Originally published November 1997

BIOMATERIALS

Polymers in Controlled Drug Delivery

Lisa Brannon-Peppas
New materials are enhancing innovative systems currently under development. 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 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 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 overdosing. Other advantages of using controlleddelivery 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 nonbiocompatibility 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. Micrograph of particles used to carry drugs to the lung. (Photo courtesy of R. Langer, Massachusetts Institute of Technology, Cambridge, MA).

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 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 deliveror cease to deliverdrugs 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 productsboth desirable and potentially nondesirablemust 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 belowa 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.1

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 scaleas through pores in the polymer matrixor on a molecular level, by passing between polymer chains. Examples of diffusion-release systems are shown in Figures 2 and 3. 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. Figure 2. Drug delivery from a typical matrix drug delivery system.

For the reservoir systems shown in Figures 3a and 3b, the drug delivery rate can remain fairly constant. In this design, a reservoirwhether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrixis 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.

Stimulus pH

Hydrogel Acidic or basic hydrogel Ionic hydrogel

Mechanism Change in pH swelling release of drug

Ionic strength

Change in ionic strength change in concentration of ions inside gel change in swelling release of drug Electron-donating compounds formation of charge/transfer complex change in swelling release of drug Substrate present enzymatic conversion product changes swelling of gel release of drug

Table I. Environmentally sensitive polymers for drug delivery.4

Chemical species

Hydrogel containing electronaccepting groups

ENVIRONMENTALLY RESPONSIVE SYSTEMS

It is also possible for a drug delivery system to be designed so that it is Magnetic Magnetic particles dispersed in Applied magnetic field change in pores in gel incapable of releasing its alginate microshperes change in swelling release of drug agent or agents until it is placed in an appropriate Thermal Thermoresponsive hrydrogel Change in temperature change in polymer-polymer and biological environment. poly(N-isoprowater-polymer interactions change in swelling Swelling-controlled pylacrylamide) release of drug release systems are initially dry and, when Electrical Polyelectrolyte Applied electric field membrane charging placed in the body, will hydrogel electrophoresis of charged drug change in swelling absorb water or other release of drug body fluids and swell. The swelling increases the Ultrasound Ethylene-vinyl alcohol Ultrasound irradiation temperature increase release aqueous solvent content irradiation hydrogel of drug 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 6090% fluid and only 1030% polymer.
Enzymesubstrate Hydrogel containing immobilized enzymes

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. 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. Figure 6. Drug delivery from environmentally sensitive release systems.

BIODEGRADABLE SYSTEMS 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 are 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 casesas, for example, polylactides, polyglycolides, and their copolymersthe 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) surfaceeroding 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.

surface-eroding polymers. after 9 and 16 weeks of significant surface degradation, system remains intact (see Figure 10).5

A very different erosion pattern is characteristic of polyorthoesters, which are Analysis of polyorthoester rods implantation in rabbits shows but the core of the drug delivery

Figure 10. Biodegradable polyorthoester rods after (left) 9 and (right) 16 weeks of implantation in rabbits. (Photos courtesy of H. Heller, Advanced Polymer Systems, Redwood City, CA.)

DRUG DELIVERY AND THE TREATMENT OF DIABETES One disease that has received a great deal of attention because of the potential for therapies using controlled drug delivery is diabetes. For this disease, an optimal delivery system would be one that could deliver insulin upon detection of glucose in the bloodstream. Researchers have been working on this approach for more than a decade, and there are a few systems that show significant progress. Most systems under study for insulin delivery base their delivery on the reaction of glucose in the blood with glucose oxidase, which can be immobilized on polymers within the drug delivery system. The glucose/glucose-oxidase reaction causes a lowering of the pH in the delivery system's microenvironment. This can cause an increase in the swelling of the polymer system, leading to an increased release of insulin, for delivery systems that are based on copolymers containing N,N-dimethylaminoethyl methacrylate1 or polyacrylamide.2 Figure 1. Molecular gates for the delivery of insulin triggered by the presence of glucose in the bloodstream.4

Work with biodegradable polymers has also yielded polyorthoesters that are pH sensitive and that will degrade more quickly in acidic environments.3 Such polymers have been studied as the central core of a drug delivery system in which the polymer-insulin matrix is surrounded by a membrane containing grafted glucose oxidase, which provides the reaction substrate and the change in pH necessary to enhance biodegradation and subsequent insulin delivery. A recent inventive system that can deliver insulin in response to glucose uses polymers that will shrink rather than swell at low pH values. Depicted in Figure 1, this "molecular gates" system features an insulin-containing reservoir with a delivery-rate-controlling membrane of poly(methacrylic acid-g-poly(ethylene glycol)) copolymer in which glucose oxidase has been immobilized. This gel expands at high pH values (normal body pH of 7.4), closing the gates, and shrinks at low pH values (pH of approximately 4.0 due to interaction of glucose with immobilized glucose oxidase), opening the gates. Control of the insulin delivery depends on the size of the gates, the concentration of insulin, and the rate of the gates' opening or closing (response rate).4 Until such time as these self-contained delivery systems become a reality, other researchers are investigating ways to monitor glucose levels without the need for blood samples and to administer insulin without injections. An imaginative first step in noninvasive glucose monitoring has been taken by Cygnus Inc. (Redwood City, CA), where researchers have essentially reversed the process of transdermal drug delivery and used iontophoresis to bring minute quantities of glucose in the blood to the surface of the skin, where it can then be measured. This system, known as the GlucoWatch for its resemblance to a wristwatch, could permit hourly monitoring of a diabetic's blood-glucose level and also track actions taken to manage the disease, such as insulin injections, eating, and exercise. Providing insulin delivery by oral administration has been an elusive goal, one that a few researchers now appear to be nearing. Recent work by Lowman and Peppas indicates that dose-dependent oral delivery of insulin may be achievable using pH-sensitive systems.5 Early in vivo studies in rats have been promising, with additional work under way. REFERENCES 1. Kost J, Horbett TA, Ratner BD, et al., "Glucose-Sensitive Membranes Containing Glucose Oxidase: Activity, Swelling, and Permeability Studies," J Biomed Mater Res, 19:11171133, 1985. 2. Ishihara K, Kobayashi M, and Shinohara I, "Control of Insulin Permeation through a Polymer Membrane with Responsive Function for Glucose," Makromol Chem Rapid Commun, 4:327, 1983. 3. Heller J, Pangburn SH, and Penhale DWH, "Use of Bioerodible Polymers in Self-Regulated Drug Delivery Systems," in Controlled-Release Technology, Pharmaceutical Applications, Lee PI, and Good WR (eds), Washington DC, ACS Symposium Series, pp 172187, 1987. 4. Dorski CM, Doyle FJ, and Peppas NA, "Preparation and Characterization of Glucose-Sensitive P(MAA-g-EG) Hydrogels," Polym Mater Sci Eng Proceed, 76:281282, 1997. 5. Lowman AM, and Peppas NA, "Complexation Graft Copolymers as Oral Drug Delivery Systems," Polym Preprints, 38(2):566567, 1997.

