Pluronic-Functionalized SilicaâLipid Hybrid ... - ACS Publications

Article pubs.acs.org/molecularpharmaceutics

Pluronic-Functionalized Silica−Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases Shasha Rao,† Katharina Richter,‡,§ Tri-Hung Nguyen,∥ Ben J. Boyd,∥,⊥ Christopher J. H. Porter,∥,⊥ Angel Tan,‡,§ and Clive A Prestidge*,† †

School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, City East Campus, Adelaide, South Australia 5000, Australia ‡ Ian Wark Research Institute, University of South Australia, Mawson Lakes Campus, Mawson Lakes, South Australia 5095, Australia ∥ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, Victoria 3052, Australia ⊥ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, Victoria 3052, Australia S Supporting Information *

ABSTRACT: A Pluronic-functionalized silica−lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica−lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated PluSLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases. KEYWORDS: poorly water-soluble drug, weak bases, oral bioavailability improvement, silica−lipid hybrid, Pluronic, drug precipitation

1. INTRODUCTION The absorption of poorly water-soluble weak bases is often low due to pH-dependent aqueous solubility, i.e., the solubility is higher in gastric media and lower in the intestinal environment. As such, a number of formulation approaches have been developed to improve the apparent equilibrium solubility of these compounds in the gastrointestinal (GI) tract or to increase the rate of dissolution in order to facilitate oral absorption. These include the incorporation of acidifiers (e.g., organic acids) into drug formulations, reduction of particle size, salt formation, using polymorphs, formation of cyclodextrin complex or amorphous solid dispersion, and the use of lipidbased drug delivery systems (LBDDS).1−4 Except for the incorporation of acidifiers, which is often not sufficiently effective since the drug could precipitate in the intestine due to the extensive dilution of acidifiers after oral administration,5 a majority of the approaches typically require the formation of a © XXXX American Chemical Society

solution state that is higher in energy than the stable form of the drug in solution. That is, a supersaturation state is generated where the concentration of the solute within solution is above the thermodynamic equilibrium solubility. However, the supersaturated state is metastable and rapid recrystallization back to a more stable but less soluble form can occur and limit the benefit. Therefore, the identification of excipients that prolong supersaturation and slow the rate of precipitation from supersaturated solutions has become of increasing interest.6 Polymeric precipitation inhibitors (PPI), including cellulose derivatives, polyvinylpyrrolidone, and poloxamers, have been reported to stabilize metastable supersaturated systems.6−9 For Received: August 12, 2015 Revised: September 28, 2015 Accepted: November 2, 2015

A

DOI: 10.1021/acs.molpharmaceut.5b00622 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Article

Molecular Pharmaceutics

2. MATERIALS AND METHODS 2.1. Materials. CIN, Pluronic F127, sodium taurodeoxycholate (NaTDC) 99%, Trizma maleate, lecithin (60% pure phosphatidylcholine, from dried egg yolk), porcine pancreatin extract (activity equivalent to 8 × USP specification), 4bromophenylboronic acid (4-BBB), calcium chloride dehydrate, and sodium hydroxide pellets were purchased from Sigma-Aldrich (Australia). Labrasol was a gift from Gattefossé (France). Hydrophilic fumed silica (Aerosil 380) with a primary average diameter of 7 nm and a specific surface area of 380 ± 30 m2/g was purchased from Evonik Degussa (Germany). All other chemicals were of analytical grade and used as received. High purity (Milli-Q) water was used throughout the study. 2.2. Formulation Preparation. Plu-SLH microparticles were prepared following a two-step preparation process as described previously.26 Briefly, 40 mg of CIN was weighed and dissolved in Labrasol (0.96 g) following sonication for 10 min. Milli-Q water (10 mL) was added, and a coarse o/w emulsion was formed after 1 h sonication. The coarse emulsion was mixed with Pluronic (6 mL, 5%, w/v) via magnetic stirring (1 h), and then Aerosil 380 silica dispersion (8 mL, 5%, w/v) was added via magnetic stirring (overnight). The final SLH formulation was obtained following water removal from the mixture by spray drying under the following conditions: inlet temperature 160 °C, outlet temperature 65 °C, flow rate 7 mL/ min, aspiration setting 10 (BÜ CHI Mini Spray Dryer B-290, Switzerland). To understand the impact of Pluronic on the biopharmaceutical performances of SLH, a Pluronic-free Labrasol-based SLH encapsulating CIN (SLH) was fabricated following the same development process. A physical mixture of SLH and Pluronic (Plu&SLH) having the same composition as Plu-SLH was prepared via vigorous mixing using a spatula and overnight tumbling (Rotary Suspension Mixer, Ratek Laboratory Equipment, Australia). 2.3. Physicochemical Characterizations. 2.3.1. Redispersibility. The redispersed particle sizes of SLH and Plu-SLH microparticles were characterized using laser diffraction (Malvern Mastersizer 2000, UK). Phosphate buffered saline (PBS, refractive index =1.33) was used as the dispersant, and the particle refractive index was set as 1.45. 2.3.2. Composition. The lipid content was determined by thermogravimetric analysis (TGA, Hi-Res Modulated TGA 2950, TA Instruments, Australia). Each sample (approximately 10 mg) was placed in an aluminum pan and heated at a rate of 10 °C/min from 20 to 600 °C under a nitrogen gas purge. CIN, Labrasol and Pluronic were decomposed within the range of 200−500 °C, and the silica component remained thermally stable. The weight loss (after correction for water and drug content) was computed using the associated TA Universal Analysis software, which corresponded to the lipid content of the microparticles. The amount of CIN loaded into the microparticles was determined by a solvent extraction method. The encapsulated CIN was extracted by dissolving 10 mg of the formulation in 10 mL acetonitrile, sonication for 15 min, and centrifugation at 29068g for 10 min (Hermle high speed table top centrifuge Z36HK, Germany). The supernatant was diluted with HPLC mobile phase prior to HPLC analysis for CIN content as described in the Supporting Information. 2.3.3. Solid-State Characterization. The surface morphology of SLH and Plu-SLH microparticles was examined by high

