Drug Delivery Systems

Drug Delivery Systems Misty L. Noble University of Washington Engineered Biomaterials In addition to the widespread application of polymers in manufacturing different materials, they are also used in several formulations and devices for drug delivery. When developing drug delivery systems, it is important to control how much of the drug is being released – too much of the drug at once can be harmful to the body, but too little of it may limit its effectiveness. Delivery of drugs at the optimal dosage for optimal lengths of time will make them more effective and more powerful. It is with the use of polymers that manufacturers are able to deliver drugs more and more effectively. Some of the unique characteristics of polymers that make them versatile in drug delivery systems include [1]:

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wide molecular weight distributions variety of visco-elastic properties special characteristics associated with phase transitions able to contract when heated variety of dissolution times specialized chemical reactivities tolerate a variety of manufacturing methods

Drug delivery systems are classified according to the mechanism controlling the release of the drug. Some of the basic systems are described below [2]. Diffusion-Controlled Systems There are two basic devices that are driven by diffusion (a process of moving molecules from a solution of high concentration to low concentration). In these devices, the drug is released either by passing through the pores or between polymer chains, and these are the processes that control the release rate. In monolithic devices, the drug is uniformly dispersed or dissolved in the polymer, and it is released by diffusion from the polymer as shown in Figure 1. The release rates of monolithic devices decrease as a function of time and distance.

Figure 1. A schematic of the monolithic devices. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA.

In membrane-controlled reservoir devices, the drug is contained in a core, which is surrounded by a polymer membrane, and it is released by diffusion through this ratecontrolling membrane (Fig. 2) [3].

Figure 2. Reservoir devices have a coating that controls the release rate. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA. Some examples of diffusion-controlled devices include drug-eluting stents such as Cypher® (reservoir) and TAXUS Express® (monolithic), intra-uterine contraceptives such as Progestasert® and Norplant ®, and various transdermal patches such as Nicoderm® and Transderm Nitro® [4]. Water Penetration-Controlled Systems Some devices are designed using water as the main agent controlling the release of the drug. In these devices, the drug molecules cannot physically diffuse out of the device without water molecules diffusing in. There are generally two types of water penetration-controlled systems [4,5]. Swelling-controlleddevices usually incorporate drugs in a hydrophilic polymer that is stiff or glassy when dry, but swells when placed in an aqueous environment (Fig. 3). A typical oral capsule or pill is usually a swelling-controlled device. Although these devices are easy to manufacture, the release rates are often not steady.

Figure 3. A typical oral tablet is a good example of swelling-controlled devices. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA. Figures 4 and 5 are schematics of elementary and two-compartment osmoticallycontrolleddelivery devices, respectively. Basically, these devices are designed to have a semipermeable membrane that allows water to move in, but prevents salt and drug molecules from moving out. The drug molecules exit through a small opening due to the increase in pressure brought about by the volumetric increase. In the two-compartment osmotic pump, an

additional compartment for the osmotic agent, i.e. salt, is present. As water molecules diffuse into the salt compartment, the salt layer expands, pushing the drug-loaded compartment to release drugs through the device opening.

Figure 4. Oros® is a good example of an elementary osmotic pump. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA.

Figure 5. A two-compartment osmotic pump contains a salt layer that expands when hydrated. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA. Biodegradable Drug Delivery Systems The polymers used in the formulation and fabrication of biodegradable drug delivery devices erode (with or without changes to the chemical structure) or degrade (breakdown of the main chain bonds) as a result of the exposure to chemicals (water) or biologicals (enzymes). The drug molecules, which are initially dispersed in the polymer, are released as the polymer starts eroding or degrading as shown in Figure 6. The four most commonly used biodegradable polymers in drug delivery systems are poly(lactic acid), poly(lactic-co-glycolic acid), polyanhydrides, poly(ortho esters), and poly(phosphoesters).

Figure 6. The polymer erodes or degrades to release drug molecules in degradable devices. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA. Similar to the reservoir system, the degradable reservoir system has a drug-loaded core surrounded by a polymer coating that degrades or erodes. These systems combine the advantage of long-term constant rate drug release with bioerodability or biodegradability. In pendant-chain systems, the drug molecules are covalently attached to the main polymer chain via degradable linkages. So, as the polymer is exposed to water or chemicals, the linkages break down releasing the drug.

