Poly Ethylene Glycol-Stearate polymer in the design of nano-drug delivery system for oral administration by curcumin

Journal of Nanoanalysis

دوره 9، شماره 3، آذر 2022، صفحه 229-239   

نوع مقاله: Original Research Paper

شناسه دیجیتال (DOI): 10.22034/jna.2022.1944965.1279

نویسندگان

Marzihe Shahbazi¹؛ Elham Rostami^{* 1}؛ maryam kolahi²؛ alireza kiasat¹

¹Department of Chemistry, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran

²Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran

چکیده

In this work, Poly Ethylene Glycol- Stearate (PEG-SA) was used to prepare coated solid lipid nanoparticles (NPs) with loading curcumin extracted by Turmeric powder (cur-polymer coated-SLNs) by micro emulsification method. Evaluation of the release kinetic of prepared nanoparrticle was resulted. Particle size, zeta potential and polydispersity index were evaluated by Photon Correlation Spectroscopy (PCS). The particle size and zeta potential of cur PEG coated-SLNs had been measured as 153 nm. Differential scanning calorimetric indicated that the majority of curcumin loaded in PEG-NP was in amorphous state which is desirable for drug delivery. Drug entrapment efficiency (EE) was obtained 99%. The modification procedure led to a reduction in the zeta potential values, varying from -40.0 mV for the uncoated particles to -23 mV for that of (PEG-SA)-coated NP. FT-IR spectra and HPLC analysis of plain SLNs and pure curcumin exhibit no peak shifting and no loss of characteristic functional group peaks. Shape and surface morphology of particles were determined by transition electron microscopy and scanning electron microscopy that revealed spherical shape of nanoparticles. In vitro curcumin release of (PEG-SA)-coated SLNs and SLNs were showed the slight decrease performed for PEG-SA-SLNs one because of coating impact of covering layer.

کلیدواژه‌ها

Solid Lipid Nanoparticles؛ curcumin؛ extraction؛ modification؛ drug release

اصل مقاله

INTRODUCTION

Recently, expanding consideration was routed to solid lipid nanoparticles (SLNs), on account of their biodegradability and capacity to ensnare a diversity of natural dynamic mixes (Biologically active compounds) [1], in the zone of changed drug delivery technology to defeat disadvantages in traditional measurements [2-4]. In addition, SLNs indicate a selective alternative to the conventional colloidal drug delivery systems [3], for example, liposomes, emulsions, and polymeric small scale and nanoparticles (NPs), since the issues identified with modern creation scale-up, sanitization, and mid-term storage are decreased [4-6]. SLNs are made out of a solid lipid matrix regularly secured with a surfactant or phospholipid layer; for sure, their fundamental benefit of drug delivery (below 1000 nm) and to the nearness of physiological or biocompatible lipids or lipid particles, strong at room conditions, with a background marked by immune utilization in treatment. Lipophilic, just as hydrophilic medications (according to hydrophobic particle matching or lipophilic ace medication planning), can be stacked in SLNs with high ensnarement effectiveness. In the course of the most recent 20 years, a few strategies for SLN creation have been completely portrayed in writing: high-pressure homogenization [4-6], hot micro emulsions [5], dissolvable based techniques, for example, dissolvable infusion , dissolvable dispersion or dissipation from oil in water (O/W) emulsion, and unsaturated fat coacervation [6-8]. This amphiphilic block polymer has been extensively evaluated for toxicity in animals and is widely used in pharmaceutical formulations and cosmetics, generally regarded as an essentially nontoxic and nonirritant material [9]. A few examinations have been additionally progressively centered on improving their strength in body liquids after organization by coating particles by hydrophilic polymers like poly (ethylene) glycol (PEG) subsidiaries [10,11,12].

