Mol Biol Rep DOI 10.1007/s11033-014-3216-4
Preparation of solid lipid nanoparticles as drug carriers for levothyroxine sodium with in vitro drug delivery kinetic characterization E. Rostami • S. Kashanian • A. H. Azandaryani
Received: 9 December 2013 / Accepted: 28 January 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract The aim of this work was to produce and characterize solid lipid nanoparticles (SLN) containing levothyroxine sodium for oral administration, and to evaluate the kinetic release of these colloidal carriers. SLNs were prepared by microemulsion method. The particle size and zeta potential of levothyroxine sodium-loaded SLNs were determined to be around 153 nm,-43 mV (negatively charged), respectively by photon correlation spectroscopy. The levothyroxine entrapment efficiency was over 98 %. Shape and surface morphology were determined by TEM and SEM. They revealed fairly spherical shape of nanoparticles.SLN formulation was stable over a period of 6 months. There were no significant changes in particle size, zeta potential and polydispersity index and entrapment efficiency, indicating that the developed SLNs were fairly stable. Keywords Solid lipid nanoparticle Levothyroxine sodium Microemulsion Kinetic release
E. Rostami A. H. Azandaryani Young Researchers and Elite Club, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran S. Kashanian (&) Department of Chemistry, Nanoscience and Nanotechnology Research Centre and Sensor and Biosensor Research Centre, Razi University, P.O. Box: 67149, Kermanshah, Iran e-mail:
[email protected] A. H. Azandaryani Nano Drug Delivery Research Centre, Kermanshah University of Medical Sciences, Kermanshah, Iran
Introduction Solid lipid nanoparticles (SLNs) were developed in the early 1990s as an alternative carrier system to traditional colloidal systems, including emulsions, liposomes, polymeric microparticlesand nanoparticles [19, 25, 26, 31]. In the recent decade there has been a great progress in the treatment of disorders via fabricating new drug delivery carriers, including SLNs, which are made from solid lipids (i.e., lipids that are solid at room temperature as well as body temperature) and are stabilized by surfactant(s) [19]. Using solid lipids instead of liquid oils is a promising idea to achieve controlled drug release, because drug mobility in a solid lipid should be considerably lower compared with liquid oil [24]. The solid core contains the active drug dissolved or dispersed in a solid fat matrix. Thus, they are capable to carry lipophilic or hydrophilic drug(s) for diagnostic and therapeutic purposes [8, 15, 20]. Generally speaking, microemulsions, which can be made spontaneously by mixing surfactant, cosurfactant, oil and water, are thermodynamically stable colloid mixtures of two immiscible solvents. These compounds are stabilized by an adsorbed surfactant film at the liquid–liquid interface [3, 22].A clear advantage of SLNs over polymeric nanoparticles is the fact that the lipid matrix is made from physiologically compatible lipid components, which decreases the potential for acute and chronic toxicity and antigenic responses as well [3, 11, 22, 24]. Comparing to liposomes, SLNs have fewer storage and drug leakage problems. Moreover, they can be stable for 2–3 years [24]. All of the fabrication methods are based on surfactants usage, so the resulting particles have either an overall positive, neutral or negative surface charge, which could be determined by the composition and influencing the aggregation tendency in suspension [16]. SLN ingredients are usually
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physiologically well-tolerated and approved for pharmaceutical application in humans. These compounds can be produced in large scale, have acceptable storage proficiencies including freeze-drying and show low cytotoxicity. They can be sterilized for intravenous injections [27]. SLN can be produced in nano-scale size (100–200 nm). Therefore, the particles are small enough to traverse the microvascular system and prevent macrophage uptake. Moreover, they are suitable for systemic delivery and can be administrated by parenteral and non-parenteral routes [3, 27]. Among various drug delivery routes, the oral way is more attractive, comfortable and rather low cost for hydrophobic drugs [14]. There are several reports indicating the solid lipid nanoparticles to improve the oral absorption of drugs such as camptothecin, cyclosporine A, idarubicin or tobramycin [7, 33–35]. Levo isomer and monosodium salt of thyroxin, Levothyroxine sodium, is a hygroscopic and light-yellow to buff-colored powder. This compound is poorly soluble in water, slightly soluble in alcohol, and insoluble in acetone, chloroform, and ether [1]. Levothyroxine is commonly prescribed to replace endogenous hormone in hypothyroidism and for suppressive therapy of thyroid neoplasia. After oral administration, approximately 70–80 % of levothyroxine can be absorbed [21]. Measurement of total T4 by immunoassay technique is one of the most reliable and convenient screening tests available to determine the presence of thyroid disorders [6]. The aim of the present study was to investigate the achievability of the inclusion of levothyroxine sodium with poor water solubility into solid lipid nanoparticles for oral administration and its in vitro characterization.
