Ind. Eng. Chem. Res. 2009, 48, 2475–2486
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REVIEWS Drug Delivery Technologies: The Way Forward in the New Decade Eva M. Martı´n del Valle,*,† Miguel A. Gala´n,† and Ruben G. Carbonell‡ Department of Chemical Engineering, UniVersity of Salamanca, Pl. de los Caı´dos s/n, 37008 Salamanca, Spain, and Department of Chemical and Biomolecular Engineering, North Carolina State UniVersity, Raleigh, North Carolina
The design and development of drug delivery systems involves many different sciences that underpin the research. It is clear that significant advances will only be made through multidisciplinary teams that utilize the latest advances in the biological, chemical, physical, and engineering sciences. The underpinning sciences are also vital to the process of developing successful products. There are three key and interrelated areas of research. (i) Achieve a greater understanding of the biological fate and the targeting of drugs, particularly biopharmaceuticals, macromolecules and macromolecular delivery systems, at the molecular, membrane, and cellular level. (ii) Provide a greater understanding of the physicochemical properties of biopharmaceuticals, macromolecules, and macromolecular delivery systems and how these are modified within a biological environment affecting their activity. (iii) Promote the development of novel materials and delivery systems that will overcome these biological barriers. This article aims to provide a comprehensive review of the key issues to design an effective drug delivery system. Introduction Over the past few decades, the rise of modern pharmaceutical technology and the amazing growth of the biotechnology industry have revolutionized the approach to drug delivery systems development.1 For most of the industry’s existence, pharmaceuticals have primarily consisted of relatively simple, fast-acting chemical compounds that are dispensed orally (as solid pills and liquids) or injected. During the past three decades, however, complex formulations that control the rate and period of drug delivery (i.e., time-release medications) and that target specific areas of the body for treatment have become increasingly common.2 Addressing this complexity, coupled with the explosion of new and potential treatments resulting from discoveries of bioactive molecules and gene therapies, pharmaceutical research is facing challenges to, not only the development of new treatments, but also the mechanisms with which to administer them.3,4 A controlled release drug delivery system should be able to achieve the following benefits: (i) maintenance of optimum therapeutic drug concentration in the blood with minimum fluctuation; (ii) predictable and reproducible release rates for extended duration; (iii) enhancement of activity duration for short half-life drugs; (iv) elimination of side effects, frequent dosing and wastage of drug; and (v) optimized therapy and improved patient compliance.5-11 To achieve these benefits, the design of a controlled release system requires simultaneous considerations of several factors,12-15 such as the chemical and physical properties of the drug,16 the route of administration,17-19 the nature of the delivery vehicle, the mechanism of drug release, the potential for targeting,20 and biocompatibility. * To whom correspondence should be addressed. E-mail:
[email protected]. † University of Salamanca. ‡ North Carolina State University.
Due to the extensive interdependency of those factors, it is not easy to establish a sequential process for designing a controlled drug delivery system.21 Drug delivery technology can bring both therapeutic and commercial value to health care products.22 Large pharmaceutical companies are looking to extend the lifetimes of their patents by forging strategic alliances with usually smaller drug delivery technology companies aimed at presenting old drugs in new proprietary forms. Most drug delivery products reach the market as a result of joint ventures between drug delivery companies and pharmaceutical companies. For this reason, drug delivery technology companies enjoy a good return on their investments in the form of increased revenues and market share and it is a very fast growing segment of the economy.7-9 However, the design and development of drug delivery systems involves many different sciences that underpin the research. It is clear that significant advances will only be made through multidisciplinary teams that utilize the latest advances in the biological, chemical, physical, and engineering sciences. The underpinning sciences are also vital to the process of developing successful products. There are three key and interrelated areas of research.23 (i) Achieve a greater understanding of the biological fate and the targeting of drugs, particularly biopharmaceuticals, macromolecules, and macromolecular delivery systems at the molecular, membrane, and cellular level. (ii) Provide a greater understanding of the physicochemical properties of biopharmaceuticals, macromolecules, and macromolecular delivery systems and how these are modified within a biological environment affecting their activity. (iii) Promote the development of novel materials and delivery systems that will overcome these biological barriers. This article aims to provide a comprehensive review of the key issues to design an effective drug delivery system. 1. Administration Routes Drug delivery technologies are classified according to the route through which a drug is administered into the body. In
10.1021/ie800886m CCC: $40.75 2009 American Chemical Society Published on Web 02/05/2009