instance, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) has been described to inhibit the recrystallization of the poorly water-soluble compound carbamazepine (CBZ) from a supersaturated solution.10 Using proton nuclear magnetic resonance (NMR) measurements, it was suggested that the molecular mobility of CBZ was suppressed in the HPMC-AS (grade HF) solution. In addition, using nuclear Overhauser effect spectroscopy and saturation transfer difference NMR, it was revealed that there is a strong hydrophobic interaction between CBZ and the acetyl group of HPMC-AS (grade HF), which inhibited the process of drug recrystallization. PPI have also been used to enhance the bioperformance of LBDDS for the oral delivery of poorly water-soluble drugs.11−16 The solubilization capacity of LBDDS usually decreases as the formulation is dispersed in aqueous GI fluids and as the digestible lipids are digested; the reduction of the solubilization capacity thus triggers the generation of a transient supersaturated state when the initial drug concentration is significantly higher than the equilibrium drug solubility post dispersion and digestion.17 Using danazol as a model poorly water-soluble compound, Anby et al. explored the impact of PPI on the supersaturation stabilization and the consequent impact on the performance of self-emulsifying drug delivery systems (SEDDS).18 The presence of HPMC (grade E4M) significantly reduced the in vitro drug precipitation upon dispersion and digestion of the SEDDS, and maintained the supersaturated state for a prolonged period. Following oral administration to male beagle dogs, the inclusion of HPMC in the SEDDS (at moderate drug load) provided 65% increase in the oral drug absorption. Two factors are considered equally important to optimize the performance of LBDDS, the extent to which the formulation can initiate supersaturation as well as the stability of the formed supersaturated system.18,19 However, in spite a large number of studies that have explored the synergistic effects of PPI and lipid-based formulations to improve the oral delivery of poorly watersoluble compounds, methods of incorporating PPI into lipidbased formulations have not been discussed, nor has their impact on biopharmaceutical performance. Furthermore, PPI have generally been incorporated via physically mixing the PPI with lipid-based formulations.11−16 In contrast, in the current study, we aim to incorporate the PPI into a silica−lipid hybrid (SLH) drug delivery system via homogenization and spray drying and hence develop a novel Pluronic-functionalized SLH (Plu-SLH). The SLH system is an advanced solid-state LBDDS that has proven effective in improving the solubilization of a range of poorly water-soluble compounds and enhancing their oral bioavailability.20−26 Pluronic F127, an amphiphilic block copolymer consisting of two hydrophilic ethylene oxide (EO) blocks and one hydrophobic propylene oxide (PO) block, which is approved by Food and Drug Administration (FDA) for pharmaceutical applications as a solubilization enhancer and drug precipitation inhibitor, was selected as the PPI.27−29 Using cinnarizine (CIN, pKa = 1.95 and 7.47) as a model of poorly water-soluble weak base drugs, the Plu-SLH was explored for its applicability to improve the oral delivery. A SLH formulation in the absence of Pluronic was used as a control to illustrate the synergy of Pluronic and SLH to improve the oral bioavailability of CIN. Furthermore, a physical mixture of SLH and Pluronic (Plu&SLH) having the same composition as Plu-SLH was developed and investigated in parallel to study the impact of the incorporation method of PPI into lipid-based formulations on their biopharmaceutical performance. B


Article


Figure 1. Mean in vitro dissolution profiles of 10 mg cinnarizine (CIN) in 0.01 M HCl (pH 2.2, 500 mL) for the first 1 h (left), followed by adjustment to pH 6.5 (1000 mL) with phosphate buffer (right) in the absence (a) or presence (b) of Labrasol: 0% (diamond), 0.02% (square), 0.05% (triangle), 0.10% (asterisk) of Pluronic was predissolved in the dissolution medium (37 °C, mean ± SD, n = 2−3).

resolution analytical scanning electron microscopy (SEM, Zeiss Merlin). Each sample was mounted on double-faced adhesive tape prior to imaging at an accelerating voltage of 3 kV. The degree of crystallinity of encapsulated CIN was monitored by differential scanning calorimetry (DSC Q100, TA Instruments). Each sample (approximately 5 mg) was weighed and heated in an aluminum pan at a rate of 10 °C/min over a temperature range of 25−150 °C, under a flow of dry nitrogen gas (80 mL/min). 2.4. In Vitro Drug Dissolution Study. In vitro two-step dissolution studies were carried out at 37 ± 0.5 °C using a USP 23 type II apparatus (paddle method, 50 rpm). In step one (0− 60 min), pure CIN or formulations equivalent to 10 mg of CIN were added to 500 mL of simulated gastric fluid (SGF) (0.01 M HCl, pH 2.2) containing a fixed level of Pluronic (i.e., 0, 0.02, 0.05, 0.1%, w/v). At 60.01 min, 500 mL of Na2HPO4 buffer solution was added to the SGF (to simulate the intestinal condition) resulting in an increase in pH to 6.5 to simulate intestinal pH level (SIF). Aliquots of 5 mL were taken at fixed time intervals and replaced accordingly with fresh medium. The samples were centrifuged at 7267g for 5 min (37 °C); the supernatants were diluted properly with the mobile phase and analyzed by HPLC for the CIN content. 2.5. In Vitro Studies of Lipid Digestion and Drug Solubilization under Intestinal Digesting Condition.

Fasted state mixed micellar solutions consisting of bile salt (BS):phospholipids (PL) at concentrations of 4 mM BS:0.8 mM PL were prepared to simulate human intestinal conditions as described previously.30,31 The progress of lipolysis was monitored for 60 min using a TitraLab 854 pH-stat titration apparatus (Radiometer Analytical, France) in accordance with a previously established lipolysis model.32 Lipid formulation, equivalent to 100 mg of Labrasol, was weighed and dispersed in the digestion medium (37 °C, pH 7.50 ± 0.01). Lipolysis was initiated by adding pancreatin extract equivalent to lipase concentration of ∼1000 TBU per mL; free fatty acids (FFA), as a product of the lipolysis, were titrated with 0.6 M NaOH via an autoburet to maintain the pH at 7.50, and the consumption of NaOH (after background correction with the blank micellar solutions) was used to calculate the number of moles of FFA liberated. The solubilization level of CIN in the aqueous phase was examined. At 1, 5, 15, 30, and 60 min, aliquots of 1 mL of lipolysis samples were collected into individual 1.5 mL microcentrifuge tubes prefilled with 10 μL of 4-BBB as an enzyme inhibitor to stop any further lipolysis in the collected samples. Each collected sample was separated into an upper aqueous phase and a pellet phase by centrifugation at 35172g for 45 min (37 °C). The aqueous phase was collected, diluted C