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 biomaterialstailor-made copolymers with desirable functional groupsare 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, 16:1526, 1991. 2. Cleary GW, "Transdermal Drug Delivery," Cosmetics and Toiletries, 106:97107, 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 1768, 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 126133, 1996. 5. Heller J, "Controlled Drug Release from Poly(ortho esters)A Surface Eroding Polymer," J Controlled Release, 2:167177, 1985. BIBLIOGRAPHY Benita S (ed), Microencapsulation: Methods and Industrial Applications, New York, Marcel Dekker, 1996. Chasin M, and Langer R (eds), Biodegradable Polymers as Drug Delivery Systems, New York, Marcel Dekker, 1990.

Chien YW, Novel Drug Delivery Systems, New York, Marcel Dekker, 1982. Domb AJ (ed), Polymeric Site-Specific Pharmacotherapy, Chichester, UK, Wiley, 1994. Donbrow M (ed), Microcapsules and Nanoparticles in Medicine and Pharmacy, Boca Raton, FL, CRC Press, 1992. Mikos AG, Murphy RM, Bernstein H, et al. (eds), Biomaterials for Drug and Cell Delivery, Pittsburgh, Materials Research Society, 1994. Park K, Shalaby WSW, and Park H, Biodegradable Hydrogels for Drug Delivery, Lancaster, PA, Technomic, 1993. Peppas NA (ed), Hydrogels in Medicine and Pharmacy, Boca Raton, FL, CRC Press, 1986. Ratner BD, Hoffman AS, Schoen FJ, et al. (eds), Biomaterials Science: An Introduction to Materials in Medicine, San Diego, Academic Press, 1997. Robinson JR, and Lee VHL (eds), Controlled Drug Delivery: Fundamentals and Applications (2nd ed), New York, Marcel Dekker, 1987. Shalaby SW, Ikada Y, Langer R, et al. (eds), Polymers of Biological and Biomedical Significance, Washington DC, ACS Symposium Series, 1994. Lisa Brannon-Peppas, PhD, is president and founder of Biogel Technology, Inc. (Indianapolis, IN). The company, created in 1991, is a research-driven enterprise that specializes in applying the technologies of polymer science to controlled delivery, separations, biomaterials, bioadhesives, and other areas. The company is active in research, development, and preparation of polymeric materials in biotechnology, bioengineering, medical sciences, and industrial pharmacy.

Copyright 1997 Medical Plastics and Biomaterials

POLYMERIC DRUG DELIVERY A BRIEF REVIEW

Back to the Main Page Please Note: You could contribute to this

Introduction
In recent years, there has been a rapid growth in the area of drug

section via expert commentary/articles. The discovery, facilitated by novel technologies such as combinatorial Please contact webmaster@drugdel.com if chemistry and high-throughput screening. These novel approaches have you want to make a contribution. led to drugs which are generally more potent and have poorer solubility than drugs developed from traditional approaches of medicinal chemistry (Lipinsky, 1998). The development of these complex drugs TECHNOLOGY OVERVIEW has resulted in a more urgent focus on developing novel techniques, to To obtain a custon-made industry report on this deliver these drugs more effectively and efficiently.
field, contact the sales division. Some of the salient features of the report will include:

1. A list of approved products as well as

products in various clinical trials.

2. Sales figures of the approved products

along with future sales forecasts.

3. A detailed scientific overview of the field

and the emerging technologies.

4. A list of potential candidates suitable for

5. this technology. A list of consultants and researchers working in this field and a review of new developments in their labs.

Table 1: Some commercial suppliers of GMP grade PLA/PLGA polymers. Absorbable Polymer Tech, AL Alkermes, MA Birmingham Polymers Inc., AL Boehringer Ingelheim, Germany Table 2: A list of companies working in the field of polymeric drug delivery. Purac America, IL Figure 1: Conventional and Ideal drug release profiles As can be seen in Figure 1, the conventional oral and intravenous routes of drug administration do not provide ideal pharmacokinetic profiles especially for drugs, which display high toxicity and/or narrow therapeutic windows. For such drugs the ideal pharmacokinetic profile will be one wherein the drug concentration reached therapeutic levels without exceeding the maximum tolerable dose and maintains these concentrations for extended periods of time till the desired therapeutic effect is reached. One of the ways such a profile can be achieved in an ideal case scenario would be by encapsulating the drug in a polymer matrix. The technology of polymeric drug delivery has been studied in details over the past 30 years and numerous excellent reviews are available (Gombotz and Pettie, 1995; Sinha and Khosla, 1998; Langer, 1998). This brief review is intended to introduce the practical aspects in commercialization of polymeric drug delivery products. For more comprehensive reviews of the underlying science, the reader can refer to the many excellent review articles listed at the end of this report. The three key advantages that polymeric drug delivery products can

Abbott Laboratories Absorbable Polymers Access Pharmaceuticals Advanced Polymer Systems Alkermes Inc. Alliance Pharmaceuticals Alza Corporation Angiotech Atrix Laboratories Avant Immunotherapeutics Bend Research Inc. Biogel Corp. Biosyntech Corp Birmingham Polymers Inc. CeNeS Chiron Corporation Corixa Flamel Technologies Focal Inc. Genzyme Corporation Guilford Pharmaceuticals Nobex Corp. Oakwood Laboratories Orapharma Inc. Perio Products Ltd, Israel Praecis Pharmaceuticals Protein Polymer Tech Quadrant PLC Shearwater Polymers Skyepharma Corporation Southern Biosystems Southern Research Institute West Pharmaceuticals Inc. Zycos

offer are: 1. Localized delivery of drug: The product can be implanted directly at the site where drug action is needed and hence systemic exposure of the drug can be reduced. This becomes especially important for toxic drugs which are related to various sytemic side effects (such as the chemotherapeutic drugs). 2. Sustained delivery of drugs: The drug encapsulated is released over extended periods and hence eliminates the need for multiple injections. This feature can improve patient compliance especially for drugs for chronic indications, requiring frequent injections (such as for deficiency of certain proteins). 3. Stabilization of the drug: The polymer can protect the drug from the physiological environment and hence improve its stability in vivo. This particular feature makes this technology attractive for the delivery of labile drugs such as proteins. Interest in this field has increased considerably, especially after the commercial success of products such as Lupron Depot , Zoladex , Norplant and Gliadel , all of which use the principles of sustained and localized drug release.

