Scholarly article on topic 'Release behavior of trans,trans-farnesol entrapped in amorphous silica capsules'

Release behavior of trans,trans-farnesol entrapped in amorphous silica capsules Academic research paper on "Chemical sciences"

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{"Silica nanoparticles" / "Multiple emulsions" / Farnesol / Encapsulation}

Abstract of research paper on Chemical sciences, author of scientific article — Filipa L. Sousa, Sara Horta, Magda Santos, Sílvia M. Rocha, Tito Trindade

Abstract Farnesol, a compound widely found in several agro-food by-products, is an important bioactive agent that can be exploited in cosmetics and pharmaceutics but the direct bioapplication of this compound is limited by its volatility. Here the entrapment of farnesol in silica capsules was investigated to control the release of this bioactive compound in the vapor phase and in ethanol solutions. The preparation of silica capsules with oil cores was obtained by employing a sol–gel method using O/W/O multiple emulsions. Two distinct chemical vehicles for farnesol have been investigated, retinol and oleic acid, that afterwards have been emulsified as internal oil phases. The volatile release of farnesol from the as-prepared SiO2 capsules was investigated by headspace solid phase microextraction (HS-SPME) followed by gas chromatographic analysis (GC), and the release to ethanol was carried out by direct injection of the ethanolic fraction into the GC system. It is demonstrated that these capsules are efficient for the long controlled release of farnesol and that the respective profiles depend on the chemical parameters employed in the synthesis of the capsules.

Academic research paper on topic "Release behavior of trans,trans-farnesol entrapped in amorphous silica capsules"

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Results in Pharma Sciences

journal homepage:www.elsevier.com/locate/rinphs

Release behavior of trans,trans-farnesol entrapped in amorphous silica capsules

Filipa L. Sousaa, Sara Hortaa,b, Magda Santosb, Silvia M. Rochab, Tito Trindadea'*

aCICECO, Department of Chemistry, University ofAveiro, Campus de Santiago, 3810-193 Aveiro, Portugal bQOPNA, Department of Chemistry, University ofAveiro, Campus de Santiago, 3810-193 Aveiro, Portugal

ARTICLE INFO

ABSTRACT

Article history:

Received 7 May 2012

Received in revised form 23 July 2012

Accepted 31 July 2012

Keywords: Silica nanoparticles Multiple emulsions Farnesol Encapsulation

Farnesol, a compound widely found in several agro-food by-products, is an important bioactive agent that can be exploited in cosmetics and pharmaceutics but the direct bioapplication of this compound is limited by its volatility. Here the entrapment of farnesol in silica capsules was investigated to control the release of this bioactive compound in the vapor phase and in ethanol solutions. The preparation of silica capsules with oil cores was obtained by employing a sol-gel method using O/W/O multiple emulsions. Two distinct chemical vehicles for farnesol have been investigated, retinol and oleic acid, that afterwards have been emulsified as internal oil phases. The volatile release of farnesol from the as-prepared SiO2 capsules was investigated by headspace solid phase microextraction (HS-SPME) followed by gas chromatographic analysis (GC), and the release to ethanol was carried out by direct injection of the ethanolic fraction into the GC system. It is demonstrated that these capsules are efficient for the long controlled release of farnesol and that the respective profiles depend on the chemical parameters employed in the synthesis of the capsules.

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

Over the past decade, a major trend in the emerging area of encapsulation technology has been the design of increasingly sophisticated capsules for controlled release of bioactive molecules [1,2]. These materials find many applications in a wide spectrum of fields such as medicine, pharmaceutics, food and paint industries [3]. In addition, it is known that the encapsulation of materials using inorganic particles and organic polymers can alter the surface characteristics of the cores and enhance the storage stability of the entrapped materials [1]. Diverse nanocarriers for drug delivery applications have been investigated, these include liposomes [4], cyclodextrines [5], colloidosomes [6], silica microcapsules [1-3] and metal-organic frameworks [7].