Article


of dynamic equilibrium: drug partitions between the core of oil droplet, the interfacial surfactant layer, and the aqueous medium.15 Therefore, the affinity of drug molecules for the lipid colloids and the stability of these lipid colloids determine the risk of drug precipitation. When released from Labrasol, CIN was immediately soluble under acidic gastric dissolution condition at a level of ∼20 μg/mL (Figure 1b). Upon the increase in pH to a more neutral value, drug precipitation was observed. However, the level of drug solubilization was considerably higher than that of pure CIN, with up to 4 μg/ mL (equivalent to 40% of initial dose) remaining solubilized for 2 h (Figure 1b). Furthermore, the combination of Labrasol and Pluronic resulted in a synergistic effect on inhibiting drug precipitation upon pH adjustment below the CMC of Pluronic. At all levels of Pluronic, the drug solubilization level at pH 6.5 was nearly 9 μg/mL for up to 2 h, which was equivalent to approximately 90% of the initial dosage. This is in agreement with previous findings where Pluronic was able to inhibit drug precipitation from Labrasol formulations at levels below the CMC.34 In these previous studies, it was suggested that the amphiphilic Pluronic molecules reside at the interface of a Labrasol o/w emulsion, expanding the hydrophobic core of the emulsion and stabilizing the o/w emulsion droplet interface. This improved the affinity of CIN for the lipid colloids and thus benefited the drug dissolution at the intestinal pH.15,35 3.2. Development and Characterization of CIN Formulations. 3.2.1. Preparation of Plu-SLH/SLH and Physicochemical Characterization. Given the synergy of Labrasol and Pluronic in improving the solubilization level of CIN in the simulated intestinal environment, Pluronicfunctionalized SLH microparticles encapsulating CIN (PluSLH) were subsequently fabricated. The content of Pluronic 127 was selected based on its recommended maximum potency in an oral tablet (110 mg) in accordance with the FDA regulation of inactive ingredients36 and considering that CIN dose in current oral dosage forms is 15 mg. In addition, to understand the impact of Pluronic on the biopharmaceutical performance of SLH, a Pluronic-free Labrasol-based SLH encapsulating CIN (SLH) was fabricated following the same development process. Both SLH and Plu-SLH microparticles appeared as white, agglomerated and free-flowing powders. Using scanning electronic microscopy (SEM), both microparticle populations were found to be spherical, with diameters ranging from 1 to 5 μm (Figure 2). However, differences were observed in the external textures of the microparticles. While the SLH microparticles exhibited smooth surfaces with internal porous structure, the Plu-SLH microparticles were characterized by rough surfaces with visible structured nanoparticle layering on the surface. Figure 2 illustrates a schematic of the fabrication process of the hybrid microparticles, and the morphological differences seen were probably a consequence of the different interfacial structures of the emulsion droplets formed during fabrication.37 Previous investigations have revealed that Aerosil silica nanoparticle stabilized emulsions appear as sparsely coated droplets with extensive silica nanoparticles bridging between neighboring lipid droplets.38 When silica nanoparticles were added to the Pluronic stabilized Labrasol emulsion, increased flocculation occurred, and consequently more rigid and larger aggregates were formed.39 Using dynamic light scattering, it was revealed that the addition of silica nanoparticles to the Pluronic stabilized emulsion increased the mean diameter of the droplets from 95

with acetonitrile and then mobile phase, and analyzed by HPLC for CIN content. 2.6. In Vivo Oral Administration of CIN Formulations. All animal experiments were approved by the Monash Institute of Pharmaceutical Sciences Animal Ethics Committee (Australia). Sixteen male Sprague−Dawley (SD) rats (270−310 g) were divided into four groups and used for each absorption study. Prior to the study rats were cannulated with 0.96 × 0.58 mm polyethylene cannula (Microtube Extrusion, Australia) under light anesthesia to facilitate blood collection. Rats were allowed to recover overnight prior to dosing and fasted up to 12 h prior to and 8 h post administration with water provided ad libitum. The rats were administered one of four formulations at 10 mg/kg via oral gavage after being lightly anesthetized (2% v/v isoflurane): (i) CIN suspended in 0.5% (w/v) sodium carboxymethylcellulose and 0.4% (w/v) Tween 80, (ii) SLH, (iii) Plu-SLH, and (iv) Plu&SLH. The formulations in groups ii−iv were redispersed in Milli-Q water (at levels equivalent to 10 mg of CIN/mL) immediately prior to dose administration. After each dose administration blood samples (0.2 mL) were collected up to 24 h with the cannula flushed with 10 IU/mL heparin in normal saline between samples. Blood samples were centrifuged for 5 min at 6700g to facilitate the collection of plasma. Plasma samples were stored at −20 °C until analysis as described in the Supporting Information.

3. RESULTS AND DISCUSSION 3.1. In Vitro Dissolution Studies of CIN: Impact of Labrasol and Pluronic on the pH-Provoked Precipitation. For a weakly basic drug such as CIN, the molecule is ionized in the acidic gastric environment and is significantly more soluble in the largely acidic gastric content than in intestinal fluids.9 In simulated gastric medium (pH 2.2), CIN dissolved rapidly reaching a concentration of 20 μg/mL; and more than 18 μg/mL of CIN remained solubilized in the followed 50 min (Figure 1a). When the solution was diluted and the pH was increased to mimic the intestinal pH (pH 6.5), substantial and rapid drug precipitation was observed, leaving a low and erratic amount of CIN (0.87−1.50 μg/mL) remaining solubilized. When CIN was coadministered with Pluronic, the initial drug precipitation upon pH adjustment was inhibited, with the extent of precipitation inhibition dependent on the Pluronic concentration. When the Pluronic was present at a level below its CMC (0.1%, w/v at 37 °C6), it existed in the form of “unimers”.33 The presence of the unimers may disrupt the crystal growth of CIN, via altering the surface tension or adsorbing onto the crystal interface. Therefore, when the Pluronic was present at 0.02% and 0.05%, it increased the remaining soluble drug concentration to 3.68 ± 0.15 μg/mL or 5.13 ± 0.79 μg/mL at 80 min, respectively, after switching to intestinal conditions (Figure 1a). However, the % dissolution subsequently decreased over the following 110 min (i.e., from 70 to 180 min), and leveled off to a value that was comparable with that of pure CIN, suggesting that the solution conditions in the presence of Pluronic unimers were metastable.33 When the Pluronic concentrations exceed the CMC, the unimers selfassociate to form micelles with a hydrophobic PO core and EO corona.34 It is likely that CIN partitions into the corona/core of the micelles, which preserved more than 60% of the initial dose in the solubilized state for the entire 2 h at pH 6.5 (Figure 1a). In the presence of Labrasol, the drug is no longer in a simple aqueous environment. Instead, drug solubilization is a process D


Article


Figure 3. DSC profiles of cinnarizine (CIN) formulations. Each test was conducted using an approximately 5 mg sample: silica−lipid hybrid microparticle (SLH) containing CIN (1.80%, w/w, blue), Pluronic-functionalized SLH containing CIN (1.91%, w/w, red), and physical mixture of CIN (2.00%, w/w) and Aerosil 380 silica (black).