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the oral route, a drug is taken by mouth into the gastrointestinal (GI) tract to be absorbed. Other important routes include intravenous injection, intramuscular injection, subcutaneous injection, pulmonary, ocular, buccal (through the internal wall of the cheeks), sublingual (under the tongue), nasal, vaginal, rectal, transdermal, and implanted (inside a body cavity). Drug delivery research focuses on how a drug is delivered into the body without much consideration of the fate and effects of the drug in the body.24 Those aspects are normally the domain of studies in pharmacokinetics, although obviously, these aspects are closely linked to the delivery route. Highly sophisticated drug delivery systems are being developed to exert their effects after they are administered into the body, in particular, into the systemic circulation.25 They usually consist of particles in the size range of nanometers that have unique combinations of capacities such as controlled release and biological site-specific targeting. This new group of delivery systems is definitely an important component of modern drug delivery technology. A myriad of novel drug delivery technologies are under development and significant advances are being made in nearly all branches of drug delivery. This section briefly reviews the main routes of delivery. 1.1. Oral. The oral route has long been the most convenient and most widely used drug delivery method worldwide. However, many drugs including the emerging biotechnology drugs such as peptides, proteins, and nucleic acids are not suitable for this route because they are subject to massive degradation in the GI tract and low permeability through the intestinal epithelium. As a result, considerable efforts are being made to develop devices able to protect these drugs in the GI tract from degradation and enhance drug absorption. Such advanced oral drug delivery systems include liposomes,24 mucoadhesive patches,25,26 nanoparticles,27 absorption enhancing agents,28 and microfabricated devices.29-31 Oral vaccination is also attracting significant interest.32 1.2. Pulmonary. Pulmonary drug delivery is an important research area which impacts the treatment of illnesses including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Inhalation gives the most direct access to drug target. In the treatment of obstructive respiratory diseases, pulmonary delivery can minimize systemic side effects, provide rapid response, and minimize the required dose since the drug is delivered directly to the conducting zone of the lungs.33 Inhalation is also an attractive option for systemic therapies because the respiratory region (mainly alveoli) of the lung provides an enormous surface area (80-100 m2/adult) and a highly permeable membrane for the absorption of medication into the blood. It is a needle-free delivery system capable of administering a variety of therapeutic substances.34 Large protein molecules which degrade in the harsh gastrointestinal conditions and are eliminated by the first-pass metabolism in the liver can be delivered via the pulmonary route if deposited in the respiratory zone of the lungs. The dry powder inhaler device-formulation combination has been shown to be an effective method for delivering drugs to the lung for treatment of asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Even with advanced designs, however, delivery efficiency is still poor mainly due to powder dispersion problems which cause poor lung deposition and high dose variability. Drug particles used in current inhalers must be 1-5 µm in diameter for effective deposition in smalldiameter airways and alveoli.35 These powders are very cohesive, have poor flowability, and are difficult to disperse into aerosol due to cohesion arising from van der Waals
attraction. These problems are well-known in fluidization research, much of which is highly relevant to pulmonary drug delivery. Processing methods such as spray drying allow control over critical particle design features, such as particle size and distribution, surface energy, surface rugosity, particle density, surface area, porosity, and microviscosity. Control of these features has enabled new classes of therapeutics to be delivered by inhalation.33-35 These include therapeutics that have a narrow therapeutic index, require a high delivered dose, and/or elicit their action systemically. Engineered particles are also being utilized for immune modulation, with exciting advances being made in the delivery of antibodies and inhaled vaccines. Continued advances are expected to result in “smart” therapeutics capable of active targeting and intracellular trafficking.36 Considerable effort is currently being focused on the systemic delivery of therapeutic peptides and proteins via this route because the lungs have large surface area, a rich supply of blood, and an alveolar membrane with very high permeability.37 Moreover, pulmonary delivery is noninvasive in contrast to injection and tends to exhibit less drug degradation than the oral route. Insulin (for diabetes) is the drug receiving the most intense interest for this delivery method as a substitute for injection, because the disease requires long-term management and frequent administration.38 Some encouraging scientific and engineering developments, such as large porous particles for deep lung deposition,37 have been made in this area in recent years and pulmonary delivery of drugs to the systemic circulation will likely become a reality in the near future. 1.3. Injection. Injection is the gold standard for systemic drug delivery and the major delivery method for the drugs that are not suitable for oral delivery. However, this method is associated with various problems such as pain, burst drug release, needle phobia, risk of infections, and involvement of health care workers. For chronic diseases (e.g., insulin-dependent diabetes) requiring repetitive drug administrations, these problems become more serious.39 Two strategies are being taken to address these problems. One is to improve the current injection technology, and the other is to develop alternative delivery methods. A successful example of improving the current injection technology is an injectable depot system based on biodegradable microspheres to lower the injection frequency and enable constant drug release.3 Many more efforts are being made to develop alternative delivery methods to injections such as oral, pulmonary, and transdermal. 