Formulation and Chemical Stability in Aqueous Media of Cannabidiol

Research Article pubs.acs.org/journal/ascecg

Formulation and Chemical Stability in Aqueous Media of Cannabidiol Embedded in Cardanol-Based Nanovesicles Maria Pia Di Bello,† Ermelinda Bloise,† Selma E. Mazzetto,‡ and Giuseppe Mele*,† †

Department of Engineering for Innovation, University of Salento, via Arnesano, 73100 Lecce, Italy Laboratory of Products and Processes Technology (LPT), Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza 6021, Brazil

‡

ABSTRACT: With relevance to an increasingly large set of environmentally friendly products and processes, a green nanoformulation based on renewables was proposed. Our attention was devoted to cannabidiol (CBD), a cannabis extract compound known for its intrinsically low chemical stability that limits its therapeutic potential. In this work, the environmental stability of CBD was improved, adopting a new sustainable formulation. In particular, for the first time, CBD was embedded into a vesicular nanosystem based on cardanol (CA) known for its antioxidant properties which stabilize and avoid its degradation in an aqueous environment. Chemical and physical characterization of nanovesicles was carried out by dynamic light scattering (DLS) and nuclear magnetic resonance (NMR). Exhaustive dialysis was used to purify samples, and the presence of CBD not embedded into nanodispersions was monitored by UV−vis spectrometry measurements until its disappearance. Identification and quantification of CA and CBD were performed after lysis of nanovesicles through a high-performance liquid chromatograph coupled to diode a array and mass spectrometer detectors (HPLC−DAD−MS). Furthermore, stability studies of green nanoformulations were performed at two different temperatures (20 and 4 °C) to ascertain their better preservation. KEYWORDS: Cannabidiol, Cardanol, Green nanoformulation, Renewables, Stability

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INTRODUCTION

remarkable lack of unwanted cognitive and psychoactive actions.5 Many dispersion systems are currently in use or being explored for use as carriers of substances, particularly biologically active compounds. These systems are designed to protect the substance from the environment during delivery and to provide a controlled release of the substance to a targeted area.6,7 In other cases, the goal is to prepare a drug carrier system that acts as a reservoir at the site of injection. Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or particles ranging in size from a few nanometers up to hundreds of microns, dispersed in an aqueous or nonaqueous medium using suspending agents. However, the therapeutic activity of certain existing drugs is limited because of several reasons such as poor water solubility, poor targeting ability, low drug stability, and inability of the drug to cross the lipophilic cell membranes. These demands led to continuous research on different drug carrying vehicles and mechanisms to carry the therapeutic agent into a specific body part or cell compartments to repair or detect the damages, called drug delivery systems.8

Cannabis-based medicines are registered as a treatment for various symptoms such as pain and spasms in multiple sclerosis patients, and anorexia and nausea in patients with HIV or receiving cancer treatment.1,2 However, the pharmacokinetics of the various administration routes of cannabis and cannabisbased medicines depends on their stability, and for this reason, their dosing is hard to regulate.3 In this context, cannabidiol (CBD, Figure 1) is the main nonpsychotropic component of the Cannabis4 extract that displays many actions such as antiinflammatory, anticonvulsive, sedative, hypnotic, antipsychotic, and neuroprotective properties. It represents one of the most promising candidates for clinical utilization due to its

Received: May 26, 2017 Revised: August 11, 2017 Published: August 28, 2017

Figure 1. Chemical structure of cannabidiol. © 2017 American Chemical Society

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DOI: 10.1021/acssuschemeng.7b01658 ACS Sustainable Chem. Eng. 2017, 5, 8870−8875

