ON THE IMPORTANCE AND MECHANISMS OF BURST RELEASE IN MATRIX

Journal of Controlled Release 73 (2001) 121–136 www.elsevier.com / locate / jconrel

Review

On the importance and mechanisms of burst release in matrix-controlled drug delivery systems Xiao Huang, Christopher S. Brazel* Department of Chemical Engineering, The University of Alabama, A127 Bevill Research Center, Tuscaloosa, AL 35487 -0203, USA Received 22 November 2000; accepted 15 February 2001

Abstract Although the significance of burst release in controlled delivery systems has not been entirely ignored, no successful theories have been put forth to fully describe the phenomenon. Despite the fact that the fast release of drug in a burst stage is utilized in certain drug administration strategies, the negative effects brought about by burst can be pharmacologically dangerous and economically inefficient. Therefore a thorough understanding of the burst effect in controlled release systems is undoubtedly necessary. In this article, we review experimental observations of burst release in monolithic polymer controlled drug delivery systems, theories of the physical mechanisms causing burst, some of the unique ideas used to prevent burst, and the treatment of burst release in controlled release models.  2001 Elsevier Science B.V. All rights reserved. Keywords: Controlled release; Burst release; Drug delivery; Review; Modeling

1. Introduction In recent years, the study of controlled release of drugs and other bioactive agents from polymeric devices has attracted many researchers from around the world. Controlled drug delivery applications include both sustained delivery over days / weeks / months / years and targeted (e.g., to a tumor, diseased blood vessel, etc.) delivery on a one-time or sustained basis [1]. Controlled release formulations can be used to reduce the amount of drug necessary to cause the same therapeutic effect in patients. The convenience of fewer and more effective doses also increases patient compliance [2]. Over the years of *Corresponding author. E-mail address: [email protected] (C.S. Brazel).

controlled release research, different systems, ranging from coated tablets and gels to biodegradable microspheres and osmotic systems, have been explored experimentally and computationally to get predesigned release profiles. In many of the controlled release formulations, immediately upon placement in the release medium, an initial large bolus of drug is released before the release rate reaches a stable profile. This phenomenon is typically referred to as ‘burst release.’ As shown in Fig. 1, burst release leads to higher initial drug delivery and also reduces the effective lifetime of the device. Because burst release happens in a very short time compared to the entire release process, it has not been specifically investigated in most published results, and it has been ignored in most mathematical models. However, among the plethora of controlled release

0168-3659 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 01 )00248-6

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X. Huang, C.S. Brazel / Journal of Controlled Release 73 (2001) 121 – 136

Fig. 1. Schematic showing the burst effect in a zero-order drug delivery system.

publications, burst phenomena have been observed and studied [3–15]. Several researchers [3–6] have observed burst release without giving advanced explanations; some [7–11] tried to find the mechanisms of burst and prevent it technologically; and some [10,12,13] have made an effort to include burst in models to simulate the release process. At the opposite end of spectrum, burst release has been utilized to deliver drugs at high release rates as part of the drug administration strategy [14].

2. Significance of burst release Normally short in duration, burst release is worth thorough study due to the high release rates that can be reached in the initial stages after activation. The burst effect can be viewed from two perspectives: it is often regarded as a negative consequence of

creating long-term controlled release devices, or, in certain situations, rapid release or high initial rates of delivery may be desirable (Table 1). Burst release may be the optimal mechanism of delivery in several instances. One of the current difficulties with burst release is that it is unpredictable, and even when the burst is desired, the amount of burst cannot be significantly controlled. It has been shown that many drugs need to be administered at varying rates, and for some drugs, such as those used at the beginning of wound treatment, an initial burst provides immediate relief followed by prolonged release to promote gradual healing [14]. Food companies also have a vested interest in the development of burst release systems: coatings are desired to protect flavors and aromas during processing and storage, but must allow rapid release when the product is consumed. Recent advances in the ability to target specific cells and organs, through either surface modification or implantation, allows the location of the delivery to be highly specific, and either burst or prolonged release may be desired at that site, after the coating has served its purpose of sequestering the drug to protect it from denaturation and first-pass metabolism. In several pulsatile delivery processes, burst release may also be a goal, so that the active agent can be delivered rapidly upon changes in environmental conditions that trigger the release. Most of the published work related to burst release has been in the pharmaceutical field, and has focused on ways to prevent it from occurring in controlled release formulations, especially with low molecular weight drugs which are more likely to have burst release profiles due to their molecular size and

Table 1 Applications where burst release may be advantageous or detrimental Favorable burst release situations

Negative burst release effects

Wound treatment (burst release followed by a diminishing need for drug)

Local or systemic toxicity (from high drug concentrations)

Encapsulated flavors

Short half-life of drugs in vivo (rapid loss in activity)

Targeted delivery (triggered burst release)

Economically and therapeutically wasteful of drug

Pulsatile release

Shortened release profile; requires more frequent dosing


osmotic pressures which accentuate the concentration gradient. Researchers seek to avoid burst release, because the initial high release rates may lead to drug concentrations near or above the toxic level in vivo [5,15]. Any drug released during the burst stage may also be metabolized and excreted without being effectively utilized. Even if no harm is done during the burst release, this amount of drug is essentially wasted, and the ineffective drug usage may have therapeutic and economic effects. Because of the important roles of burst release, both favorable and unfavorable, researchers have begun to focus on the study of its mechanism. One of the most important questions in developing controlled release devices is to know how to predict when burst release will occur and quantify its effects a priori.