Curcumin, a phenolic compound from the plant Curcuma Longa as a customary zest have numerous pharmacological exercises including: anti-diabetic, anti-inflammatory, anti-cancer, anti-oxidant, antibacterial, anti-HIV and anti-aging activity and hepato defensive action just as cardiovascular advantages [13]. Curcumin is an ineffectively water-dissolvable medication with low oral bioavailability and touchy to photo degradation. Utilization of lipids for bioavailability improvement of poor dissolvable medications is promising. Since the vast majority of the segments associated with plan of solid lipid nanoparticles are of common source, they are perfect with segments of organic layer, and for the most part less toxicological hazard is encountered. The principle favorable circumstances of this examination is to adjust the outside of strong lipid NPs for expanding intestinal ingestion and diminishing nanoparticles take-up by invulnerable framework because of incomplete balance of solid negative or positive charge on nano carrier surface [14-16]. In addition, surface alteration of strong lipid NPs by covering a hydrophilic polymer for example PEG-SA resulted in improvement of surface hydrophilicity of NPs which brings about augmentation of nanoparticles transmucosal transport for tranquilize conveyance by nasal, oral and visual way [11,13,17]. Controlled discharge effectiveness and intestinal the wrapped drug obliteration in the stomach and digestive system and likely ingestion of drug through the intestinal mucosa are two diverse assimilation models of medication [18-20]. PEG-SA polymer possessing bioadhesive property can help in devising a delivery system capable of delivering a bioactive agent for a prolonged period of time at a specific delivery site. The intestinal ingestion of medication was accepted as a notable and particular way. Up to now, there is no report on using PEG-SA coated solid lipid nanoparticles carrier for curcumin oral administration therefore future clarification of the parameters governing particle uptake will surely lead to the design of new and more efficient colloidal carriers.

The main approach of the present study is to develop a new nanoparticulate carrier for a hydrophobic drug to be used in oral administration. Colloidal drug carriers prepared from solid triglycerides have been presented as a promising alternative to polymer nanoparticles. The present work is aimed at developing surface modified lipid nanoparticles intended to encapsulate curcumin within their structure and to study their physicochemical properties and in vitro stability in gastrointestinal fluids. The final goal is to explore their potential as oral delivery vehicles for macromolecules. The new carrier is composed of a lipid core aimed to protect and control the release of the curcumin that is supposed to facilitate the interaction of the carrier with the intestinal mucosa and the further transport of the hydrophobic drug.

The present research is planned for creating surface altered lipid NPs proposed to encapsulate curcumin inside their framework and to examine their physicochemical features and in vitro dependability in gastrointestinal liquids. The last objective is to investigate their potential as oral conveyance vehicles for curcumin loaded by modified SLN. The novel carrier is made out of a lipid center intended to secure and control the release of curcumin that should encourage the cooperation of the transporter with the intestinal mucosa and the further vehicle of the hydrophobic medication.

 

METHODS AND MATERIALS

Instrument

Nano-suspension was prepared using the micro-emulsification technique. The following materials were obtained from the indicated sources and used in our study without further purification. Tripalmitin glyceride was purchased from Alfa Aesar (Germany), and palmitic acid from Sigma-Aldrich (St Louis, MO). Polysorbate 20 (Tween 20) and sucrose were obtained from Merck (Darmstadt, Germany). Curcumin purchased from Sigma Company. High-pressure liquid chromatography (HPLC) grade butanol and analytical grade chloroform and ethanol were also purchased from Merck. Other reagents were of analytical or HPLC grade. Double-distilled water was prepared in our laboratory.

The morphology and size of the PEG-SA-SLNs was analyzed by TEM (Zeiss-EM 10C-Germany) at an accelerating voltage of 80 kV fit for highlight point. Prior to examination, the examples were weakened 1:2 and applied on a carbon-coated grid, at that point recolored with uranyl acetate acid derivation for 30s and set on copper g Differential Scanning Calorimetry (DSC) examination of NP components and PEG-SA-SLNs were performed utilizing a Shimadzu DSC-50 outfitted with a Shimadzu warm analyzer TA-50 (Shimadzu, Japan) rids with films for perception. A warming amount of 10°C/min was utilized in the 0°C–300°C temperature extend. The potential interaction between the solid lipid core and incorporated drug was investigated using FT-IR studies (Perkin-Elmer).