Materials and method
22, 24, 26]. SLNs are made by stirring an optically transparent mixture at 65°–70° which is typically composed of a low melting 2 % W/W fatty acid (Tripalmitin glyceride, palmitic acid by the ratio of 8:2) and 0.05 % W/W levothyroxine sodium, an emulsifier 2 % W/V (polysorbate80), co-emulsifiers 1 % W/V (butanol) and water. The hot microemulsion is dispersed in cold water (2–3 °C) under stirring (100 rpm). Typical volume ratio of the hot microemulsion to cold water is in the range of 1:10. The dilution process is critically determined by the composition of the microemulsion. The SLN dispersions were then washed twice with water using a Dialysis bag (cut off 8,000 Da) in an ultrasonic cleaning tank in order to remove proportions of the surfactant molecules used to prepare the microemulsion [16, 24, 26]. A two-step method is applied to prepare the aqueous SLN dispersions: firstly formulation of an oil-in-water microemulsion and secondly preparation of the SLN by dispersing the warm microemulsion into cold water. The lipid including co-surfactant and the water phase were heated separately, mixed and subsequently titrated with the surfactant until preparing a microemulsion. The microemulsion was dispersed in ice-cold water by the ratio of 1:10 at a constant speed (2 mL/min) using a syringe with a needle gauge of 25, and a stirring speed of 100 rpm [7, 16, 24, 26]. Assay for levothyroxine sodium ELISA assay was performed on a Multiskan Lab system plate reader by quantification of light absorbance at 450 nm referenced against absorbance at 630 nm. Also the UV–Vis spectra were obtained using an Agilent 8453 spectrophotometer for analysis of levothyroxine sodium. The drug concentration in the samples was determined using UV spectrophotometry at the drug kmax of 225 nm.
Materials Tripalmitin glyceride was purchased from Alfa Aesar (Germany), palmitic acidfrom Sigma-Aldrich (St Louis, MO) and Butanol from Fluka (Germny). Polysorbate 80 and sucrose were obtained from Merck (Darmstadt, Germany). Levothyroxine sodium was kindly provided by Iran Hormone, Tehran, Iran.T4 ELISA (Enzyme-linked immunosorbent assay) kit human was purchased from Pishtaz Teb Diagnostic Company, Iran. Other reagents were of analytical or HPLC grade. Double-distilled water was prepared in our laboratory. Micro emulsion based SLN preparations Researchers [3] developed SLN preparation techniques which are based on the dilution of microemulsions [7, 16,
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Determination of entrapment efficiency and drugloading capacity The percentage of incorporated levothyroxine sodium (entrapment efficiency) was evaluated using spectrophotometric determination at 225 nm and absorbance at 450 nm by ELISA reader, after ultracentrifugation of the aqueous dispersion (45,000 rpm for 30 min). The amount of free drug was detected in the supernatant and the amount of incorporated drug was calculated as the initial drug minus the free drug. The drug entrapment efficiency and drug-loading in the SLNs were calculated using Eqs. (1) and (2): Wa Ws EE ð%Þ ¼ 100 ð1Þ Wa
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DL ð%Þ ¼
Wa Ws Wa Ws + WL
100
ð2Þ
where EE is entrapment efficiency, DL is drug-loading, and Wa, Ws, and WL are the weight of drug added into the system, analyzed weight of drug in the supernatant, and weight of lipid added into the system, respectively [17]. Particle diameter, polydispersity index, and zeta potential Measurement of polydispersity index, diameter of nanoparticle and zeta potential (ZP) of the nanoparticles were determined using photon correlation spectroscopy (Nano ZS4700, Malvern Instruments, Worcestershire, UK). All formulations were diluted by double distillated water to eliminate the effect of viscosity caused by the ingredients for size measurement. Zeta potential measurements were conducted to detect the size of the prepared samples [19]. Scanning electron microscopy (SEM) The morphology of SLNs was characterized using scanning electron microscopy (SEM, KYKY-EM3200, China). The samples were prepared on aluminum stabs and coated with gold prior to examination by SEM. Transmission electron microscopy (TEM) Combination of bright field imaging at increasing magnification and of diffraction modes was used to reveal the form and size of the nanoemulsion [29]. The morphology and structure of the levothyroxine sodium-SLNs were examined by transition electron microscope (Zeiss- EM 10C- Germany) at an accelerating voltage of 80 kV capable of point-to-point transmission. Prior to analysis, the samples were diluted 1:2 and applied on a carbon-coated grid, and were stained with uranyl acetate for 30 s and placed on copper grids with films for observation [23, 29]. We used freshly prepared levothyroxine loaded SLN to obtain TEM image.