3.1. Reservoir systems

3. Causes of burst release

DCo l2 Mt 5 ]] t 1 ] l 6D

Although the importance of burst release has been realized as controlled release research is developed to higher levels, publications referring to burst as their specific topic are rare. A number of research papers [5–12,16–33] have observed burst release experimentally and a few [10,12,17,24,28,30,31] have put forth theories to explain it in different devices. Some of the potential reasons that may lead to burst release are listed in Table 2. Burst release has been attributed to a variety of physical, chemical and processing parameters, but for the most part, no substantial results have been shown to understand the underlying mechanisms of burst release in monolithic polymeric systems. Before continuing with a discussion of burst release in such drug delivery systems, we will first look at membrane reservoir systems, about which burst release has been explored and defined more explicitly. Table 2 Potential reasons for burst release in hydrogels Processing conditions Surface characteristics of host material Sample geometry Host / drug interactions (surface adsorption) Morphology and porous structure of dry material

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Reservoir drug delivery devices have an inert membrane enclosing the active agent, which, upon activation, diffuses through the membrane at a finite, controllable rate [12]. These systems are especially good at achieving zero-order, or constant, drug delivery, although there is a risk of dose dumping due to minor flaws in capsule coatings that lead to significant burst release even prior to patient administration. Burst release has been observed in membrane reservoir systems, and credited to the storage effect [12] This happens when reservoir systems are stored for some time prior to use, and the agent saturates the entire membrane enclosing the drug reservoir. When placed in a release medium, the agent that has diffused to the surface of the membrane is released immediately, causing a burst effect. The amount of drug released with an initial burst, Mt , from these systems is estimated by:

S

D

(1)

where D is the drug diffusion coefficient, Co is the drug concentration on the inside of the membrane, and l is the membrane thickness [12], with a given burst of Co l / 6, but the release profile during burst stage (t.0) was not predictable.

3.2. Injectable hydrogel systems The polymers and copolymers that exhibit reversible gel–sol transitions have potential applications as injectable drug delivery systems. Burst release is observed in these systems because the polymer precursors do not set immediately, causing some drug not to be successfully encapsulated, thus allowing free drug to ‘release’ in a burst. Systems based on injectable polymer precursors heave the benefit of localizing internal treatment in a minimally invasive manner. In one such system, an initial burst of naltrexone from an injectable formulation based on poly(lactide-co-glycolide), PLGA, was attributed to slow implant gel formation [5].

3.3. Matrix systems Matrix, or monolithic, drug delivery systems,

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where the drug is dispersed in a porous network are also widely used. These systems include both swellable (usually referred to as ‘hydrogel’) and nonswellable matrices. Compared to reservoir systems, the preparation process for monolithic devices requires less quality control, hence lowering the fabrication cost with less risk of dose dumping [12,16]. Of the two systems listed above, burst release from monolithic, or matrix, formulations can be attributed to reasons similar to those used to describe burst from reservoir devices, including synthesis and manufacturing conditions, the heterogeneity of polymer matrices, drug properties, and percolation-limited diffusion. Each is discussed below.

3.3.1. Synthesis /manufacture conditions One suggested explanation for the burst effect in monolithic systems is that some drug becomes trapped on the surface of the polymer matrix during the manufacturing process [17], especially in the case of high drug loading [6], and is released immediately upon activation in a release medium. When polymeric devices are loaded with drugs by equilibrium partitioning in highly concentration drug solutions, this problem may happen, as shown in Brazel and Peppas’ research [18]. Both the polymeric system (Fig. 2) and the solute size (Figs. 3 and 4) are important factors in determining both release profiles and the fraction of drug released in a burst. Generally, burst release of theophylline was observed in hydrogels with larger swelling ratios and thus larger mesh spaces for diffusion upon swelling (Fig. 2). There is, however, a sharp distinction between burst release and short-term controlled release. For the same polymer system, there exists a molecular weight cut-off above which diffusion is strictly hindered by the gel. Below this molecular weight, controlled release is still achieved, but the time frame for release may be shorter (note vitamin B 12 release in Fig. 3). Migration of drugs during drying and storage steps may result in a heterogeneous distribution of drug in the polymer matrix and lead to burst release [8,11]. The mechanism by which drugs are released requires dissolution of the drugs followed by diffusion through the swelling porous structure to reach the release medium, usually water or a pH buffer solution for in vitro studies. In the same manner, the

Fig. 2. Effect of polymer structure and composition on theophylline release. Release was conducted from P(HEMA-co-MMA) hydrogels of 75% mol% (s) and 100 mol% (h) HEMA composition with crosslinking ratios of x50.01, and from ] glutaraldehyde-crosslinked PVA samples with initial Mn 548 200, ] 99% hydrolyzed, and x50.01 (n), Mn 535 700, X50.01, with ] 99% hydrolysis (,), Mn 515 800, X50.01, with 85% hydrolysis ] (앳), and Mn 515,800, X50.10, with 85% hydrolysis (d). Reprinted from Ref. [18],  (1999), with permission from Elsevier Science.