Figure 2. Schematic illustrating the formation of silica−lipid hybrid (SLH) and Pluronic-functionalized SLH (Plu-SLH) microparticles and the SEM images (silica nanoparticles, gray; Labrasol, yellow; Pluronic, red; scale bar = 1 μm).

3.2.2. In Vitro Dissolution Studies of CIN in Simulated GI Medium. In order to analyze the impact of the formulations on the precipitation behavior of CIN in the gastrointestinal environment, CIN formulations were assessed using a simulated two-step acidic-to-neutral dissolution test and under intestinal digesting conditions (fasted state), respectively. The extent of drug solubilization and precipitation was assessed, where drug precipitation triggered by the pH gradient and lipid digestion were considered separately. 3.2.2.1. In Vitro Dissolution Studies of CIN under Nondigesting Condition. The in vitro drug dissolution properties of the different SLH formulations under simulated two-phase gastrointestinal medium are shown in Figure 4. When dispersed in the simulated gastric medium, SLH showed rapid and complete drug dissolution. However, when the pH of the dissolution medium was adjusted to 6.5, drug precipitated immediately, resulting in very low concentrations of CIN remaining in solution. When Pluronic was predispersed in the dissolution medium, no effects were apparent in the gastric medium, but drug redissolution was stimulated starting at 10 min after pH adjustment. CIN solubility increased gradually from 1.2 μg/mL at 70 min to 3.1 μg/mL at 120 min, and was maintained at levels above 2.0 μg/mL up to 180 min. Drug dissolution from Plu-SLH in the acidic medium was rapid but incomplete, i.e., approximately 15−16 μg/mL CIN (equivalent to 70% of the initial dosage) was dissolved at 15 min and remained solubilized for the following 45 min. This may indicate delayed desorption of liquid Labrasol from the silica matrix due to the reduced redispersibility as shown in Table 1.30,40 When the pH was adjusted to 6.5, drug precipitation was also observed. However, the solubilized concentration of CIN from Plu-SLH was 3.1 ± 0.8 μg/mL at 70 min, which was significantly higher than that of SLH in the absence of Pluronic. Importantly, the solubilization level of Plu-SLH was comparable to that of SLH in the presence of Pluronic for the following 110 min. The dissolution profiles of CIN from the solid-state formulations at pH 6.5 were all lower than the equivalent liquid formulations (Figure 1b). This may inherently reflect the solidification process during fabrication, but it is also possible that CIN precipitated as a result of adsorption onto the negatively charged silanol group on the silica surface. The

nm (PDI = 0.2) to approximately 1200 nm (PDI = 0.4). The different morphology thus had a major impact on the redispersibility; i.e., using laser diffraction analysis, the redispersed size of the SLH microparticles was 4−16 μm, while the redispersed Plu-SLH microparticles were significantly larger, with 90% ranging from 16 to 63 μm (Table 1). Table 1. Properties of Cinnarizine (CIN) Silica−Lipid Hybrid (SLH) and Pluronic-Functionalized SLH (Plu-SLH) Microparticles (Mean ± SD, n = 3) formulation

SLH

Plu-SLH

Composition (mg) CIN 40 40 Labrasol 960 960 Aerosil 380 500 400 Pluronic F127 300 Experimental CIN or Lipid Loading (%) CIN 1.80 ± 0.03 1.91 ± 0.04 lipid excipient 65.52 ± 0.05 76.08 ± 0.10 Particle Size (μm) D (v, 0.1) 4.64 ± 0.05 16.53 ± 1.49 D (v, 0.5) 8.62 ± 0.08 34.56 ± 3.06 D (v, 0.9) 15.96 ± 0.45 62.73 ± 5.61

The SLH and Plu-SLH microparticles were composed of 65% and 76% lipidic excipient (i.e., Labrasol and Pluronic) according to the TGA results, which reflect the theoretical lipid loading levels (i.e., 64% and 74%, respectively), thus confirming essentially complete encapsulation of lipid excipients following the drying process. Figure 3 illustrates the DSC profiles of the CIN (2%, w/w)−silica physical mixture, SLH, and Plu-SLH. The CIN−silica physical mixture showed an endothermic peak at 122 °C, which corresponded to its melting point and confirms its crystalline nature. DSC profiles of both SLH and Plu-SLH microparticles revealed no endothermic peaks, indicating that the approximately 2% encapsulated CIN existed in an amorphous/molecular state in both microparticle systems. E


Article


Figure 4. Mean in vitro dissolution profiles of 10 mg of cinnarizine (CIN) in 0.01 M HCl (pH 2.2, 500 mL) for the first 1 h (left), followed by adjustment to pH 6.5 (1000 mL) with phosphate buffer (right): silica−lipid hybrid (SLH) microparticle (diamond), Pluronic-functionalized SLH (triangle), and SLH microparticle with Pluronic predissolved in the dissolution medium (square) (37 °C, mean ± SD, n = 3).

