Characterization of the Solutol® HS15/water phase diagram and the impact of the Δ9-tetrahydrocannabinol solubilization

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Abstract

Here, the phase behavior of the commercial non-ionic surfactant Solutol® HS15 in water was investigated. The focus was on the evolution of the system nanostructure at low water content. Particularly, it was demonstrated that spherical micelles found in dilute surfactant solutions coalesce at a surfactant volume fraction close to 0.5. As consequence, a heterogeneous pseudo-binary mixture occurs. No liquid crystalline phases were detected even at the highest HS15 concentrations in water. Alteration of the micellar morphology induced by the addition of Δ9-tetrahydrocannabinol to the surfactant/water binary system was also investigated. It was found that the cannabinoid molecules become entrapped within the surfactant hydrophobic tails, thus increasing the surfactant effective packing parameter and inducing a radical change of the micelle shape. At sufficiently low water content (18–35 wt.%), such alteration of the interfacial packing results in a lamellar organization of the surfactant molecules.

Highlights

► The phase behavior of the surfactant Solutol HS15 in water was investigated. ► At low water content, spherical micelles are present. ► Micelles coalesce at a surfactant volume fraction close to 0.5. ► A morphological change of the micelles occurred on addition of the cannabinoid THC. ► THC entraps within the surfactant tails modifying the micelle shape.

Introduction

The development of suitable vehicles for drug delivery has always represented a challenging task for the formulation scientist. Nowadays, difficulties are growing rapidly because of the increasing demand for drug delivery systems that must properly satisfy the mandatory requisites imposed by innovative therapies. Improvement of bioavailability, stability and convenience to the patient, as well as protection and selective release of the drug represent some of them. To reach these goals, a plethora of innovative formulations was proposed, mainly exploiting archetype colloidal systems. These include emulsions [1], [2], microemulsions [3], [4], [5], organogels [6], liquid crystals [7], liposomes and cubosomes [8], along with microspheres and nanoparticles based on both solid lipid and biocompatible polymers [9], [10], [11], [12]. It is also worth mentioning that a significant percentage of the recently discovered molecules with potential application as therapeutic agents are poorly water-soluble. Therefore, the aptitude of solubilizing such hydrophobic molecules is another character of paramount importance that innovative formulations should possess, especially (but not only) when the intravenous administration route must be pursued.

Pre-formulation studies represent a crucial key to the development of a successful drug delivery formulation. Physico-chemical characterization of both carriers and drugs, as well as their mutual interaction at a molecular level is fundamental in drug discovery.

Drug solubility and bioavailability are important parameters and can be addressed by a suitable choice of both carrier and administration route. When therapeutics cannot be transformed in water-soluble derivatives, the role of a surfactant carrier becomes a determinant factor. This surfactant must achieve different goals: it must promote solubilization of therapeutics in aqueous environment, protection without interactions that modify the therapeutic activity or prevent the release, and eventually, it must enhance adhesion and permeation at the biological membranes. Another important factor that affects the choice of the surfactant carrier is the requirement of low toxicity. This is the case of Solutol® HS15 (HS15) that has largely been used in intravenous and oral drug delivery formulations to carry lipophilic therapeutics due to its high capacity to solubilize hydrophobic drugs and low toxicity (LD50 > 20 mg/kg) [13]. Originally developed for use in parenteral formulations with hydrophobic drugs and vitamins [14], commercially available HS15 is a mixture of poly(ethylene glycol)15 mono- and di-esters of 12-hydroxystearic acid (HS, see Scheme 1) and free poly-ethylene glycol (PEG) in the 70/30 wt.% ratio. Essentially, it is a water-soluble non-ionic surfactant/polymer mixture with an HLB in the range of 12–14. The macroscopic and/or indirect effects of Solutol HS15 at a biological level have been reported by several authors [15]. It was demonstrated that it inhibits the clearance of midazolam, induces significant effects on the pharmacokinetics behavior of different drugs, may alter plasma protein binding, and addresses adsorption behavior.

Although HS15 is indicated by the producer (BASF GmbH) as approved non-ionic surfactant for pharmaceutical preparations for parenteral administration, it is quite a surprise that the investigation of the complete phase diagram of the HS15/water pseudo-binary system, so far, has never been reported in detail. As a result, our knowledge on the response of the system microstructure is amazingly poor. This paper is mainly devoted to fill these gaps.

The concentration of this solubilizing surfactants/PEG mixture in a pharmaceutical formulation is always very low; however, the full characterization of the phase behavior in aqueous environment may give important information on the possible interactions with different types of drugs depending on their shape, size, and polarity.

Not less important are the rheological features of nanostructures formed by two different types of surfactants (mono- and di-glycerides) in the presence of a significant amount of PEG in aqueous solutions.

Another aim of this study is related to evaluate the effect on the Solutol HS15 self-assembly behavior of the solubilization of Δ9-tetrahydrocannabinol (THC, see Scheme 1), the main active principle of Cannabis sativa L. Indeed, according to previous results [16], the HS15/THC/water system shows the existence of a self-microemulsifying region. Interestingly, two important features are worth mentioning, for example, the spontaneous formation of a thermodynamically stable o/w microemulsion, and the fact that no other additives were needed to prepare the formulations. This is a relatively new type of drug delivery system that can find innovative application also in the oral delivery of highly lipophilic therapeutics.

In fact, despite the availability of THC based commercial drugs (i.e., Sativex®, Marinol®), which have been tested in different practical applications [17], drawbacks have been evidenced, with particular reference to the use of Sativex®, which shows irritation, significant inter-subject variability, and bad taste [18]. Therefore, great interest is posed on the obtainment of new formulations for this active principle and/or for its mixtures with other cannabinoid ligands.

Turning the attention to the HS15 based microemulsions, here the effect of THC on HS15 at high non-ionic surfactant concentrations as well as at very high water dilution was investigated in order to obtain a deeper knowledge of this system and to increase the predictive ability in challenging choice of suitable drug carriers.

Section snippets

Materials

Commercial Solutol® HS15, namely poly(ethylene glycol)15 12-hydroxystearate, was kindly provided by BASF GmbH, Germany. According to the technical information sheet by BASF, Solutol® HS15 consists of poly-ethylene glycol mono and di-esters of 12-hydroxystearic acid (HS) and of about 30 wt.% of free poly-ethylene glycol (PEG). Throughout the paper, the content of HS15 is referred to the commercial sample composition of the non-ionic surfactant.

The HS15 density was assumed to be 1.03 g/mL without

Phase diagram

In investigating the phase behavior of surfactant aqueous mixture, a great help may derive from conductivity and quadrupolar splitting NMR measurements. Therefore, rather than in pure distilled water, samples used in the present study were prepared using a dilute (5 mM) NaCl solution in heavy water (D2O). It is here worth noticing that the presence of small amounts of NaCl and the use of D2O do not alter significantly the system phase boundaries in comparison with the previously reported phase

Conclusions

HS15 is one of the most common components of drug delivery systems used in customary pre-clinical practice. Notwithstanding the widespread literature on its applications in pharmaceutics, presently, its colloidal properties are not fully investigated. Particularly, HS15 behavior upon water dilution, mimetic of the drug administration, has not been previously studied. Moreover, a detailed knowledge of the phase behavior may also help in clarifying the profound influence that HS15 has on oral

Acknowledgments

MIUR (PRIN 2008, Grant number 2006030935) is acknowledged for financial support. Emiliano Fratini (University of Florence and CSGI) is kindly acknowledged for the support in SAXRD measurements. BASF GmbH Germany is acknowledged for Solutol® HS15 supply.

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