DOI:
10.1039/C4RA03107E
(Paper)
RSC Adv., 2014,
4, 30186-30192
Paliperidone-loaded spherical solid lipid nanoparticles†
Received
7th April 2014
, Accepted 17th June 2014
First published on 17th June 2014
Abstract
Gelucire® 50/13, a macrogol glyceride, was used as a surfactant for the preparation and stabilization of paliperidone-loaded Capmul® GMS-50K matrix-based solid lipid nanoparticles (SLNs). Z-average particle size of the SLNs was found to be directly proportional to the concentration of Gelucire® 50/13. 10 mg ml−1 was found to be optimum amount of Gelucire® 50/13 for the formation of a monolayer around the SLNs. SLNs with the optimised amount of surfactant were characterised thoroughly by transmission electron microscopy (TEM) and atomic force microscopy (AFM). X-ray diffraction (XRD) and FTIR spectroscopy analysis showed that the lipid matrix crystallised in the triclinic form in the SLNs. Homogeneously distributed paliperidone did not affect the crystal structure of the lipid matrix in the SLNs. The entrapment efficiency of the optimised formulation was 75% with a 7% drug loading.
Introduction
The last decade witnessed a proficient interest towards drug targeting of the brain. Annually, antipsychotic drugs have a market share of $22–25 billion.1–3 Central nervous system (CNS) disorders are increasing among the population worldwide.3 The neurological disorders are multi-systemic and difficult to treat as portal entry to the brain is restricted on account of its anatomical and physiological barriers.4 The growing knowledge about the brain capillary endothelium, and the discovery of the specific mechanisms for the uptake of substances enables the development of various strategies to enhance the drug delivery rate into the brain.5 Among the different strategies, nanodrugs are promising candidates for drug delivery to the brain due to their potential in encapsulating drugs. Among the many nanodrug carrier systems, SLNs have many advantages over the others. SLNs have been used for the bio-availability enhancement of drugs, controlled release and drug targeting.6 Due to the high biocompatibility of lipids, all the existing administration routes are virtually possible for SLNs.
Among the CNS disorders, schizophrenia is a brain disorder that is usually treated with antipsychotic drugs, which include “typical” or “first generation” and “atypical” or “second generation” drugs. Paliperidone or 9-hydroxyrisperidone is the most recently available atypical antipsychotic drug. It is the primary active metabolite of risperidone, which is a well-established second-generation antipsychotic drug.7–9 Paliperidone has been developed as an extended-release (ER) tablet formulation and is approved in the US and EU for the treatment of schizophrenia in adults.
Formulating the surfactant coating of nanoparticles was considered as a potential approach to improve brain drug uptake of paliperidone. In our previous work, we have used Capmul® GMS-50K as a lipid and sodium deoxcycholate as a surfactant to encapsulate paliperidone.9 Capmul® GMS-50K is the trade name of glycerol monostearate and is a mono-triglyceride of hydrogenated vegetable oil. Sodium deoxycholate has been reported to enhance permeability across the blood-brain barrier (BBB).10 We could achieve an entrapment efficiency of 55% with a 4.15% of drug loading in this lipid matrix.
In the present study, Gelucire® 50/13 has been used as the non-ionic surfactant while keeping the lipid carrier the same to make SLNs loaded with paliperidone. Note that Gelucire® 50/13 is a glyceride of polyethylene glycol (PEG) and fatty acids. Gelucire® 50/13 is well known to enhance the oral bioavailability of drugs.11–14 Gelucires could facilitate the production of SLNs with a narrow size distribution with enhanced drug encapsulation for poorly soluble drugs.15 Gelucire® 50/13 stabilized SLNs remain stable at different pH values. However, sodium deoxycholate stabilized SLNs may be destabilized at acidic pH.16 Gelucire® 50/13 is generally recognised as safe (GRAS) by the FDA, whereas sodium deoxycholate does not fall in this category. Non-ionic surfactants such as Gelucire® 50/13 are much less toxic than anionic surfactants.15 Drug-loaded SLNs were prepared by ultrasound-assisted melt homogenization and structural characterization was performed using XRD and FTIR spectroscopy. The morphology of the SLNs was characterized by dynamic light scattering (DLS), TEM and AFM imaging.