In particular, there has been an increasing interest in the development of mesoporous and hollow SiO2 materials for controlled drug delivery due to their attractive features [8-11]. In fact, owing to their chemical robustness and biocompatibility, silica capsules offer an interesting alternative to pure organic based delivery systems, which generally show lower drug loading capability and rapid drug release. Several methods for the preparation of silica capsules have been developed, these include Pickering emulsions [12,13], water-in-oil-in-water multiple emulsion templating using sodium silicate as precursor [14], water-in-oil (W/O) or oil-in-water (O/W) emulsions using tetraethylorthosilicate (TEOS) as silica precursor [9,15-17]. Among these systems, multiple emulsions, both of oil-in-water-in-oil (O/W/ O) or water-in-oil-in-water (W/O/W) type, have been used as a tool

* Corresponding author. Tel.: +351 234 370 726; fax: +351 234 370 084. E-mail address: tito@ua.pt (T. Trindade).

2211-2863/$ - see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.rinphs.2012.07.001

to drug delivery in specific body targets, by prolonging the release of drugs with a short biological half-life [1]. Although less investigated, O/W/O multiple emulsions are good candidates for the controlled release and stabilization of lipophilic drugs [18]. In this context, the entrapment and in vitro release of Vitamin A (retinol) in silica particles has been previously reported [1,19]. Additionally, a comparative study for the stability of retinol in three types of emulsions: O/W, W/O and O/W/O, has shown the highest stability when the O/W/O emulsion was used [20].

Farnesol, a natural sesquiterpenoid (C15) occurs in many essential oils, mainly in rose and orange blossoms. Farnesol is a fragrance ingredient widely used in cosmetics, fine fragrances, shampoos, and toilet soaps as well as in non-cosmetic products such as household cleaners [21]. Also, recent studies have shown that farnesol affects the growth of a number of bacteria and fungi, pointing to a potential role as an antimicrobial agent [22,23]. For example, farnesol has been incorporated into microcapsules that can be degraded by the action of bacteria. These microcapsules, composed of natural proteins, were filled with two active compounds that can be released upon reaching targeted temperatures, allowing the delivery in perspiration conditions [24].

Despite the relevance of farnesol in diverse applications, its use has also been limited due to the volatility of this compound, leading to unnecessary losses. This research describes for the first time the entrapment of trans,trans-farnesol in SiO2 capsules using O/W/O multiple emulsions. The emulsions act as soft organic templates to produce amorphous SiO2 capsules by hydrolysis and condensation reactions using TEOS as the sol/gel precursor. Due to their chemical and thermal stability and biocompatibility, silica capsules are an

advantageous alternative to conventional pure organic based delivery systems (e.g. micelles, liposomes, and polymer particles), which generally also show lower drug loading capability and rapid drug release. It will be shown that oleic acid can be used as an efficient drug vehicle thus presenting economical advantages in relation to the use of the more expensive vehicle retinol. In addition, with the method here reported the surface of these SiO2 capsules can be easily chemical functionalized in order to meet the demands in terms of the release profile of active substances. In principle, this process can be adapted to the production of amorphous SiO2 capsules containing other volatile bioactive cores, but here this will be demonstrated using SPME-GC-MS monitoring for farnesol releasing behavior.

2. Experimental

2.1. Materials

Tetraethyl orthosilicate (TEOS, 98%), polyoxyethylene sorbitan monolaurate (Tween20), sorbitan monoleate (Span 80) N-decyl alcohol (>98%) were purchased from Sigma-Aldrich. Triblock copoly-merpluronic P123 (EO2OPO7OEO2O, Mw. 5800), polyvinylpyridinone, hydroxypropyl-cellulose (Mw. 100,000), polyethylene glycol, retinol (95%) and oleic acid (90%) were also purchased from Aldrich Chemical Company. Ammonia (25%, Merck), ethanol (Riedel-de Haen) and trans,trans--farnesol (95%) Fluka (for sake of simplicity the term far-nesol will be used therein). All the reagents were of analytical grade and used without further purification.

2.2. Preparation of multiple emulsions

O/W/O multiple emulsions were prepared through a two-step emulsification process. In a first step, the primary O/W emulsion was prepared. Tween 20 as high HLB surfactant (1 wt%) was added to an aqueous solution containing a stabilizing polymer. The use of three types of polymers (PEG, PVP and P123) was investigated. Farnesol was added either to retinol or to oleic acid, and then dispersed in the water phase. After 30min of stirring, NH4OH (2 wt%) was added to the water phase. In a second step the primary emulsion was slowly added to n-decyl alcohol as external oil phase containing Span 80 as low HLB surfactant (2 wt%) and 0.8 wt% HPC. The weight ratio of the O/W primary emulsion in the external oil phase was kept at 1:9, and the resulting O/W/O emulsion was stirred at low shear for 30 min. All the experimental compositions are shown in Table 1.