Curcumin extracted and extract concentrations were determined using an HPLC system (LC-10AS Liquid Chromatograph, SCL-10A System Controller, SIL-10AV UV-Vis Detector, C-R6A Chromatopac, shimadzu, Japan).

 

Preparation of lipid NPs and lyophilization

Gasco et al. created SLN arrangement methods which depend on the dilution of microemulsions [21, 22]. Both lipid NPs were delivered by the strategy portrayed by microemulsion technique. In brief, NPs were prepared utilizing a hot liquefy Tripalmitin glyceride lipid and palmitic acid, by stacking curcumin at a last grouping of 25 mg/mL. At that point, 0.04 mg of PEG-SA was added to the natural stage containing an emulsifier polysorbate 80, co-emulsifiers (butanol) and water. The hot microemulsion was scattered in cool water (2-3°) under mixing (750 rpm) [21]. Regular volume proportion of the hot microemulsion was balanced 1:10 to water [21]. The SLN mixture was then washed twice with water utilizing a membrane (cut off 10,000–12,000 Da) in ultrasonic cleaning tank due to the deletion of the extent of the surfactant atoms applied for getting the microemulsion [23-25].

Sucrose was utilized in the freeze-drying process as cryoprotectants at a centralization of 3 wt%. The suspension of lipid NPs solidified in a fluid sucrose arrangement at −70 ◦C overnight, and afterward as an example moved to the freeze-dryer (ZiRBuS innovation VaCo 5, D-37539) at −50 ◦C for 72 h, and then SLN powders were gathered for additional trials.

 

The stability of lipid NPs in simulated gastrointestinal media

1% (w/v) of NPs were incubation in HCL medium (0.063M) at pH 1.2. Optical Density (OD) was investigated at λ = 345 nm [13] previously and 1 h after incubation to assess the NPs aggregation and arrangement turbidity. The assessment of the strength of PEG-SA-SLNs and SLNs that incubated in acid solution for 1 h, additionally performed. At that point, NPs were isolated from the medium utilizing centrifugation at 5000 × g for 5 min. The size of NPs in the higher arrangement was estimated by Photon Coloration Spectroscopy (PCS) [20, 21, and 23].

 

The feature of lipid NPs

PCS (Nanotrac Wave II Instruments, UK) was utilized for the assessment of size and zeta potential was estimated by photon relationship spectroscopy (Nanotrac Wave II Tools, UK). Examination of surface morphology of PEG-SA-SLNs was accomplished by scanning electron microscopy (SEM) (SEM, KYKY-EM3200, China).

 

Determining Percent Entrapment Efficiency and Drug-Loading Capacity

The proficiency of drug entrapment and drug loading were inspected by deciding the convergence of curcumin in the supernatant of ultra-centrifuged Nps arrangement. NPs suspension were centrifuged at 15,000 g for 45 min to isolate the unentrapped tranquilize. Supernatant was decanted and assimilation of supernatant arrangement was analyzed by Ultraviolet spectrophotometer at 345 nm (Agilent 8453) [13, 14]. At that point, the amount of free curcumin was accomplished. The curcumin entanglement proficiency and medication stacking of curcumin in the PEG-SA-SLNs and SLNs were considered as follows:

 

where, EE is entrapment effectiveness, DL is rug loading, and Wa, Ws, and W_L are the heaviness of drug included in the system, broke down weight of drug in the supernatant, and weight of lipid included into the system, separately [24-26].

 

In vitro release of curcumin from lipid NPs

The present investigation which directed by a dialysis bag was for the assessment of the measure of curcumin release [13]. A dialysis bag with a molecular weight cutoff of 12,000 Da was set on diffusion cell. The receptor medium was 50 mL in volume and made out of a fluid arrangement of physiological saline, phosphate cradle arrangement, which blended by an attractive stirrer at 750 rpm to homogenize the medium (pH=7.4). 2 ml of prepared SLNs suspension was poured in the receptor part of diffusion cell. The medium temperature was controlled at 37°C. 2 ml of the phosphate buffer was tacked by a syringe needle and a similar volume of new phosphate buffer was supplanted at certain time spans. The samples were dissected utilizing a spectroscopic technique as depicted beforehand [24, 25, and 27]. The analyses were rehashed multiple times for alleviation of blunders.