1.4. Transdermal. Delivering drugs across the skin is attractive for several reasons: ease of access, application, and cessation of delivery; sustained and steady drug release; reduced systemic side effects; avoidance of drug degradation in the GI tract and first-pass hepatic metabolism; and absence of pain.40,41 However, the skin functions naturally as a barrier to foreign substances, preventing the entrance of the majority of drugs. Therefore, researchers are developing various methods to enhance the drug permeation across the skin. The more notable new technologies to meet this goal include electroporation, ionophoresis, sonophoresis, jet injection, laser irradiation, and microneedles.41-43 Delivery of many drugs including biological drugs such as insulin has been successfully demonstrated using these technologies.44,45 1.5. Implantable. Implantable drug delivery systems (IDDS) have the advantage of maintaining a steady release of drug to the specific site of action so that they are safer and more reliable. IDDS can be classified into three major categories: biodegradable or nonbiodegradable implants, implantable pump systems,
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Figure 1. Concentration profiles for drug delivered by tablet, sustained release device or controlled release device.
and the newest atypical class of implants.46-51 Biodegradable and nonbiodegradable implants are available as monolithic systems or reservoir systems. The release kinetics of drugs from such systems depend on both the solubility and diffusion coefficient of the drug in the polymer, the drug load, as well as the in vivo degradation rate of the polymer in the case of the biodegradable systems.52 Controlled release of drugs from an implantable pump is generally achieved utilizing the microtechnology of electronic systems and remote-controlled flow rate manipulation through the maintenance of a constant pressure difference. The third IDDS system, the atypical class, includes recently developed systems such as ceramic hydroxyapatite antibiotic systems used in the treatment of bone infections, intraocular implants for the treatment of glaucoma, and transurethral implants utilized in the treatment of impotence. The major advantages of these systems include targeted local delivery of drugs at a constant rate, less drug required to treat the disease state, minimization of possible side effects, and enhanced efficacy of treatment. Also, these forms of delivery systems are capable of protecting drugs which are unstable in vivo and that would normally require frequent dosing intervals.53 Due to the development of such sustained release formulations, it is now possible to administer unstable drugs once a week to once a year that in the past required frequent daily dosing. Preliminary studies using these systems have shown superior effectiveness over conventional methods of treatment.54 However, one limitation of these newly developed drug delivery systems is the fact that their cost-to-benefit ratio is high which restricts their use over conventional dosage forms. Hopefully, in the future, new implantable systems can be developed at a lower cost, enhancing their use in standard therapeutic practice. Some of the most recently discovered implants are in the early developmental stages and more rigorous clinical testing is required prior to their use in standard practice.52 2. Mechanisms for Drug Delivery The traditional methods and routes of drug administration result in a rate of drug uptake that is controlled by the drug properties (solubility, charge, molecular size, etc.) and the characteristics of the site of administration (pH, surface area, presence of enzymes, active transport mechanisms, etc.).52 With traditional tablets or injections, the drug level in the blood follows the profile shown in Figure 1, 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 longterm administration, the drug level in the blood follows the profile also shown in Figure 1, remaining constant, between the desired maximum and minimum, for an extended period of time.55 For decades, polymeric systems have been used for pharmaceutical applications, especially to provide controlled release of drugs. Drug-polymer systems may also be useful in protecting the drug from biological degradation prior to its release. The development of these devices starts with the use of nonbiodegradable polymers, which rely on the diffusion process, and subsequently progresses to the use of biodegradable polymers, in which swelling and erosion take place. On the basis of the physical or chemical characteristics of polymer, drug release mechanisms from a polymer matrix can be categorized in accordance to three main processes (systems), which are the followinf:56 1. Drug diffusion from the nondegraded polymer (diffusioncontrolled system). 2. Enhanced drug diffusion due to polymer swelling (swelling-controlled system). 3. Drug release due to polymer degradation and erosion (erosion-controlled system). In all three systems, diffusion is always involved. For a nonbiodegradable polymer matrix, drug release is due to the concentration gradient by either diffusion or matrix swelling (enhanced diffusion). For a biodegradable polymer matrix, release is normally controlled by the hydrolytic cleavage of polymer chains that lead to matrix erosion, even though diffusion may be still dominant when the erosion is slow. 2.1. Diffusion.39,58,.59 Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device. The main devices are classified into reservoir systems and matrix systems. 2.1.1. Reservoir Systems. One widely used polymeric system is called the reservoir system. In these systems the drug is retained in a central compartment and surrounded by a polymeric membrane through which it must diffuse, thus controlling the rate of delivery. Figure 2 shows a schematic diagram of this type of system. Reservoir systems could also be in the form of microcapsules or hollow fibers.34 The various factors that can affect the diffusion process may readily be applied to reservoir devices (e.g., the effects of additives, polymer functionality, and, hence, sink-solution pH, porosity, film casting conditions, etc.). Also, the choice of
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Figure 2. Reservoir System.