Figure 2. Possible drug release mechanisms for polymeric drug delivery As shown in Figure 2, the drug will be released over time either by diffusion out of the polymer matrix or by degradation of the polymer backbone. This continuous release of the drug could potentially lead to a pharmacokinetic profile close to the ideal case scenario depicted in Figure 1. The continuous release of drugs from the polymer matrix could occur either by diffusion of the drug from the polymer matrix, or by the

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erosion of the polymer (due to degradation) or by a combination of the two mechanisms. Several reviews have been presented on the mechanisms and the mathematical aspects of release of drugs from polymer matrices (Batycky et al., 1997;Brazel and Peppas, 2000; Comets et al., 2000). For a given drug, the release kinetics from the polymer matrix are governed predominantly by three factors, viz. the polymer type, polymer morphology and the excipients present in the system. The subsequent sections will focus on each of these three factors to describe their role on drug release characteristics of a polymeric system.

The Polymer
An appropriate selection of the polymer matrix is necessary in order to develop a successful drug delivery system. The polymer could be nondegradable or degradable. A major disadvantage with non-degradable polymers is that a surgery is required to harvest these polymers out of the body once they are depleted of the drug. Hence, non-degradable polymers can be used only if removal of the implant is easy (such as an ocular implant). Degradable polymers on the other hand do not require surgical removal and hence are preferred for drug delivery applications. However, since they degrade to smaller absorbable molecules, it is important to make sure that the monomers are non-toxic in nature. The most commonly used polymers for this application are Polylactide (PLA) and Poly(Lactide-co-Glycolide) (PLGA). These polymers have been used in biomedical applications for more than 20 years and are known to be biodegradable, biocompatible and non-toxic. These polymers are commercially available from various vendors, some of whom are listed in Table 1. A vast amount of literature is available on the characterization of these polymers and their biodegradation and drug release properties. Degradation of lactide based polymers and in general all hydrolytically degradable polymers, depends on the following properties:
1. Chemical composition: The rate of degradation of polymers

depends the type of degradable bonds present on the polymer. In general, the rate of degradation of different chemical bonds follows as Anhydride > Esters > Amides. 2. Crystallinity: Higher than crystallinity of a polymer, slower is its rate of degradation. 3. Hydrophilicity: If the polymer has a lot of hydrophobic groups present on it, then it is likely to degrade slower than a polymer which is hydrophilic in nature.

Polylactides are known to be more hydrophobic as compared to PLGA and take a longer time to degrade. Among the polylactides, DL-PLA, which is a polymer of D and L-lactide, degrades faster than L-PLA, which is a homopolymer of L-lactide, presumably due to lesser crystallinity. Similarly, the more hydrophobic end-capped PLGA polymers degrade faster than the carboxyl-ended PLGA. In spite of the several apparent advantages of PLA and PLGA based polymers, commercialization of products based on these polymers has certain limitations. One of the major concerns is that more than 500 patents have been issued for various applications of these polymers. Hence, patent infringement may become a concern in developing new products. In addition, PLA and PLGA polymers have certain inherent limitations in terms of flexibility for applications. Due to these concerns, several new polymers are presently being explored for applications in drug delivery. Some of the new polymers which are in clinical or preclinical development stage are: 1. Polyorthoesters (Heller et al., 2000) 2. Polyphosphazenes (Allcock, 1994) 3. Polyanhydrides (Shieh et al., 1994) 4. Polyphosphoesters (Richards et al., 1991)

Polymer Morphology
Morphology of the polymer matrix plays an important role in governing the release characteristics of the encapsulated drug. The polymer matrix could be formulated as either micro/nano-spheres, gel, film or an extruded shape (such as cylinder, rod etc). The shape of the extruded polymer can be important to the drug release kinetics. For example, it has been shown that zero order drug release can be achieved using a hemispherical polymer form. Polymer microspheres are the most popular form due to manufacturing advantages as well as ease of administration (injectability by suspending in a vehicle). As depicted in Figure 2, polymer microspheres can be manufactured by using various techniques such as spray drying, solvent evaporation etc (ODonnell and McGinity 1997; Hermann and Bodmeier 1998; Witschi and Doelker 1998). The type of technique used affects factors such as porosity, size distribution and surface morphology of the microspheres and may subsequently affect the performance of the drug delivery product.

Excipients
Polymeric drug delivery products can be formulated with excipients

added to the polymer matrix. The main objective of having excipients in the polymer matrix could be either to modulate the drug release, or to stabilize the drug or to modulate the polymer degradation kinetics. Recent studies by Schwendeman and coworkers (Zhu and Schwendeman, 1999; Zhu et al., 2000) have shown that by incorporating basic salts as excipients in polymeric microspheres, the stability of the incorporated protein can be improved. It has shown that these basic salts however also slow the degradation of the polymer. Similarly, hydrophilic excipients can accelerate the release of drugs, though they may also increase the initial burst effect.

Bibliography
1. Lipinsky C. American Association of Pharmaceutical Sciences, Annual Meeting 1998. 2. Heller J, Barr J, Ng SY, Shen HR, Schwach-Abdellaoui K, Emmahl S, Rothen-Weinhold A, Gurny R. Poly(ortho esters) their development and some recent applications. Eur J Pharm Biopharm. 2000 Jul;50(1):121-8. 3. Bibby DC, Davies NM, Tucker IG. Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems. Int J Pharm. 2000 Mar 20;197(1-2):1-11. 4. Gutman RL, Peacock G, Lu DR. Targeted drug delivery for brain cancer treatment. J Control Release. 2000 Mar 1;65(12):31-41. 5. Sinha VR, Khosla L. Bioabsorbable polymers for implantable therapeutic systems. Drug Dev Ind Pharm. 1998 Dec;24(12):1129-38. 6. Jain R, Shah NH, Malick AW, Rhodes CT. Controlled drug delivery by biodegradable poly(ester) devices: different preparative approaches. Drug Dev Ind Pharm. 1998 Aug;24(8):703-27. 7. Vert M, Schwach G, Engel R, Coudane J. Something new in the field of PLA/GA bioresorbable polymers? J Control Release. 1998 Apr 30;53(1-3):85-92. 8. Ulbrich K, Pechar M, Strohalm J, Subr V, Rihova B. Synthesis of biodegradable polymers for controlled drug release. Ann N Y Acad Sci. 1997 Dec 31;831:47-56. 9. Langer R. Drug delivery and targeting. Nature. 1998 Apr 30;392(6679 Suppl):5-10. 10. Cleland JL. Solvent evaporation processes for the production of controlled release biodegradable microsphere formulations for therapeutics and vaccines. Biotechnol Prog. 1998 Jan-