dissolution at pH 6.5 was then a dynamic process that reflected the equilibrium of drug redissolution from the silica and CIN partition into solubilized emulsion droplets. Nonetheless, the studies confirm the superiority of Plu-SLH in comparison to SLH in reducing the extent of drug precipitation during simulated gastric emptying. 3.2.2.2. In Vitro Dissolution Studies of CIN under Digesting Condition. To simulate the intestinal digesting condition, a dynamic in vitro lipolysis model was applied using a biorelevant intestinal medium in the presence of enzymes, bile salts, and phospholipids. Lipid hydrolysis and drug solubilization were investigated in parallel. Upon dispersion in the biorelevant intestinal medium, unformulated CIN was poorly soluble, and the drug concentration in solution fluctuated between 3.15 and 5.54 μg/mL (Figure 5a). However, compared with the drug concentration in simple aqueous intestinal medium (Figure 4), this was approximately 2.1−3.7-fold higher. It is likely that the hydrophobic drug molecule partitioned to the hydrophobic core of the bile salt and phospholipid micelles, which improved the level of solubilization. The solubilization of CIN from SLH or Plu-SLH in the biorelevant medium is more complex; the drug was initially present in Labrasol, and as the digestion of Labrasol occurred, the drug then partitioned between Labrasol and hydrolysis products depending on the affinity. Therefore, the extent and rate of lipid digestion may have a significant impact on drug solubilization or precipitation. Following the dispersion and digestion of the SLH microparticles, the drug concentration in the medium was initially 15.38 ± 5.38 μg/mL at 0 min and 14.62 ± 0.91 μg/mL at 1 min, and this decreased to 8.61 ± 0.39 μg/mL at 5 min and then leveled off until 30 min (Figure 5a). Simultaneous analysis of the profile of lipid digestion showed that the lipid digestion evidenced by the release of fatty acid mainly occurred within the first 5 min, which indicated that CIN had less affinity to the digestion product of Labrasol and thus triggered drug precipitation (Figure 5b). The lipid digestion and drug solubilization profiles were similar in shape across the SLH and Plu-SLH formulations. However, the extent of lipolysis was reduced and drug solubilization increased with the Plu-SLH. After the dispersion and lipolysis of PluSLH, the drug concentration was 52.21 ± 5.24 μg/mL at 0 min, 49.77 ± 0.31 μg/mL at 1 min, and 37.04 ± 11.32 μg/mL at 30

Figure 5. In vitro performance of cinnarizine (CIN) formulations under simulated in vitro intestinal digesting conditions (mean ± SD, n = 3): silica−lipid hybrid (SLH, diamond, blue), Pluronic-functionalized SLH (triangle, red), and pure CIN (square, black). Both (a) solubilized concentration of CIN versus time and (b) the amount of fatty acid released during the process of lipid digestion are illustrated. In all cases, the initial dosage was equivalent to 100 mg of Labrasol per 20 mL of intestinal medium, variations of % lipolysis ≤ 7%.

min. In addition, a separate solubility study was conducted, which suggests that the solubility of CIN in the intestinal medium in the presence of Pluronic alone was 36.35 ± 17.26 μg/mL. The improved solubility was consistent with the same F


Article


SLH was consistent with the in vitro dissolution/solubilization data, and may be credited to the synergy of Labrasol and Pluronic in inhibiting the pH and digestion provoked CIN precipitation during gastrointestinal passage and in doing so improving the apparent drug solubility in the intestinal fluid. An interesting finding was that, in spite of the superiority of Plu-SLH in improving the oral bioavailability of CIN, a physical mixture of Plu&SLH of the same composition did not provide a statistically significant difference in AUC0−last when compared with either the aqueous suspension or the SLH. This is contrary to the positive impact of the physical mixture on drug dissolution in the simulated intestinal medium under nondigesting conditions (Figure 4), and highlights the challenges of in vitro−in vivo correlation for complex formulations. Nevertheless, the absence of in vivo benefit provided by Plu&SLH in comparison with SLH alone is in agreement with a number of previous studies where the incorporation of PPI such as HPMC into SEDDS via physical mixing does not always enhance drug exposure.11,12,14,18 Therefore, it seems likely that the physical properties of the solid-state formulations can have a significant impact on the drug solubilization/precipitation in the dynamic in vivo environment. In this regard, the silica−lipid hybrid system may be a more promising approach to incorporating PPI into lipid-based formulations. Figure 7 illustrates a proposed scheme for the in vivo fate of CIN formulations suggesting that CIN was likely to be present at the intestinal enterocyte brush border either in the free drug form or solubilized in lipolysis products. This resulted from, first, release of lipid droplets to the bulk medium as the hydrophilic silica disintegrated from the hybrid; and second, adsorption of pancreatic lipase/colipase to the emulsion interface initiating subsequent lipolysis.43 Given the different morphology between Plu&SLH and Plu-SLH, it is reasonable to expect a great variation in the rate of water penetration through the solid-state formulations and the subsequent disintegration of silica particles, desorption and wetting of Pluronic, and formation of lipid colloids.6 In the case of Plu&SLH, it is likely that the Pluronic wet rapidly, possibly before Labrasol was released; gelation of the Pluronic may occur if the local concentration was greater than 20% (w/w), forming a solid clear gel (cubic phase) consisting of a densely packed array of micelles.44,45 In this case, Pluronic was not available to assist the solubilization process that presumably was behind the enhanced bioavailability in the intimately mixed Labrasol/Pluronic system. On the other hand, the dispersion of Plu-SLH was more likely to produce a homogeneous Pluronicstabilized Labrasol emulsion with a hydrophobic PEO moiety intercalated at the interface, thus creating an increasingly hydrophobic microenvironment in comparison with Labrasol emulsion, consequently improving the solubilization capacity for CIN in the intestine. In addition, Pluronic at the emulsion

trend illustrated in the dissolution profiles (Figure 4), thus confirming the superiority of Plu-SLH in comparison with systems composed of Labrasol or Pluronic alone in creating a more hydrophobic microenvironment for the partition of CIN and reducing the risk of drug precipitation upon intestinal lipid digestion. 3.3. In Vivo Pharmacokinetic Study. The mean plasma concentration−time profiles of CIN following a single oral dose of each formulation to fasted male SD rats are presented in Figure 6. The corresponding pharmacokinetic data is summarized in Table 2.

Figure 6. Plasma cinnarizine (CIN) concentration (mean ± SEM, n = 4) following oral administration of cinnarizine (CIN) formulations: aqueous suspension (filled circles), silica−lipid hybrid (SLH, unfilled circles), Pluronic-functionalized SLH (Plu-SLH, filled reversed triangles), and physical mixture of SLH and Pluronic F127 having the same composition as Plu-SLH (Plu&SLH, unfilled triangles) at 10 mg of CIN per kg. Plasma concentrations were dose normalized to 10 mg/kg to account for variation in animal weight.