2.3. Fabrication of silica capsules entrapping farnesol

To prepare silica capsules by the sol-gel method, an amount of TEOS equivalent to the molar ratio H2 O/TEOS = 4 was gently added to the multiple emulsions. The mixture was then stirred with a magnetic stirrer for 7 h at room temperature. After the reaction was completed, the sample was centrifuged at 3000 rpm for 15 min; in order to remove non-reacted chemicals the as prepared particles were washed twice with ethanol.

2.4. Characterization

The droplet size and morphology of the multiple emulsions were investigated by optical microscopy using an Olympus BX51 microscope. The FT-IR spectra of KBr pellets of the samples were recorded by using a Mattson 7000 spectrometer, at 64 scans at a resolution of 4 cm-1. Transmission electron microscopy (TEM) was carried out on a Hitachi H-9000 microscope operating at 300 kV. To prepare the TEM samples, a drop ofthe diluted ethanolic solutions ofthe samples were deposited on a carbon-coated copper grid, and the solvent was left to evaporate. Scanning electron microscopy (SEM) images were carried

out using a Hitachi SU-70 and average sizes for the sample have been estimated directly from the images.

2.5. Farnesol controlled release

In order to evaluate the release of farnesol from SiO2 capsules prepared in a O/W/O multiple emulsion, two assays were performed for 500 h: the release to the vapor phase was evaluated using headspace solid phase microextraction (HS-SPME) followed by gas chromato-graphic analysis (GC), and the release to ethanol was carried out by direct injection of the ethanolic fraction into the GC system. For headspace sampling, ca 23.8-26.8 mg of the SiO2 capsules with 1 mL ethanol were introduced into a 2 mL glass vial. The vial was capped with a PTFE septum and a cap (Chromacol, Hertfordshire, UK), and was stored at room temperature for 500 h. At each sampling moment, the SPME fiber was introduced for 10 min into the vial to promote the transfer of the farnesol from the headspace to the coating fiber. The SPME device included a fused silica fibre coating partially cross-linked with 50/30 |im divinylbenzene-carboxen-poly(dimethylsiloxane). For ethanol release assay, ca 39.5-41.1 mgof the SiO2 capsules and 2 mL of ethanol were introduced into a 2 mL glass vial. At each sampling moment, 5 | L of each ethanolic solution was injected into a gas chromatograph. A PerkinElmer Clarus 400 gas chromatograph with split injector and a flame ionization detector (FID) was used to performed both analysis (SPME and direct injection of solutions), equipped with a 30 m x 0.32 mm (i.d.), 0.25 |m film thickness DB-FFAP fused silica capillary column (J&W Scientific Inc., Folsom, CA, USA). The oven temperature was programmed from 100 to 200 °C at 20 °C/min (hold 1 min at 200 °C). The injector and detector temperatures were 250 °C. The flow rate of the carrier gas (H2) was set at 2.6 mL/min. The injection port was lined with a 0.75 mm (i.d.) glass liner, in the case of SPME analysis. Split injection mode was used (154 mL/min). The GC area data were used as an approach to estimate the relative content of farnesol.

3. Results and discussion

In this study, O/W/O multiple emulsions have been investigated using various chemical compositions, which include the use of retinol or oleic acid as vehicles for farnesol encapsulation. The prepared multiple emulsions were then employed as soft organic templates to prepare silica capsules by a sol-gel method involving the hydrolysis and condensation of silane oligomers derived from TEOS used as precursor. The hydrolysis and condensation reactions take place in the water phase though TEOS was previously added to the oil phase (n-decyl alcohol). This is because vigorous stirring of the external oil phase facilitate the penetration of TEOS through the surfactant layer surrounding the water phase in which the hydrolysis occur. As the hydrolysis proceed, the water-soluble silica oligomers are kept inside the aqueous droplet [1,8,9]. Thus the aqueous phase acts as space-limiting micro-reactors for the hydrolysis process, and the internal oil droplets serve as templates for cores.