Feb;14(1):102-7. 11. Wyatt TL, Saltzman WM. Protein delivery from nondegradable polymer matrices. Pharm Biotechnol. 1997;10:119-37. 12. Batycky RP, Hanes J, Langer R, Edwards DA. A theoretical model of erosion and macromolecular drug release from biodegrading microspheres. J Pharm Sci. 1997 Dec;86(12):146477. 13. Peppas NA, Sahlin JJ. Hydrogels as mucoadhesive and bioadhesive materials: a review. Biomaterials. 1996 Aug;17(16):1553-61. 14. Wheeler JC, Woods JA, Cox MJ, Cantrell RW, Watkins FH, Edlich RF. Evolution of hydrogel polymers as contact lenses, surface coatings, dressings, and drug delivery systems. J Long Term Eff Med Implants. 1996;6(3-4):207-17. 15. Gombotz WR, Pettit DK. Biodegradable polymers for protein and peptide drug delivery. Bioconjug Chem. 1995 JulAug;6(4):332-51. 16. Okada H, Toguchi H. Biodegradable microspheres in drug delivery. Crit Rev Ther Drug Carrier Syst. 1995;12(1):1-99. 17. Payne LG, Jenkins SA, Andrianov A, Roberts BE. Water-soluble phosphazene polymers for parenteral and mucosal vaccine delivery. Pharm Biotechnol. 1995;6:473-93. 18. Tanguay JF, Zidar JP, Phillips HR 3rd, Stack RS. Current status of biodegradable stents. Cardiol Clin. 1994 Nov;12(4):699-713. 19. Kim SW, Bae YH, Okano T. Hydrogels: swelling, drug loading, and release. Pharm Res. 1992 Mar;9(3):283-90. 20. Patrick B. O'Donnell and James W. McGinity, Preparation of microspheres by the solvent evaporation technique, Advanced Drug Delivery Reviews 28(1) (1997) pp. 25-42 21. Zhu G, Schwendeman SP. Stabilization of proteins encapsulated in cylindrical poly(lactide-co-glycolide) implants: mechanism of stabilization by basic additives. Pharm Res. 2000 Mar;17(3):351-7. 22. Zhu G, Mallery SR, Schwendeman SP. Stabilization of proteins encapsulated in injectable poly (lactide- co-glycolide). Nat Biotechnol 2000 Jan;18(1):52-7. 23. Shieh L, Tamada J, Chen I, Pang J, Domb A, Langer R. Erosion of a new family of biodegradable polyanhydrides. J. Biomed. Mater. Res., 28, 1465-1475, 1994. 24. Shive MS, Anderson JM. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Del. Rev. 28, 524,1997. Back to the Main Page

Remote Control Drug Delivery Possible

By Scott Fields, Special to LiveScience posted: 10 March 2006 08:41 am ET

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Before becoming nanotubes, these nanofibers are mixed with the drug dexamethasone. Credit:

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1 of 3 Tiny remote-controlled tubes may one day let doctors deliver potent drugs to the exact spots in the body they are most needed. The nanotubes, which are typically about 100 nanometers long, or one ten-millionth of an inch, are made from a special polymer that conducts electricity. Here's how it's done:

Drug molecules and fibers of a polymer that breaks down in the body are mixed together. The mixture is placed on the tip of a tiny gold electrode, a type of medical probe that can transmit or receive electrical signals.

The coated electrode is placed in a solution that contains another type of polymer, the one that conducts the electricity.

An electrical current is applied to the solution, causing the conductive polymer to form tubes around the drug-and-fiber mixture, like microscopic cannoli.

"So now what you can do is control the release of the drugs out from the inside of these little tubes because these conducting polymers can be actuated," David Martin, a professor of materials science and engineering at the University of Michigan, told LiveScience. "You can expand them or contract them when you put an electric field on them," Martin said. "So what you end up with are these little tubes that are filled with drugs that you can then squeeze or open to get the drugs that are inside the tubes to come out when you want them and where you want them." To get the drugs where they belong, the coated electrode is inserted into the tissue where it is needed. Then an electrical charge as small as one volt, less than the charge of a triple-A battery, is sent through the electrode, releasing the drugs. Whether the nanotubes contract or expand depends on the tube design and the kind of voltage applied to it. Martin's groupwhose primary interest is linking brains to computers to replace such lost functions as eyesight or hearingdeveloped the technology to deliver an anti-inflammation drug that is meant to help brain tissue better accept electrodes. But, he says, the nanotubes could also deliver other drugs directly to other types of tissues, such as cancerous tumors. Because nanotubes are tiny, they can deliver only minute quantities of a drug. But, Martin says, contracting tubes could serve as remote-controlled valves for attached, somewhat larger, drug reservoirs. This technology has been tested on cells in Petri dishes, but not yet in animals.

Fantastic Voyage to Save the Heart Gold Probes Could Reveal Cancer in Your Body Manufactured Nanoparticles Might Pose Health Threat Nanotechnology May Need Regulation

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Nanomaterials Used To Localize And Control Drug Delivery

ScienceDaily (Jan. 24, 2008) Using nanotechnology, scientists from UCLA and Northwestern University have developed a localized and controlled drug delivery method that is invisible to the immune system, a discovery that could provide newer and more effective treatments for cancer and other diseases.
See also: Health & Medicine

Colon Cancer Lung Cancer Breast Cancer

Matter & Energy Nanotechnology Materials Science Physics

Reference Nanomedicine Heat shock protein Transplant rejection Detox

The study, published Jan. 22, 2008 in the journal ACS Nano, provides an example of the enormous potential and clinical significance that nanomaterials may represent in such fields as oncology, endocrinology and cardiology. The researchers used nanoscale polymer films, about four nanometers per layer, to build a sort of matrix or platform to hold and slowly release an anti-inflammatory drug. The films are orders of magnitude thinner than conventional drug deliver coatings, said Genhong Cheng, a researcher at UCLA's Jonsson Comprehensive Cancer Center and one of the study's authors. A nanometer is one billionth of a meter. "Using this system, drugs could be released slowly and under control for weeks or longer," said Cheng, a professor of microbiology, immunology and molecular genetics. "A drug that is given orally or through the bloodstream travels throughout the system and dissipates from the body much more quickly. Using a more localized and controlled approach could limit side effects, particularly with chemotherapy drugs." Researchers coated tiny chips with layers of the nanoscale polymer films, which are inert and helped provide a Harry Potter-like invisibility cloak for the chips, hiding them from the body's natural defenses. They then added Dexamethasone, an antiinflammatory drug, between the layers. The chips were implanted in mice, and researchers found that the Dexamethasone-coated films suppressed the expression of cytokines, proteins released by the cells of the immune system to initiate a response to a foreign invader. Mice without implants and those with uncoated implants were studied to compare immune response. The uncoated implants generated an inflammatory response from the surrounding tissue, which ultimately would have led to the body's rejection of the implant and the breakdown of its functionality. However, tissue from the mice without implants and the mice with the nano-cloaked implants were virtually identical, proving that the film-coated