 

In vitro release kinetics calculation

In this dissolution study, model-dependent methodologies utilized for correlation of disintegration profiles. In model-dependent methodologies, discharge information was fitted to five dynamic models including the zero-order (Eq. 3), first-order [28] (Eq. 4), Higuchi grid (Eq. 5), Krosmeyer–Peppas [29] (Eq. 6), and Hixson–Crowell (Eq. 7) discharge conditions, so as to find the best fit condition [28, 30].  Zero-order (Eq. 3) data is plotted as a cumulative percentage drug released versus time.

 

Where C is the concentration, K₀ is the zero-order rate constant expressed as concentration/time, and t is time in hours [28-30]. First order (Eq. 4) is obtained by plotting log cumulative percentage drug released versus time [29].

 

Where C₀ is the initial concentration of the drug, K is the first-order rate constant, and t is the time.

 

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 [27].

The mechanism of drug release is evaluated by plotting the percentage of drug released versus log time according to Krosmeyer–Peppas equation. Exponent n indicates the mechanism of drug release calculated through the slope of the straight line. Researchers used the 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 [28-30].

 

Scientists reported that 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:

 

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 Hixson-Crowell rate equation [28, 30-31]

 

RESULTS AND DISCUSSION

Preparation of lipid NPs, drug entrapment efficiency, and loading capacity

A wide range of drugs was fused in SLNs. The essential for getting an adequate loading capacity is an adequately high solvency of drug in the lipid melt. Moderately higher epitome effectiveness comprises one of the significant favorable circumstances of SLNs [14]. For computations of capture productivity and loading capacity, adjustment bends for the bright examines of curcumin led to five arrangements in the focus scopes of 1.3 × 10^–3 to 1.00 × 10^–5mol/L; embodiment proficiency and drug loading were 99.00% and 41%, individually. The high ensnarement proficiency of drug is believed to be the consequences of the lipophilic features and high similarity between drug and lipid [23, 25, and 32]. Fig. 1 showed the appearance difference between SLNs loaded by curcumin (a) curcumin (b) in water.

 

Characterization of SLNs

A decrement in zeta potential can be plainly observed because of SLNs adjustment by PEG-SA from - 40 mV for SLNs to - 23 mV for those provided with PEG-SA (Table 1). The nearness of PEG-SA causes a decrease of surface charge. Because the adsorption of steric stabilizers will decrease the zeta potential due to the shift of the shear plane of the particle [33]. The Zeta potential outcomes show that a solid negative charge of SLN surface is incompletely neutralized with coating. As the NPs size is a significant thing for particles to be consumed by the intestinal mucosa, the conglomeration of particles will moderate the availability of intestinal mucosa [27]. The consequences of soundness of the NPs in gastric media show that the low pH of the gastric medium and the pancreatic proteins in intestinal medium are answerable for the genuine conglomeration and degradation of SLNs. In this work, Colloidal drug transporters arranged from strong triglycerides have been introduced as a promising option in contrast to polymer NPs. PEG-SA planned for creating surface changed lipid NPs proposed to embody strong triglycerides inside their structure and to contemplate their physicochemical properties and in vitro dependability in gastrointestinal liquids. The last objective is to investigate their potential as oral conveyance vehicles for macromolecules. PEG-SA-SLNs were progressively steady as their polymer covering layer forestalled collection of NPs in gastrointestinal media (acidic medium) [21]. So that research whether pH is an essential role in the accumulation of SLNs recognized in the gastric medium (acidic medium), the solidness of SLNs in an acidic medium (pH 1.2) was estimated by evaluating the turbidity now and again 0 and 1 h post-incubation [21, 23]. SLNs indicated an expansion in turbidity during the examination. No adjustment in turbidity was seen on account of PEG-SA-SLNs (Fig. 2). Likewise, polymer coating prompted abatement in the burst discharge impact because of diminishing the surface association. Following the underlying burst, the systems gave a consistent and moderate arrival of the curcumin [34, 35]. This moderate discharge was credited to the proclivity of the hydrophobic drug for the lipids just as the nonattendance of debasement of the lipid grid under the in vitro discharge conditions [21, 36, and 37].

