Biodegradable Polymers in Controlled Drug Delivery

Abstract
               Controlled drug delivery take place when a polymer, whether natural or synthetic, is sensibly 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. 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 activated 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 overdosing.
INTRODUCTION
               Controlled drug delivery take place when a polymer, whether natural or synthetic, is sensibly 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. 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 activated 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 overdosing.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 by-products 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. 
                

                Providing control over the drug delivery can be the most important factor at times when traditional oral or injectable drug formulations cannot be used. These include situations requiring the slow release of water-soluble drugs, the fast release of low-solubility drugs, drug delivery to specific sites, drug delivery using nanoparticulate systems, delivery of two or more agents with the same formulation, and systems 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.

                The goal of many of the original controlled-release systems was to achieve a delivery profile that would yield a high blood level of the drug over a long period of time. With traditional tablets or injections, the drug level in the blood follows the profile shown in Figure 1a, in which the level rises after each administration of the drug and then decreases until the next administration. The key point with traditional drug administration is that the blood level of the agent should remain between a maximum value, which may represent a toxic level, and a minimum value, below which the drug is no longer effective. In controlled drug delivery systems designed for long-term administration, the drug level in the blood follows the profile shown in below Figure (1b), remaining constant, between the desired maximum and minimum, for an extended period of time. Depending on the formulation and the application, this time may be anywhere from 24 hours (Procardia XL) to 1 month (Lupron Depot) to 5 years (Norplant).

Figure 1.
Drug levels in the blood with (a) traditional drug dosing and (b) controlled- delivery dosing.

                 In recent years, controlled drug delivery formulations and the polymers used in these systems have become much more sophisticated, with the ability to do more than simply extend the effective release period for a particular drug. For example, current controlled-release systems can respond to changes in the biological environment and deliver—or cease to deliver—drugs based on these changes. In addition, materials have been developed that should lead to targeted delivery systems, in which a particular formulation can be directed to the specific cell, tissue, or site where the drug it contains is to be delivered. While much of this work is still in its early stages, emerging technologies offer possibilities that scientists have only begun to explore.
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, nonbiological 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).
• Polyacrylamide.
• 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 by-products that must be tolerated with little or no adverse reactions within the biological environment.

               These degradation products—both desirable and potentially nondesirable—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.
Factors Affecting Biodegradation of Polymers
• Chemical structure.
• Chemical composition.
• Distribution of repeat units in multimers.
• Presents of ionic groups.
• Presence of unexpected units or chain defects.
• Configuration structure.
• Molecular weight.
• Molecular-weight distribution.
• Morphology (amorphous/semicrystalline, microstructures, residual stresses).
• Presence of low-molecular-weight compounds.
• Processing conditions.
• Annealing.
• Sterilization process.
• Storage history.
• Shape.
• Site of implantation.
• Adsorbed and absorbed compounds (water, lipids, ions, etc.).
• Physicochemical factors (ion exchange, ionic strength, pH).
• Physical factors (shape and size changes, variations of diffusion coefficients, mechanical stresses, stress- and solvent-induced cracking, etc.).
• Mechanism of hydrolysis (enzymes versus water).

CONTROLLED-RELEASE MECHANISMS
There are three primary mechanisms by which active agents can be released from a delivery system: diffusion, degradation, and swelling followed by diffusion. Any or all of these mechanisms may occur in a given release system.Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device. The diffusion can occur on a macroscopic scale—as through pores in the polymer matrix—or on a molecular level, by passing between polymer chains. Examples of diffusion-release systems are shown in Figures 2 and 3.

Figure 2.Drug delivery from a typical matrix drug delivery system.

In Figure 2, a polymer and active agent have been mixed to form a homogeneous system, also referred to as a matrix system. Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues, its rate normally decreases with this type of system, since the active agent has a progressively longer distance to travel and therefore requires a longer diffusion time to release.

For the reservoir systems shown in Figures 3a and 3b, the drug delivery rate can remain fairly constant. In this design, a reservoir—whether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix—is surrounded by a film or membrane of a rate-controlling material. The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir. Since this polymer coating is essentially uniform and of a nonchanging thickness, the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery system. The system shown in Figure 3a is representative of an implantable or oral reservoir delivery system, whereas the system shown in Figure 3b illustrates a transdermal drug delivery system, in which only one side of the device will actually be delivering the drug.

Figure 3.
Drug delivery from typical reservoir devices: (a) implantable or oral systems, and (b) transdermal systems.

Once the active agent has been released into the external environment, one might assume that any structural control over drug delivery has been relinquished. However, this is not always the case. For transdermal drug delivery, the penetration of the drug through the skin constitutes an additional series of diffusional and active transport steps, as shown schematically in Figure 4.2 (A thorough analysis of transdermal drug delivery may be found in a review by Cleary3 or in other sources listed in the bibliography.)

Figure 4.Transport processes in transdermal drug delivery. (Diagram courtesy of G. Cleary, Cygnus Inc., Redwood City, CA.)

For the diffusion-controlled systems described thus far, the drug delivery device is fundamentally stable in the biological environment and does not change its size either through swelling or degradation.In these systems, the combinations of polymer matrices and bioactive agents chosen must allow for the drug to diffuse through the pores or macromolecular structure of the polymer upon introduction of the delivery system into the biological environment without inducing any change in the polymer itself.