implants were effectively shielded from the body's defense system, said Edward Chow, a former UCLA graduate student who participated in the study and is one of its authors. "The polymer films provided a cloak of invisibility for the implants, keeping the immune system from attacking," Chow said. The nanomaterial technology serves as a non-invasive and biocompatible platform for the delivery of a broad range of therapeutics, said Dean Ho, an assistant professor of biomedical and mechanical engineering with the McCormick School of Engineering and Applied Science, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the study's senior author. The technology also may prove to be an effective approach for delivering multiple drugs, controlling the sequence of multi-drug delivery strategies and enhancing the life spans of commonly implanted devises such as cardiac stents, pacemakers and continuous glucose monitors. "For chemotherapy, this system could enhance treatment efficacy while preventing uncontrolled delivery and the resultant patient side effects," Ho said. "Furthermore, as implantable devices continue to find widespread application in cardiovascular medicine, neural disorders and diabetes, the nano-cloaking capabilities can serve as a widely applicable approach to enhance the lifetime of these devices. This would eliminate unnecessary surgeries and enhance the efficiency of patient care." Many cancer drugs, chemotherapies for example, are delivered systemically through the blood stream. The drugs attack cancer cells, but also other fast growing cells causing side effects such as anemia, nausea and hair loss. If the chemotherapy could be delivered by implant directly to the tumor site, such side effects would be limited, said Cheng, who also is a member of the Center for Cell Control at the UCLA Henry Samueli School of Engineering and Applied Sciences. "Say you have a localized cancer such as breast cancer, the drugs we give are not directly targeted to the breast," Cheng said. "If we could apply the treatment locally and control the release of the drugs, the therapy might be more effective in treating the cancer." Chemotherapy drugs could potentially be placed in high concentration between the polymer films and an implant placed at the tumor site. The drugs would be released slowly, over time, delivering more of the toxic chemicals directly to the cancer cells. This study provided the proof of principle that implants in animal models could be coated with materials that made them invisible to the immune system. Cheng and Ho are now testing in animal models whether cancer therapies can be effectively and safely administered and locally delivered using the nanomaterials.

The study was funded by the Center for Cell Control and Northwestern University, with additional support from the Jonsson Cancer Center, National Institute of Allergy and Infectious Disease of the National Institutes of Health and the V Foundation for Cancer Research. The Center for Cell Control is one of the Nanomedicine Development Centers funded by the National Institutes of Health through the Roadmap for Medical Research.
Adapted from materials provided by University of California - Los Angeles. Need to cite this story in your essay, paper, or report? Use one of the following formats: APA MLA University of California - Los Angeles (2008, January 24). Nanomaterials Used To Localize And Control Drug Delivery. ScienceDaily. Retrieved October 11, 2008, from http://www.sciencedaily.com /releases/2008/01/080122110045.htm
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Titre du document / Document title Enzymatic erosion of bioartificial membranes to control drug delivery Auteur(s) / Author(s) COLUCCIO Maria Laura (1) ; CIARDELLI Gianluca (1 2) ; BERTONI Franca (1) ; SILVESTRI Davide (1) ; CRISTALLINI Caterina (3) ; GIUSTI Paolo (1) ; BARBANI Niccoletta (1) ; Affiliation(s) du ou des auteurs / Author(s) Affiliation(s) (1) Department of Chemical Engineering, Industrial Chemistry and Science of Materials, University of Pisa, Via Diotisalvi 2, 56126 Pisa, ITALIE (2) Department of Mechanics, Politecnico in Turin, 10129, ITALIE (3) Institute for Composite and Biomedical Materials (IMCB-CNR), Pisa 56126, ITALIE Rsum / Abstract The preparation of an enzymatic controlled drug release system from blends of PVA/starch/aA, in the form of films, is described. It was shown that A hydrolyses the starch within these films, resulting in a timedependent change of the porosity in the matrix. Films were characterized by calorimetric analysis to study the interactions between the enzyme and the polymeric constituents at the molecular level. The presence of A, in fact, influenced the PVA cristallization in the blends. Release tests and permeability experiments were carried out to evaluate the transport properties of the films. An increase in porosity and permeability was observed by increasing A content (16-28 wt.-%). Films loaded with theophylline and caffeine were also prepared to analyze drug release properties of the matrix. Drug release kinetics were coherent with the measured changes in porosity: at higher A concentrations the amount of released drug increased under the influence of diffusion and erosion processes. The results obtained are promising for the realization of drug delivery devices for a rapid release or for the release of poorly soluble drugs which usually remain entrapped in the matrix. Revue / Journal Title Macromolecular bioscience ISSN 1616-5187 Source / Source 2006, vol. 6, no6, pp. 403-411 [9 page(s) (article)] (28 ref.) Langue / Language Anglais Editeur / Publisher Wiley-VCH, Weinheim, ALLEMAGNE (2001) (Revue) Mots-cls anglais / English Keywords Transport properties ; Enzyme ; Hydrolases ; Glycosidases ; O-Glycosidases ; Oside polymer ; Experimental study ; Morphology ; Permeability ; Kinetics ; Caffeine ; Maltose ; Theophylline ; Release ; Erosion ; Enzymatic digestion ; Drug carrier ; Control release polymer ; Immobilized enzyme ; -Amylase ; Crosslinked polymer ; Linear polymer ; Starch ; Polymer blends ; Polyvinylalcohol ; Porous membrane ; Mots-cls franais / French Keywords Proprit transport ; Enzyme ; Hydrolases ; Glycosidases ; O-Glycosidases ; Oside polymre ; Erosion enzymatique ; Etude exprimentale ; Morphologie ; Permabilit ; Cintique ; Cafine ; Maltose ; Thophylline ; Libration ; Erosion ; Dgradation enzymatique ; Vecteur mdicament ; Polymre vecteur ; Enzyme immobilise ; -Amylase ; Polymre rticul ; Polymre linaire ; Amidon ; Mlange polymre ; Vinylique alcool polymre ; Membrane poreuse ; Mots-cls espagnols / Spanish Keywords Propiedad transporte ; Enzima ; Hydrolases ; Glycosidases ; O-Glycosidases ; Osido polmero ; Estudio experimental ; Morfologa ; Permeabilidad ; Cintica ; Cafena ; Maltosa ; Teofilina ; Liberacin ; Erosin ; Degradacin enzimtica ; Vector medicamento ; Polmero vector ; Enzima inmovilizada ; -Amylase ; Polmero reticulado ; Polmero lineal ; Almidn ; Vinlico alcohol polmero ; Membrana porosa ; Localisation / Location

POLYMERIC DRUG

DELIVERY A BRIEF REVIEW

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Introduction

Please Note: You could contribute to this In recent years, there has been a rapid growth in the area of drug section via expert commentary/articles. The discovery, facilitated by novel technologies such as combinatorial Please contact webmaster@drugdel.com if chemistry and high-throughput screening. These novel approaches have you want to make a contribution. led to drugs which are generally more potent and have poorer solubility than drugs developed from traditional approaches of medicinal TECHNOLOGY OVERVIEW chemistry (Lipinsky, 1998). The development of these complex drugs has resulted in a more urgent focus on developing novel techniques, to To obtain a custon-made industry report on this deliver these drugs more effectively and efficiently. field, contact the sales division. Some of the salient
features of the report will include:

1. A list of approved products as well as

products in various clinical trials.

2. Sales figures of the approved products

along with future sales forecasts.

3. A detailed scientific overview of the field

and the emerging technologies.