Figure 4. Diffusion from a matrix system. Figure 3. Matrix devices.
polymer must be an important consideration in the development of reservoir devices.34,60-62 2.1.2. Matrix Devices. Matrix devices consist of a polymer throughout which drug is dispersed (Figure 3). Matrix devices are probably the most common devices for controlling the release of drugs. This is partly because they are relatively easy to fabricate, compared to reservoir devices, and there is no the danger of an accidental high dosage that could result from rupture of the membrane of a reservoir device. In a matrix device the active agent is present as a dispersion within the polymer matrix, and they are typically formed by the compression of a polymer/drug mixture or by dissolution or melting.39 The dosage release properties of matrix devices may be dependent upon the solubility of the drug in the polymer matrix or, in the case of porous matrixes, the solubility of the drug in the sink solution within the particle’s pore network and the tortuosity of the network.62,63 The diffusion can occur on a macroscopic scalesas through pores in the polymer matrixsor on a molecular level, by transport between polymer chains. Examples of diffusion-release systems are shown in Figures 4 and 5. In Figure 4, a polymer and active agent have been mixed to form a homogeneous matrix system. Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues, the rate normally decreases, since the active agent has a progressively longer distance to diffuse and a lower concentration gradient. For the reservoir systems shown in Figure 5, the drug delivery rate can remain fairly constant. In this design, a reservoirswhether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrixsis 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 constant throughout the lifetime of the delivery system. The system shown in Figure 5a is representative of an implantable or oral reservoir delivery system, whereas the system shown in Figure 5b illustrates a transdermal drug
Figure 5. Diffusion from a reservoir system: (a) implantable or oral reservoir; (b) transdermal drug delivery system.
delivery system, in which only one side of the device will actually be delivering the drug.56,60 For the diffusion-controlled systems described thus far, the drug delivery devices need to be stable in the biological environment and not change their 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.39 2.2. Swelling Followed by Diffusion. 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
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Figure 6. Drug delivery from (a) reservoir and (b) matrix swelling-controlled release systems.
biological environment. Swelling-controlled release systems are initially dry and, when placed in the body, will absorb water or other body fluids and swell.56,57 The swelling increases the aqueous solvent content within the formulation as well as the polymer free volume, enabling the drug to diffuse through the swollen network into the external environment. Examples of these types of devices are shown in Figure 6a and b 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. The polymer structure is able to retain the solvents forming a swollen gel phase. Since these are cross-linked systems, they will not dissolve regardless of the solvent properties.57 Drug loading by the swelling method can be performed based on the selection of the drug for therapeutic efficacy and hydrogel swelling data in the selected solvent.60,64 The drug loading content is controlled by the polymer composition and can be estimated from the swelling level in the loading solvent. The synthesis of a hydrogel matrix for a specific drug carrier should be tailored considering the physical properties of drugs, loading level, and desired release kinetics.60 These hydrogels can absorb a great deal of fluid and, at equilibrium, typically comprise 60-90% fluid and only 10-40% polymer.64-66 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.67 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.68 A number of these environmentally sensitive or “intelligent” hydrogel materials are listed in Table 1. For most of these polymers, the structural changes are reversible and repeatable upon additional changes in the external environment, and the diagrams in Figure 7 illustrate the basic changes in structure of these sensitive systems.56,67,69,70 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.71