Results and discussion
Capmul® GMS-50K- and Gelucire® 50/13-based SLNs were stabilized by a self-emulsification process through ultrasound assisted melt homogenization. Optimization of process parameters like temperature, stirring speed, stirring time, ultra sonication power, ultra-sonication time and cooling conditions were carried out previously and maintained constant for the synthesis of the SLNs.17 The effect of the surfactant on the particle size and shape was studied carefully, and the results are discussed in the following sections.
The effect of surfactant content, presence of drug and temperature on the SLNs
Without using surfactants, it was impossible to prepare SLNs with Capmul® GMS-50K. The effect of varying the quantity of Gelucire® 50/13 on the particle size was studied by DLS, which gave a Z-average size of SLNs. The Z-average size and PDI recorded with respect to Gelucire® 50/13 content are reported in Table 1. The particle size of the SLNs decreased from 392 nm to 100 nm with an increase in the concentration of Gelucire® 50/13 from 2.5 mg ml−1 to 20 mg ml−1. There was no specific trend in PDI. It was observed that the particle size of the SLNs decreased sharply with increase in Gelucire® 50/13 content up to 10 mg ml−1, which is equivalent to a 1
:
1 weight ratio of the surfactant and lipid. This is because the particle size of the dispersions depends strongly on the nominal surfactant concentration that is needed to form a dense adsorption monolayer on the particles. A plot of Z-average size against Gelucire® 50/13 content gave a hyperbolic fit (Fig. S1, ESI†). The hyperbolic fit showed that particle size decreased sharply with an increasing in the concentration of Gelucire® 50/13 until 10 mg ml−1 (1
:
1 wt/wt). The particle size of the SLNs decreased relatively less abruptly with a change in Gelucire® 50/13 content at concentrations above 10 mg ml−1. This may be because the surfactant concentration needed for the formation of a dense monolayer is approximately 10 mg ml−1. A similar trend was reported in the model proposed by Tcholakova et al.18 High concentrations of surfactants above the concentration required for monolayer formation controls the particle size by preventing the drop–drop coalescence.19 The zeta potential was not affected by the Gelucire® 50/13 content, as it was found to be around −19 to −21 mV for all the samples shown in Table 1. This may be due to the non-ionic nature of the surfactant used. Above 20 mg ml−1 of Gelucire® 50/13 content gelling of the sample starts to a large extent and hence higher concentrations were not used. Thus, the minimum surfactant concentration that is needed for obtaining a monolayer covered SLN was determined to be 10 mg ml−1. Further studies on the paliperidone-loaded Gelucire® 50/13-stabilized SLNs were performed with this optimum concentration.
Table 1 The effect of Gelucire 50/13 concentration on the Z-average size and polydispersity index (PDI), which were measured by PCS/DLS of the SLNs
Sr. no. |
Ratio (wt/wt) of Gelucire® 50/13 & Capmul® GMS-50K |
Z-average size (nm) |
PDI |
Zeta potential (mV) |
1. |
1 : 4 |
392.5 |
0.44 |
−19.4 |
2. |
2 : 4 |
223.3 |
0.66 |
−20.1 |
3. |
3 : 4 |
187.5 |
0.58 |
−20.0 |
4. |
1 : 1 |
163.2 |
0.67 |
−21.1 |
5. |
5 : 4 |
147.8 |
0.63 |
−20.3 |
6. |
3 : 2 |
133.8 |
0.46 |
−21.1 |
7. |
7 : 4 |
119.2 |
0.46 |
−19.8 |
8. |
2 : 1 |
100.3 |
0.68 |
−20.2 |
When we used sodium deoxycholate in our previous work, SLNs with a particle size of 200 nm was obtained with a weight ratio of 1
:
4 of the surfactant and lipid. With Gelucire® 50/13 as surfactant, the particle size of the SLNs was around 392 nm at the same weight ratio. However, the particle size of the SLNs could be lowered further, even up to 100 nm with Gelucire® 50/13 using a higher concentration of the surfactant. However, higher concentration of sodium deoxycholate could not be used in the SLNs due to its relatively high toxicity.