4. A list of potential candidates suitable for

5. this technology. A list of consultants and researchers working in this field and a review of new developments in their labs.

Table 1: Some commercial suppliers of GMP grade PLA/PLGA polymers. Absorbable Polymer Tech, AL Alkermes, MA Birmingham Polymers Inc., AL Boehringer Ingelheim, Germany Table 2: A list of companies working in the field of polymeric drug delivery. Purac America, IL Figure 1: Conventional and Ideal drug release profiles As can be seen in Figure 1, the conventional oral and intravenous routes of drug administration do not provide ideal pharmacokinetic profiles especially for drugs, which display high toxicity and/or narrow therapeutic windows. For such drugs the ideal pharmacokinetic profile will be one wherein the drug concentration reached therapeutic levels without exceeding the maximum tolerable dose and maintains these concentrations for extended periods of time till the desired therapeutic effect is reached. One of the ways such a profile can be achieved in an ideal case scenario would be by encapsulating the drug in a polymer matrix. The technology of polymeric drug delivery has been studied in details over the past 30 years and numerous excellent reviews are available (Gombotz and Pettie, 1995; Sinha and Khosla, 1998; Langer, 1998). This brief review is intended to introduce the practical aspects in

Abbott Laboratories Absorbable Polymers Access Pharmaceuticals Advanced Polymer Systems Alkermes Inc. Alliance Pharmaceuticals Alza Corporation Angiotech Atrix Laboratories Avant Immunotherapeutics Bend Research Inc. Biogel Corp. Biosyntech Corp Birmingham Polymers Inc. CeNeS Chiron Corporation Corixa Flamel Technologies Focal Inc. Genzyme Corporation Guilford Pharmaceuticals Nobex Corp. Oakwood Laboratories Orapharma Inc. Perio Products Ltd, Israel Praecis Pharmaceuticals Protein Polymer Tech Quadrant PLC Shearwater Polymers Skyepharma Corporation Southern Biosystems Southern Research Institute West Pharmaceuticals Inc. Zycos

commercialization of polymeric drug delivery products. For more comprehensive reviews of the underlying science, the reader can refer to the many excellent review articles listed at the end of this report. The three key advantages that polymeric drug delivery products can offer are: 1. Localized delivery of drug: The product can be implanted directly at the site where drug action is needed and hence systemic exposure of the drug can be reduced. This becomes especially important for toxic drugs which are related to various sytemic side effects (such as the chemotherapeutic drugs). 2. Sustained delivery of drugs: The drug encapsulated is released over extended periods and hence eliminates the need for multiple injections. This feature can improve patient compliance especially for drugs for chronic indications, requiring frequent injections (such as for deficiency of certain proteins). 3. Stabilization of the drug: The polymer can protect the drug from the physiological environment and hence improve its stability in vivo. This particular feature makes this technology attractive for the delivery of labile drugs such as proteins. Interest in this field has increased considerably, especially after the commercial success of products such as Lupron Depot , Zoladex , Norplant and Gliadel , all of which use the principles of sustained and localized drug release.

Figure 2. Possible drug release mechanisms for polymeric drug delivery As shown in Figure 2, the drug will be released over time either by diffusion out of the polymer matrix or by degradation of the polymer backbone. This continuous release of the drug could potentially lead to a

pharmacokinetic profile close to the ideal case scenario depicted in Figure 1. The continuous release of drugs from the polymer matrix could occur either by diffusion of the drug from the polymer matrix, or by the erosion of the polymer (due to degradation) or by a combination of the two mechanisms. Several reviews have been presented on the mechanisms and the mathematical aspects of release of drugs from polymer matrices (Batycky et al., 1997;Brazel and Peppas, 2000; Comets et al., 2000). For a given drug, the release kinetics from the polymer matrix are governed predominantly by three factors, viz. the polymer type, polymer morphology and the excipients present in the system. The subsequent sections will focus on each of these three factors to describe their role on drug release characteristics of a polymeric system.

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The Polymer
An appropriate selection of the polymer matrix is necessary in order to develop a successful drug delivery system. The polymer could be nondegradable or degradable. A major disadvantage with non-degradable polymers is that a surgery is required to harvest these polymers out of the body once they are depleted of the drug. Hence, non-degradable polymers can be used only if removal of the implant is easy (such as an ocular implant). Degradable polymers on the other hand do not require surgical removal and hence are preferred for drug delivery applications. However, since they degrade to smaller absorbable molecules, it is important to make sure that the monomers are non-toxic in nature. The most commonly used polymers for this application are Polylactide (PLA) and Poly(Lactide-co-Glycolide) (PLGA). These polymers have been used in biomedical applications for more than 20 years and are known to be biodegradable, biocompatible and non-toxic. These polymers are commercially available from various vendors, some of whom are listed in Table 1. A vast amount of literature is available on the characterization of these polymers and their biodegradation and drug release properties. Degradation of lactide based polymers and in general all hydrolytically degradable polymers, depends on the following properties:
1. Chemical composition: The rate of degradation of polymers

depends the type of degradable bonds present on the polymer. In general, the rate of degradation of different chemical bonds follows as Anhydride > Esters > Amides. 2. Crystallinity: Higher than crystallinity of a polymer, slower is

its rate of degradation. 3. Hydrophilicity: If the polymer has a lot of hydrophobic groups present on it, then it is likely to degrade slower than a polymer which is hydrophilic in nature. Polylactides are known to be more hydrophobic as compared to PLGA and take a longer time to degrade. Among the polylactides, DL-PLA, which is a polymer of D and L-lactide, degrades faster than L-PLA, which is a homopolymer of L-lactide, presumably due to lesser crystallinity. Similarly, the more hydrophobic end-capped PLGA polymers degrade faster than the carboxyl-ended PLGA. In spite of the several apparent advantages of PLA and PLGA based polymers, commercialization of products based on these polymers has certain limitations. One of the major concerns is that more than 500 patents have been issued for various applications of these polymers. Hence, patent infringement may become a concern in developing new products. In addition, PLA and PLGA polymers have certain inherent limitations in terms of flexibility for applications. Due to these concerns, several new polymers are presently being explored for applications in drug delivery. Some of the new polymers which are in clinical or preclinical development stage are: 1. Polyorthoesters (Heller et al., 2000) 2. Polyphosphazenes (Allcock, 1994) 3. Polyanhydrides (Shieh et al., 1994) 4. Polyphosphoesters (Richards et al., 1991)

Polymer Morphology
Morphology of the polymer matrix plays an important role in governing the release characteristics of the encapsulated drug. The polymer matrix could be formulated as either micro/nano-spheres, gel, film or an extruded shape (such as cylinder, rod etc). The shape of the extruded polymer can be important to the drug release kinetics. For example, it has been shown that zero order drug release can be achieved using a hemispherical polymer form. Polymer microspheres are the most popular form due to manufacturing advantages as well as ease of administration (injectability by suspending in a vehicle). As depicted in Figure 2, polymer microspheres can be manufactured by using various techniques such as spray drying, solvent evaporation etc (ODonnell and McGinity 1997; Hermann and Bodmeier 1998; Witschi and Doelker 1998). The type of technique used affects factors such as porosity, size distribution and surface morphology of the microspheres and may subsequently affect the performance of the drug delivery product.

