Can sonication enhance release from liquid-core capsules with a hydrogel membrane?

https://doi.org/10.1016/j.jcis.2011.11.038Get rights and content

Abstract

The objective is to investigate the influence of sonication on the mechanical and release properties of hydrogel capsules. A new fabrication process is developed to fabricate millimetric capsules made of a highly-viscous liquid core protected by a thin hyperelastic alginate membrane. At high intensities and/or long exposure times, sonication can lead to the capsule rupture, because it induces fatigue in the membrane. Below the breakup threshold, no remnant effect of sonication is, however, measured on the capsule mechanical properties. The release is studied by sonicating capsules filled with blue dextran suspended in an aqueous solution. The mass release that results from sonication is found to be proportional to the sonication duration time and pressure wave amplitude. A possible physical interpretation is that the acoustic streaming flow induced by the ultrasonic wave enhances convection in the vicinity of the capsule membrane and thus mass release. We have finally quantified the passive release subsequent to low-intensity sonications: it is on average identical to the one measured on non-sonicated capsules. Overall the membrane therefore recovers its physical and mechanical properties after sonication. If sonication leads to an increase in porosity of the capsule membrane, the increase is temporary and reverses back at the end of the ultrasonic stimulation.

Highlights

Sonication leads to a mass release increase proportional to its duration and ultrasonic pressure. ► At high intensities and/or long durations, sonication can lead to the capsule rupture. ► Below the breakup threshold, sonication has no remnant effect on the capsules. ► The capsules recover their physical and mechanical properties after sonication.

Introduction

Drug release from polymeric delivery systems responsive to external stimulations is receiving increasing attention in therapeutic medicine [1]. It is used to remotely control not only the rate of drug delivery to efficiently meet the time-evolving needs of patients, but also the site of delivery to induce a targeted delivery. The release rate mainly depends on the sensitivity of the drug vector to the stimulation. Among possible stimulations, one finds temperature change [2], pH [3], light exposure [4], magnetism [5]. External force stimulation is another method to induce release from drug carriers. Zanina et al. [6] studied the influence of shear stress on the release from gel particles and found that release is only reversible at low shear stress. Lee et al. [7] observed that when compression is applied on drug-loaded alginate gels, the gel reacts like a sponge and the drug is squeezed out of the gel. Such experience has never been conducted on capsules.

Less attention has been paid on ultrasonic stimulation. Three decades ago, it has been suggested that ultrasounds could increase the degradation and permeability [8] of polymeric matrices and hence the release of embedded drugs. Currently, ultrasonic stimulation of microbubbles is routinely used in the field of medical imaging. Microbubbles (<2 μm in size) have been found to be natural innocuous contrast agents, when stimulated by ultrasounds [9]. As the bubbles need to be coated by a lipid layer to be stabilized, they can simultaneously serve as drug vectors for targeted delivery. The drug release results from the large oscillations induced by the ultrasonic stimulation in the gas core. The efficiency of encapsulated bubbles as drug carrier is, however, limited owing to the small quantity of active material that can be carried in the shell and their short lifetime [10]. Liquid-filled carriers offer a good alternative, as drugs are typically aqueous solutions. But, if larger quantities of drugs can be encapsulated, the release mechanism induced by sonication needs to be established for each vector type.

A few studies have tested the effect of sonication on drug release from liquid-filled carriers. Schroeder et al. [11] sonicated liposomes, consisting of a lipid bilayer encapsulating a liquid drug. They showed that sonication induces transitory reversible pores on the liposome, which leads to an increase in the encapsulated drug release. They found that sonication at low frequency (20 kHz) is more efficient than at high frequency (>1 MHz) and that the higher the ultrasonic power density, the larger the drug release. Similar results were obtained on Pluronic micelles, which are spherical structures with a lipid monolayer [12].

Capsules are another type of drug carriers, for which the liquid core is protected by a solid membrane with elastic properties. The membrane can be made of various constituents, e.g. reticulated polymers [13], reticulated proteins [14], polyelectrolytes [15]. Their self-release ability is determined essentially by the membrane properties. The use of ultrasonic stimulation to promote the release rate has only been studied on submicron-sized capsules with a rigid polyelectrolyte shell [16]. Drug release only occurs if the particle rigid wall is broken up. Shchukin et al. [16] showed that a low-frequency stimulation (20 kHz) can lead to the capsule breakup and that, for a constant intensity of sonication, the duration time of sonication required for breakup increases with the membrane rigidity. But the particles used can be considered rather as liquid-filled rigid microcontainers than as actual capsules, as capsules intrinsically have a deformable membrane by definition.

No study has yet considered the effect of sonication on soft-membrane liquid-filled capsules. Our present objective is to measure the effects of sonication on polyelectrolyte capsules in order to understand the release mechanism that can be induced by sonication. As a first exploratory study, we test millimetric alginate capsules. We measure the evolution of the geometrical and mechanical properties varying the sonication parameters. Kühtreiber et al. [17] has indeed shown that the mechanical properties of hydrogel capsules play an important role on their release properties and that any damage on the capsule membrane might change the release behavior.