The effect of the presence of the drug on the particle size of the optimized formulation was also studied using DLS. From the data reported in Fig. S2a and S2b (ESI†), it is clear that there is an apparent increase in the Z-average particle size when the drug is present in the SLNs. However, this observation is not sufficient to conclude that presence of drug increases the particle size. The apparent increase in Z-average particle size was due to slight increase in the population of micron-sized particles that was present even in the absence of the drug.
The effect of temperature on the size of the SLNs was studied by DLS to understand the thermal stability of the SLNs. The temperature of the suspension of the SLNs in water was increased gradually from 20 °C to 65 °C by varying the temperature of the sample chamber of the DLS instrument. The particle size was measured after equilibrating the sample for 120 s at the pre-set temperature. A plot of particle size versus temperature is shown in Fig. 1. Temperature did not appear to have any effect on the particle size of the SLNs up until 56 °C. The particle size started to decrease when the temperature is raised beyond 56 °C. This may be due to a change in phase of the SLNs in the dispersion at 56 °C.20
 |
| Fig. 1 Plot of the particle size of the SLNs against temperature. | |
Studies on the morphology of the SLNs
The particle size and shape of SLNs was observed by TEM and non-contact mode AFM imaging. The representative TEM images of negatively stained SLNs without paliperidone-loading and with paliperidone-loading are shown in Fig. 2a and b, respectively. Sphere-shaped SLNs of diameter in the range of 150 nm to 250 nm were observed in the TEM images. There were some poorly stained white spots observed in the SLNs loaded with paliperidone. This may be due to the presence of paliperidone on the surface of the SLNs. Paliperidone may not have any staining of it by phosphotungstic acid (PTA), which results in white spots in paliperidone-loaded SLNs. PTA can work as negative stain because it contains heavy metal ions. It can interact specifically with certain functional groups such as carboxylate, hydroxyl and amides.21 PTA may be specifically interacting strongly with the polar functional groups of the surfactant, whereas there may not be any such interactions possible with paliperidone.
 |
| Fig. 2 HRTEM images of Gelucire® 50/13 based (a) SLNs without paliperidone and (b) SLNs loaded with paliperidone. | |
The 3-dimensional structure of the SLNs was studied using non-contact mode AFM imaging. The AFM images of paliperidone-loaded SLNs are shown in Fig. 3. Spherical SLNs were observed with almost similar particle size. The particles were observed with their individuality intact and no agglomeration was observed in both TEM and AFM images. This is important as we have redistributed dried SLN powder in water to prepare the suspensions for both TEM and AFM imaging. Thus, TEM and AFM imaging revealed that the particles do not get agglomerated even after drying and storage. DLS, TEM and AFM data confirmed that the size of SLNs is in the range of 150 nm to 250 nm.
 |
| Fig. 3 AFM topography images of Gelucire® 50/13 stabilized paliperidone-loaded SLNs showing a homogeneous distribution of nanoparticles. | |
In our previous study, we observed that the sodium deoxycholate-stabilized SLNs were doughnut-shaped;9 however, the Gelucire® 50/13 stabilized SLNs in the present study are spherical. This change in shape with a change in surfactant may be due to the nature of the surfactant. Sodium deoxycholate is anionic in nature, whereas Gelucire® 50/13 is non-ionic in nature. The surfactant may be affecting the crystallinity of the lipid and thus directing the shape of the SLNs. Some studies on the effect of crystallization on shape of SLNs have showed that the surfactant can influence the crystallinity and shape.22
Physico-chemical characterization of the SLNs
The compatibility and interaction of the ingredients determines the physicochemical properties of the SLNs. Powder XRD of the pure ingredients as well as the SLNs (loaded with paliperidone and without paliperidone) are shown in Fig. 4. Gelucire® 50/13 and Capmul® GMS-50K have triclinic subshell packing and the XRD patterns matched well with the already reported data.23 Both Gelucire® 50/13 and Capmul® GMS-50K have a lipid-like XRD pattern with polymeric chains of macrogol. The XRD pattern of paliperidone has the most intense peak at 14.6° with other characteristic peaks as reported in literature.24 The XRD pattern of SLNs without paliperidone showed triclinic subshell packing in the β-polymorphic form with two prominent peaks at 19° and 23°. The SLNs loaded with paliperidone also showed similar XRD patterns; hence, a similar crystal structure to that of SLNs without paliperidone.