TEM picture of the examples containing drug loaded PEG-SA-SLNs are shown in Fig. 3 where in the particle size of PEG-SA-SLNs are in concurrence with the outcomes got with PCS and SEM. Moreover, the imaging investigations demonstrated that these particles show a circular shape, and a thick lipid matrix without accumulation [18]. The consequences of PCS, TEM and SEM pictures of the PEG-SA-SLNs are introduced in Figs. 3, 4, 5 and Table 1, separately. TEM and SEM strategies affirm that the NPs are round fit as a fiddle and very much scattered and isolated on a superficial level. The spans of the NPs dictated by PCS are in acceptable concurrence with TEM results. The measurement controlled by PCS is around 150 nm, which is fundamentally the same as the information got by TEM. The normal breadth dictated by the two PCS and TEM was found around 150 nm. TEM pictures affirmed that the NPs were roundabout to ellipsoidal fit as a fiddle with a smooth surface [35-37].

Due to Table 1, the size of SLNs increments after incubation in gastric medium while the PEG-SA-SLNs are pitifully developed [34-36]. This strategy was chosen since it made the exemplification of curcumin plausible. Moreover, the outside of the particles can be altered through the joining of Tween 20 or the lipid derivative PEG-SA into the definition [18]. This alteration prompted a decrease in the zeta likely qualities, shifting from −40 mV for SLNs to −23 mV for those provided with PEG-SA. Consequences of the solidness of the NPs in gastric and intestinal media show that the low pH of the gastric medium and the pancreatic compounds in intestinal medium are liable for the broad collection and corruption of SLNs (80% degradation in 1 h) [18, 23]. Interestingly, PEG-SA- SLNs were increasingly steady, as their polymer coating layer completely forestalled total in the two media and essentially decreased pancreatin-initiated corruption (40% around in 1 h. In the other word, the PEG-SA layer can mostly cover the negative surface charge of NPs [18, 19, and 38]. Besides, from the data of particle size, it may very well be presumed that the obstruction of NPs against total and lipolytic proteins is expanded by diminishing particle size [18, 19, and 34]. DSC thermograms for curcumin, tripalmitin glyceride, physical blend of curcumin, tripalmitin glyceride, palmitic corrosive, PEG SA, and lyophilized PEG-SA- SLNs are appeared in Fig. 6. Curcumin powder had a sharp melting top at 183°C. DSC data did not show the melting peak of curcumin in the lyophilized PEG-SA- SLNs suspension. In any case, we saw the melting peak of curcumin in the physical blend. This recommended curcumin sodium that may be available in an amorphous state.

In FT-IR studies (Fig. 7), Curcumin showed its signature peaks at 3414 cm⁻¹ (phenolic O-H stretching vibration), 1625 cm⁻¹ (aromatic moiety C=C stretching), 1585 cm⁻¹ (benzene ring stretching vibrations), 1512 cm⁻¹ (C=O and C=C vibrations), 1428 cm⁻¹ (olefinic C-H bending vibrations), 1282 cm⁻¹ (aromatic C–O stretching vibrations), 1031 cm⁻¹ (C–O–C stretching vibrations) [39]. The peaks at 1293 cm^-1 and 940 cm^-1 are corresponding to the in-plane and out-plane bending vibration of the OH group of PA. The symmetric peaks at 719 and 688 cm^-1 correspond to the swinging vibration of the OH functional group. The peaks appeared at 3430 cm^-1 are related to the tensile vibrations of alcoholic OH and the peaks at 2918 and 2853 cm^-1 are related to the tensile vibrations of aliphatic CHs. C=O peaks appeared at 1737 cm^-1 and the peaks observed at 1180 cm^-1 are related to C-O tensile vibrations. Long peaks in 2919 and 2878 cm^-1 are related to the tensile vibrations of alkane CHs. Also, C=O peak is shown at 1737 cm^-1 and the strong tensile vibrations related to C-O are observed at 1111 cm^-1  [40, 28].