Excipients
Polymeric drug delivery products can be formulated with excipients added to the polymer matrix. The main objective of having excipients in the polymer matrix could be either to modulate the drug release, or to stabilize the drug or to modulate the polymer degradation kinetics. Recent studies by Schwendeman and coworkers (Zhu and Schwendeman, 1999; Zhu et al., 2000) have shown that by incorporating basic salts as excipients in polymeric microspheres, the stability of the incorporated protein can be improved. It has shown that these basic salts however also slow the degradation of the polymer. Similarly, hydrophilic excipients can accelerate the release of drugs, though they may also increase the initial burst effect.

Bibliography
1. Lipinsky C. American Association of Pharmaceutical Sciences, Annual Meeting 1998. 2. Heller J, Barr J, Ng SY, Shen HR, Schwach-Abdellaoui K, Emmahl S, Rothen-Weinhold A, Gurny R. Poly(ortho esters) their development and some recent applications. Eur J Pharm Biopharm. 2000 Jul;50(1):121-8. 3. Bibby DC, Davies NM, Tucker IG. Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems. Int J Pharm. 2000 Mar 20;197(1-2):1-11. 4. Gutman RL, Peacock G, Lu DR. Targeted drug delivery for brain cancer treatment. J Control Release. 2000 Mar 1;65(12):31-41. 5. Sinha VR, Khosla L. Bioabsorbable polymers for implantable therapeutic systems. Drug Dev Ind Pharm. 1998 Dec;24(12):1129-38. 6. Jain R, Shah NH, Malick AW, Rhodes CT. Controlled drug delivery by biodegradable poly(ester) devices: different preparative approaches. Drug Dev Ind Pharm. 1998 Aug;24(8):703-27. 7. Vert M, Schwach G, Engel R, Coudane J. Something new in the field of PLA/GA bioresorbable polymers? J Control Release. 1998 Apr 30;53(1-3):85-92. 8. Ulbrich K, Pechar M, Strohalm J, Subr V, Rihova B. Synthesis of biodegradable polymers for controlled drug release. Ann N Y Acad Sci. 1997 Dec 31;831:47-56. 9. Langer R. Drug delivery and targeting. Nature. 1998 Apr

30;392(6679 Suppl):5-10. 10. Cleland JL. Solvent evaporation processes for the production of controlled release biodegradable microsphere formulations for therapeutics and vaccines. Biotechnol Prog. 1998 JanFeb;14(1):102-7. 11. Wyatt TL, Saltzman WM. Protein delivery from nondegradable polymer matrices. Pharm Biotechnol. 1997;10:119-37. 12. Batycky RP, Hanes J, Langer R, Edwards DA. A theoretical model of erosion and macromolecular drug release from biodegrading microspheres. J Pharm Sci. 1997 Dec;86(12):1464-77. 13. Peppas NA, Sahlin JJ. Hydrogels as mucoadhesive and bioadhesive materials: a review. Biomaterials. 1996 Aug;17(16):1553-61. 14. Wheeler JC, Woods JA, Cox MJ, Cantrell RW, Watkins FH, Edlich RF. Evolution of hydrogel polymers as contact lenses, surface coatings, dressings, and drug delivery systems. J Long Term Eff Med Implants. 1996;6(3-4):207-17. 15. Gombotz WR, Pettit DK. Biodegradable polymers for protein and peptide drug delivery. Bioconjug Chem. 1995 JulAug;6(4):332-51. 16. Okada H, Toguchi H. Biodegradable microspheres in drug delivery. Crit Rev Ther Drug Carrier Syst. 1995;12(1):1-99. 17. Payne LG, Jenkins SA, Andrianov A, Roberts BE. Water-soluble phosphazene polymers for parenteral and mucosal vaccine delivery. Pharm Biotechnol. 1995;6:473-93. 18. Tanguay JF, Zidar JP, Phillips HR 3rd, Stack RS. Current status of biodegradable stents. Cardiol Clin. 1994 Nov;12(4):699-713. 19. Kim SW, Bae YH, Okano T. Hydrogels: swelling, drug loading, and release. Pharm Res. 1992 Mar;9(3):283-90. 20. Patrick B. O'Donnell and James W. McGinity, Preparation of microspheres by the solvent evaporation technique, Advanced Drug Delivery Reviews 28(1) (1997) pp. 25-42 21. Zhu G, Schwendeman SP. Stabilization of proteins encapsulated in cylindrical poly(lactide-co-glycolide) implants: mechanism of stabilization by basic additives. Pharm Res. 2000 Mar;17(3):351-7. 22. Zhu G, Mallery SR, Schwendeman SP. Stabilization of proteins encapsulated in injectable poly (lactide- co-glycolide). Nat Biotechnol 2000 Jan;18(1):52-7. 23. Shieh L, Tamada J, Chen I, Pang J, Domb A, Langer R. Erosion of a new family of biodegradable polyanhydrides. J. Biomed. Mater. Res., 28, 1465-1475, 1994. 24. Shive MS, Anderson JM. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Del. Rev. 28, 524,1997.

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INIST-CNRS, Cote INIST : 27117, 35400014245980.0020

Polymer Electronics Research Centre

Microactuator Pumps for Drug Delivery (NERF)

OBJECTIVE LEADER: Dr Jadranka Travas-Sejdic

This project has been funded from the New Economy Research Fund (NERF) from the Foundation for Research, Science and Technology (FRST) for four years beginning in July 2004. The original objective statement for the project was defined as follows: This objective aims to develop a new generation of polymer-based pump nanotechnologies which can be fabricated to move micro- and nano-litre quantities of fluids with precision for use in implantable drug-delivery systems. The objective involves the construction of novel actuating elements to power the micropump and integrates polymer and materials chemistry, electronic and modelling engineering, and physiology in device design and testing. This objective contributes to the programme outcome by significantly expanding the platform knowledge base on conducting polymer materials and integrating such materials into functional micro-structured devices by means of novel microelectronics. The Objective brings together experts from several disciplines that will contribute significantly in building a capability of the involved researchers and students in the emerging micro/nano-technologies

Microfluidics
Dr. Rosalind Archer is developing mathematical models used in the process of designing microfluidic pumping devices. The mathematical models of these devices are intended as design tools which link the volume changes observed in the conducting polymer material (and therefore the forces applied to the fluid being pumped) to velocities in the fluid and stresses in the conducting polymer.

