Biodegradable Polymers in Controlled Drug Delivery
Biodegradable Polymers in Controlled Drug Delivery
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.
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).
- 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).
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.
- Sterilization process.
- Storage history.
- 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).
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.
|pH||Acidic or basic
|Change in pH — swelling — release of drug|
|Ionic strength||Ionic hydrogel||Change in ionic strength — change in concentration of ions inside gel — change in swelling — release of drug|
|Chemical species||Hydrogel containing electron-accepting groups||Electron-donating compounds — formation of charge/transfer complex — change in swelling — release of drug|
|Enzyme-substrate||Hydrogel containing immobilized enzymes||Substrate present — enzymatic conversion — product changes swelling of gel — release of drug|
|Magnetic||Magnetic particles dispersed in alginate microshperes||Applied magnetic field — change in pores in gel — change in swelling — release of drug|
|Thermal||Thermoresponsive hrydrogel poly(N-isopro-
|Change in temperature — change in polymer-polymer and water-polymer interactions — change in swelling — release of drug|
|Applied electric field — membrane charging — electrophoresis of charged drug — change in swelling — release of drug|
|Ultrasound irradiation||Ethylene-vinyl alcohol hydrogel||Ultrasound irradiation — temperature increase — release of drug|
Table I. Environmentally sensitive polymers for drug delivery.4
ENVIRONMENTALLY RESPONSIVE SYSTEMS
It is also possible for a drug delivery system to be designed so that it is incapable of releasing its agent or agents until it is placed in an appropriate biological environment. Swelling-controlled release systems are initially dry and, when placed in the body will absorb water or other body fluids and swell. The swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. Examples of these types of devices are shown in Figures 5a and 5b for reservoir and matrix systems, respectively. Most of the materials used in swelling-controlled release systems are based on hydrogels, which are polymers that will swell without dissolving when placed in water or other biological fluids. These hydrogels can absorb a great deal of fluid and, at equilibrium, typically comprise 60–90% fluid and only 10–30% polymer.
Figure 5. Drug delivery from (a) reservoir and (b) matrix swelling-controlled release systems.
One of the most remarkable, and useful, features of a polymer's swelling ability manifests itself when that swelling can be triggered by a change in the environment surrounding the delivery system. Depending upon the polymer, the environmental change can involve pH, temperature, or ionic strength, and the system can either shrink or swell upon a change in any of these environmental factors. A number of these environmentally sensitive or "intelligent" hydrogel materials are listed in Table I.4 For most of these polymers, the structural changes are reversible and repeatable upon additional changes in the external environment.
Figure 6. Drug delivery from environmentally sensitive release systems.
The diagrams in Figure 6 illustrate the basic changes in structure of these sensitive systems. Once again, for this type of system, the drug release is accomplished only when the polymer swells. Because many of the potentially most useful pH-sensitive polymers swell at high pH values and collapse at low pH values, the triggered drug delivery occurs upon an increase in the pH of the environment. Such materials are ideal for systems such as oral delivery, in which the drug is not released at low pH values in the stomach but rather at high pH values in the upper small intestine.
All of the previously described systems are based on polymers that do not change their chemical structure beyond what occurs during swelling. However, a great deal of attention and research effort is being concentrated on biodegradable polymers. These materials degrade within the body as a result of natural biological processes, eliminating the need to remove a drug delivery system after release of the active agent has been completed. Most biodegradable polymers are designed to degrade as a result of hydrolysis of the polymer chains into biologically acceptable, and progressively smaller, compounds. In some cases—as, for example, polylactides, polyglycolides, and their copolymers—the polymers will eventually break down to lactic acid and glycolic acid, enter the Kreb's cycle, and be further broken down into carbon dioxide and water and excreted through normal processes. Degradation may take place through bulk hydrolysis, in which the polymer degrades in a fairly uniform manner throughout the matrix, as shown schematically in Figure 7a. For some degradable polymers, most notably the polyanhydrides and polyorthoesters, the degradation occurs only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system (see Figure 7b).
Figure 7. Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems.
The most common formulation for these biodegradable materials is that of microparticles, which have been used in oral delivery systems and, even more often, in subcutaneously injected delivery systems. Given appropriate fabrication methods, microparticles of poly(lactide-co-glycolide) (PLGA) can be prepared in a fairly uniform manner to provide essentially nonporous microspheres, as shown in Figure 8. These particles will degrade through bulk hydrolysis in water or body fluids, yielding polymer fragments over time. The polymer fragments shown in Figure 9, for example, are of a 75:25 lactide:glycolide PLGA microparticle after 133 days of degradation in water.
Figure 8. Biodegradable microparticles of 60:40 lactide:glycolide PLGA. (Photo courtesy of T. Tice, Southern Research Institute, Birmingham, AL.)
Figure 9. Biodegradable microparticle of 75:25 lactide: glycolide PLGA after 133 days of degradation in water.
A very different erosion pattern is characteristic of polyorthoesters, which are surface-eroding polymers. Analysis of polyorthoester rods after 9 and 16 weeks of implantation in rabbits shows significant surface degradation, but the core of the drug delivery system remains intact (see Figure 10).5
Figure 10. Biodegradable polyorthoester rods after (left) 9 and (right) 16 weeks of implantation in rabbits. (Photos courtesy of H. Heller, Advanced Polymer Systems, RedwoodCity,CA.)
FUTURE DIRECTIONS IN CONTROLLED DRUG DELIVERY
The 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.
These new biomaterials—tailor-made copolymers with desirable functional groups—are being created by researchers who envision their use not only for innovative drug delivery systems but also as potential linings for artificial organs, as substrates for cell growth or chemical reactors, as agents in drug targeting and immunology testing, as biomedical adhesives and bioseparation membranes, and as substances able to mimic biological systems. Successfully developing these novel formulations will obviously require assimilation of a great deal of emerging information about the chemical nature and physical structure of these new materials. REFERENCES 1. Vert M, Li S, and Garreau H, "More About the Degradation of LA/GA-derived Matrices in Aqueous Media," J Controlled Release, 16:15–26, 1991. 2. Cleary GW, "Transdermal Drug Delivery," Cosmetics and Toiletries, 106:97–107, 1991. 3. Cleary GW, "Transdermal Delivery Systems: A Medical Rationale," in Topical Drug Bioavailability, Bioequivalence, and Penetration, Shah VP, and Maibach HI (eds), New York, Plenum, pp 17–68, 1993. 4. Kim SW, "Temperature Sensitive Polymers for Delivery of Macromolecular Drugs," in Advanced Biomaterials in Biomedical Engineering and Drug Delivery Systems, Ogata N, Kim SW, Feijen J, et al. (eds), Tokyo, Springer, pp 126–133, 1996. 5. Heller J, "Controlled Drug Release from Poly(ortho esters)—A Surface Eroding Polymer," J Controlled Release, 2:167–177, 1985.