diffusion and migration of drugs may occur during the drying process as water moves to the gel surfaces and evaporates. Drugs may diffuse by convection with the water, leaving an uneven drug distribution across the gel, with higher concentrations at the surface (Fig. 5). Theories indicate that the rate of

Fig. 3. Effect of solute size on drug release characteristics from crosslinked PHEMA samples. Release of vitamin B 12 (s), inulin (h), FITC-dextran 4400 (n), and myoglobin (,) from PHEMA hydrogels. Reprinted from Ref. [18],  (1999), with permission from Elsevier Science.


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Fig. 4. Effect of solute size on drug release characteristics from crosslinked PVA samples, including theophylline (s), triamterene (h), and vitamin B 12 (n). Reprinted from Ref. [18],  (1999), with permission from Elsevier Science.

drying may have an impact on drug migration and subsequent burst release. For drug distribution in matrices, confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) are both important imaging techniques for investigation. Fig. 6 shows a scanning electron micrograph X-ray scan of oxprenolol HCl concentration across a poly(2-hydroxyethyl methacrylate), PHEMA, microsphere [19]. The initial drug concentration was shown to be relatively uniform even

Fig. 6. SEM X-ray microprobe chlorine scans from oxprenolol HCl on the cross-sections of hydrogel beads. Reprinted from Ref. [19],  (1984), with permission from Elsevier Science.

Fig. 5. Potential drug redistribution due to convection during the drying stage.

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Fig. 7. Effect of storage time on the in vitro oxprenolol HCl release from PHEMA hydrogels. (a) Original, with no storage time; (b) 59 days of storage: (A) loaded control; (B) controlledextracted in water for 20 min; (C) controlled extracted in water for 30 min. Reprinted from Ref. [19],  (1984), with permission from Elsevier Science.

though the release profile showed a burst effect (Fig. 7). Another important factor in burst release is the conditions used for synthesis, especially the polymer:drug and polymer:solvent ratios. Burst was observed by Sah et al. [20] for the release of bovine serum albumin (BSA) from microspheres composed of PLGA with a 75:25 lactide–glycolide ratio and poly-D,L-lactic acid (PLA). Burst was more pronounced when the total amount of polymers used in preparing microspheres decreased, although the experimental design did not hold the drug:polymer ratio constant. The researchers proposed that the decrease in the polymer:suspending phase ratio produced microparticles with a less compact polymer phase. This could allow movement of BSA towards the surface of microspheres during the drying process as well as forming larger pores where diffusion is not controlled by the polymer. Cohen et al. [21] studied the in vitro release of fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) from erodible PLGA microspheres. The protein

microparticles were prepared by a modified solvent evaporation method using a double emulsion. Since FITC-BSA is a water-soluble protein, increasing the inner water phase volume can presumably avoid a nonuniform distribution of large protein islands closer to the microsphere surface in the matrix, which causes an initial protein burst. Even in cases where the drug is uniformly dissolved or dispersed in polymer matrices, the release rates continuously diminish with time due to the increasing diffusional distance that hinders drug diffusion from the center of the device [19,22,34], although this is technically different from the burst effect in the time-scale of release. One proposed method to improve the consistency of release was described by Lee [19] to use systems with uneven initial drug distributions, with higher loading concentrations towards the center of the device. The diminishing release rates due to increased diffusional distances could be overcome by an increase in the concentration gradient. However, much of Lee’s work focused on modeling to determine the appropriate uneven loading profiles to achieve zero-order release, and the practicality of these designs is limited to multilaminate devices. Hydrogel matrices are also subject to the diminishing release rates, despite the theoretical prospect of having a totally relaxation-controlled (Case II) situation thereby achieving zero-order release [34]. This explanation was made more explicit as it was observed in bioerodible swelling devices that the thickness of the gel layer (consisting of the distance between the polymer / dissolution medium interface and swelling front at the glassy / rubbery polymer interface) is the decisive factor of the rate of drug release, and that zero-order release is achieved when the synchronization of these two fronts is obtained [35,36]. Lee [34] also recognized that a third front, the diffusion front at the boundary between solid and dissolved drug, was important to the release process. This front is especially prevalent when drug-loading levels in hydrogels are high, and the dissolved drug gel layer thickness (distance between diffusion and erosion front) is the reference element for drug release instead of the entire gel layer thickness [37,38]. In each of these systems, burst release is often observed prior to diffusion through a developing gel layer, due to the release from the surface and the time needed for the formation of an efficient gel


layer capable of controlling water penetration and drug diffusion [39,40].