The FT-IR spectra of NP components and Curcumin NPs are presented in Fig. 7. FT-IR spectra of plain NPs and pure curcumin exhibit no peak shifting and no loss of characteristic functional group peaks. Therefore, our FT-IR analysis detected no interaction between curcumin and solid lipid core, suggesting that curcumin is compatible with the lipid component of NPs as a drug formulation.

The results of high performance liquid chromatographic analysis for the extract (a) and extracted curcumin (b) showed three peaks at specific retention times. The peak of curcumin in the extract samples and the extracted curcumin are shown at the retention times of 16 and 19 minutes, respectively. In the study of the area of these peaks, the amount of pure curcumin in the extract was estimated to be 39.8% and the curcumin in the extracted curcumin was estimated to be 81.7%. The results of this analysis showed a 42% increase in the purity of curcumin extract powder compared to the resulting extract (Fig. 8).

 

In vitro release characterization

As it is clear in Fig. 9, contrast of two discharge percent plots of PEG-SA-SLNs and SLNs show the slightest decrease performed for PEG-SA-SLNs because of the coating impact of covering layer [34, 36]. The underlying burst discharge diminishes because of higher thickness of the coated NPs dependent on Fickian diffusion [36, 37]. Covering surface prompts a lessening in the burst discharge impact contrasted with SLNs in light of the fact that the adsorbed curcumin on lipid surface step by step discharges from PEG-SA-SLNs. To be sure, the coating layer obstruction against diffusion of curcumin prompts decrease of drug release.

 

In vitro drug release kinetic characterization

The release data were dissected utilizing the accompanying Higuchi dynamic condition: [30] Regarding the discharge model of PEG-SA-SLNs, it was discovered that the normal drawn out discharge for curcumin was fitted to Higuchi’s square root model, as announced for drug loaded PEG-SA-SLNs frameworks [16, 23].

The relapse coefficient (R²) of discharge data of coated NPs acquired by bend fitting technique on different active models is accounted for in Table 2.

Direct fits confirmed that the release profile of curcumin from homogenous and granular matrix systems is dissemination controlled. In view of the R² value in Table 2, the best information wellness was offered by Higuchi model proposing a dissemination controlled instrument for drug release [34].

 

CONCLUSION

The particular point of our work was to grow new lipid NP carriers that may be appropriate for oral administration of hydrophobic medications. Modification of the nanocarrier surface resulted in a reduction in the values ​​of the zeta potential, varying from -0.40 mV for unmodified carriers to -23 mV for modified carriers. These results showed that a strong negative charge of SLN surface is partially neutralized by coating. The results of scanning electron microscopy and transmission electron microscopy showed that nanocarrier is spherical and segregated. The results of DSC confirmed the amorphous nature of curcumin in the nanocarrier and also showed that curcumin has no interaction with other nanocarrier components. The results of high performance liquid chromatography showed that the amount of curcumin in extract and extracted curcumin was obtained in comparison with standard curcumin 39.8% and 81.7%. The encapsulation efficiency of the nanocarrier was high and about 99%.  Examination of the release of prepared nanocarrier in vitro showed a decrease in the initial explosive release of modified carriers, as well as a slight decrease in the release of curcumin for these carriers due to the coating effect on the nanocarrier surface. The results of stability of nanocarrier in acidic medium showed low pH as responsible for increasing the size, aggregation and degradation of unmodified lipid nanocarriers. Nanocarriers modified with PEG-SA were more stable due to the polymer coating layer that prevents the aggregation of nanocarriers, so it is possible that PEG-SA reduces the destruction of their lipid nucleus by encapsulating the carriers be in the environment of the stomach and intestines. Studies on the stability of nanocarrier at 25 ± 2 ° C for 9 months in aqueous suspension showed minimal changes in size, polydispersity index, curcumin leakage and changes in appearance.