The methods used to assess the mechanical properties of capsule membranes are typically based on the measurement of deformation under a well-defined stress; a mechanical model of the capsule deformation, based on an assumed constitutive law, is needed to infer the membrane elastic properties from the experimental data by inverse analysis. Large artificial capsule can be subjected to a shear force in a spinning rheometer [18]; the technique is, however, limited by the rather low level of mechanical stress that can be applied to the capsules. They can also be squeezed between two rigid parallel plates: both the distance between the plates and the compression force are measured simultaneously. This technique is often used to evaluate a bursting force only [19]. It is, however, possible to also extract the membrane mechanical properties through inverse analysis [20], [21]. In the present study, we will apply this technique following the method developed by Carin et al. [22].

The release properties will then be investigated on capsules filled with a 0.5% blue dextran solution. A few methods exist to evaluate the release of an encapsulated substance. The fluorescence detection method requires the encapsulated fluid molecules to be labeled by fluorescence. The evolution of the fluorescence intensity is measured either in the encapsulated fluid or in the surrounding medium in order to estimate the release [23]. High-pressure liquid chromatography (HPLC), another technique used to detect chemical substances in a mixture, may also be applied to quantify released substances [24]. But the method we have chosen is spectrophotometry, which is the most frequently used owing to its high precision and simplicity of use [25]. The absorbance value is measured with the spectrophotometer at various instants of time in the external solution containing the capsules. The corresponding mass released can be calculated calibrating the measurements on samples of known concentrations.

All the experimental techniques used in the study are described in Section 2. We present the new method developed to fabricate the capsules, as well as those used to expose them to ultrasounds and measure their mechanical properties and release. The results are then presented and discussed in Section 3. We first show the effect of sonication on the capsule mechanical properties and possible breakup, before considering its influence on the release of encapsulated molecules. The release induced by sonication is compared with the one induced by compression. We finally show the influence of sonication on the passive release, to study whether sonication has a permanent effect on the capsule porosity. Conclusions on the influence of sonication on capsule release are provided in Section 4.

Section snippets

Preparation of liquid-core alginate-membrane capsules

A new fabrication method has been designed to produce calcium alginate capsules. It is inspired from the fabrication processes of Nigam et al. [15] and Nussinovitch et al. [26]: the hydrogel membrane capsules are likewise obtained by extrusion in a one-step process. A solution containing 40% (w/v) sucrose of molecular weight 342.3 Da (84100, Sigma Aldrich, USA) and 0.5% (w/v) calcium chloride serves as the liquid core of the capsule (solution A). Sucrose is used as a non-gelling polymer to

Capsule breakup induced by sonication

We have observed that sonication could lead to the capsule breakup depending on the time and power of sonication. We have therefore investigated the breakup threshold varying the conditions of sonication. For each test, the capsule final state (ruptured or unruptured) has been determined by naked eye. Fig. 2 is a log–log plot of the breakup threshold power Psthr as a function of the sonication time. Depending on the sonication power, breakup occurs in a matter of minutes (with a maximum of

Conclusion

We have investigated the influence of sonication on capsules with a soft membrane made of hydrogel. No measurable effect has been found on the capsule mechanical properties, as long as the times and powers of sonication remain below a certain threshold. Above threshold, sonication leads to the capsule breakup because of the fatigue of the membrane. When a substance is encapsulated, sonication leads to an increase in the mass release. The increase measured during sonication is found to be

Acknowledgments

This work was supported by the China Scholarship Council (PhD scholarship of L. Zhang). We would like to thank the reviewers for their valuable comments and suggestions.

References (41)

  • J. Kost et al.

    Adv. Drug Delivery Rev.

    (2001)
  • L.E. Bromberg et al.

    Adv. Drug Delivery Rev.

    (1998)
  • P. Gupta et al.

    Drug Discovery Today

    (2002)
  • H. Richert et al.

    J. Magn. Magn. Mater.

    (2005)
  • A. Zanina et al.

    Int. J. Pharm.

    (2002)
  • K.W. Ferrara

    Adv. Drug Delivery. Rev.

    (2008)
  • A. Schroeder et al.

    Chem. Phys. Lipids

    (2009)
  • N. Rapoport et al.

    J. Controlled Release

    (2003)
  • D. Poncelet et al.

    J. Membr. Sci.

    (1990)
  • F. Edwards-Lévy et al.

    Int. J. Pharm.

    (1993)
  • M. Husmann et al.

    J. Colloid Interface Sci.

    (2005)
  • F. Edwards-Lévy et al.

    Biomaterials

    (1999)
  • M. Rachik et al.

    J. Colloid Interface Sci.

    (2006)
  • A. Kikuchi et al.

    J. Controlled Release

    (1997)
  • H. Yu et al.

    J. Controlled Release

    (1995)
  • H. Ai et al.

    J. Controlled Release

    (2003)
  • A. Nussinovitch et al.

    Food Hydrocolloids

    (1996)
  • P. Pujara et al.

    J. Biomech.

    (1979)
  • S. Vervoort et al.

    Polymer

    (2005)
  • I. Rousseau et al.

    Eur. Polym. J

    (2004)
  • Cited by (0)

    View full text