Preparation of solid lipid microcapsules via solid-in-oil-in-water dispersions by premix membrane emulsification

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Abstract

This study presents a novel method for the preparation of hydrophilic drug-encapsulated solid lipid microcapsules (SLMCs) with a narrow particle size distribution for drug delivery systems via solid-in-oil-in-water (S/O/W) dispersions by premix membrane emulsification and subsequent solidification of the oil phase in the S/O/W dispersion. The primary aspect of this work is to form nano-order solid particles of hydrophilic drugs in solid lipids and the secondary is to encapsulate of the nano-order particles in size-controlled lipid microcapsules. The prepared capsules had a matrix type structure composed of a high-melting triglyceride, glycerol trimyristate with a melting point of 55 °C. In the lipophilic matrix of the capsule, nano-order particles of a hydrophilic drug, vitamin B12 (VB12) were embedded. Initially, a solid-in-oil (S/O) dispersion was prepared by water removal of the water droplets containing 1.1 wt.% VB12 in a water-in-oil emulsion preliminary prepared, followed by mixing with an external water phase at 60 °C to form a coarse S/O/W dispersion. By forcing the resultant S/O/W dispersion through a Shirasu porous glass (SPG) membrane with a mean pore diameter of 14.8 μm at this temperature under a transmembrane pressure of 25 kPa, uniformly sized S/O droplets were formed at a very high transmembrane flux (11.8 m3 m−2 h−1). Subsequent solidification of the oil phase in the S/O/W dispersion resulted in SLMCs with a mean particle diameter of 15.4 μm and a high encapsulation efficiency (up to 93.5%). In premix membrane emulsification the transmembrane pressure affected the properties of the S/O/W dispersion and the resultant SLMCs. At the higher transmembrane pressures, smaller S/O droplets with broader size distributions and lower encapsulation efficiencies were produced, due to the higher shear stresses inside the membrane pores. The particle size of SLMCs was controlled by adjusting the membrane pore size and transmembrane pressure in premix membrane emulsification.

Introduction

Microcapsules are used in many different applications in chemical, cosmetic, food and pharmaceutical industries. In most microcapsules the shell materials are commonly natural and synthetic polymers; however, fats and oils are also used. Solid lipid microcapsules (SLMCs) are an interesting particulate carrier system for controlled drug delivery because they hold several advantages of a lower toxicity, a better biocompatibility and a higher bioavailability. For oral administration in drug delivery systems, the drugs encapsulated in SLMCs are released mainly due to the gradual degradation of the solid lipid by lipase present in the small intestine in human body [1]. This mechanism enables both the prolonged release of drugs and minimization of unfavorable toxic side effects. The drug-release properties of SLMCs for oral drug delivery systems are closely related to their size and size distribution. Therefore, it is very important to control the size and size distribution of SLMCs.

In the past few years, a few studies have been made on the preparation of lipophilic drug-encapsulated SLMCs using oil-in-water (O/W) emulsions [2], [3], [4]. Pietkiewicz et al. [2] and Jaspart et al. [4] prepared SLMCs from O/W emulsions by hot emulsification technique with a high-shear homogenizer and subsequent cold solidification. However, the hot emulsification results in broad size distributions of the emulsion droplets and the resultant SLMCs, due to the high mechanical shear [5], [6]. Furthermore, it is difficult to encapsulate hydrophilic drugs (e. g. peptide and protein drugs) into SLMCs. Our previous study [7] proposed a novel method for the preparation of uniformly sized SLMCs encapsulating hydrophilic drugs from water-in-oil-in-water (W/O/W) emulsions by direct membrane emulsification [8], [9] using Shirasu porous glass (SPG) membranes with a narrow pore size distribution [10], [11] and subsequent solidification of the oil phase in the W/O/W emulsions. SLMCs of this type contain small water droplets within larger solid lipid particles and hydrophilic drugs are dissolved into the water droplets, as shown in Fig. 1(a). With this method, a preliminary prepared water-in-oil (W/O) emulsion, in which a high-melting lipid is used as the oil phase and a hydrophilic drug is dissolved in the water phase, is forced through an SPG membrane into an external water phase at a temperature higher than the melting point of the oil phase to form a W/O/W emulsion with a narrow droplet size distribution. Subsequently, the W/O/W emulsion is cooled to room temperature to solidify the oil phase and then dried to produce SLMCs [7]. The droplet size of W/O/W emulsions and the particle size of the resultant SLMCs can be controlled by the pore size of SPG membranes employed. Furthermore, this method yields high encapsulation efficiencies because direct membrane emulsification allows the preparation of W/O/W emulsions under lower shear conditions than mechanical emulsification methods [7], [12].

Despite of these advantages, there are still problems preventing the successful introduction of SLMCs to the pharmaceutical market with this method. Firstly, the SLMCs contain a considerable amount of water (up to 40 wt.%), which is a consequence of the fact that the water droplets within the SLMCs remain unchanged after the solidification of the oil phase in the W/O/W emulsions [7]. To ensure a microbiological stability of SLMCs and avoid the risk of biological degradation, it is desired that water content in SLMCs is as low as possible. Secondly, the direct membrane emulsification technique used for the production of W/O/W emulsions has the disadvantage of the low production rate. Typically, dispersed-phase fluxes through SPG membranes in direct membrane emulsification are between 0.01 and 0.1 m3 m−2 h−1 [12]. The dispersed-phase flux in direct membrane emulsification has to be restrained to avoid the transition from a “size-stable” to “continuous outflow” zone [12], [14], [15] and to avoid the steric hindrance between droplets that may be formed simultaneously at the adjacent pores [16], [17]. In direct membrane emulsification, the formation of uniform droplets is only possible within the size-stable zone, in which the mean droplet size is almost independent on the disperse phase flux [18].