The oral absorption of CIN from the aqueous suspension was low, which is consistent with that previously reported by Nguyen et al. 41 Statistical analysis showed that the pharmacokinetic data obtained for the SLH formulation was not significantly different from that of the aqueous suspension. This is in accordance with previous reports showing only small differences in the oral bioavailability of CIN after coadministration with medium chain triacylglycerides.42 In contrast, the PluSLH formulation resulted in a greater than 2.1-fold improvement in the AUC0−last and 1.6-fold improvement in Cmax of CIN in comparison to the aqueous suspension formulation, and approximately 1.6-fold higher AUC0−last and Cmax when compared to the SLH formulation (427 vs 262 ng/mL). The improved bioavailability of CIN after oral administration of Plu-

Table 2. Comparison of Mean Pharmacokinetic Parameters (Mean ± SEM, n = 4) after Oral Administration of Cinnarizine (CIN) Suspension, Silica−Lipid Hybrid (SLH), Pluronic-Functionalized SLH (Plu-SLH), and Physical Mixture of SLH and Pluronic F127 (Plu&SLH) Having the Same Composition as Plu-SLHa

a

formulation

Tmax (h)

Cmax (ng/mL)

suspension SLH Plu-SLH Plu&SLH

0.6 1.0 1.3 1.1

± ± ± ±

262 ± 41 258 ± 23 427 ± 57*b 326 ± 39

0.1 0.0 0.3 0.3

half-life (h) 4.1 4.4 4.5 4.1

± ± ± ±

0.4 0.4 0.5 0.3

AUC

0−last

(ng·h/mL)

656 ± 64 859 ± 133 1400 ± 135 971 ± 161

F% 100 131 213* 148

Dosage was equivalent to 10 mg of CIN per kg in all cases. b*p < 0.05 relative to the suspension and SLH formulation. G


Article


drug precipitation upon dispersion/digestion, the unique physiochemical properties and structure of Plu-SLH also provided benefits in promoting the generation of drug supersaturation at the site so close to the absorption, and further studies will be carried out at our laboratory to improve the mechanistic understanding in this aspect.

4. CONCLUSIONS A novel Pluronic-functionalized silica−lipid hybrid microparticle system (Plu-SLH) was successfully fabricated for the oral delivery of the poorly water-soluble weak base CIN. The microparticles exhibit a spherical structure characterized by visible nanoparticle layering on the surface. In simulated gastrointestinal medium under both digesting and nondigesting conditions, Plu-SLH improved the extent of drug solubilization when compared with the unformulated drug. Following oral administration to SD rats, the Plu-SLH formulation resulted in more than 2-fold improvement in the in vivo absorption of CIN. A comparison of Plu-SLH and SLH highlights the synergy of Pluronic F127 and Labrasol in improving the rate and extent of in vitro solubilization of poorly water-soluble compounds in the intestinal environment. Furthermore, the Plu-SLH was superior to a simple physical mixture of SLH and Pluronic F127 in improving the oral bioavailability of CIN. The data confirmed that Pluronic F127 can be used as a precipitation inhibitor to enhance the bioperformance of lipid-based formulations, however, the method of incorporating it into solid-state lipid-based formulations will have a major impact on the bioperformance. Plu-SLH therefore provides a promising approach to incorporate Pluronic into solid-state lipid-based drug delivery systems and results in enhanced oral delivery of the poorly water-soluble weak base CIN.

Figure 7. Schematic showing the proposed in vivo processing of cinnarizine formulations following oral administration. Proposed mechanism of the improved drug absorption following the oral administration of Plu-SLH in comparison with Plu&SLH: (a) Pluronic wet before Labrasol was released; and if the local concentration was greater than 20% (w/w), the Pluronic may form a solid clear gel (cubic phase) consisting of a densely packed array of micelles. (b) Pluronicstabilized Labrasol emulsion with hydrophobic PEO moiety intercalated at the interface was formed after dispersion, which created an increasingly hydrophobic microenvironment in comparison with Labrasol emulsion and thus reduced the risk of drug precipitation. (c, d) Pluronic at the emulsion droplet interface formed a barrier to the access of lipase, and thus delayed/suppressed lipolysis.

■

droplet interface may present a barrier to the access of pancreatic lipase/colipase and thus suppressed or delayed lipolysis.46 This was reflected in in vitro lipid digestion studies where reduced extent of lipolysis was observed with Plu-SLH compared to SLH (Figure 5) and the in vivo pharmacokinetic studies where relatively longer Tmax for Plu-SLH was observed in comparison to that of Plu&SLH and SLH, although the difference was not statistically significant (Table 2). The positive impact of the generation of a Pluronic barrier at the lipid interface on drug absorption was consistent with a previous study showing improved oral absorption of poorly water-soluble danazol when a stealth poly(ethylene glycol) (PEG) barrier at the lipid−water interface led to an inhibited digestion of coadministered lipids.47 It was suggested that the reduced rate of lipid hydrolysis may reduce the maximal supersaturation ratio and reduce the risk of drug precipitation upon lipid digestion, which in turn resulted in improved drug absorption. Furthermore, the presence of Pluronic at the lipid− water interface probably altered the endogenous lipid processing in the intestinal lumen and at the intestinal unstirred water layer, which contributed to the improved drug absorption. Using a jejunum perfusion model, Yeap et al. demonstrated that both the dilution of postdigested lipid colloids with continuous secreted bile and the absorption of fatty acid triggered the generation of supersaturation of CIN, and both benefited the drug absorption as evidenced by the increased drug absorption flux through the jejunum membrane.48−50 It is postulated that, besides the synergistic advantage of Labrasol and Pluronic in reducing the risk of

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.5b00622.

■

Analytical methods, plasma sample preparation, and the pharmacokinetic assay (PDF)

AUTHOR INFORMATION

Corresponding Author

*Phone: +61-8-83022438. E-mail: [email protected]. au. Present Address §

K.R.: The Queen Elizabeth Hospital, The University of Adelaide, Woodville, SA 5011, Australia. A.T.: Centre for International Research on Micronano Mechatronics, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The Australian Research Council (Discovery grant scheme, DP120101065), ITEK Pty. Ltd., Bioinnovation South Australia, and the Australian Biotech Ceridia Pty. Ltd. are greatly acknowledged for research funding and support. H