Linear Actuation of PPy and PEDOT in Propylene Carbonate

Conducting polymers such as polypyrrole (PPy) and poly-3,4-ethylenedioxythiophene (PEDOT) undergo volumetric changes as they are oxidized or reduced. Dr Rudolf Kiefer is investigating

the actuation properties of free standing PPy and PEDOT films. These films are prepared from propylene carbonate solutions of TBACF3SO3 or TBAPF6 by performing electrochemo mechanical deformation measurements during cyclic voltammetry and potential step experiments.

Properties of Free-Standing Trifluoromethanesulfonate Doped Polypyrrole Films

In the MSc project of Shu Yi Chu the effects of electrochemical synthesis conditions (i.e. electrolyte concentration, solvent and deposition current) on the actuation performance and electrochemistry of free-standing films of polypyrrole are investigated. The films are synthesised galvanostatically on stainless steels in the presence of TBACF3SO3 in propylene carbonate or methyl benzoate.

Conducting Polymer Actuating Elements

Polypyrrole undergoes a large dimensional change upon doping and dedoping, both in-plane and out-of-plane. The PhD research of Jing Sui is focusing on the use of the out-of-plane actuation and exploiting the large out-of-plane volume change of polypyrrole in particular, for application in microfluidic devices such as micro pumps and micro valves.

Electronic Control for Micro-Pumps

A further project is being undertaken by Chad Wijeratne, from Electrical and Computer Engineering, in which a control circuit for a Voltage-Stepped Micro-pump is being developed. The control system is prototyped on a fixed point microcontroller system and the next stage of development is the introduction of analogue and digital feedback techniques to enhance the stability and noise performance of the overall system.

Organic electronics
PhD student Eric Wong is investigating organic semiconductor materials, such as pentacene, for applications in organic electronics. The relatively cheap and low-temperature processing of these organic semiconductor materials may lead to applications such as flexible displays and disposable electronics.

Outputs
S.Y. Chu, P.A. Kilmartin, J. Sui, G.A. Bowmaker, R.P. Cooney and J. Travas-Sejdic, "The effect of monomer and electrolyte concentrations during synthesis on the actuation of PPy(CF3SO3) films

in aqueous electrolytes", Synthetic Metals 158 (2008) 38-44. R. Kiefer, G.A. Bowmaker, R.P. Cooney, P.A. Kilmartin and J. Travas-Sejdic, "Cation driven actuation for free standing PEDOT films prepared from propylene carbonate electrolytes containing TBACF3SO3", Electrochimica Acta 53 (2008) 2593-2599. S.Y. Chu, H. Peng, P.A. Kilmartin, G.A. Bowmaker, R.P. Cooney and J. Travas-Sejdic, "Effect of deposition current density on the linear actuation behaviour of PPy(CF3SO3) films", Current Applied Physics 8 (2008) 324-327. R. Kiefer, P.A. Kilmartin, G.A. Bowmaker, R.P. Cooney and J. Travas-Sejdic, "Mixed-ion linear actuation of PPy and PEDOT in propylene carbonate-triflate electrolytes", Proceedings of SPIEThe International Society for Optical Engineering (2007) 6524 (Electroactive Polymer Actuators and Devices (EAPAD) San Diego) 6524OU. M.B. Cannell, P. Kilmartin, M. Jacobs, S. Valiavalappil, J. Travas-Sejdic and C. Soeller, "Chapter 14: Nanoscale fluid motion via molecular pores and polymer actuators", Nano Biophotonics: Science and Technology, Ed. H. Masuhara, S. Kawata and F. Tokunaga, Elsevier, 2007, p.207226. R. Kiefer, P.A. Kilmartin, G.A. Bowmaker, R.P. Cooney and J. Travas-Sejdic, "Actuation of polypyrrole films in propylene carbonate electrolytes", Sensors and Actuators B 125 (2007) 628634. R. Kiefer, S.Y. Chu, P.A. Kilmartin, G. Bowmaker, R. Cooney and J. Travas-Sejdic, "Mixed-ion linear actuation behaviour of polypyrrole", Electrochimica Acta 52 (2007) 2386-2391. P.A. Kilmartin, K.C. Li, G.A. Bowmaker, N.A. Vigar, R.P. Cooney and J. Travas-Sejdic, "Spectroscopic studies of doping reactions in polypyrrole actuators", Current Applied Physics 6 (2006) 567-570. J. Travas-Sejdic, R. Kiefer, S. Valiavalappil, K-C. Li and P.A. Kilmartin, "Polypyrrole actuators for micro-pump applications", Proceedings of SPIE-The International Society for Optical Engineering (2006) 6168 (Electroactive Polymer Actuators and Devices (EAPAD) San Diego) 61682I/161682I/11. E. Wong, A. Bigdeli and M. Biglari-Abhari, "A conducting polymer-based self-regulating insulin delivery system", International Journal of Scientific Research 16 (2006) 235-239.
Titre du document / Document title Effects of polymer formulation on electrophoretic drug delivery

Auteur(s) / Author(s) D'EMANUELE A. (1) ; STANIFORTH J. N. ; Affiliation(s) du ou des auteurs / Author(s) Affiliation(s) (1) Univ. Manchester, dep. pharmacy, Manchester Greater Manchester M13 9PL, ROYAUME-UNI Rsum / Abstract A controlled drug delivery device based on the principle of electrophoresis is described in this paper. A model system using propranolol HCl and PHEMA films is used to demonstrate how control over the release of a model drug may be achieved using low constant electric currents. Polymer formulation is shown to be important, highly crosslinked polymer producing a different effect to low crosslinked polymer. The model is used to demonstrate the low power requirements for control over drug transport and indicates the feasibility of using an electrophoretically controlled drug delivery device to provide truly controllable and predictable release rates Revue / Journal Title International journal of pharmaceutics ISSN 0378-5173 CODEN IJPHDE Source / Source 1993, vol. 92, no1-3, pp. 225-231 (20 ref.) Langue / Language Anglais Editeur / Publisher Elsevier, Amsterdam, PAYS-BAS (1978) (Revue) Mots-cls anglais / English Keywords Beta blocking agent ; Pharmaceutical technology ; Dosage form ; Formulation ; Release ; Active ingredient ; In vitro ; Controlled release form ; Electrophoresis ; Control release polymer ; Crosslinking ; Crosslinked polymer ; Mots-cls franais / French Keywords Propranolol ; Bloquant -adrnergique ; Technologie pharmaceutique ; Forme pharmaceutique ; Formulation ; Libration ; Principe actif ; In vitro ; Forme libration contrle ; Electrophorse ; Polymre vecteur ; Rticulation ; Polymre rticul ; Mots-cls espagnols / Spanish Keywords Bloqueador -adrenrgico ; Tecnologa farmacutica ; Forma farmacutica ; Formulacin ; Liberacin ; Principio activo ; In vitro ; Forma liberacin controlada ; Electroforesis ; Polmero vector ; Reticulacin ; Polmero reticulado ; Localisation / Location INIST-CNRS, Cote INIST : 16510, 35400003367324.0280 Copyright 2008 INIST-CNRS. All rights reserved
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