homogenize the medium. 2 mL aliquots were loaded onto the membrane in the donor compartment. The temperature of the assay was controlled at precisely 37 °C. At predetermined time intervals, 1 mL aliquots of the release medium were withdrawn using a syringe needle, and the same volumes of freshly prepared receptor medium were added. The samples were analyzed using a spectroscopic method as previously described [10]. Stability studies After 3 and 6 months, nanoparticle stability was determined for free SLN and drug loaded SLN using photo correlation spectroscopy.
Calculations In vitro release kinetics calculation Several methods can be used to compare dissolution profiles, such as analysis of variance, model-independent and model-dependent approaches [30]. In this dissolution study, model-dependent approaches were used for comparison of dissolution profiles. In model-dependent approaches, release data were fitted to five kinetic models including the zero-order [5, 9, 32] (Eq. 3), first-order [30] (Eq. 4), Higuchi matrix [28] (Eq. 5), Peppas–Korsmeyer [5, 9, 32] (Eq. 6), and Hixson–Crowell (Eq. 7) release equations, in order to find the best fit equation [5, 9, 32]. Zero-order (Eq. 3) data is plotted as cumulative percentage drug released versus time. C ¼ K0 t
ð3Þ
where C is the concentration, K0 is the zero-order rate constant expressed as concentration/time, and t is time in hours [5, 9, 32]. First order (Eq. 4) is obtained by plotting log cumulative percentage drug released versus time [30]. Log C ¼ Log C0 Kt=2:303
ð4Þ
where C0 is the initial concentration of the drug, K is the first-order rate constant, and t is the time.
In vitro release of levothyroxine from SLNs
Q ¼ Kt1=2
This experiment was conducted using a static horizontal Franz diffusion cell to evaluate the amount of levothyroxine sodium released from this formulation [19]. A Cellulose acetate membrane with a molecular weight cutoff of 12,000 Da and a surface area of 2.0 cm2 was used and mounted on the Franz diffusion cell. The receptor medium was precisely 50 mL in volume and composed of an aqueous solution of physiological saline, phosphate buffer solution, stirred by a magnetic bar at 750 rpm to
As per Higuchi’s (Eq. 5) data is plotted as cumulative percentage drug released versus the square root of time. Where K is the constant of the system, and t is the time [19, 28]. The mechanism of drug release is evaluated by plotting the percentage of drug released versus log time according to Krosmeyer–Peppas equation (equation). Exponent n indicates the mechanism of drug release calculated through the slope of the straight line. Researchers used the
ð5Þ
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n value for characterization of different release mechanisms, concluding for values for a slab, of n \ 0.5 for Fick diffusion and higher values of n between 0.5 and 1.0, or n [ 1.0, for mass transfer following a non-Fickian model [5, 9, 30, 32]. Mt =M1 ¼ Kt
n
Table 1 Particle size poly dispersity index and zeta potential (ZP) for solid lipid nanoparticles in colloidal suspension Free nanoparticles Size (nm)
PDI
ZP (mV)
Size (nm)
PDI
ZP (mV)
Freshly prepared
112.2
0.189
-40.0
153
0.182
-43.3
After 3 months After 6 months
153.4
0.184
-28.3
187
0.238
-33.6
187.9
0.288
-22.4
198
0.338
-19.3
ð6Þ