Article


■

(19) Vandecruys, R.; Peeters, J.; Verreck, G.; Brewster, M. E. Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design. Int. J. Pharm. 2007, 342 (1−2), 168−175. (20) Tan, A.; Rao, S.; Prestidge, C. Transforming lipid-based oral drug delivery systems into solid dosage forms: an overview of solid carriers, physicochemical properties, and biopharmaceutical performance. Pharm. Res. 2013, 30 (12), 2993−3017. (21) Tan, A.; Eskandar, N.; Rao, S.; Prestidge, C. First in man bioavailability and tolerability studies of a silica−lipid hybrid (Lipoceramic) formulation: a Phase I study with ibuprofen. Drug Delivery Transl. Res. 2014, 4 (3), 212−221. (22) Rao, S.; Tan, A.; Boyd, B. J.; Prestidge, C. A. Synergistic role of self-emulsifying lipids and nanostructured porous silica particles in optimizing the oral delivery of lovastatin. Nanomedicine 2014, 9 (18), 2745−2759. (23) Tan, A.; Prestidge, C. Nanostructured silica-lipid hybrid microparticles: a supersaturating carrier for water- and lipid-resistant compounds. Chem. Lett. 2012, 41 (10), 1334−1336. (24) Nguyen, T.-H.; Tan, A.; Santos, L.; Ngo, D.; Edwards, G. A.; Porter, C. J. H.; Prestidge, C. A.; Boyd, B. J. Silica−lipid hybrid (SLH) formulations enhance the oral bioavailability and efficacy of celecoxib: An in vivo evaluation. J. Controlled Release 2013, 167 (1), 85−91. (25) Lim, L. H.; Tan, A.; Simovic, S.; Prestidge, C. A. Silica-lipid hybrid microcapsules: Influence of lipid and emulsifier type on in vitro performance. Int. J. Pharm. 2011, 409 (1−2), 297−306. (26) Tan, A.; Simovic, S.; Davey, A. K.; Rades, T.; Prestidge, C. A. Silica-lipid hybrid (SLH) microcapsules: a novel oral delivery system for poorly soluble drugs. J. Controlled Release 2009, 134 (1), 62−70. (27) Dai, W. G.; Dong, L. C.; Li, S.; Deng, Z. Y. Combination of Pluronic/Vitamin E TPGS as a potential inhibitor of drug precipitation. Int. J. Pharm. 2008, 355 (1−2), 31−37. (28) Li, S.; Pollock-Dove, C.; Dong, L. C.; Chen, J.; Creasey, A. A.; Dai, W. G. Enhanced bioavailability of a poorly water-soluble weakly basic compound using a combination approach of solubilization agents and precipitation inhibitors: a case study. Mol. Pharmaceutics 2012, 9 (5), 1100−1108. (29) Zhu, Q. L.; Guo, T.; Xia, D. N.; Li, X. Y.; Zhu, C. L.; Li, H. Y.; Ouyang, D. F.; Zhang, J. W.; Gan, Y. Pluronic F127-modified liposome-containing tacrolimus-cyclodextrin inclusion complexes: improved solubility, cellular uptake and intestinal penetration. J. Pharm. Pharmacol. 2013, 65 (8), 1107−1117. (30) Alinaghi, A.; Tan, A.; Rao, S.; Prestidge, C. A. Impact of solidification on the performance of lipid-based colloidal carriers: oilbased versus self-emulsifying systems. Curr. Drug Delivery 2015, 12 (1), 16−25. (31) Sek, L.; Porter, C. J. H.; Kaukonen, A. M.; Charman, W. N. Evaluation of the in-vitro digestion profiles of long and medium chain glycerides and the phase behaviour of their lipolytic products. J. Pharm. Pharmacol. 2002, 54 (1), 29−41. (32) Sek, L.; Porter, C. J. H.; Charman, W. N. Characterisation and quantification of medium chain and long chain triglycerides and their in vitro digestion products, by HPTLC coupled with in situ densitometric analysis. J. Pharm. Biomed. Anal. 2001, 25 (3−4), 651−661. (33) Batrakova, E. V.; Kabanov, A. V. Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers. J. Controlled Release 2008, 130 (2), 98−106. (34) Adams, M. L.; Lavasanifar, A.; Kwon, G. S. Amphiphilic block copolymers for drug delivery. J. Pharm. Sci. 2003, 92 (7), 1343−1355. (35) Creasey, A. A.; Dong, L. C.; Dai, W. G. Inhibiting the precipitation of poorly water-soluble drugs from Labrasol formulations. Pharm. Technol. 2011, 35, (6). (36) FDA. Inactive Ingredient Search for Approved Drug Products; U.S. Food and Drug Administration: http://www.fda.gov/Drugs/ InformationOnDrugs/default.htm, 2013. (37) Simovic, S.; Heard, P.; Hui, H.; Song, Y.; Peddie, F.; Davey, A. K.; Lewis, A.; Rades, T.; Prestidge, C. A. Dry hybrid lipid-silica

