Precision Polymer Microparticles for Controlled-Release Drug Delivery

Chapter 14

Precision Polymer Microparticles for Controlled -Release Drug Delivery 1

2

Downloaded by COLUMBIA UNIV on September 2, 2012 | http://pubs.acs.org Publication Date: May 5, 2004 | doi: 10.1021/bk-2004-0879.ch014

Cory Berkland , Kyekyoon (Kevin) Kim , and Daniel W. Pack

1,*

1

Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, IL 61801 Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL 61801 *Corresponding author: email: [email protected]

2

Fabrication of biodegradable polymer microparticles with precise size control provides a means for enhanced control of drug delivery rates. The ability to control delivery kinetics is important for many applications. For example, the frequent administrations needed for highly potent drugs with narrow therapeutic windows could be reduced with a system capable of delivering the drug at a constant rate for a prolonged time. We have developed a precision particle fabrication (PPF) methodology that generates monodisperse microdroplets comprising a variety of materials. We have fabricated poly(lactide-co-glycolide) (PLG) particles of precisely 10, 50, and 100 µm in diameter, encapsulating the model compound piroxicam. We show that drug release rates and the shape of the drug release profile depend strongly on the particle diameter. Further, combinations of microparticles of appropriate sizes and in appropriate ratios release the drug at a constant rate (zero-order release) for 14 days. We have also fabricated PLG microcapsules with unprecedented control of the polymer shell thickness. These unique technologies may provide improved methods to tailor drug release kinetics from simple, biodegradable polymer microparticles.

© 2004 American Chemical Society

In Carrier-Based Drug Delivery; Svenson, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2004.

197

198


Introduction Controlled-release technologies provide continuous delivery of pharma ceuticals for prolonged durations (hours, days, or weeks, depending on the application) following a single administration of a drug-loaded device. Such devices include miniature pumps, multi-layered tablets/capsules, and polymeric structures such as microparticles, rods, disks, and pellets. Controlled release technology has been developed to address formulation problems stemming from drug instability, short in vivo half-life, the need for local administration due to systemic toxicity and/or the need for high local concentrations, drugs for which compliance is a nuisance or difficult to achieve, highly potent drugs which exhibit severe peak-concentration-related side effects, etc. These needs are growing more urgent as an increasing fraction of pharmaceuticals comprise peptides, proteins, and nucleic acids, which most often require frequent injections or infusions due to their instability in the gastrointestinal system, short half-lives, and high potency. Biodegradable microspheres have been one of the most studied controlled release systems due to their relatively simple fabrication, versatility, and facile administration to a variety of locations. Early studies focused on the mecha nisms and kinetics of polymer degradation and drug release. A combination of experiments and theory has led to an excellent understanding of the various effects of polymer composition and molecular weight, device shape and size, and the presence of excipients, in order to allow design of delivery systems with desirable properties for a given application. (1-4) Another focus of research has been the instability of therapeutic proteins during device fabrication, storage, and delivery, and these issues are being addressed for many important systems. (5-9) A key limitation that remains is the lack of true control of drug release rates and the shapes of the release rate profiles. Release from matrix-type microspheres is governed largely by the diameter of the particles, the drug loading (i.e., concentration within the microsphere), the size of the encapsu lated molecule (governing its rate of diffusion through the device), and degra dation kinetics of the microsphere-forming polymer. A variety of polymers with varying molecular weight and comonomer ratios exhibiting different degradation kinetics is available commercially. For example, poly(lactide-coglycolide) (PLG) ranging in molecular weight from several thousand to over one hundred thousand, and comprising lactide/glycolide ratios from 100/0 to 50/50, can be purchased from several manufacturers. These polymer choices allow some control of the release rates, especially the duration. However, drug is released most commonly via diffusion through the device - either through the polymer matrix or through aqueous pores within the device. As a result,