From the acquired outcomes for drug release, the underlying burst discharge diminishes because of higher thickness of altered NPs dependent on Fickian diffusion. Concerning discharge model everything being equal, it was discovered that the delayed normal discharge for curcumin was well fitted to Higuchi’s square root model, as has been accounted for drug loaded PEG-SA-SLNs systems.

 

CONFLICT OF INTEREST

The authors declare no conflict of interest.

 

ACKNOWLEDGEMENT

The authors gratefully acknowledge financial support (Grant No.: SCU.SC98.31316) from the Shahid Chamran University of Ahvaz.

مراجع

[1] Üner M, Yener G (2007) Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int. J. Nanomed 2:289

[2] Müller RH, MaÈder K, Gohla S ) 2000( Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art Eur .J .Pharm .Biopharm 50:161-177
https://doi.org/10.1016/S0939-6411(00)00087-4

[3] Lingayat VJ, Zarekar NS, Shendge RS (2017) Solid lipid nanoparticles: a review. J. Nanosci. Nanotechnol 2:67-72

[4] Carbone C, Cupri S, Leonardi A, Puglisi G, Pignatello R) 2013( Lipid-based nanocarriers for drug delivery and targeting: a patent survey of methods of production and characterization. Pharm. Pat. Anal 2:665-677
https://doi.org/10.4155/ppa.13.43

[5] Schubert MA, Müller-Goymann CC (2003) Solvent injection as a new approach for manufacturing lipid nanoparticles-evaluation of the method and process parameters. Eur. J. Pharm. Biopharm 55:125-131
https://doi.org/10.1016/S0939-6411(02)00130-3

[6] Cassano R, Ferrarelli T, Mauro MV, Cavalcanti P, Picci N and Trombino S (2016) Preparation, characterization and in vitro activities evaluation of solid lipid nanoparticles based on PEG-40 stearate for antifungal drugs vaginal delivery. Drug Deliv 23:1047-1056
https://doi.org/10.3109/10717544.2014.932862

[7] Cassano R, Trombino S (2019) Solid Lipid Nanoparticles Based on L-Cysteine for Progesterone Intravaginal Delivery. Int. J. Poly.Sci 60:45-55
https://doi.org/10.1155/2019/8690145

[8] Khan I, Saeed K, Khan I (2019) Nanoparticles: Properties, applications and toxicities. Arab. J. Chem 12:908-931
https://doi.org/10.1016/j.arabjc.2017.05.011

[9] Banshoya K, Nakamura T, Tanaka T, Kaneo Y (2020) Coenzyme Q10-polyethylene glycol monostearate nanoparticles: an injectable water-soluble formulation. Antioxidants 9:86
https://doi.org/10.3390/antiox9010086

[10] Battaglia L, Gallarate M, Cavalli R, Trotta M (2010) Solid lipid nanoparticles produced through a coacervation method. J. Microencapsul 27:78-85
https://doi.org/10.3109/02652040903031279

[11] Trombino S, Russo R, Mellace S (2019) Solid lipid nanoparticles made of trehalose monooleate for cyclosporin-A topic release. J Drug Deliv Sci Technol 49:563-569
https://doi.org/10.1016/j.jddst.2018.12.026

[12] Yuan H, Miao J, Du YZ, You J, Hu FQ, Zeng S (2008) Cellular uptake of solid lipid nanoparticles and cytotoxicity of encapsulated paclitaxel in A549 cancer cells. Int. J. Pharm 348:137-145
https://doi.org/10.1016/j.ijpharm.2007.07.012

[13] Prado-Audelo D, María L, Caballero-Florán IH, Meza-Toledo JA, Mendoza-Muñoz N, González-Torres M, Floran B, cortes H, Leyva-Gómez G (2019) Formulations of curcumin nanoparticles for brain diseases. Biomolecules 9:56
https://doi.org/10.3390/biom9020056