 |
| Fig. 4 XRD patterns of paliperidone, Gelucire® 50/13, Capmul® GMS-50K, SLNs loaded with paliperidone and SLNs without paliperidone. | |
The relative crystallinity of the samples was calculated by an area under curve method and the data is reported in Table 2. The results show that the SLNs loaded with paliperidone have a lower crystallinity with respect to the initial lipid matrix. Prominence of the peak at 23° increased relative to the peak at 19° in the SLNs when compared to the XRD pattern of the lipid. The characteristic peaks for paliperidone were completely absent in the SLNs. This shows that the drug is either molecularly dispersed in the lipid matrix or is present in an amorphous form. This is highly desirable as this might enhance the solubility and bioavailability of the drug.
Table 2 The absolute and relative crystallinity of the SLNs relative to Capmul® GMS-50K
Sr. no. |
Sample |
Absolute crystallinity (%) |
Relative crystallinity (%) |
1. |
Capmul® GMS 50K |
64.6 |
100 |
2. |
SLNs without paliperidone |
64.0 |
98.9 |
3. |
SLNs with paliperidone |
30.6 |
47.3 |
The FTIR spectra of the SLNs and the pure ingredients are shown in Fig. 5. A single band at 720 cm−1, corresponding to the CH2 rocking vibration in the triclinic subshell packing was found in the spectra for the SLNs, pure lipid and the surfactant.25 Splitting of this band occurs when the crystal structure is orthorhombic.25 The presence of the triclinic subshell packing was thus confirmed further as there was no splitting of this band in the SLNs. A CH2 wagging vibration due to adjacent polar end groups in the region from 1380 cm−1 to 1180 cm−1 may help in the determination of the chain length of polymethylene. The stearate ester in the lipid, surfactant and the SLNs was confirmed by a single band at 1174 cm−1 due to C–O stretching. C
O stretching in the triglyceride ester was observed at 1730 cm−1 in the SLNs, pure lipid and the surfactant. No unique and distinct peak was present in the SLNs and there was no shifting of the peaks compared to the pure lipid and the surfactant. This clearly shows that there was no chemical interaction between the drug and the excipients.
 |
| Fig. 5 FTIR spectra of (A) paliperidone, (B) Capmul® GMS-50K, (C) Gelucire® 50/13, (D) SLNs without paliperidone and (E) SLNs loaded with paliperidone. | |
DSC thermal curves for the drug and pure excipients are shown in Fig. 6 along with the thermal curves for the SLNs loaded with paliperidone and the DSC curve for a physical mixture of the lipid and surfactant. All the samples showed one or more endothermic phase transitions. An endotherm starting from 56 °C with a peak at 66 °C and another hump at 72 °C was observed for pure Capmul® GMS-50K. Gelucire® 50/13 has an endothermic phase transition starting at 40 °C with the peak temperature at 48 °C. An endotherm was observed for paliperidone at 172 °C. The melting point of paliperidone is reported to be in the range of 166–172 °C.26 The thermal response of the SLNs was more or less similar to the physical mixture. The SLNs showed three melting peaks at 46 °C, 53 °C and 61 °C. These correspond to the crystalline melting of Gelucire® 50/13 and the two-step melting of Capmul® GMS-50K, respectively. The outer polymeric shell, which has a low melting point will melt first, followed by Capmul® GMS-50K as shown in Fig. 6. The melting point of the SLNs was relatively lower than the melting temperature of the bulk material. This may be because of the small particles size of the SLNs.27 The SLNs loaded with paliperidone showed relative crystallinity at 46.2% w.r.t. Capmul GMS 50K computed by an area under curve method, which was found to be very close to the value calculated by XRD. The SLNs loaded with paliperidone did not show any peak due to paliperidone melting because paliperidone becomes solubilized in the molten lipid matrix.