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.55 2.3. Polymer Degradation and Erosion. 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.59,60,72-74 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 accomplished.73 With regard to biodegradable polymers, it is essential to recognize that degradation is a chemical process, whereas erosion is a physical phenomenon dependent on dissolution and diffusion processes.75 Depending on the chemical structure of the polymer backbone, erosion can occur by either surface or bulk erosion. Surface erosion occurs when the rate of erosion exceeds the rate of water permeation into the bulk of the polymer and is desirable because the kinetics of erosion and rate of drug release (zero order) are highly reproducible. Bulk erosion occurs when water molecules permeate into the bulk of the matrix at a faster rate than erosion, thus exhibiting complex degradation/ erosion kinetics. Most of the biodegradable polymers used in drug delivery undergo bulk erosion.79 Some of the most widely studied polymers for this purpose are poly lactides and poly glycolides, which are commonly used as biodegradable sutures in surgery and have FDA approval, but have the disadvantage of eroding by bulk erosion. In all cases, care has to be taken to ensure that the breakdown products of the polymer are nontoxic and do not interact with the drug46 and affect is efficacy. 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 casessfor example, in the case of polylactides, polyglycolides,76,77 and their copolymerssthe 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 8. 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 8b). The most common formulation for these biodegradable materials is in the form 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.54 These particles will degrade through bulk hydrolysis in water or body fluids, yielding polymer fragments over time. 3. Materials for Drug Delivery 3.1. Polymers. The selection of a polymer for drug delivery requires a thorough understanding of the surface and bulk properties of the polymer to provide the desired chemical, interfacial, mechanical, and biological functions. The choice of polymer, in addition to its physicochemical properties, is dependent on the need for extensive biochemical characterization and specific preclinical tests to prove its safety.
2480 Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009 Table 1. Swelling Stimuli and Mechanisms stimulus pH ionic strength
hydrogel
mechanism
acidic or basic hydrogel ionic hydrogel
change in pHsswellingsrelease of drug change in ionic strengthschange in concentration of ions inside gelschange in swellingsrelease of drug chemical species hydrogel containing electron-accepting groups electron-donating compoundssformation of charge/transfer complexschange in swellingsrelease of drug enzyme-substrate hydrogel containing immobilized enzymes substrate presentsenzymatic conversionsproduct changes swelling of gelsrelease of drug magnetic magnetic particles dispersed in alginate microshperes applied magnetic fieldschange in pores in gelschange in swellingsrelease of drug thermal thermoresponsive hrydrogel poly(N-isopro-pylacrylamide) change in temperatureschange in polymer-polymer and water-polymer interactionsschange in swellingsrelease of drug electrical polyelectrolyte hydrogel applied electric fieldsmembrane chargingselectrophoresis of charged drugschange in swellingsrelease of drug ultrasound irradiation ethylene-vinyl alcohol hydrogel ultrasound irradiationstemperature increasesrelease of drug
Surface properties such as hydrophilicity, lubricity, smoothness, and surface energy govern the biocompatibility with tissues and blood, in addition to influencing physical properties such as durability, permeability, and degradability. The surface properties also determine the water sorption capacity of the polymers, which can undergo hydrolytic degradation and swelling.61 Moreover, bulk properties that need to be considered for controlled delivery systems include molecular weight, bulk modulus, and solubility based on the release mechanism (diffusion- or dissolution-control), and it is the properties of its potential site of action.78 The structural properties of the matrix,
Figure 7. Drug delivery from environmentally sensitive release systems.
Figure 8. Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems.