3.3.2. Heterogeneity of matrices Another explanation put forth for burst release in swellable monolithic systems is the heterogeneous nature of some hydrogels. Patil et al. [10] used cross-linked poly(sucrose acrylate) hydrogels immediately after preparation (i.e., without drying) to test the theory of drug migration during drying, but the initial burst of protein was found even without drying the samples. The morphology of the hydrogels in this study was described as a structure consisting of high-density microgel domains in a continuous low-density matrix as shown by SEM (Fig. 8). The relative pore sizes were largely in-

Fig. 8. Scanning electron micrographs of poly(sucrose acrylate) hydrogel surfaces prepared with different initial monomer concentrations: (a) 15% (w / v); (b) 30% (w / v); (c) 50% (w / v). Reprinted from Ref. [10],  (1996), with permission from Elsevier Science.

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fluenced by the preparation technique, with smaller pores formed from more concentrated monomer solutions. Vasudev et al. [9] also ascribed burst release to the existence of macro- and micro-domains for release of heparin from polyethylene vinyl acetate. In their research of the controlled release of FITCBSA from polymer matrices based on blends of PLA with Pluronic  , Park et al. [24,25] pointed out that the burst phenomenon that happened in many cases was partly due to the formation of pores and cracks in polymeric matrices during the device fabrication similar to the large pores seen in Fig. 8. This phenomenon is particularly acute when devices are prepared by solvent evaporation as an increased removal rate of the organic solvent causes an increase in porosity of the matrices [26]. These microparticles were formed at 858C, a high temperature that led to fast removal of the solvent. In the work of Ahmed et al. [27], drug release from biodegradable PLGA microparticles prepared by a w / o / w emulsion method was characterized by a high initial burst release of about 60%, which was attributed to diffusion of the drug through pre-existing pores and channels in the microparticles formed during the solvent evaporation process. The remainder of the drug was released slowly as the PLGA eroded in water. Research of van de Weert’s group [28] suggested the same explanation of burst by observing the porous surface structure of PLGA microspheres by SEM and proving the loaded lysozyme is homogeneously distributed throughout the device instead of being concentrated at the surface with the aid of infrared microscopy and CLSM. Chia et al. [29] were able to prove the influence of surface and internal morphology of the PLGA microsphere devices on the initial burst and the release behavior by studying the effect of preparation temperature. Higher temperatures tended to speed up microsphere formation, and led to increased surface proteins due to faster diffusion at high temperature. Therefore, microspheres formed at high temperature were denser, with rough surfaces (high surface area), resulting in a high initial burst release from the surface followed by slower release of imbedded proteins. Low temperature microspheres formed more slowly, and were thus smoother and had lower initial bursts. Wang et al. [30] also assumed the porous structure of

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microspheres is the main reason that causes burst. Varied extents of burst of BSA from 50:50 PLGA microparticles prepared by different methods were observed in this research, with the greatest (60%) found for vacuum-dried microspheres formulated using the (w / o) / w method.

3.3.3. Effect of drug properties The chemical and physical structure of various drug or active agent molecules can also have a profound effect on the burst effect in controlled release systems. The burst effect has been noted to occur in systems with both small molecular weight solutes and those for delivery of peptides and proteins. The specific mechanisms for burst release may be radically different in these systems, as small molecular weight solutes are often highly soluble in aqueous systems and can pass easily through the porous structure of hydrogels even prior to swelling. The observed burst release of proteins from controlled delivery systems is often attributed to surface adhesion and desorption. The solubility of drugs as well as their partition coefficients affect the driving forces for release, and can lead to rapid release due to thermodynamic imbalances. This effect has been observed by a number of researchers, including Narasimhan and Langer [41] who studied release of sodium salicylate and bovine serum albumin from hemispherical devices and developed a model capable or predicting burst release based on solute solubility differences and diffusivities. 3.3.4. Percolation limited diffusion Tzafriri [31] offers another theory to explain burst release of small molecular weight active agents from bulk degrading non-swelling polymer devices. The initial loading of active agent is theorized to be composed of two separate pools: a pool of mobile active agent which is free to diffuse upon hydration of the matrix, and a pool of immobilized active agent which can diffuse only after pore sizes increase due to hydrolytic degradation of the matrix. This is basically the same as percolation theory, where solute molecules connected by pores may diffuse, while isolated solute is trapped or immobilized by the matrix. Modeling work simulating experimental data supporting this theory is detailed later.

3.4. Triggered burst One example where burst release is desirable is the use of environmentally sensitive materials to achieve pulsatile release where rapid (burst) release is triggered by changes in the device’s chemical environment. Hydrogels based on anionic or cationic polymers exhibit pH-sensitive swelling and the ability to control diffusion in an on / off pattern. Similarly, lower critical solution temperature (LCST) polymer gels exhibit temperature sensitivity. These gels are highly swollen at low temperatures and deswell rapidly as the temperature is raised above the LCST with rapid burst release observed due to the shrinking of the gels [32]. Similar burst release has been observed from macroporous gels based on pH-sensitive polymers. The release of heparin from thermosensitive hydrogels has been studied by researchers aiming to improve cardiovascular targeting [33,42]. Heparin was loaded into the N-isopropylacrylamide-based hydrogels at low temperature (18C) as the gels were swelling, and release experiments were carried out at physiological conditions (378C) immediately after the loading process. The release profiles were characterized by a rapid initial release due to the squeezing effect of the collapsing polymer network, followed by a slower release, and the initial rapid release was found to correspond to the initial rapid deswelling of the gels as the temperature was raised above the lower critical solution temperature of the polymer gels. The cases of squeezing burst release are exceptions to the often-mentioned burst release, since a mechanical force is used to cause fast release rates.