 |
| Fig. 6 DSC thermal curves of (A) Capmul® GMS-50K, (B) Gelucire® 50/13, (C) physical mixture, (D) SLNs loaded with paliperidone and (E) paliperidone. | |
The entrapment efficiency and percentage drug loading
The determination of entrapment efficiency was performed by UV-visible spectroscopy. Paliperidone has very good solubility in an acidic medium.9 Hence, 0.1 N HCl solution was used to dissolve paliperidone selectively from the SLNs. Centrifugation was used to separate the nanoparticles from the acidified dispersion. The concentration of free drug after dissolution was found to be 0.248 mg ml−1. The entrapment efficiency and drug loading were calculated to be 75% and 7%, respectively. Gelucire® 50/13-stabilized SLNs seems to be better in terms of increasing the drug loading and entrapment efficiency compared to sodium deoxycholate-stabilized SLNs.17 This is primarily because a higher concentration of Gelucire® 50/13 can be used to form the SLNs, whereas sodium deoxycholate is limited by its toxicity at high concentrations. The lower relative crystallinity of Gelucire® 50/13-stabilized SLNs with respect to the bulk lipid can also be a reason for the high entrapment efficiency and high drug loading efficiency.28
Experimental
Materials
Capmul® GMS-50K was provided by Abitech USA as a gift sample. Gelucire® 50/13 pellets were provided by Gattefosse France also as a gift sample. Double distilled water from a Bioage water purification system was used in all the preparations and washing. Hydrochloric acid, potassium bromide, sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate were purchased from Fischer chemicals.
Methods
Preparation of Gelucire® 50/13-stabilized SLNs with and without paliperidone. Melt homogenization and self-emulsification was utilized to obtain the Gelucire® 50/13-stabilized SLNs.29 Preparation of SLNs involved three steps. An appropriate quantity of Capmul® GMS-50K and Gelucire® 50/13 was primarily weighed and heated to 75 °C so that the whole mixture melts completely. Paliperidone was subsequently weighed and suspended in the molten lipid with stirring at 75 °C. Afterwards, water was added to the drug–lipid–stabilizer mixture with incessant stirring to make a pre-emulsion. The pre-emulsion was further homogenized by a ultrasound homogenizer to trim down the particle size to the nanosize range. The hot micro-emulsion was cooled slowly to 4 °C for solidification. A series of formulations with varying concentration of stabilizer were prepared. Extra amounts of stabilizer was removed by centrifugation at 10
000 rpm for 2 hours and the particle pellets obtained were dried in a vacuum oven at 40 °C to obtain dried samples for further analysis.
Z-average size/hydrodynamic diameter measurement. Photon correlation spectroscopy/dynamic light scattering measurement was performed using a Zetasizer Nano ZS (Malvern Instruments, Malvern, UK) equipped with a 632.8 nm red laser with a detector angle of 173°. DLS measurements of the diluted samples were performed in a glass cell with a round aperture at 25 °C with a 120 s incubation time. A cumulant analysis method was used to compute the autocorrelation function. Data was recorded in triplicate and mean plotted. The mean value of size (Z-average) and a width parameter known as the polydispersity index (Pdi) are reported.