Research Article

ACS Sustainable Chemistry & Engineering

Figure 2. Schematic representation of the formation of a CA−CH−CBD vesicular nanosystem. furnished by Aneva Italia s.r.l.; cholesterol (CH), potassium chloride (KCl), boric acid (H3BO4), sodium hydroxide (NaOH), acetonitrile (CH3CN), methanol (MeOH) for HPLC, and acetic acid were purchased from Sigma-Aldrich (Steinheim, Germany). Borate buffer solution pH 9.0 is a Milli-Q water solution of H3BO4 30 mM, KCl 70 mM, and NaOH 18 mM. Ultra pure (UP) water was delivered by a Zeneer UP 900 Human Corporation system. Sonication was carried out using a Sonorex RK 102H ultrasonic water bath from Bandelin Electronic. Centrifugation was carried out with a PK121 multispeed centrifuge from Thermo Electron Corporation. Preparation of CA Nanovesicles Embedded with CBD. A schematic representation of the formation of a CA−CH−CBD vesicular nanosystem is shown in Figure 2. CBD was mixed with CA, CH (molar ratio 0.5:1:0.6, respectively), and glass beads (10 g, diameter of 4 mm) by mechanical stirring at 200 rpm at 90 °C for 1 h to form a lipid film on the flask’s wall under constant flux of nitrogen. The resulting film was hydrated with 40 mL of buffer borate at pH 9.0, preheated at 50 °C, under mechanical stirring (800 rpm), and finally heated at 90 °C for 1 h, with a maintained nitrogen atmosphere. The as-obtained vesicle nanodispersion was submitted to a sonication step (15 min at 60 °C) and then centrifuged (7000 rpm for 15 min). The suspension was removed from the precipitate and collected as sample (CA−CH− CBD). Then, a dialysis process was adopted to purify the sample by removing the CBD not entrapped into nanovesicles. The sample was transferred into a dialysis tubing cellulose membrane (12 kDa), which has been treated according to the Fenton method before use,29 and then sealed at both ends with clips and dialyzed against borate buffer solution pH 9.0 for some days. Fresh buffer solution was replaced every day, and the free CBD was monitored at 280 nm through UV− vis measurements using a Jasco V-660 spectrophotometer until disappearance of the signal. All preparation steps and dialysis took place in the dark to avoid the photodecomposition of CBD induced by ambient light illumination. A blank sample (CA−CH), without any addition of CBD, was prepared by mixing CA oil with CH under the experimental conditions previously reported. Nanovesicle Characterization. The size distribution and Zpotential (ZP) of all samples were measured using a Malvern Zetasizer Nano ZS90 device (Worcestershire, United Kingdom). The hydrodynamic diameter (d) of the nanodispersions has been determined with a scattering angle of 90°, for which samples were diluted with ultrapure water. Measurements were performed in triplicate at a temperature of 25 °C. The ZP of nanovesicles was measured from dilute samples with ultrapure water from an average of 3 measurements of 30 runs each. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Advance 400 NMR spectrometer at room temperature. The nanovesicle samples (1 mL) were lysed in methanol (5 mL), then dried and redissolved in CDCl3, and chemical shifts were reported relative to tetramethylsilane. HPLC−DAD−MS Analysis. Separation and quantification of CA and CBD in nanodispersions were performed by high-performance liquid chromatography (HPLC) analyses. The analyses were performed on an Agilent Technologies (Waldbronn, Germany) modular model 1200 system, consisting of a vacuum degasser, a binary pump, an autosampler, a thermostatted column compartment, and a diode array detector (DAD). Nanovesicles were lysed by adding

With this perspective, cardanol-based nanomorphologies are receiving great attention as potential drug delivery vehicles due to their unique structural advantages. Industrial-grade cardanol (CA) is a low-cost, widely available renewable material obtained by thermal treatment and subsequent distillation of cashew nut shell liquid (CNSL). The latter is a yellow-brown oil containing mostly CA with smaller percentages of cardol and methylcardol and is available in large amounts in some developing countries.9 To find useful applications of this renewable raw material, new processes and specific chemical transformations have been designed for the preparation of fine chemicals and multifunctional hybrid materials,10−13 and responsive vesicular nanoscaffolds for drug delivery.14 CNSL is rich in various bioactive compounds and could be used in nutraceutical, pharmaceutical, and other applications.15 Indeed, different studies indicate that this underutilized compound displays interesting in vitro and in vivo biological properties,15−22 probably related to its high content of CA and cardol. In particular, the use of technical CA as an antioxidant offers many advantages, since it is a renewable raw material, abundant in equatorial countries, and therefore might be an interesting alternative to replace synthetic antioxidant products.23 CA, a monohydroxyl phenol with a long unsaturated hydrophobic alkyl side chain at the meta-position, combined with cholesterol (CH), was used as an amphiphilic building block to produce stable supramolecular architectures.24 In analogy with the formation of other vesicular systems, CH acted as a cosurfactant, and it was used to complete the hydrophobic moiety of single alkyl chain nonionic surfactants for vesicle formation.25 Intercalation of CH in the bilayer membrane was required in the formulation to stabilize the vesicular system avoiding the formation of aggregates by repulsive steric or electrostatic effects, and it was crucial to achieve suitable molecular geometry and hydrophobicity for bilayer vesicle formation.26 The self-assembly of CA−CH as the main component of nanoscale molecular objects has recently attracted considerable interest in terms of the bottom-up fabrication of nanomaterials hosting both hydrophilic27 and hydrophobic28 bioactive molecules. For the first time in this work, a new approach was devised for the preparation of a stable nanodispersion based on CBD embedded into CA as the main vesicular component. First, the thermo-oxidative degradation of CBD was prevented by using a nitrogen atmosphere during the formulation process; moreover, the stability of CBD in aqueous media was preserved because of the antioxidant properties of the CA component.