4. Prevention of burst release Although favorable in some limited situations, under most of the circumstances in drug delivery, burst release is considered a negative effect. The importance of avoiding burst release can be seen in the number of publications focused on developing methods to prevent or minimize the burst effect in a wide range of polymer / drug systems. A system for controlled release would be ideal if it could be processed in a single step to include high drug loading and have no burst release. Several advanced


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technologies to avoid burst include surface extraction of the active agent prior to in vivo usage, using double-walled microspheres with layers made of different inert or erodible polymers [6], and modifying the surfaces of the drug-loaded matrix via an outer layer polymer coating [9,24]. Unfortunately, of the suggestions that have been given to prevent burst, many involve additional costly steps, which also result in reduced drug loading percentages or the introduction of additional materials.

sustained. The molecular weight of the encapsulated species was also considered to be an important factor influencing the release profiles. Results showed that a sustained release with lower burst effect could be obtained when higher molecular weight dextrans were used, attributed to a greater hindrance to pore diffusion due to the solute molecular size. Colombo and co-workers [43,44] have done extensive work in understanding the influence of exposed surface area on drug release. They defined a dimensionless parameter, Sa , the swelling area number as:

4.1. Surface extraction

1 dA Sa 5 ] ? ] D dt

Some fairly simple approaches have been taken to reduce the initial burst, such as extracting the drug formulations for a short period of time in vitro before using them in an in vivo application [4]. This method is effective at reducing burst because drug is removed from the outer layers of controlled release devices, but one important issue is still the cost of extraction and the reduction in the effective use of (often expensive) drugs. For those systems with a higher drug concentration on the surface, surface extraction by washing the sample briefly before carrying out the release experiment has been shown to be effective, but the fraction of drug removed in the extraction step may be significant [11,19]. This technique may be more applicable to larger release devices where the surface area to volume ratio is relatively small compared to microsphere formulations, where extraction may remove a significant portion of the active agent. Experimentally, Lee showed the effectiveness of surface extraction in reducing burst release [19] of oxprenolol HCl from PHEMA hydrogels (Fig. 7).

4.2. Coated surfaces Another popular method used to prevent burst release is surface modification by additional coating steps to provide an outer layer with no drug. In a study on the delivery of biomacromolecules including proteins and dextrans, Wheatley et al. [23] used alginate beads coated three times with a polycation, either poly( L-lysine HBr) or poly(vinyl amine), to prevent the initial burst release. It was found that increasing the polycation concentration decreased the burst effect, and caused the release profile to be more

(2)

in which dA / dt is the rate of releasing area change and D is the drug diffusion coefficient in the swollen polymer. Although not investigating burst release directly, Colombo and co-workers’ experimental results show burst release of diltiazem from Methocel  matrices. By coating the base or lateral surfaces of swellable hydrophilic tablets with partially water-impermeable coatings, bursts of different magnitudes were exhibited, among which the least burst was achieved by the sample with one base plus the lateral surfaces coated, so that the minimum surface area was exposed (Fig. 9). Additionally, following the burst release, modified systems with greater impermeable surface coverage exhibited more linear drug release profiles, with release rate curves proportional to the surface area available for release. When normalizing the instantaneous release rate with releasing area, it was shown that the release rates per unit area are practically identical for all of the systems examined [45]. One conclusion that might be drawn from this work is that the burst effect is a surface phenomenon and the entire release profile is proportional to the surface area exposed to the release medium. Although their research was not targeted at preventing burst, Colombo and co-workers did provide useful information in understanding the influence of surface area in burst release. Multilaminate systems also utilize overcoat layers to reduce burst release [46]. Zhou and Wu [16] developed a model using a finite element method to simulate release and showed that initial burst can be reduced by using a composite material to construct multi-layered tablets, and that near zero-order release can be obtained by combined use of composite material and non-uniform drug loading.

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though this technique shows promise at preventing burst release, the difficulty of achieving non-uniform drug loading makes this approach impractical in most situations.

4.4. Polymer morphology and composition

Fig. 9. Instantaneous diltiazem release rate from the five systems prepared versus time. Case 0 (empty squares), case 1 (solid diamonds), case 2 (squares with empty circle), case 3 (empty diamonds), case 4 (solid squares). Case 0 was tablets with no impermeable coating used; Case 1 had one lateral surface coated, Case 2 had both lateral surfaces (top and bottom) coated, Case 3 had circumferential coverage with the impermeable coating, and Case 4 had all but one lateral surface coated. Reprinted from Ref. [43],  (1992), with permission from Elsevier Science.