Scientists reported the particle regular area is proportional to the cubic root of its volume, this finding led to derive an equation that can be defined as follows: ffiffiffiffiffiffi ffiffiffiffiffiffi p p 3 W0 3 Wt ¼ Ks t ð7Þ where W0 is the initial amount of drug in the pharmaceutical dosage form, W is the remaining amount of drug in the pharmaceutical dosage form at time t and K is a constant incorporating the surface–volume relation for HixsonCrowell rate equation [5, 9, 32]. Drug entrapment efficiency and loading capacity Many different drugs have been incorporated in the SLNs [19, 24–26, 29, 31].The requirement to obtain a sufficient loading capacity is an adequate high solubility of the drug in the lipid melt. The relatively higher encapsulation efficiency provides one of the major advantages of SLNs [2, 24–26]. To determine loading capacity, entrapment efficiency and standard curve for the UV assays of levothyroxine sodium were conducted on five solutions in the concentration ranges of 1.3 9 10-3 to 1.00 9 10-5mol/L; encapsulation efficiency and drug-loading were calculated to be 98.00 and 19.46 %, respectively. The high compatibility between the drug and the lipid is indicative of lipophilic characteristics of the drug and consequently leads to high entrapment efficiency [2, 19].
Drug-loaded nanoparticles
dispersion [17]. For a colloidal formulation, the absolute value of the zeta potential showing its electrochemical stability, if this value is higher than 30 mV, indicating the particles are electrochemically stable under the experimental condition [19]. Zeta potential values of -43.3 and -40.0 mV were obtained for the drug-loaded and free SLNs, respectively (Table 1). As Table 1 demonstrates, as time passes, increases are observed in size, polydispersity index, and zeta potential as a result of light and other factors that cause gelation [13]. However, it is obvious from these values that the prepared nanosuspension has an acceptable electrochemical and physical stability potential during 6 months of storage. In order to consider the stability of SLNs microemulsion after 6 months, sample was sustained in refrigerator distilled in water and was evaluated. The values for particle diameter, polydispersity index, and zeta potential were 198 nm, 0.338, and -19.6 mV, respectively. These results indicate that the particle size remains in the nanometric range; similar results have been reported by other researchers [2, 17, 19]. Characterization of SLNs
Results and discussion Nanoparticle characterization Asshown in Table 1, the particle size, zeta potential and polydispersity index of the SLNs with and without levothyroxine were determined using photon correlation spectroscopy for Stability studies. As previously has been reported, the mean particle sizes of 153 nm and 112.2 nm were obtained for drug-loaded and free SLNs, respectively (Table 1). The size of drug-loaded SLN is higher than that of drug-free one, which is indicative of drug incorporation in the SLN matrix [17]. The results of this formulation showed a narrow size distribution with a polydispersity index of 0.182 which indicating SLN monodispersity, an average diameter of 153 nm [5, 9, 28, 32]. Zeta potential has an important role in the stability of nanoparticles
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TEM image of the samples containing drug loaded SLNs are shown in Fig. 1. The image showed spherical shape and smoothly surface with a particle size in nanometric range. The results of SEM image (Fig. 2) confirmed that the SLNs were globular shape with a smooth surface. The particle size of levothyroxine-loaded SLN represented in TEM images is in agreement with the results obtained with photon correlation spectroscopy (PCS) and SEM. Furthermore, the imaging analyses showed that these particles exhibit a spherical shape, and a dense lipid matrix without aggregation [23, 29].The results of PCS, TEM and SEM images of the SLNs are presented in Figs. 1, 2 and Table 1, respectively. TEM and SEM techniques confirm that the SLNs are circular in shape and well dispersed and separated on the surface. The sizes of the SLNs determined by PCS are in good agreement with TEM results. The
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Fig. 3 Drug-enriched shell model
Fig. 1 TEM image of the samples containing drug loaded SLNs
Fig. 2 SEM image of the samples containing drug loaded SLNs