REFERENCES

(1) Williams, H. D.; Trevaskis, N. L.; Charman, S. A.; Shanker, R. M.; Charman, W. N.; Pouton, C. W.; Porter, C. J. H. Strategies to address low drug solubility in discovery and development. Pharmacol. Rev. 2013, 65 (1), 315−499. (2) Gabr, K. E. Effect of organic acids on the release patterns of weakly basic drugs from inert sustained-release matrix tablets. Eur. J. Pharm. Biopharm. 1992, 38 (6), 199−202. (3) Kohri, N.; Yamayoshi, Y.; Xin, H. E.; Iseki, K. E. N.; Sato, N.; Todo, S.; Miyazaki, K. Improving the oral bioavailability of albendazole in rabbits by the solid dispersion technique. J. Pharm. Pharmacol. 1999, 51 (2), 159−164. (4) Lindfors, L.; Skantze, P.; Skantze, U.; Rasmusson, M.; Zackrisson, A.; Olsson, U. Amorphous drug nanosuspensions. 1. inhibition of Ostwald Ripening. Langmuir 2006, 22 (3), 906−910. (5) Tran, T. T.; Tran, P. H.; Choi, H.; Han, H.; Lee, B. The roles of acidifiers in solid dispersions and physical mixtures. Int. J. Pharm. 2010, 384 (1−2), 60−66. (6) Guzmán, H. R.; Tawa, M.; Zhang, Z.; Ratanabanangkoon, P.; Shaw, P.; Gardner, C. R.; Chen, H.; Moreau, J.-P.; Almarsson, Ö .; Remenar, J. F. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J. Pharm. Sci. 2007, 96 (10), 2686−2702. (7) Alhalaweh, A.; Ali, H. R. H.; Velaga, S. P. Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media. Cryst. Growth Des. 2014, 14 (2), 643−648. (8) Xu, S.; Dai, W.-G. Drug precipitation inhibitors in supersaturable formulations. Int. J. Pharm. 2013, 453 (1), 36−43. (9) Warren, D. B.; Benameur, H.; Porter, C. J. H.; Pouton, C. W. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility. J. Drug Target. 2010, 18 (10), 704−731. (10) Ueda, K.; Higashi, K.; Yamamoto, K.; Moribe, K. Inhibitory effect of Hydroxypropyl Methylcellulose Acetate Succinate on drug recrystallization from a supersaturated solution assessed using nuclear magnetic resonance measurements. Mol. Pharmaceutics 2013, 10 (10), 3801−3811. (11) Gao, P.; Akrami, A.; Alvarez, F.; Hu, J.; Li, L.; Ma, C.; Surapaneni, S. Characterization and optimization of AMG 517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption. J. Pharm. Sci. 2009, 98 (2), 516−528. (12) Gao, P.; Guyton, M. E.; Huang, T.; Bauer, J. M.; Stefanski, K. J.; Lu, Q. Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations. Drug Dev. Ind. Pharm. 2004, 30 (2), 221−229. (13) Gao, P.; Morozowich, W. Development of supersaturatable selfemulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert Opin. Drug Delivery 2006, 3 (1), 97−110. (14) Gao, P.; Rush, B. D.; Pfund, W. P.; Huang, T.; Bauer, J. M.; Morozowich, W.; Kuo, M.-S.; Hageman, M. J. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J. Pharm. Sci. 2003, 92 (12), 2386−2398. (15) Song, W.; Park, J.; Yeom, D.; Ahn, B.; Lee, K.; Lee, S.; Woo, H.; Choi, Y. Enhanced dissolution of celecoxib by supersaturating selfemulsifying drug delivery system (S-SEDDS) formulation. Arch. Pharmacal Res. 2013, 36 (1), 69−78. (16) Stillhart, C.; Dürr, D.; Kuentz, M. Toward an improved understanding of the precipitation behavior of weakly basic drugs from oral lipid-based formulations. J. Pharm. Sci. 2014, 103 (4), 1194−1203. (17) Williams, H.; Trevaskis, N.; Yeap, Y.; Anby, M.; Pouton, C.; Porter, C. H. Lipid-based formulations and drug supersaturation: harnessing the unique benefits of the lipid digestion/absorption pathway. Pharm. Res. 2013, 30 (12), 2976−2992. (18) Anby, M. U.; Williams, H. D.; McIntosh, M.; Benameur, H.; Edwards, G. A.; Pouton, C. W.; Porter, C. J. H. Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems. Mol. Pharmaceutics 2012, 9 (7), 2063−2079. I


Article

Molecular Pharmaceutics microcapsules engineered from submicron lipid droplets and nanoparticles as a novel delivery system for poorly soluble drugs. Mol. Pharmaceutics 2009, 6 (3), 861−872. (38) Tan, A.; Martin, A.; Nguyen, T.-H.; Boyd, B. J.; Prestidge, C. A. Hybrid nanomaterials that mimic the food effect: controlling enzymatic digestion for enhanced oral drug absorption. Angew. Chem., Int. Ed. 2012, 51 (22), 5475−5479. (39) Binks, B. P.; Desforges, A.; Duff, D. G. Synergistic stabilization of emulsions by a mixture of surface-active nanoparticles and surfactant. Langmuir 2007, 23 (3), 1098−1106. (40) Van Speybroeck, M.; Williams, H. D.; Nguyen, T.-H.; Anby, M. U.; Porter, C. J. H.; Augustijns, P. Incomplete desorption of liquid excipients reduces the in vitro and in vivo performance of selfemulsifying drug delivery systems solidified by adsorption onto an inorganic mesoporous carrier. Mol. Pharmaceutics 2012, 9 (9), 2750− 2760. (41) Nguyen, T.-H.; Hanley, T.; Porter, C. J. H.; Larson, I.; Boyd, B. J. Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained-release oral drug delivery systems for poorly water-soluble drugs II. In-vivo evaluation. J. Pharm. Pharmacol. 2010, 62 (7), 856− 865. (42) Lee, K. W. Y.; Porter, C. J. H.; Boyd, B. J. The effect of administered dose of lipid-based formulations on the In Vitro and In Vivo performance of cinnarizine as a model poorly water-soluble drug. J. Pharm. Sci. 2013, 102 (2), 565−578. (43) Tan, A.; Simovic, S.; Davey, A. K.; Rades, T.; Boyd, B. J.; Prestidge, C. A. Silica nanoparticles to control the lipase-mediated digestion of lipid-based oral delivery systems. Mol. Pharmaceutics 2010, 7 (2), 522−532. (44) Lawrence, M. J. Surfactant systems: their use in drug delivery. Chem. Soc. Rev. 1994, 23 (6), 417−424. (45) Malmsten, M.; Lindman, B. Self-assembly in aqueous block copolymer solutions. Macromolecules 1992, 25 (20), 5440−5445. (46) Wulff-Pérez, M.; Gálvez-Ruíz, M. J.; de Vicente, J.; MartínRodríguez, A. Delaying lipid digestion through steric surfactant Pluronic F68: A novel in vitro approach. Food Res. Int. 2010, 43 (6), 1629−1633. (47) Feeney, O. M.; Williams, H. D.; Pouton, C. W.; Porter, C. J. H. ‘Stealth’ lipid-based formulations: Poly(ethylene glycol)-mediated digestion inhibition improves oral bioavailability of a model poorly water soluble drug. J. Controlled Release 2014, 192 (0), 219−227. (48) Yeap, Y.; Trevaskis, N.; Porter, C. H. Lipid absorption triggers drug supersaturation at the intestinal unstirred water layer and promotes drug absorption from mixed micelles. Pharm. Res. 2013, 30 (12), 3045−3058. (49) Yeap, Y. Y.; Trevaskis, N. L.; Porter, C. J. H. The potential for drug supersaturation during intestinal processing of lipid-based formulations may be enhanced for basic drugs. Mol. Pharmaceutics 2013, 10 (7), 2601−2615. (50) Yeap, Y. Y.; Trevaskis, N. L.; Quach, T.; Tso, P.; Charman, W. N.; Porter, C. J. H. Intestinal bile secretion promotes drug absorption from lipid colloidal phases via induction of supersaturation. Mol. Pharmaceutics 2013, 10 (5), 1874−1889.

J


Pluronic-Functionalized SilicaâLipid Hybrid ... - ACS Publications

Recommend Documents

Pluronic-Functionalized SilicaâLipid Hybrid ... - ACS Publications