4.3. Drug loading distribution Non-uniform drug loading, though difficult to achieve in real systems, is one method that has been successful at reducing the burst effect in monolithic systems. Lee [19] mathematically and experimentally examined the effect of initial drug distribution on the kinetics of drug release from polymer matrices, and illustrated that an initial sigmoidal drug distribution with highest concentrations at the center of a gel slab was capable of introducing a characteristic inflection point, resulting in near zero-order sustained release behavior. The increasing concentrations away from the surfaces overcame the growing rubbery gel layer. This gel layer typically leads to diminishing release rates with time in uniformly loaded gels. Recently, Lu et al. [46] proposed using multilaminate systems to produce matrix systems with non-uniform drug distributions, but their work, like Lee’s [19], was focused on improving sustained release, not prevention of burst release. The models gave insight into the importance of drug distribution in matrices but did not address the issue of burst release, only improved non-diminishing sustained release. Al-

The polymer microstructure and hydrophilic / hydrophobic interactions also play an important role in determining drug distribution profiles and release characteristics. Kishida et al. [8] decreased the hydrophilicity of biodegradable poly(g-glutamic acid) matrices by adding a hydrophobic benzyl group, which depressed the initial penetration of water into polymer films, and hence was able to inhibit burst release of 5-fluorouracil. Patil et al. [10] reduced the magnitude of protein burst from poly(sucrose acrylate) gels by increasing the initial monomer concentration during polymerization to change the morphology of the polymer. They also observed that burst release was decreased with increasing molecular weight of proteins, from blactoglobulin to BSA and g-globulin, similar to the observations seen in Fig. 4 [18]. Both of these methods changed the relative size between the polymer pores and protein molecules, decreasing the mobility of the proteins in the polymers. Similarly, Cohen et al. [21] found the extent of FITC-BSA burst from PLGA microspheres was reduced as the molecular weight of PLGA was increased, which was confirmed in other investigations of solute release from poly(vinyl alcohol), PVA, hydrogels [18]. Certain polymers are also amenable to crystallization, so that pore sizes and morphology can be controlled by the annealing conditions. Mallapragada et al. [11] showed that burst release of metronidazole was reduced in semi-crystalline PVA samples annealed at higher temperatures for longer times (Fig. 10). Since the rate of water uptake in hydrogel devices controls the drug release rate, release kinetics can be shifted by proper use of swellable excipients. Catellani et al. [47] showed that release rate variability could be reduced by adding swellable and soluble polymers, such as HPMC (hydroxypropyl methylcellulose) and PVA, to the inert base matrix, leading to a quasi-constant rate. Improved zero-order release can also be obtained by mixing polymers with different swelling and erosion prop-


Fig. 10. Influence of annealing conditions on metronidazole ] release at 378C from PVA-controlled release systems (PVA Mn 5 17 600; metronidazole loading, 2 wt%); (filled circles) annealed at 1108C for 20 min; (filled squares) annealed at 1208C for 1 h. The standard deviation is too small to be drawn. Reprinted from Ref. [11],  (1997), reprinted by permission of John Wiley & Sons, Inc.

erties, like HPMC and sodium carboxymethylcellulose [39].

4.5. Surface modification To prevent burst release from porous polymer structures caused by solvent evaporation during processing, many methods have been attempted [24,25,27,29,30], most of which are based on changing the surface characteristics of the devices. In one study [24], two methods were used to form PLA gels. The first method utilized a second coating added by dipping the film into a poly(vinyl alcohol)– dioxane solution and then transferring it to distilled water to precipitate PVA onto the surface of the film while dioxane was dissolved in water. An alternative approach proposed was to coat PLA polymer powder tablets on both sides via compression molding above the glass transition temperature of PLA. Both of these two methods helped to reduce burst to some extent. Another approach [25] was to modify the polymer morphology by blending it with nonionic polymeric surfactants to form a matrix where the surfactants become entangled in the amorphous region of PLA. Upon hydration, the blends acquired an additional liquid–crystalline phase that was im-

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bedded between the PLA crystalline phases, producing an overall intact surface morphology, which resulted in a minimum initial protein burst and a longer release period [25]. It was later discovered when the above blend matrices were treated with an aqueous solution of polyethyleneimine (PEI), there was an even more pronounced decrease in the protein burst as well as a significant extension of the release. The mechanism of this approach was believed to be that PEI chains adsorb onto or diffuse into the polymer matrices; thereby ionically crosslinking protein molecules present near the surface region. When this method was used, it was important to optimize the PEI treatment as well as the proteinloading amount to minimize loss of the loaded BSA caused by the formation of the PEI-BSA cross-linked layer. In a study on PLGA microparticles prepared by solvent evaporation, the control of preparation temperature may change the microstructure of the particles, thus reducing the burst [29]. Other suggested methods of burst prevention in PLGA systems include treating the wet microparticles with an organic solvent / water mixture and adding organic solvents to the external aqueous phase during microparticle preparation, both of which resulted in a reduction in the pores present on the microsphere surface, as well as burst [27]. Burst was reported to be entirely eliminated by lyophilizing the poly( D,Llactide / glycolide, 50:50) microspheres prepared by a (w / o) / w emulsion method [30]. The proposed mechanism behind this result was either that the microspheres were more completely dried or that smaller pores were formed by evaporation of solvent during the sublimation process of freeze-drying. Burst release is a common phenomenon, reported in many published instances, and a selection of experimental evidence of burst release in various polymer matrix / drug systems is given in Table 3. According to the table, the burst of macromolecular agents such as proteins is frequently reported. This is due to two factors: the recent increased interest in developing controlled release systems to stabilize and release fragile proteins and the requirement that to achieve successful protein delivery, matrices must be macroporous. Although few recent publications have focused on burst release with small molecular weight drugs, this area still receives attention, since


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Table 3 Examples of burst release observed in published work Release agent

Molecular weight

Controlled release matrix materials

Highest burst observed

Ref.