diameter determined by PCS is around 150 nm, which is very similar to the data obtained by TEM. In vitro release characterization Levothyroxine is a drug with poor water solubility and high lipophilicity, which makes it suitable for SLN encapsulation [24]. In general, for hypothyroidism individuals, lev-
othyroxine therapy should be instituted at full replacement doses as soon as possible. Delays in diagnosis and institution of therapy may have serious effects on the child’s intellectual and physical growth and development [6]. In this study, the in vitro release of levothyroxine sodium from SLN was studied for 72 h at 37 °C using a Franz diffusion cell [10, 28]. ELISA assay was applied to consider the drug release (Fig. 3). The first burst release of SLNs before 12 h can be explained by fast diffusion of levothyroxine sodium from the outer solid core matrix of the formulations and after 12 h, drug can be diffused from solid core. Therefore according to release profile (Fig. 4), drug release is 81 % for SLN. During SLN fabrication, a small portion of the drug can easily diffuse in the lipid core which usually cannot be released. So, in such cases there is only partial drug release. We suggest the drug-enriched shell model describes the situation when the drug is present at such a concentration that it is fully solubilized by the lipid [12, 18, 26]. In the course of SLN production, the solidification of lipid starts first, and thensolidification of drug-enriched lipid melt will be started around the lipid cores (Fig. 4). Therefore, regularly near the surface of the particle a levothyroxine-enriched shell will be produced via lipid precipitation mechanism. After homogenization, the mixture of drug and lipid will be cooled. It is notable precipitation of lipid before the drug, may result to fabrication of a not adequate or even to free drug cores [12, 18, 26]. The release of the drug from such SLNs will be fast, and the burst release may occur shortly after the administration of the drug [11].
Table 2 The R2 values from in vitro release kinetics and the K values or release rate constant Kinetic model
Zero order
First order
Higuchi model
R2 K
Krosmeyer–Peppas Model
Hixson–Crowell
0.922 ± 0.0024
0.939 ± 0.0042
0.998 ± 0.0014
0.912 ± 0.0031
0.934 ± 0.0053
4.24 ± 0.013
0.054 ± 0.015
0.01 ± 0.010
0.895 ± 0.018
0.016 ± 0.020
R2 determination coefficient and K dissolution rate constant (lgml-1h-1/2). Each value represents the mean of three experiments ± SD
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Fig. 4 Release of Levothyroxine sodium
In vitro drug release kinetic characterization The release data were analyzed using the following Higuchi kinetic equation [28]. According to the release model of such fabrications, it was clear that the prolonged release characteristic of levothyroxine sodium was well fitted to Higuchi’s square root model, as has been reported for drugloaded SLN systems [28]. The regression coefficient (R2) of release date of all the formulations obtained by the curve fitting method on various kinetic models is reported in Table 2 [4]. Linear fits were obtained, indicating that the release profile of levothyroxine sodium from homogenous and granular matrix system is diffusion-controlled. The R2 values from in vitro release kinetics and the K values or release rate constant obtained from the Higuchi model plot are presented in Table 2. The regression coefficient (R2) values of release data of all formulations obtained by the curve fitting method for zero-order, first-order, Higuchi model, Krosmeyer–Peppas and Hixson-Crowell Model are reported in Table 2. For the optimized formulation F, the R2 value of Higuchi 0.998 (nearer to 1) is the most probable model comparing to other models which indicates that the drug release is determined by the square root of the time (Eq. 5).