199 drug release profiles are generally concave downward, with the highest release rates at t = 0 and decreasing rates thereafter. Some drugs, including proteins and plasmid DNA, often exhibit a "burst" at early times followed by a lag phase wherein very little drug is released, and a subsequent concave downward release profile. In contrast, zero-order (linear) release is most desirable for many applications, while pulsatile release - in which drug is released in given amounts after predefined periods of little or no release - is needed for some indications including for many vaccines. Both zero-order and pulsatile release have been difficult to achieve with simple polymer microsphere devices. Enhanced control of microparticle morphology may provide more precise control of release rates. Certainly, precise control of particle size can afford better control of drug release as size is a critical factor; smaller particles release drug at a faster rate than larger particles, all other parameters being equal, due to the increase in surface area/volume ratio with decreasing particle size. Furthermore, multi-wall particles, consisting of a core of one material (aqueous or polymeric) surrounded by one or more shells of a second material, provide another means for enhanced control of drug release. In these particles, not only the overall size, but also the thickness of the shells, will critically impact the drug release rates. Current particle manufacturing techniques typically produce particles exhibiting reproducible but broad size distributions with little control over shell thickness. Thus, control of drug release rates is limited. We are developing a precision particle fabrication (PPF) methodology that provides unprecedented control of particle size, size distribution, and shell thickness. (10,11) PPF is a spraying technology in which a solution of polymer, with entrained drug (codissolved, as a particle suspension, or as an aqueous-inoil emulsion) is extruded through a small nozzle to form a stable laminar jet. This stream is disrupted into uniformly sized microdroplets by acoustic excitation of the apparatus. Thus, the particle size is controlled by the size of the nozzle opening, the solution flow rate, and the vibration frequency. Droplets can be "hardened" to form particles by a variety of methods such as spray drying, spray freezing, or phase inversion in a non-solvent phase. Here we describe the PPF methodology and its use to fabricate uniform PLG particles encapsulating model drug compounds. In addition, we will describe how precise control of particle size can translate into control of drug release rates.

Materials and Methods Overview Of The Precision Particle Fabrication Technology The PPF technique consists of modifications and novel combinations of methods originally developed for fabrication of micro- and nanoparticles com-


200


prising various materials. (10,12-16) The main apparatus (Figure 1) is based on extruding a solution containing the sphere material through a small nozzle or other orifice to form a stable, laminar jet. To break the fluid into droplets, the nozzle is vibrated at a chosen frequency, launching a wave of acoustic energy along the liquid jet and generating periodic instabilities that break the stream into a train of monodisperse droplets.

Figure 1. Schematic diagram of the precision particle fabrication apparatu The basic PPF methodology has been used for several years to form particles of various sizes and morphologies from a variety of materials and for diverse applications. For example, uniform particles have been fabricated from silica, iron oxide, tantalum oxide, barium-titanium oxide, elemental silver and frozen hydrogen in sizes ranging from 10 nm to 2 mm in diameter. In our recent work, we have extended the PPF techniques to fabrication of particles comprising biomedical materials, most notably biodegradable polymers. (10,11) We can reduce droplet size, and in fact form droplets smaller than the nozzle opening, by employing an annular flow of a non-solvent phase around the polymer jet, termed a "carrier stream". The carrier stream is pumped at a linear velocity greater than that of the polymer stream. Thus, frictional contact between the two streams generates a downward force that effectively "pulls" the polymer solution away from the tip of the nozzle. The polymer stream is accelerated by this force and, therefore, thinned to a degree depending on the



201 difference in linear velocities of the two streams. Finally, we may employ electrohydrodynamic forces to further reduce the jet size, allowing us to generate polymer nanoparticles as well. Formation of uniform microdroplets and control of their size can be predicted by theory. A stream of liquid under the influence of surface tension alone is dynamically unstable and will naturally break into random-sized droplets. Rayleigh first derived the jet instability equations for a cylindrical, inviscid jet subject to disturbances from the equilibrium configuration. (17) Although additional work has since been carried out on this problem, his work still stands as the foundation of jet instability studies. Lord Rayleigh found that the most unstable wavelength (X^) of a disturbance imposed on the jet surface, giving rise to maximum growth rate and consequently in breakup of the jet into uniform droplets, is 9.016 times the radius of the unperturbed jet, rj. However, a range of wavelengths around this maximum can be used to generate uniform droplets, and typically the practical range is given in Equation (1). (18) lv

Precision Polymer Microparticles for Controlled-Release Drug Delivery

Recommend Documents