Figure 7. Pendant-chain systems have degradable linkages that release drug molecules upon exposure to water. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA. Responsive Drug Delivery Systems Responsive drug delivery systems can be classified as open- or closed-loop systems. Openloop systems are also called pulse or externally regulated systems; the amount of drug released is not dependent on the environmental conditions the device is in. Among the most advanced externally-regulated devices are mechanical pumps, which dispense drugs from a reservoir outside the body via a catheter. Insulin-delivering pumps are commercially available with sophisticated control mechanisms and computers that can allow a programmed insulin delivery [4]. Although these devices are not primarily made of polymers, the device-tissue interface can be expected to be polymeric. The rate of drug released can also be controlled and enhanced using external stimulants, like magnetism and ultrasound [6]. In magnetically-controlled drug delivery devices, small magnetic spheres are embedded in a drug-containing polymer, which release a significant amount of drug when exposed to an oscillating field. Similarly, the release rate also increases when analogous drug-containing polymers are exposed to ultrasound. Ultrasound was found to enhance erosion and degradation of some biodegradable polymers, [7] and it can also act as an on-off switch as in certain drug delivery systems being developed here in UWEB [8,9] .

Figure 8. A schematic of a temperature-responsive biodegradable device. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA. In closed-loop systems, or self-regulated systems, the release is in direct response to the conditions detected, be it temperature, type of solvent, pH, or concentration, to name a few. Poly(N-isopropylacrylamide) is a well-known example of a thermo-responsive polymer. At its transition of 32oC, the polymer is soluble in water; but, as temperature is increased, the polymer precipitates and phase separates. Poly(ethylene glycol) and poly(propylene glycol) copolymers and poly(lactic acid) and poly(glycolic acid) copolymers also exhibit thermoresponsiveness. These polymers are useful in developing thermogelling systems (Atridox®); the drug is dissolved in the liquid form of the polymer at room temperature as shown in Figure 8. When this mixture is injected in the body, the polymer turns into a gel, which eventually degrades and releases the drug molecules. Self-regulating insulin-delivery devices depend on the concentration of glucose in the blood to control the release of insulin. One system proposed immobilizing glucose oxidase (an enzyme) to a pH-responsive polymeric hydrogel, which encloses a saturated insulin solution. At high glucose levels, glucose is catalyzed by glucose oxidase and converts it to gluconic acid, thus lowering the pH. This decrease in pH causes the membrane to swell, forcing the insulin out of the device [10,11]. Other Drug Delivery Systems There are many other drug delivery systems that are currently being investigated but are not included in this tutorial. The last two systems, polyelectrolyte complex and polymeric micelle systems, are discussed below because of their emerging popularity and valuable potential in the field of gene therapy and drug delivery. With the near completion of the human genome project, scientists understand more and more the biological processes and chemical make up of the human body. The origins of diseases are being discovered, and working out potential strategies to treat and prevent them is underway. Thus, the emergence of gene therapy – which is the insertion of genetic material (DNA, RNA, siRNA, etc.) into the cell nucleus either to express new proteins or to prevent the expression of existing proteins. To deliver genetic material, negatively-charged nucleic acid chains are blended with polycation polymers (ex. chitosan, poly-L-lysine, etc.) or with cationic lipids (ex. DOPE, DOTMA, DOGS) to form polyelectrolyte complexes: polyplexes or lipoplexes, respectively to be more specific (Fig. 9) [2].

Figure 9. Polyelectrolyte complexes are made by incorporating DNA or RNA plasmids into polycations or cationic liposomes. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA. Unlike hydrophilic drugs that can be delivered easily using a number of different systems, delivery of hydrophobic drugs are more complicated. They are more difficult to dissolve and incorporate into the more common drug delivery systems. However, the use of polymeric micelles has been found to be effective in delivering hydrophobic molecules. When amphiphilic block co-polymers (i.e. have hydrophilic and hydrophobic segments) are placed in an aqueous environment, the large solubility difference between the hydrophilic and hydrophobic segments drives the formation of polymeric micelles. The hydrophobic segments form an inner core, where hydrophobic drugs can be loaded, while the hydrophilic segments (ex. Poly(ethylene glycol)) surround the core to stabilize and increase the solubility of the device [4]. Polymeric micelles are currently used in the delivery of tumor-targeting drugs, like Doxorubicin.

Figure 10. Polymeric micelles are used in delivering hydrophobic drugs more effectively. Diagram courtesy of AS Hoffman, University of Washington, Seattle, WA.