Conclusion As mentioned previously, SLNs offer an attractive means of drug delivery, particularly for poorly water-soluble drugs. The important and clear advantages of SLN include the composition (solid lipid similar to physiological lipid), large scale production is possible because it can rapidly and effectively be produced, and avoidance of organic solvent (except solvent emulsification-diffusion and solvent emulsification-evaporation). Among various drug delivery
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routes, the oral way is more attractive, comfortable and rather low cost for hydrophobic drugs. The mean particle size, Zeta potential and entrapment efficiency of optimized SLN were found to be 153 nm, -43.3 mV, 98 % respectively. The particle sizes of unloaded and levothyroxine-loaded SLNs represented in TEM and SEM images were in good agreement with the results obtained with PCS. Furthermore, the imaging analysis showed that these particles exhibit a spherical shape, and a dense lipid matrix without aggregation. The PCS results during 6 months demonstrate that the carrier has suitable stability in colloidal form.Zeta potential data could indicate the stability of the nanosuspension. After 6 months, PCS data did not indicate any obvious changes in diameter, polydispersity index, and zeta potential. Regarding the release model of all formulations, it was found that the prolonged release characteristic of levothyroxine sodium was well fitted to Higuchi’s square root model, as has been reported for drug-loaded SLN systems.
References 1. Alexander KS, Kothapalli MR, Dollimor D (1997) Stability of an extemporaneously formulated levothyroxine sodium syrup compounded from commercial tablets. Int J Pharm Compd 1(1):60–64 2. Ali H, El-Sayed K, Sylvester PW, Nazzal S (2010) Molecular interaction and localization of tocotrienol-rich fraction (TRF) within the matrices of lipid nanoparticles: evidence studies by differential scanning calorimetry (DSC) and proton nuclear magnetic resonance spectroscopy (1H NMR). Colloids Surf B 77(2):286–297 3. Almeida AJ, Souto E (2007) Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv Drug Deliv Rev 59(6):478–490 4. Arza RAK, Gonugunta CSR, Veerareddy PR (2009) Formulation and evaluation of swellable and floating gastroretentive ciprofloxacin hydrochloride tablets. Am Assoc Pharm Sci 1(10):220–226 5. Barzegar-Jalali M, Adibkia K, Valizadeh H, Siahi-Shadbad MR, Nokhodchi A, Omidi Y, Mohammadi G, Hallaj-Nezhadi S, Hasan M (2008) Kinetic analysis of drug release from nanoparticles. J Pharm Pharm Sci 11(1):167–177 6. Blakesley VA (2005) Current methodology to assess bioequivalence of levothyroxine sodium products is inadequate. J Am Assoc Pharm Sci 7(1):E42–E46 7. Cavalli R, Bargoni A, Podio V, Muntoni E, Zara GP, Gasco MR (2003) Duodenal administration of solid lipid nanoparticles loaded with different percentages of Tobramycin. J Pharm Sci 92(5):1085–1094 8. Chen DB, Yang TZ, Lu WL, Zhang Q (2001) In vitro and in vivo study of two types of long-circulating solid lipid nanoparticles containing paclitaxel. Chem Pharm Bull 49(11):1444–1447 9. Costa P, Sousa Lobo JM (2001) Modeling and comparison of dissolution profiles. Eur J Pharm Sci 13(2):123–133 10. Derakhshandeh K, Erfan M, Dadashzadeh S (2007) Encapsulation of 9-nitrocamptothecin, a novel anticancer drug, in
Mol Biol Rep
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