The use of multiple emulsions in materials synthesis requires judicious control over several experimental parameters in order to achieve emulsion stability. In order to obtain suitable emulsions for the encapsulation of farnesol, several concentrations for Tween 20 and Span 80 were investigated and here results are presented among those that result in the more morphological uniform droplets as evaluated by optical microscopy. Moreover, the droplets average size and size distribution have a major role in the emulsion stability in a way that emulsions with precisely controlled droplet size exhibit better stability. As the interfacial curvature of the internal droplets is tensed due to the small size of the droplets, the addition of surfactant in the external phase will help the formation of a hole in the external film when the internal drops are close to the surface. This enables a decrease of the curvature tension that becomes more positive and

Table 1

Chemical composition of the emulsions used for the fabrication of SiO2 capsules.

Formulation Primary O/W External oil phase

Internal

Tween 20 NH4OH PEG PVP P123 oil phase* HPC Span 80

E1 (retinol) (wt%) 1 2 0.6 4 0.8 2

E2 (retinol) (wt%) 1 2 0.6 4 0.8 2

E3 (retinol) (wt%) 1 2 0.6 4 0.8 2

E4 (O.A.) (wt%) 1 2 0.6 4 0.8 2

E5 (O.A.) (wt%) 1 2 0.6 4 0.8 2

E6 (O.A.) (wt%) 1 2 0.6 4 0.8 2

* The internal oil phase, composed by the vehicle and farnesol were prepared using 3.96 (wt%) of the vehicle and 0.04 (wt%) of farnesol. O. A.—oleic acid.

Fig. 1. Optical microscope images of O/W/O emulsions: formulation E6 (top); formulation E5 (bottom).

therefore entropically favorable. In this regards, additional stabilizers such as HPC, PEG, PVP and P123 were used in this study to improve the stability of both external oil and water phases as reported elsewhere [19]. Fig. 1 shows an optical microphotograph of typical O/W/ O multiple emulsions employed in this study. These emulsions were used immediately after their preparation.

Because TEOS was added to O/W/O emulsions as precursor of the sol-gel method, amorphous SiO2 forms through a series of hydrolysis and condensation reactions involving oligomeric silane species at the O/W interphase. The literature reports attempts to explain the mechanism of formation of SiO2 via the sol-gel method using microemulsions as nanoreactors [1]. In brief, TEOS that is initially solubilized in the oil phase migrate to the O/W interphase where hydrolysis and condensation occurs. The formed hydrophilic oligomers act as precursor species for the growth of an amorphous siliceous

\ I / 0 days

■ . I.......................

3000 1500 1000 500

Waveriumberfcm

Fig. 2. FT-IR spectra of formulation E6 after keeping the sample at 60 °C for distinct times. Highlighted spectral regions show contribution from farnesol.

network in the inner water phase. The infrared spectra of the capsules are dominated by characteristic bands of amorphous SiO2 (Fig. 2). Thus the bands centered at 1095 and 465 cm-1 are respectively attributed to asymmetric and symmetric Si-O-Si stretching vibrations of the silica shells. A weak absorption band at 955 cm-1 and a broad band at about 3427-3456 cm-1 are respectively assigned to Si-OH bending and stretching modes [25]. Note that vibrational bands of the organic compounds employed in the encapsulation process have also been detected though a unequivocal assignment was not possible due to overlap of bands due to the presence of several compounds in the capsules. Nevertheless, the spectral regions between 29662854 cm-1 and 1380-1327 cm-1, in which the C-H stretching and bending modes of pure farnesol are observed, have been analysed in more detail. Thus the IR spectra of the capsules were recorded at distinct times after keeping the sample at 60 ° C. Fig. 2 shows a typical behavior for the formulation E6, revealing a decrease of the bands intensities in the spectral regions mentioned above, which is a first indication of slow release of farnesol.

The release behavior of retinol has been investigated in SiO2 capsules, mainly due to its relevance as a skin cosmetic [1,19]. Therefore, in the present work this compound was also used as a vehicle for far-nesol in SiO2 capsules to obtain materials that combine the benefits of both compounds. However, because retinol is expensive, oleic acid was also investigated here as an alternative lipophilic vehicle, which though not presenting the retinol bioactivity is less expensive. Fig. 3 shows SEM images for SiO2 capsules prepared using distinct vehicles (retinol and oleic acid) and for the several formulations investigated.

Fig. 3. SEM images of capsules prepared in O/W/O emulsions. Upper pannel: formulations using retinol as vehicle: (A) E1, (B) E2 and (C) E3; bottom pannel: formulations using oleic acid as vehicle: (D) E4, (E) E5 and (F) E6.