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EXPERIMENTAL SECTION

Materials. Materials were obtained as follows: cardanol (CA) was kindly furnished by Oltremare S.r.l.; cannabidiol (CBD) was kindly 8871


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Figure 3. HPLC−DAD chromatograms and MS spectra of CA (A) and CBD (B). Nanovesicle Stability Studies. The stability of nanodispersions was determined on stored samples at two different temperatures, 4 and 20 °C, with their protection from light for 7, 14, 21, and 30 days. Stability profiles were performed monitoring their d and ZP by DLS analysis and the CA and CBD concentrations by HPLC−DAD. The equation used to calculate the percentage of the CA and CBD in nanodispersion samples [analyte(%)] is as follows:

5 mL of MeOH to 1 mL of samples, then dried, resuspended in 1 mL of CH3CN, and passed through a 0.22 μm nylon filter before injection. For avoidance of the formation of potential degradation products in the presence of methanol at long times,30 all CA−CH−CBD nanodispersion samples were lysed using CH3CN and processed similarly. The chromatograms were recorded using Agilent Mass Hunter software (rev. B.06.00). Chromatography separation was carried out on a 150 × 4.6 mm i.d., 5 μm Gemini C18 column thermostatted at 25 °C. The mobile phase was composed of water/ acetic acid 0.1% v/v (solvent A) and CH3CN (solvent B). The chromatograms were acquired at the wavelength of 280 nm working at a flow rate of 0.8 mL/min, with the following gradient: 0 min, 50% B; 20 min, 100% B; and 32 min, 100% B. Three injections were performed for each sample, and the results are the average of those values. CA used for sample preparation is a mixture of natural extract and was used as standard to develop a calibration curve in the range 10− 1000 mg/L. Quantifications of CBD were performed using a curve in the range 20−1000 mg/L. Qualitative analyses of CA and CBD were recorded after chromatographic separation using the same system equipped with a 6540 quadrupole time-of-flight (QTOF) mass analyzer with an electrospray ionization (ESI) source. The HPLC−ESI−MS system was operated in positive-ion mode. The experimental parameters were set as follows: the capillary voltage was 4 kV, the nebulizer (N2) pressure was 60 psi, the drying gas temperature was 325 °C, the drying gas flow was 12 L/min, the fragmentor potential was 150 V, and the skimmer voltage was 45 V. Data were acquired by Agilent Mass Hunter system software (version 6.0). The mass spectrometer was operated in full-scan mode in the m/z range 100−1000. Finally, the HPLC−ESI−MS analyses of the CA components by negative-ion mode under the same detection parameter conditions were also performed. Cannabidiol Encapsulation Efficiency. The CBD encapsulation efficiency, E(%), was expressed as the concentration of CBD entrapped in dialyzed vesicular formulations with respect to the correspondent nondialyzed vesicles. Aliquots (1 mL) of dialyzed and nondialyzed samples were lysed then dried and finally dissolved in 1 mL of CH3CN. Afterward, solutions were filtered through a 0.22 nylon filter and analyzed by HPLC−DAD to quantify the CBD content. The equation used to calculate E(%) is as follows:

E(%) =

D 100 ND

analyte(%) =

CD 100 CP

(2)

where CD is the analyte concentration determined at different days, whereas CP is the analyte concentration determined on the sample purified after dialysis.