its micromorphology, and pore size are important with respect to mass transport (of water) into and (of drug) out of the polymer. Several polymers have been investigated for drug-delivery applications and can be broadly classified into natural and synthetic, biodegradable, and nonbiodegradable, as shown in Table 2. However, drug delivery polymer design is highly dependent on the specific device application. For that reason, certain basic criteria should be considered for any polymeric biomaterial used in drug delivery systems. Figure 9 illustrates some questions and guidelines that could be followed by those whishing to rationalize material selection. The numbers in Figure 9 refers to the types of polymers that could meet the desired requirements, as listed in Table 2. 3.1.1. Biodegradable and Nondegradable Polymers. A variety of biodegradable polymers have been synthesized to deliver drugs, macromolecules, cells, and enzymes. The wide acceptability of these polymers can be appreciated from the fact that the biodegradability can be manipulated by incorporating a variety of labile groups such as esters, orthoesters, anhydrides, carbonate, amides, ureas, and urethanes in their backbone. Biodegradation can be of enzymatic, chemical, or microbial origin, and these may operate either separately or simultaneously and are often influenced by many other factors61 as shown in Table 3. Polyester-based polymers are one of the most widely investigated for drug delivery. Poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymers poly(lactic acid-co-glycolic acid) (PLGA) are some of the most well-defined biomaterials with regard to design and performance for drug-delivery applications.72 Although PLGA is by far the most extensively studied biodegradable polymers (exemplified by more than 500 patents), increased local acidity because of degradation can lead to irritation at the site of polymer application.80 Polyorthoesters have been in development since the 1970s, and most research has focused on the synthesis of polymers by addition of polyols to diketene acetals. They are unique among all biodegradable polymers, as mechanical properties can be readily varied by choosing appropriate diols or mixture of diols in their synthesis.72 A number of applications have been found for polyorthoesters and cross-linked polyorthoestes such as delivery of 5-flurouracil, periodontal delivery of tetracycline, and pH-sensitive polymer systems for insulin delivery. Polyanhydrides are characterized by their fast degradation followed by rapid erosion of the material but at the same time can be designed to release drugs that last from days to weeks by suitable choice of monomers.80
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Table 2. Classification of Polymers Used in Drug Delivery and Codes for Selection Natural Polymers protein-based polymers (2)
polysaccharides (2)
collagen, albumin, gelatin
agarose, alginate (3), carrageenan (8), hyaluronic acid, chitosan (3, 7) Synthetic Polymers
biodegradable
nonbiodegradable
polyesters (2) poly (lactic acid), poly (glycolic acid), poly(hydroxy butyrate), poly(ε-caprolactone), poly(β-malic acid), poly(dioxanones) polyamides (2) poly(imino carbonates), polyamino acids phosphorus-based polymers polyphosphates, polyphosphonates, polyphosphazenes
cellulose derivatives (7) carboxymethyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate propionate, hydroxypropyl met hyl cellulose silicones (6) colloidal silica, polysiloxanes acrylic polymers (5, 6) polymethacrylates, poly(methyl methacrylate), poly hydro(ethylmethacrylate) others (8) polyvinyl pyrrolidone, ethyl vinyl acetate, poloxamers, poloxamines
others (1) poly(cyano acrylates), polyurethanes, polyortho esters, polydihydropyrans, polyacetals a
The parenthesized numbers refer to the selection polymer in Figure 9.
Figure 9. Guidelines to rationalize material selection.
Polyaminoacids that have good biocompatibility have been investigated for the delivery of low-molecular-weight compounds. However, their widespread use is limited by their antigenic potentials and poor control of release because of the
dependence on enzymes for biodegradation. Poly(imino carbonates), which are “pseudo” polyaminoacids, have been synthesized from tyrosine dipeptide to overcome the abovementioned limitations.61
2482 Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009 Table 3. Factors Affecting Biodegradation of Polymers chemical structure and composition physicochemical factors (ion exchange, ionic strength, pH) molecular-weight distribution route of administration or side sterilization process physical factors (shape and size changes, stresses, variation of diffusion coefficients) morphology (amorphous/semicrystalline, microstructures)
A variety of nondegradable polymers are used in drug delivery of which polysaccharide-based and acrylic-based polymers have found wide application in the fabrication of peroral dosage forms, transdermal films, and devices.81 Polyethylene oxide (PEO) and polyoxypropylene (POP) copolymers are one of the most interesting classes used for nanoparticulate drug delivery systems. They are commercially available in a wide range of states including liquids, pastes, and solids. Since their first introduction as nonionic surfactants in the 1950s, they have found a wide range of applications in the pharmaceutical and biomedical fields.68 Soluble block copolymers based on PEO-PLA can self-assemble into novel supramolecular structures and are being investigated for delivery of anticancer agents, proteins, and plasmid DNA.39 They are advantageous in terms of drug targeting and safety, and they can mimic biological transport systems, lipoproteins, or viruses. Polysiloxanes are a unique class of nondeformable polymer possessing good low-temperature flexibility, excellent electrical properties, water repellency, and remarkable biocompatibility, features that are not common with hydrocarbon polymers.41 Because of ease of fabrication and high permeability, polydimethyl siloxanes (PDMSs) are useful for water-soluble drugs and