controlled delivery systems can include the maintenance of drug levels within a desired range, the need for fewer administrations, optimal use of the drug in question, and increased patient compliance. While these advantages can be significant, the potential disadvantages cannot be ignored: the possible toxicity or non biocompatibility of the materials used, undesirable byproducts of degradation, any surgery required to implant or remove the system, the chance of patient discomfort from the delivery device, and the higher cost of controlled release systems compared with traditional pharmaceutical formulations. An ideal drug delivery system should be able to deliver an adequate amount of drug, preferably for an extended period of time for its optimum therapeutic activity. Most of the drugs are inherently not long lasting in the body and require multiple daily dosing to achieve the desired blood concentration to produce therapeutic activity. To overcome such problem, controlled release and sustained release delivery systems are receiving considerable attention from pharma industries worldwide. A controlled release drug delivery system not only prolongs the duration of action, but also results in predictable and reproducible drug release kinetics. One advantage of controlled release dosage forms is enhanced patient compliance. Drug delivery systems are based on the principles of solid dispersion. For most of the pharma industries existence, drug delivery induced simple, fast-acting responses via oral or injection delivery routes. Problems associated with this approach are: Reduced potencies because of partial degradation; Toxic levels of administration; Increase in costs associated with excess dosing; Compliance issue due to administration pain. Sustained release systems are the methods that can achieve therapeutically effective concentration of drug in the systemic circulation over an extended period of time, thus achieving better compliance of patients. Although sustained release oral dosage forms such as membrane-controlled systems, matrices with water-soluble/insoluble polymers or waxes and osmotic systems have been developed; intense research has recently been focused on the designation of sustained release systems for water-soluble drugs. For the development of sustained release dosage form for poorly water-soluble drugs, high solubility of drugs is the most important issue to be improved. In order to overcome the problem, a combination of solid dispersion and sustained release techniques is one of the attractive approaches. Solid dispersion technique, which has been widely used to improve the drug release, solubility and oral absorption of poorly water-soluble drugs, is a method that can achieve a super saturation of drugs. In addition to the improvement of bioavailability, most of recent researches on solid dispersion systems have been being directed toward their application to the development of extended-release dosage forms. However, several factors such as complicated preparation method, low reproducibility of physicochemical properties, difficulty of formulation development and scale-up and physical instability for solid dispersion make it difficult to apply the systems to solid dispersion dosage forms. Especially in order to maintain a super saturation level of drug for an extended time, re-crystallization of drug must be prevented during its release from dosage form. Why control drug delivery? As the cost and complexity of individual drug molecules has raised the problems with the classical delivery strategies over took their benefits. Goal of more sophisticated drug delivery techniques: " Deploy to a target site to limit side effects " Shepard drugs through specific areas of the body without degradation " Maintain a therapeutic drug level for prolonged periods of time " Predictable controllable release rates " Reduce dosing frequent and increase patient compliance Controlled release may be defined as a technique or approach by which active chemicals are made available to a specified target at a rate and duration designed to accomplish an intended effect. Controlled release technology may provide increased chemical value as well as extended product life. Advantages of an ideal controlled release dosage form over an immediate release product include: " Improved patient compliance due to reduced dosing frequency " A decreased incidence and/or intensity of the side effects " Greater selectivity of pharmacological activity " More constant and therapeutic effect " Increase of cost effectiveness Drug properties The physicochemical characteristics of the drug, in particular its aqueous solubility, should first be considered in the selection of appropriate delivery mechanism. Other drug properties effecting system design include drug stability in the system and at the site of absorption, pH dependency of the solubility, particle size, and specific surface area. The aqueous solubility and intestinal permeability of drug compounds are of paramount importance. A classification has been made whereby drugs can be considered to belong to one of the four categories: " High solubility and high permeability (best case) " High solubility and low permeability " Low solubility and high permeability " Low solubility and low permeability (worst case) This is now codified as biopharmaceutical classification system (BCS). Consider first the influence of solubility. A drug that is highly soluble at intestinal pH and absorbed by passive diffusion would probably present the ideal properties for inclusion in a sustained release dosage form. At the other end of the scale, compounds that have a low aqueous solubility (<1 mg/ml) may already posses inherent sustained release potential as a result of their low solubility. The innate advantages of low aqueous solubility in relation to sustained release would be negated if the drug also had low membrane permeability. Having achieved dissolution of the drug in gastrointestinal tract then permeability considerations become important. More than 90% absorption in vivo may be expected for compounds with permeability, P, values > 4 × 10-6 mm/s, whereas less than 20% absorption is expected when P is < 0.5 × 10-6 mm/s. Drug candidates with a permeability < 0.5 × 10-6 mm/s are likely to be unsuitable for presentation as sustained release preparations. Drug compounds that satisfy the solubility and permeability requirements should also ideally have: " A biological half life of between 2 and 6 hours so that accumulation in the body does not occur " A lack of capability to form pharmacologically active metabolites by, for example, first pass metabolism. " A dosage not exceeding 125-325 mg in