Although the SiO2 capsules appear as spheroidal particles with rough surfaces using either retinol or oleic acid, the presence of PEG (formulations E1 and E4) seems necessary to control the polydispersity of the system. It should be noted that the stabilizers dissolved in the water phase have a strong influence on the size and morphology of the capsules prepared in the presence of either retinol or oleic acid. The particles were in average slightly bigger for formulations containing PVP as compared to those in which PEG and P123 were employed. On the other hand, the use of PEG in water phase result in spherical capsules with a porous surface (Fig. 3A and 3D), with the use of retinol leading to capsule surfaces smother than those obtained in the presence of oleic acid.

TEM analysis was performed on selected samples (E1 and E4) described above in order to elucidate the type of internal microstructure of the capsules. The TEM images shown in Fig. 4 indicate that the capsules are made of porous shells, which in turn are composed of smaller SiO2 particles. Therefore the silica capsules formed in O/W/O multiple emulsions seem to result from the assembly of nanosized silica previously formed during the sol-gel process. The assembly of these SiO2 nanoparticles into shells occurs preferentially in the water phase thus yielding a porous material in which the nanoparticles are filled with the lipophilic substances present in the inner oil phase.

The in vitro release of farnesol from the capsules in function of time was investigated either in the vapor phase or by redispersing the silica in ethanol. The curves of drug release from SiO2 obtained in different formulations are shown in Fig. 5. The results show that the capsules exhibit a controlled release of farnesol. Taking in consideration the analytical methods employed in each case, the release profiles seem comparable for each sample analysed in the vapor phase and in ethanol.

The polymer used as stabilizer in the water phase influences the morphology/surface of the as prepared SiO2 capsules, therefore it is expected that the capsule morphological features influence the release profile of farnesol. However, the most striking feature in Fig. 5 is the distinct release profile observed when using capsules of formulation E1, as compared to the other SiO2 samples, in both release media. For example, the stabilizer employed in E1 and E4 formulations was PEG, in both cases, leading to capsules that share similar morphologies, namely a porous surface (Fig. 3) and still exhibit distinct release behavior. Although in these cases the SiO2 capsules have distinct mean diameters, respectively 0.94 ^m (S.D. = 0.32 ^m) and 0.44 |(m (S.D. = 0.13 |m) for E1 and E4, the sizes estimated for the capsules are of the same order of magnitude. Thus it is unlikely that the release behavior results solely from differences on the morphological characteristics of the capsules. A possible explanation relies on a conjugated effect arising not only from differences in the size of the capsules but also on the type of interactions between farnesol molecules and the vehicle, retinol or oleic acid. The lower release was observed for E4, which may infer that stronger interactions between farnesol and oleic acid had occurred, in fact both compounds

Fig. 4. TEM images of SiO2 capsules prepared in O/W/O emulsions using formulations E1 (top) and E4 (bottom).

are composed of long unsaturated alkyl chains with a polar head. 4. Conclusions

In this research, it was demonstrated for the first time the direct encapsulation of farnesol into amorphous silica capsules using multiple emulsions. All systems analysed exhibit good sustained release properties for this bioactive compound. In particular, the capsules prepared in the presence of PEG and using retinol as the vehicle showed intense release over a short initial period of time, as compared to capsules prepared using other formulations. It is well known that terpene compounds (e.g. trans,trans-farnesol) are praised for their beneficial effects to human health, namely as anti-oxidant agents. The release profiles reported here are compatible with the needs of an anti-oxidant effect in fast stress oxidative situations or in cases of a preventive action for longer periods of time. Noteworthy,

0 SO 100 150 ZOO 250 300 350 400 450 500 Time |h|

—E1 —-я- E4 —4 ■ E6

Fig. 5. Release of farnesol from SiO2 capsules prepared in O/W/O multiple emulsions in function of time. A: Vapor phase; B: Ethanol medium.

farnesol can be obtained from grape pomace, which is a by product of the wine industry, thus in line with the strategy described here to develop non-expensive capsules for cosmetics, in particular those carrying oleic acid as the vehicle. Moreover, considering recent developments on the production of highly sophisticated nanocapsules [26], the materials reported here can be further exploited in contexts aiming multifunctionality.

Acknowledgments

F. L. Sousa is thankful to FCT for the grant SFRH/BPD/71033/2010. S. Horta thanks FCT for a BII grant. The authors thank Dr A.V. Girao for the SEM and TEM images.

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