steroids for long-acting DDSs such as subdermal implants and intravagnial systems.46 3.1.2. Natural Polymers.79 Naturally derived polymers are abundant, usually biodegradable, and offer excellent biocompatibility. Their principal disadvantage lies in the development of reproducible production methods, because their structural complexity often renders modification and purification difficult. Additionally, significant batch-to-batch variations occur because of their “biopreparation” in living organisms (plants, crustaceans). A variety of natural polymers have been used as biomaterials, including albumin, hyaluronic acid and derivates, alginate, and chitosan.82 Hyaluronic acid is an interesting biomaterial that is employed in surgical procedures. Modified hyaluronic acid materials are available. These have been fabricated into microspheres and could well have applications in controlled release of drug injection or nasal administration.83 Of special interest is the natural material chitin; which can be deacetylated to produce the soluble biopolymer chitosan. The physical and chemical properties of chitosan, such as inter- and intramolecular hydrogen bonding and the cationic charge in acidic medium, makes this polymer attractive for the development of conventional and novel pharmaceutical products. Chitosan has favorable biological properties, such as nontoxicity, biocompatibility, biodegradability, and antibacterial characteristics. Chitosan has unique properties of bioadhesion, absorption enhancement by increasing the residence time of dosage forms at mucosal sites, inhibiting proteolytic enzymes, and increasing the permeability of various drugs across mucosal membranes. Since chitosan degrades due to the action of microbial flora present in the colon, it is a good candidate for site-specific drug delivery. Low toxicity coupled with wide applicability makes
it a promising candidate for drug delivery for a host of drug moieties (anti-inflammatory, peptides, etc), and as a biologically active agent.69,79 Polymer science has played a crucial role in the development of new drug delivery systems for the past few decades. Future advances will be based on modifying the chemical and physical properties of the polymer and creating novel combinations of copolymers with targeting and bioresponsive components that can deliver a wide variety of bioactive agents. Further, newer fabrication and manufacturing processes such as molecular imprinting,84 supercritical fluid technology,85 and nanoscale engineering are bound to revolutionize the design, development, and performance of polymer-based drug delivery systems. 3.1.3. Silicon versus Polymer in Drug Delivery. The firstgeneration microfabricated drug delivery devices were mostly made of silicon-based materials, due to the availability of highly advanced technology developed for fabricating these devices by the microelectronics industry. Unfortunately, the physical and chemical properties of silicon-based materials, including poor impact strength/toughness, lack of optical clarity, nonbiodegradability, and high manufacturing cost (especially for relatively small numbers of devices), are not appropriate for many biomedical applications. On the other hand, polymeric materials can have a wide variety of properties, including toughness, optical clarity, good biocompatibility, and biodegradability. Polymers can also be therapeutically active, environment-sensitive, versatile in surface properties, and relatively inexpensive in materials and processing, making them attractive for numerous biomedical applications. Moreover, conducting polymer-based microelectronics are under rapid development and show great promise to be used in certain low-cost, biomedical applications that do not require high-speed performance.86 Aside from the materials, conventional microfabrication techniques for silicon-based processing, such as low-pressure chemical vapor deposition (LPCVD) of thin films, photolithography, and etching, are also not desirable for many biomedical uses because ionizing radiation, toxic solvents, corrosive enchants, and elevated temperatures are commonly employed in silicon-based processing and they may damage therapeutic agents such as macrolides, biological macromolecules, or cells. Polymer-based microfabrication technology is superior to silicon-based microfabrication in terms of cost and versatility. Many techniques have been developed or are under development for polymer microfabrication. Some of them are the “microversion” of conventional polymer processing techniques such as solution casting, injection molding, and hot embossing. Some are developed mainly for polymer microfabrication such as soft lithography,87 which uses an elastomeric mold with surface relief features to generate micro- and even nanostructures. All these techniques rely on the use of a master with microfeatures made by micromachining or photolithography. Masters can be used to generate polymer devices directly or to make a silicone mold. The master and mold can be used repeatedly to create many polymer devices in a noncleanroom environment, lowering the cost of these methods significantly. Although many polymer microfabrication techniques also use ionizing radiation, organic solvents, and elevated temperature and pressure, due to the large variety of polymers and processing techniques, the chance of finding appropriate materials and techniques for the fabrication of drug delivery devices that are compatible with the incorporated drugs and clinical applications is relatively high.88
Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009 2483 Table 4. Criteria for the Physicochemical Properties of Drug Administrated for Different Routesa route
MW
HA
HD
PSA
RB
ClogP
oral transdermal buccal/sublingual nasal vaginal
0 < X < 500 295.9c (188.0-411.7)d 275.1 (163.3-342.3) 391.6 (227.5-575.7) 321.3 (171.8-416.1)
0 < X < 11 3.36 (1-6) 2.93 (1-5) 4.77 (2-8.8) 2.93 (1.6-5)
0 AHD good poor Dn < 0.1 0.1 < Dn < 10 Dn > 10 AP > 1
moderate good good
See Table 5 for equations. b AHD ) anticipated human dose.