The objective of the present study is to produce hydrophilic drug-encapsulated SLMCs with a narrow particle size distribution at higher production rates and to reduce the amount of water contained in the SLMCs. This study involves two main aspects: the primary aspect of this study is to form nano-order solid particles of hydrophilic drugs in solid lipids. The secondary aspect is to encapsulate of the nano-order particles in size-controlled lipid microcapsules. To minimize the water content in SLMCs, the preparation was based on solid-in-oil-water (S/O/W) dispersions instead of W/O/W emulsions. S/O/W dispersions of this type contain nano-order particles of hydrophilic drugs dispersed within the oil droplets, which are dispersed in an external water phase. In the present work, an S/O/W dispersion was prepared by water removal (dehydration) of the water droplets in a submicron-sized W/O emulsion and subsequent dispersing the resultant S/O dispersion into an external water phase by a mechanical stirring method at a temperature higher than the melting point of the high-melting triglyceride. In the W/O emulsion, hydrophilic drugs are dissolved into the water droplets. In contrast to conventional methods for preparing S/O/W dispersions reported by other authors [19], [20], this process uses no organic solvents with toxic effects and allows nano-order particles of hydrophilic drugs to be dispersed into the oil phase in the S/O/W dispersion. The method chosen to produce S/O/W dispersion with a narrow droplet diameter distribution at high production rates is premix membrane emulsification [21], [22], which allows the production of uniformly sized emulsion droplets at high transmembrane fluxes by forcing of a coarsely emulsified mixture (pre-mixed emulsion) through an SPG membrane. The SPG membrane acts here as a special kind of low-pressure homogenizing valve [23]. The optimal transmembrane fluxes with regard to droplet uniformity are typically above 1 m3 m−2 h−1, which are one to two orders of magnitude higher than in direct membrane emulsification [23]. In this work, the coarse S/O/W dispersion prepared by the above technique was forced through an SPG membrane to disrupt the large S/O droplets in the S/O/W dispersion into uniformly sized small S/O droplets at the same temperature, followed by solidification of the oil phase in the S/O/W dispersion to form uniformly sized SLMCs. The uniformity of droplets produced by premix membrane emulsification can be often improved by passing several times through the membrane, as reported by Vladisavljevic et al. [23]. However, a single pass through the membrane is a simpler and easier process than several passes. From the viewpoint of a large-scale production of SLMCs, a simpler or easier operation is desirable for premix membrane emulsification. Therefore, the coarse S/O/W dispersion was passed only once through the membrane. Fig. 1(b) illustrates the inner structure of this type of SLMCs. In the lipid matrix of the capsule, nano-order particle of hydrophilic drugs are embedded. This work presents operating parameters involved in the preparation stages of S/O dispersions, S/O/W dispersions and SLMCs. The properties of the resultant SLMCs including particle size and size distribution, surface morphology and encapsulation efficiency of a hydrophilic model drug are reported.

Section snippets

Materials

Vitamin B12 (VB12; cyanocobalamin, molecular weight of Mw = 1355 g mol−1) with a melting point higher than 300 °C was used as a hydrophilic model drug. The density of VB12 determined with a pycnometer (Quantachrome-1000, YUASA-IONICS, Co., Ltd., Osaka, Japan) was 1.09 g cm−3. Glycerol trimyristate with a melting point of 55 °C was used as a high-melting lipid. The lipophilic emulsifier selected for the preparation of W/O emulsions was polyglycerol polyricinoleate (PGPR), due to the fact that PGCR has a

Preparation of S/O dispersions

S/O dispersions were prepared from preliminary prepared W/O emulsions by water removal of the water droplets containing VB12. This study is the first attempt to prepare S/O dispersions by dehydration of water droplets in W/O emulsions. Fig. 5 shows the particle diameter distributions of S/O dispersions prepared by dehydration of the water droplets with a mean droplet diameter of 590 nm in the W/O emulsions prepared using a high-shear homogenizer. Under the condition, VB12 particles with mean

Conclusions

For drug delivery applications, a novel method for the production of uniformly sized SLMCs encapsulating hydrophilic drugs via S/O/W dispersions by premix membrane emulsification was developed using a high-melting triglyceride. The prepared SLMCs had a matrix type structure with nano-order particles of hydrophilic drugs embedded in the capsule. Initially, a coarse S/O/W dispersion was prepared by water removal of W/O emulsions and subsequent mixing with an external water phase at a higher

Nomenclature

    A

    effective membrane area (m2)

    C

    concentration of VB12 (wt.%)

    Cd

    constant in Eq. (7)

    CL

    constant in Eq. (9)

    Dd

    mean diameter of S/O droplets in the permeated S/O/W dispersion (m)

    Dd,f

    mean diameter of water droplets in the feed S/O/W dispersion (m)

    Dd,w

    mean diameter of water droplets (m)

    Dp

    mean particle diameter (m)

    nD

    droplet/particle diameter at n% of cumulative volume (m)

    Do

    diameter of oil cylinder in a pore (m)

    Dm

    membrane pore diameter (m)

    h

    thickness of lubrication layer (s)

    J

    transmembrane flux (m3 m−2 h−1)

    L

References (29)

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