order to limit the size of delivery system Biomaterials for delivery systems A range of materials have been employed to control the release of drugs and other active agents. The earliest of these polymers were originally intended for other, non biological uses, and were selected because of their desirable physical properties, for example: " Poly (urethanes) for elasticity. " Poly (siloxanes) or silicones for insulating ability. " Poly (methyl methacrylate) for physical strength and transparency. " Poly (vinyl alcohol) for hydrophilicity and strength. " Poly (ethylene) for toughness and lack of swelling. " Poly (vinyl pyrrolidone) for suspension capabilities. To be successfully used in controlled drug delivery formulations, a material must be chemically inert and free of leachable impurities. It must also have an appropriate physical structure, with minimal undesired aging, and be readily processable. Some of the materials that are currently being used or studied for controlled drug delivery include: " Poly (2-hydroxy ethyl methacrylate). " Poly (N-vinyl pyrrolidone). " Poly (methyl methacrylate). " Poly (vinyl alcohol). " Poly (acrylic acid). " Poly (acrylamide) " Poly (ethylene-co-vinyl acetate). " Poly (ethylene glycol). " Poly (methacrylic acid). However, in recent years additional polymers designed primarily for medical applications have entered the arena of controlled release. Many of these materials are designed to degrade within the body, among them " Polylactides (PLA). " Polyglycolides (PGA). " Poly (lactide-co-glycolides) (PLGA). " Polyanhydrides. Polyorthoesters. Originally, polylactides and polyglycolides were used as absorbable suture material, and it was a natural step to work with these polymers in controlled drug delivery systems. The greatest advantage of these degradable polymers is that they are broken down into biologically acceptable molecules that are metabolized and removed from the body via normal metabolic pathways. However, biodegradable materials do produce degradation byproducts that must be tolerated with little or no adverse reactions within the biological environment. These degradation products -both desirable and potentially non desirable - must be tested thoroughly, since there are a number of factors that will affect the biodegradation of the original materials. The most important of these factors are shown in the box below - a list that is by no means complete, but does provide an indication of the breadth of structural, chemical, and processing properties that can affect biodegradable drug delivery systems. Drug release mechanisms Two basic mechanisms controlling drug release are dissolution of the active component and the diffusion of dissolved or solubilized species. Within the context of these mechanisms there are four processes operating: " Hydrating of the device (swelling of the hydrocolloid or dissolution of channeling agent) " Diffusion of water into the device " Dissolution of the drug " Diffusion of the dissolved (or solubilized) drug out of the device These mechanisms may operate independently, together or consecutively. Drug delivery systems can be designed to have either continuous release, a delayed gastrointestinal transit while continuously releasing, or delayed release. Drug release may be constant, declining or bimodal. Constant release Ideal controlled release system should provide and maintain constant drug plasma concentrations. This led to considerable effort being put into developing systems that release drugs at a constant rate. (Although with the advent of chronotherapy, i.e. drug delivered at both the appropriate time and rate, zero-order release may not be such a desirable goal in the future.) Declining release Drug release from these systems is commonly a function of the square root of time or follows first order kinetics. These systems cannot maintain a constant plasma drug concentration but can provide sustained release. Bimodal release Although constant drug release may be ideal, this may not always be the case. If gastrointestinal tract behaves as a one compartment model, i.e. the different segments are homogenous, then the situation is ideal. However, absorption rate is not invariant along the gastrointestinal tract. So, the rate of release from the dosage form must regulate drug absorption - in other words, release rate must always be slower than absorption rate. This situation may not be easy to achieve a release rate suited to absorption from the intestine may be far too great for that required in the stomach or colon. One possible solution to this problem is to prepare a dosage from that provides a rapid initial delivery of drug followed by a slower rate of delivery and then an increased rate at a later time. Future directions Most exciting opportunities in controlled drug delivery lie in the arena of responsive delivery systems, with which it will be possible to deliver drugs through implantable devices in response to a measured blood level or to deliver a drug precisely to a targeted site. Much of the development of novel materials in controlled drug delivery is focusing on the preparation and use of these responsive polymers with specifically designed macroscopic and microscopic structural and chemical features. Such systems include: " Copolymers with desirable hydrophilic/hydrophobic interactions. " Block or graft copolymers. " Complexation networks responding via hydrogen or ionic bonding. " Dendrimers or star polymers as nanoparticles for immobilization of enzymes, drugs, peptides, or other biological agents. " New biodegradable polymers. " New blends of hydrocolloids and carbohydrate-based polymers Conclusion The article has outlined some of the current thinking with regard to providing control over the drug delivery can be the most important factor at times when traditional oral or injectable drug formulations cannot be used. It is proposed that two basic mechanisms controlling drug release are dissolution of the active component and the diffusion of dissolved or solubilized species. These include situations requiring the slow release of water-soluble drugs, the fast release of low-solubility drugs, and dosage forms based on carriers that can dissolve or degrade and be readily eliminated. The ideal drug delivery system should be inert, biocompatible, mechanically strong, comfortable for the patient, capable of achieving high drug loading, safe from accidental release, simple to administer and remove, and easy to fabricate and sterilize. (Ruchi Tiwari is with Jaipur National University, Jagatpura, Jaipur. Gaurav Tiwari and Awani K Rai are with Department of Pharmaceutics, Pranveer Singh Institute of Technology, Bhauti, Kanpur 208 020)