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RESULTS AND DISCUSSION HPLC−DAD−MS Analyses of CA and CBD. First, a CA solution (500 μg/mL) was analyzed by HPLC−DAD−MS to qualitatively study its composition, as it is itself a mixture of differently (un)saturated compounds. Three sharp and welltime-resolved peaks for CA were observed (Figure 3A), corresponding to three unsaturated components: 16.26% of 3-[8(Z),11(Z),14-pentadecatrienyl]phenol (C15:3); 22.70% of 3-[8(Z),11(Z)-pentadecadienyl]phenol (C15:2); 56.92% of 3[8(Z)-pentadecadecenyl]phenol (C15:1); and 4.13% of saturated component 3-n-pentadecylphenol (C15:0). The elution times for tri-, di-, and mono-unsaturated CA (C15:3, C15:2, and C15:1), and for saturated CA (C15:0), were 19.59, 21.24, 23.13, and 25.65 min, respectively. Interestingly, the positive-ion mass spectra of CA−CH3CN adducts were detected in analogy with other classes of compounds as reported in the literature.31 In particular, the adducts [M + CH3CN + H]+ (CA−C15:3, m/z 340; CA−C15:2, m/z 342; CA−C15:1, m/z 344; CA−C15:0, m/z 346) have been described, for the first time, in this work (Figure 3A). On the other hand, the analysis of highly pure CBD solution (500 μg/mL) displayed one peak at a retention time of 14.31 min (Figure 3B) with the positive-ion mass spectra of CBD [M + H]+ signal (m/z 315). The detection of the mass spectra of the CA components by negative-ion mode showed, respectively, the mass of the ion [M − H+]− (CA−C15:3, m/z 297; CA−C15:2, m/z 299; CA−C15:1, m/z 301; CA−C15:0, m/z 303).

(1)

where D and ND are the CBD concentrations in vesicles after and before the dialysis, respectively. 8872


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Figure 4. HPLC−DAD chromatogram comparison of two different preparation methods: in the presence of oxygen before (A) and after (B) dialysis; and under inert atmosphere before (C) and after (D) dialysis.

Formulation and Characterization of Nanovesicles. Our first attempt of nanodispersion preparation was carried out according to the methodology proposed by Behalo et al.28 The HPLC−DAD analysis of nanosystems before (Figure 4A) shows traces of undesired and unknown CBD degradation products at retention times of 12.60 and 17.69 min. After dialysis-based purification (see Figure 4B), the disappearance of the peak at 17.69 min was observed. Several studies in the literature confirm in fact that CBD stability depends on storage,30 basic or acidic conditions, and presence of oxygen that can oxidize it.32,33 Under inert atmosphere, the preparation of nanodispersion was improved avoiding the formation of degradation products of CBD. Figure 4C displays the chromatogram of the components of the nanodispersion sample before dialysis, which did not show any kind of degradation products of CBD. Moreover, an accurate dialysis of the sample provides the absence of free CBD nonentrapped in CA nanovesicles (Figure 4D). CA and CBD concentrations were quantified in the latter sample and used as the starting point in stability studies of the nanosystem. Dynamic light scattering (DLS) measurements of d and ZP were performed to evaluate the size distribution and the stability of nanodispersions. The dialyzed nanovesicles loaded with CBD show a mean diameter of 276.9 nm (Figure 5), and a

The stability of CBD in the nanosystem was also confirmed by 1H NMR analysis, registering spectra after lysis of nanovesicles. The comparison of the spectra of CA−CH− CBD, with those of unloaded sample (CA−CH) and CBD, showed the presence of the typical signals of the CBD moiety, that is, the broad doublet of the proton in α position to the phenyl ring and adjacent to the olefinic center (3.85 ppm), two singlet signals of the terminal methylene group protons (4.58 and 4.68 ppm), and one singlet of the alicyclic ring double bond proton (5.59 ppm) in agreement with values reported in the literature.34,35 Cannabidiol Encapsulation Efficiency. The encapsulation efficiency of CBD entrapped into vesicles and expressed as E(%) was quantified through HPLC−DAD analysis, and it was measured according to eq 1. The percentage of CBD loaded into vesicles before and after dialysis was 45.89% and 33.92%, respectively, and E(%) was 73.93%. Therefore, the dialysis step ensures that the free CBD not embedded into the nanoformulation was removed. Nanovesicles Stability Studies. The stability of CA and CBD into nanodispersions stored in glass tubes at different temperatures (20 and 4 °C) was determined by HPLC−DAD and DLS analyses. Figure 6 shows the variation of %CBD and %CA into nanovesicles as a function of time. The histograms, plotted by eq 2, showed that CBD concentration (Figure 6A) does not decrease until 30 days in samples stored at 20 °C. In fact, only a 2.4% CBD loss was observed. However, the nanovesicles stored at 4 °C showed a minor stability with a CBD loss of 13.9% at 30 days. The time and temperature effects on nanodispersion storage were more evident on the CA concentration. Indeed, CA−CH−CBD stored at 4 °C showed a %CA loss of 41.3% against 13.3% of the sample stored at 20 °C (Figure 6B). Additionally, size and ZP monitoring were performed to assess any aggregates. Table 1 shows d and ZP values of nanovesicles stored in different conditions. The DLS analysis of nanovesicular dispersions confirmed that there is not a considerable difference in dimensions for all samples. Despite this, absolute ZP values of CA−CH−CBD stored at 4 °C decrease during the time that is in good agreement with the reduction in physical stability of the nanosystem. The improved stability of the formulation observed at 20 °C was ascribed to the reduced extent of aggregation of nanovesicles; on the contrary, at a lower temperature, the