biodegradable nanoparticles: Factorial design, characterization and release kinetics. Eur J Pharm Biopharm 66(1):34–41 Ekambaram P, Hasan-Sathali AA, Priyanka K (2012) Solid lipid nanoparticles: a review. Sci Rev Chem Commun 2(1):80–102 Elgart A, Cherniakov I, Aldouby Y, Domb AJ, Hoffman A (2012) Lipospheres and pro-nanolipospheres for delivery of poorly water soluble compounds. Chem Phys Lipids 165(4):438–453 Freitas C, Muller RH (1998) Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle (SLN) dispersions. Int J Pharm 168(2):221–229 Garcia-Fuentes M, Torres D, Alonso MJ (2002) Design of lipid nanoparticles for the oral delivery of hydrophilic macromolecules. Colloids Surf B 27(2–3):159–168 Heiati H, Tawashi R, Phillips NC (1998) Solid lipid nanoparticles as drug carriers II. Plasma stability and biodistribution of solid lipid nanoparticles containing the lipophilic prodrug 3 %-azido3 %-deoxythymidinepalmitate in mice. Int J Pharm 174(4):71–80 Heydenreich AV, Westmeier R, Pedersen N, Poulsen HS, Kristensen HG (2003) Preparation and purification of cationic solid lipid nanospheres-effects on particle size, physical stability and cell toxicity. Int J Pharm 254(1):83–87 Hu FQ, Jiang SP, Du YZ, Yuan H, Ye YQ, Zeng S (2005) Preparation and characterization of stearic acid nanostructured lipid carriers by solvent diffusion method in an aqueous system. Colloids Surf B 45(3–4):167–173 Kamble MS, Vaidya KK, Bhosale AV, Chaudhari PD (2002) Solid lipid nanoparticles and nanostructure lipid carriers—an over view. Int J Pharm Chem Biol Sci 2(4):681–691 Kashanian S, Hemati Azandaryani A, Derakhshandeh K (2011) New surface modified solid lipid nanoparticles by using N-glutarylphosphatidylethanolamine as outer shell. Int J Nanomed 6(1–9):1–9 Kaura IP, Bhandari R, Bhandari S, Kakkar V (2008) Potential of solid lipid nanoparticles in brain targeting. J Control Release 127(2):97–109 Lilja JJ, Laitinen K, Neuvonen PJ (2005) Effects of grapefruit juice on the absorption of levothyroxine. Br J Clin Pharmacol 60(3):337–341 Li XW, Lin XH, Zheng LQ, Yu L, Lv F, Zhang Q, Liu WC (2008) Effect of poly(ethylene glycol) stearate on the phase behavior of monocaprate/Tween80/water system and characterization of poly(ethylene glycol) stearate-modified solid lipid nanoparticles. Colloids Surf A 317(1–3):352–359
23. Liu J, Gong T, Wang C, Zhong Z, Zhang Z (2007) Solid lipid nanoparticles loaded with insulin by sodium cholate-phosphatidylcholine-based mixed micelles: preparation and characterization. Int J Pharm 340(1–2):153–162 24. Mehnert W, Mader K (2001) Solid lipid nanoparticles Production, characterization and applications. Adv Drug Deliv Rev 47(2-3):165–196 25. Muller RH, Mader K, Gohla K (2000) Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm 50(1):161–177 26. Parhi R, Suresh P (2010) Production of solid lipid nanoparticlesdrug loading and release mechanism. J Chem Pharm Res 2(1):211–227 27. Pedersen N, Hansen S, Heydenreich AV, Kristensen HG, Poulsen HS (2006) Solid lipid nanoparticles can effectively bind DNA, streptavidin and biotinylated ligands. Eur J Pharm Biopharm 62(2):155–162 28. Ruktanonchai U, Bejrapha P, Sakulkhu U, Opanasopit P, Bunyapraphatsara N, Junyaprasert V, Puttipipatkhachorn S (2009) Physicochemical characteristics, cytotoxicity, and antioxidant activity of three lipid nanoparticulate formulations of alpha-lipoic acid. Am Assoc Pharm Sci 10(1):227–234 29. Sarmento B, Martins S, Ferreira D, Souto BE (2007) Oral insulin delivery by means of solid lipid nanoparticles. Int J Nanomed 2(4):743–749 30. Singhvi G, Singh M (2011) Review: in vitro drug release characterization. Int J Pharm Stud Res 2(1):77–84 ¨ ner M, Yener G (2007) Importance of solid lipid nanoparticles 31. U (SLN) in various administration routes and future perspectives. Int J Nanomed 2(3):289–300 32. Varelas CG, Dixon DG, Steiner CA (1995) Zero-order release from biphasic polymer hydrogels. J Control Release 34(3):185–192 33. Yang S, Zhu J, Lu Y, Liang B, Yang C (1999) Body distribution of camptothecin solid lipid nanoparticles after oral administration. Pharm Res 16(5):751–757 34. Zara GP, Bargoni A, Cavalli R, Fundaro A, Vighetto D, Gasco MR (2002) Pharmacokinetics and tissue distribution of Idarubicin-loaded solid lipid nanoparticles after duodenal administration to rats. J Pharma Sci 91(5):1324–1333 35. Zhang Q, Yie G, Li Y, Yang Q, Nagai T (2000) Studies on the cyclosporin A loaded stearic acid nanoparticles. Int J Pharm 200(2):153–159
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