Heparin; Streptokinase

3000–30 000; 47 000 17 500, 148,900 66 000 130.08 a 3000–30 000 a

Poly(N-isopropylacrylamide-comethacrylic acid) Poly(2-hydroxyethy methacrylate), p(HEMA) Poly(vinyl alcohol), PVA Poly(g-glutamic acid) and its benzyl ester Chitosan / polyethylene vinyl acetate co-matrix Poly(sucrose acrylate)

Almost all

[2,18]

–b

[3]

–b 40% –b

[4] [8] [9]

.55%

[10]

Semicrystalline PVA Polyethylene PLGA PLGA 75:25 and PLA2000 PLGA Calcium alginate coated by poly-L-lysine HBr and poly vinyl amine PLA / Pluronic 

–b –b –b 67.5% 70% –b

[11] [13] [14] [20] [21] [23]

–b

[24,25]

PLGA PLGA 50:50

50% 60%

[28] [30]

FITC-Dextran Bovine serum albumin 5-Fluorouracil Heparin b-Lactoglobulin BSA g-Globulin Metronidazole Sodium salicylate Ampicillin anhydrate BSA FITC-BSA Ovalbumin FITC-BSA; FITC-Dextran Lysozyme BSA a b

18 000 66 000 169 000 171.16 a 160.10 a 31.39 a 66 000 66 000 |45 000 a 66 000 70 000 14 4006100 a 66 000

Data from Merck Index [48]. The authors reported burst release without specifically quantifying the amount.

gels have little control over diffusion of these drugs at the early release stages.

5. Modeling Polymeric drug delivery systems can be designed to work by a variety of mechanisms. According to these mechanisms, Langer [49] categorized the systems into diffusion-controlled, chemically controlled, swelling-controlled, and magnetically controlled devices. Among these, diffusion-controlled and swelling-controlled systems have been widely studied not only experimentally, but also by establishing both simple and complex mathematical models. Significantly absent from most of the models is the ability to predict burst release except for the most general case where the release profile is shifted vertically by adding a parameter to represent burst release, a, such as in:

M ]t 5 kt n 1 a M`

(3)

where Mt /M` is the fractional drug release, n is the diffusional exponent, and k is the pre-exponential factor. In this model, the constant a is added to fit experimental data, accounting for a rapid jump in concentration at t50. It is usually determined by extrapolation of release data to the start of the experiment. The burst term a is assumed to be unrelated to time in this model and the whole release curve is simply shifted upward by adding the burst term.

5.1. Diffusion-controlled systems In diffusion-controlled systems, a substance is released from a device by permeation from its interior to the surrounding medium [12]. In these systems of polymeric matrices, including both the membranes of reservoir devices and the bulk porous


structure of matrices, drug diffusion is the ratelimiting step. A variety of models have been developed to predict release profiles in these systems [12,49,50]. In the derivation of these models, monolithic matrices were classified into two cases: monolithic solutions and monolithic dispersions. As for the release from former systems, early and late period approximations have been developed for devices of different shapes. Release behavior from monolithic dispersion systems consisting of dispersed solid release agent was modeled as well by Higuchi [51,52]. These simple and classic models have been widely used, but the burst stage is usually not explicitly defined. The burst effect has only been discussed at length for reservoir devices as caused by storage effects, as discussed above, and by Narasimhan and Langer [41], who developed an analysis of burst release from hemispherical controlled release devices with a small hole in the lateral surface, which allows diffusion. Their work showed that the burst effect in these systems is affected by the drug solubility, and they were able to predict drug release patterns with two distinct release rates, with the higher one at small times. However, their work did not attempt to explain rapid burst release, as the focus was on a long-term (hours to days time scale) ‘burst’ release.

5.2. Swelling-controlled systems In the strictest interpretations for diffusion-controlled systems, most models assume that the polymeric membranes or matrices do not change during the release process. However, for the swelling-controlled systems, absorption of solvent (water) leads to polymer expansion and thus different release kinetics [12], where convective transport of water is combined with Fickian diffusion to determine the overall release profile. The release rate is determined by the rate of diffusion of fluid in the polymer and its macromolecular relaxation [36]. The drug release in a swelling-controlled system is typically non-Fickian in nature, which is frequently expressed by the classic equation for fractional release as shown in Eq. (3) with a 50 indicating no burst release [43,45,53–57]. The value of n in this equation describes the relative importance of Fickian (n50.5) and Case II (n51.0) transport in anomalous diffu-