solubility is not a problem; while values about 10 show that the solubility is troublesome. The maximum absorbable dose (MAD) represents the amount of drug that can permeate across a barrier. Again the volume available to dissolve the drug is a critical parameter for the nonoral routes of administration. However, if the absorption rate constant is sufficiently high and a longer residence time can be achieved, a considerable amount of drug can still be absorbed. The absorption rate constant can be calculated from the permeability of the epithelium involved or estimated by the ratio of Cmax to AUC. If the MAD is higher than the AHD, no problems are to be expected with respect to absorption. The absorption potential is also suitable for acids and bases as it takes the degree of ionization of the drug into account. The criteria presented in Table 7 address the solubility as well as the permeability of drugs, which are both crucial to obtain a sufficient systemic exposure. However, the problem in drug discovery is that the new compounds tend to be more and more hydrophobic by nature, as the current high throughput screening (HTS) technologies are based on binding assays to determine whether a drug binds to a target.100 One of the major pitfalls of library screening is that the more hydrophobic compounds appear to bind better to
the targets (the so-called hydrophobic effect).101 The current analysis emphasizes that the solubility is one of the key parameters. It becomes immediately clear that in case of hydrophobic drugs a different route of administration needs to be used. The main advantage of the nonoral routes of administration is found in the circumvention of the first pass effect (FPE) in comparison to the oral route. Although metabolic enzymes are present in almost all epithelia, first pass metabolism is clearly dependent on the expression levels in the involved tissues. Only a limited number of reports are available in literature where a “first pass effect” is reported for the nonoral routes of administration (e.g., the FPE of nitroglycerin when administered transdermally40,43,44). Nonetheless, in cases where the administered dose is low, e.g. in the microgram range, presystemic metabolism might be considerable even when the expression levels of the metabolic enzymes are low. It is possible to conclude that, for the different routes of drug administration, the barriers to the systemic circulation are formed by multiple layered epithelia, with the exception of the gastrointestinal epithelium which consists of a single layer of enterocytes.102,103 Strikingly, the ranges of the molecular weight, number of hydrogen bond donor and acceptor sites, polar surfaces, number of rotatable bonds, and ClogP are all within the generally accepted ranges for passive transcellular transport after oral administration. Evaluating the solubility of drugs in terms of the “physiological” volume available for dissolution showed that this is a very critical parameter. This clearly shows that the solubility is more critical for the nonoral routes of administration. It is concluded that, for permeation across epithelia, the required properties are independent of the route of administration. If a nonoral route of administration is chosen the solubility becomes a very critical parameter, as less volume is available to dissolve the drug. Hence, for the medical chemist a change in route of administration is not suitable to increase exposure in the case of hydrophobic drugs. Outlook The delivery of drugs to their site of action at the correct time and concentration is a key requirement, and this presents a formidable challenge to overcome if the potential postgenomic benefits to healthcare are to be realized. Although this problem exists for all types of molecules, it is particularly acute for biologicals and macromolecules. These are likely to form a significant proportion of the medicines that will be used in the future as new approaches to tackling disease become established. This paper identifies the priority challenges and opportunities for precompetitive research in drug delivery for the next decade as follows. The need to gain greater understanding of the physicochemical properties of biopharmaceuticals, macromolecules, and macromolecular delivery systems and learn how these properties are modified within the biological environment will determine how drug activity will be affected. One of the pivotal challenges for the future will be the identification of technologies that can circumvent the complex biological barriers known to limit bioavailability of small and macromolecular drugs (particularly proteins, oligonucleotides, and drug-polymer conjugates). With a fundamental understanding of biological barriers advanced materials can be developed as carriers and devices for the delivery of pharmaceuticals. The creation of smart, stimulisensitive systems that respond to subtle changes in the local cellular environment is likely to yield long-term solutions to many of the current drug delivery problems.
Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009 2485
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ReceiVed for reView June 5, 2008 ReVised manuscript receiVed December 9, 2008 Accepted January 5, 2009 IE800886M