Effect of Gelucire 50/13 content on size of SLNs. The SLNs were prepared at varying quantities of Gelucire® 50/13 from 2.5 mg ml−1 to 20 mg ml−1 with 2.5 mg ml−1 increments to each sample in 40 ml of water. The ratio (wt/wt) of Gelucire® 50/13 to Capmul® GMS-50K was 1
:
4, 1
:
2, 3
:
4, 1
:
1, 5
:
4, 3
:
2, 7
:
4 and 2
:
1. Samples were prepared by the method as described above. The amount of all the other components, Capmul® GMS-50K, paliperidone and water remained constant in all the samples. All the preparation parameters were maintained the same to remove the effect of process parameters on the size of the SLNs.
Transmission electron microscopy. A Tecnai G20 S-Twin of FEI, USA was used to obtain high-resolution transmission electron microscopy images at 200 kV. The sample drop was incubated for 90 s and dried on carbon-coated copper grids. They were further stained by 2.5% phosphotungstic acid (PTA) for another 90 s. Excess stain was removed by washing the samples with purified water. The images were obtained in a darkfield and bright-field mode at different magnifications.
Atomic force microscopy. A low frequency silicon cantilever (force constant: 21 N m−1 to 98 N m−1) at a frequency from 146 kHz to 236 kHz was used with a closed loop scanner in a SPM 5500 (Agilent) system to acquire the non-contact mode AFM images. Pico image software was used for the filtration and 3D study of the AFM data.
X-ray diffraction. Panalytical Xpert Pro was used to record the XRD pattern of the processed powder samples. The data was collected in the 2θ range of 10–50° with a scan step size of 2°. Cu Kα1 with λ = 1.54060 Å was used as the anodic material.
FTIR spectroscopy. The dried powder samples were pelletized along with KBr powder for FTIR measurements. FT-IR spectra were recorded by a Perkin-Elmer Spectrum 65 spectrophotometer in the range 4000–400 cm−1 at a resolution of 1 cm−1.
Differential scanning calorimetry (DSC) analysis. Small quantities of samples were analyzed by Netzsch STA 449 F1 in hermetically sealed aluminium pans for DSC measurements at the heating rate of 2 °C min−1 from 25 °C to 200 °C under a flow of N2 at a rate of 60 ml min−1.
% Entrapment efficiency (%EE) and % drug loading (%DL) determination. Free paliperidone present in the SLN dispersion was solubilized by 0.1 N HCl and centrifugation used to separate the SLNs from the supernatant. The supernatant was further filtered through 0.45 μm syringe filter to obtain a clear solution. The concentration of paliperidone was quantified using a UV-Visible-NIR spectrophotometer. λmax at 238 nm was used to plot the standard curve (10–50 μg ml−1) for the determination of the paliperidone concentration in the filtrate. The formula mentioned below was used to compute the %EE and %DL.30 The weight in mg was used in the formula and PPN refers to paliperidone.
Conclusions
Gelucire® 50/13 when used as a surfactant to prepare SLNs influences the particle size. The particle size of the SLNs decreases with an increase in the concentration of Gelucire ® 50/13. The Gelucire® 50/13-stabilized SLNs have a good entrapment efficiency and drug loading. The particle size of the SLNs was found to be small enough (150 nm to 250 nm) for use as a nanodrug delivery system. The optimised SLN formulation with smaller particle size as compared to sodium deoxycholate-stabilized SLNs can be obtained using Gelucire® 50/13 as surfactant. The entrapment efficiency and % drug loading of these SLNs was found to be 75% and 7%, respectively, which is better than sodium deoxycholate-stabilized SLNs. The SLNs have relatively lower crystallinity as compared to the bulk lipid. The molecular solid solution of paliperidone was confirmed by XRD, DSC and FTIR analysis.
Acknowledgements
The authors acknowledge NIT Hamirpur for providing the laboratory facilities and MHRD (Govt. of India) for financial support. The authors also acknowledge IIT Mandi for providing DSC and TEM facilities.
Notes and references
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Footnotes |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra03107e |
‡ Present address: School of Engineering, Indian Institute of Technology Mandi, Himachal Pradesh-175005, India. |
|
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