133

sion. However, current models for swelling controlled release are not capable of accounting for burst release beyond simplistic equations. More sophisticated models for swelling controlled release have been established and solved numerically to accurately predict the penetrant uptake behavior and the corresponding penetrant concentration profiles in swelling systems over the long-term release period [55,56,58–61]. These models are based on Fick’s Law, assuming perfect sink conditions, rapid surface equilibrium between the polymer and water, symmetric devices, and uniformly dispersed drug in the dry samples. The drug diffusion coefficient is a function of the water concentration, so that the release behavior is intimately related to the swelling behavior. Stemming from this model, Klier and Peppas [55] incorporated the movement of swelling front (the front separating the rubbery from glassy regions of the polymer) into the solute diffusion equation, while Brazel and Peppas [56] included this as a term in the penetrant diffusion equation. However, these models have limited use in modeling burst release, since the only way in which burst release may be incorporated into these models is by changing the initial drug distribution profile so that the drug concentration is higher at the surfaces. The number of published works concerned with developing models to effectively predict the burst effect in swelling hydrogels is very small, among which Batycky et al. [17] modeled burst by the kinetic equation of desorption: dC s ]] 5 2 k d C s dt

(4)

in which C s is the surface concentration of drug on the polymer device, and k d is desorption rate constant. This model was applied in cases where macromolecular drugs are released from erodible microspheres made by a double emulsification procedure. The desorption equation was used here because burst was attributed to the release of macromolecules adsorbed to the surface of the microparticle and within preexisting mesopores. Another model developed by Patil et al. [10] was based on the assumption that the heterogeneous nature of hydrogels, with multiple pore sizes even in the dry state, causes burst release. High-density and low-density

134


polymer regions were modeled separately in this research. Protein release from each region was described by the mathematical models of solute diffusion from diffusion-controlled systems, which were given by Crank [50], and their combined additive effect led to a release profile with an initial burst followed by a long period of sustained release. The initial burst of protein was attributed to the low-density region of the gel, while the slow longterm release was from the high-density microgel region, with the relative dimensions of these two regions accounting for the size of the initial burst. Because the hydrogel synthesis conditions directly determined the structure of the matrix, this model also provided an explanation of why the size of burst can be controlled by adjusting the synthesis condition of such devices. Although the swelling behavior of the hydrogels was not considered and mathematical models of solute diffusion from diffusion-controlled systems were used, this model recognized the importance of the heterogeneous structure of hydrogels. Tzafriri [31] proposed another mathematical model that has been successful at predicting the burst effect due to enzymatic cleavage causing degradation of polymer matrices and liberation of pools of drug. In this model, the active agent is considered to be composed of two distinct solute pools, mobile and immobilized, as loaded. The concentration of the mobile active agent is governed by a diffusion equation with a source term due to the liberation of the immobilized active agent, S, by matrix degradation, which is subsequently treated as mobile solute, C, that is free to diffuse: ≠C ≠S ] 1 ] 5 D= 2 C ≠t ≠t

(5)

where C and S are concentrations of active agent in the mobile and immobilized states, respectively. Profiles of C and S are applied as the initial conditions, and mass transfer boundary conditions for the mobile active agent are also adopted due to the possible existence of a diffusion boundary layer. The amount of immobilized active agent is assumed to be evenly proportional to the amount of undegraded polymeric substrate, with its rate of liberation proportional to the degradation rate of the substrate, which is described by Michaelis–Menten kinetics. Numerical solution of the model showed that since

degradation of the matrix rather than diffusion of the mobile agent controls the long-term release process, the initial load of mobile active agent is totally depleted during a short burst. Subsequent release is then caused by degradation of the matrix, and is nearly a zero-order process. Tzafriri also claimed that this model is applicable to hydrolytically degradable PLGA matrices, in which case bulk degradation follows first order kinetics and erosion commences only after most of the polymer has degraded. This leads to the definition of three distinct mechanisms of release in biodegradable systems, with the mobile active agent accounting entirely for the burst effect.

6. Summary Although the burst effect has been reported in numerous publications in our field, much of the research has focused on methods to prevent burst but little has been done to elucidate the mechanisms of burst release. Understanding of the burst effect during controlled release is still limited but knowledge continues to grow as researchers realize both the economic and therapeutic importance of the burst period. For many applications, small burst quantities may be acceptable, as long as the burst release is predictable. Currently, mechanisms of burst in different kinds of devices have been elucidated and methods to prevent unfavorable burst release have been treated by unique, though often patchwork, solutions. Valuable results have been published which shed light on some of the important physical and chemical mechanisms for burst and may lead to further systematic research. The morphology of the polymer devices, initial drug distribution profiles and mechanisms of drug release are all among the aspects which merit further study. The total elimination of the burst effect is most likely cost-prohibitive, but a better understanding of the phenomena occurring at the early stages of release may help researchers quantifiably predict burst release. Finally, work to establish models to precisely predict and control burst are still rare and merit further effort.

Acknowledgements The authors express gratitude to the University of


Alabama College of Engineering and Department of Chemical Engineering for supporting the work leading to this paper.

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ON THE IMPORTANCE AND MECHANISMS OF BURST RELEASE IN MATRIX

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