Figure 5. Size distribution by intensity of CA−CH−CBD nanovesicles.

low value of polydispersity index (PDI = 0.12) proves a monodisperse size distribution. A considerable stability of the nanosystem was confirmed by a highly negative ZP value as −80.9 mV. The same measurements were performed on the blank sample, but insignificant differences were found. The morphology expected for the nanodispersions was a spherical vesicular structure in agreement with TEM analyses of similar nanosystems reported in the literature.24,27,28 8873


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Figure 6. Percentage of CBD (A) and CA (B) in nanovesicles over time at different temperatures.

Funding

Table 1. Size and ZP Values of CA−CH−CBD Stored at 20 and at 4 °C CA−CH−CBD before dialysis after dialysis 7 days 20 °C 14 days 20 °C 21 days 20 °C 30 days 20 °C 7 days 4 °C 14 days 4 °C 21 days 4 °C 30 days 4 °C

d (nm)

PDI

± ± ± ± ± ± ± ± ± ±

0.136 0.124 0.078 0.066 0.068 0.070 0.066 0.066 0.053 0.055

278.3 276.9 274.3 272.2 271.8 271.0 269.6 271.4 276.3 277.1

80.2 74.1 79.5 96.9 87.6 80.2 74.0 90.8 77.9 79.2

Apulia Region Programs: Future in Research [Grant XYA7HY5] and Cluster ATS SISTEMA [Grant T7WGSJ3]. CNPq [Grant PVE 401359/2014−0 2015−2017].

ZP (mV) −81.3 −80.9 −82.1 −84.5 −71.6 −68.7 −81.6 −73.1 −68.5 −63.2

± ± ± ± ± ± ± ± ± ±

9.5 9.0 9.7 10.5 9.3 8.1 10.7 10.4 9.5 11.2

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.P.D.B., E.B., and G.M. thank Apulian Region for financial support; G.M. and S.E.M. thank CNPqPVE (Professor Visitante Estrangeiro = Desenvolvimento Tecnológico de ́ Produtos e Processos da Quimica Fina Dedicados a Biomassa da Castanha de Caju).

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formation of aggregates and precipitation appeared after 18 days of conservation at 4 °C.

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CONCLUSIONS In this work, a sustainable formulation embedding CBD into a nanovesicular dispersion has been developed by using CA, a well-known side product of the cashew agro-industry, as the main component. The use of inert gases such as nitrogen provided the inert atmosphere required to avoid the thermooxidative degradation of CBD during the initial step of this formulation. The embedded CBD structure was also preserved because of the antioxidant properties of CA. The nanoassembled structures were stable when stored until 30 days at 20 °C while their tendency to aggregate was observed at 4 °C after 21 days. These results are in agreement with the decrease in concentration observed for CBD and CA especially for the nanodispersion stored at low temperature. These results could be useful to promote further studies related to the use of green nanocarriers for the safe transport of CBD whose structure was preserved for a relatively long time in aqueous media. The mechanism of release of active ingredient from these novel formulations in biological systems will be one of the hottest topics. This will be investigated carefully in future studies.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 00 39 0832 297281. Fax: 00 39 0832 297733. ORCID

Giuseppe Mele: 0000-0002-6684-990X Author Contributions

All the authors have equally contributed to this work. 8874


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Formulation and Chemical Stability in Aqueous Media of Cannabidiol

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