[14] Ghalandarlaki N, Alizadeh AM, Ashkani-Esfahani S (2014)‏ Nanotechnology-applied curcumin for different diseases therapy. Biomed Res. Int 2014
https://doi.org/10.1155/2014/394264

[15] Baek JS, Cho CW (2017) Surface modification of solid lipid nanoparticles for oral delivery of curcumin: Improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake. Eur. J. Pharm. Biopharm 117:132-140 https://doi.org/10.1016/j.ejpb.2017.04.013

[16] Maiti P, Paladugu L, Dunbar GL (2018) Solid lipid curcumin particles provide greater anti-amyloid, anti-inflammatory and neuroprotective effects than curcumin in the 5xFAD mouse model of Alzheimer’s disease. BMC Neurosci 19:1-18
https://doi.org/10.1186/s12868-018-0406-3

[17] Liu Z, Okeke CI, Zhang L, Zhao H, Li J, Aggrey, M O, Guo L (2014) Mixed polyethylene glycol-modified breviscapine-loaded solid lipid nanoparticles for improved brain bioavailability: preparation, characterization, and in vivo cerebral microdialysis evaluation in adult Sprague dawley rats. AAPS Pharm SciTech 15:483-496
https://doi.org/10.1208/s12249-014-0080-4

[18] Deljoo S, Rabiee N, Rabiee M (2019) Curcumin-hybrid nanoparticles in drug delivery system. Asian j. nanosci. mater 2:66-91

[19] Bocca C, Caputo O, Cavalli R, Gabriel L, Miglietta A, Gasco MR Phagocytic uptake of fluorescent stealth and non-stealth solid lipid nanoparticles. Int. J. Pharm 175:185-193
https://doi.org/10.1016/S0378-5173(98)00282-8

[20] Ganesan P, Ramalingam P, Karthivashan G, Ko YT, Choi DK (2018) Recent developments in solid lipid nanoparticle and surface-modified solid lipid nanoparticle delivery systems for oral delivery of phyto-bioactive compounds in various chronic diseases. Int. J. Nanomed 13:1569
https://doi.org/10.2147/IJN.S155593

[21] Garcia-Fuentes M, Prego C, Torres D, Alonso MJ (2005) A comparative study of the potential of solid triglyceride nanostructures coated with chitosan or poly (ethylene glycol) as carriers for oral calcitonin delivery. Eur. J. Pharm. Sci 25:133-143
https://doi.org/10.1016/j.ejps.2005.02.008

[22] Damge C, Michel C, Aprahamian M, Couvreur P, JP Devissaguet JP (1990) Nanocapsules as carriers for oral peptide delivery. J. Control. Release 13:233-239
https://doi.org/10.1016/0168-3659(90)90013-J

[23] Garcia-Fuentes M, Alonso MJ, Torres D (2005) Design and characterization of a new drug nanocarrier made from solid-liquid lipid mixtures. J. Colloid Interface Sci 285:590-598‏
https://doi.org/10.1016/j.jcis.2004.10.012

[24] Garcia-Fuentes M, Torres D, Alonso MJ ) 2005 (New surface-modified lipid nanoparticles as delivery vehicles for salmon calcitonin. Int .J. Pharm 296:122-132
https://doi.org/10.1016/j.ijpharm.2004.12.030

[25] Florence AT (1997) The oral absorption of micro-and nanoparticulates: neither exceptional nor unusual. Pharm. Res 14:259-266
https://doi.org/10.1023/A:1012029517394

[26] Subedi RK, Kang KW, Choi HK (2009) Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin. Eur. J. Pharm Biopharm. 37:508-513
https://doi.org/10.1016/j.ejps.2009.04.008

[27] Garcıa-Fuentes M, Torres D, Alonso MJ (2003) Design of lipid nanoparticles for the oral delivery of hydrophilic macromolecules. Colloids Surf B Biointerfaces 27:159-168
https://doi.org/10.1016/S0927-7765(02)00053-X

[28] Singhvi G, Singh M )2011 ( In-vitro drug release characterization models. Int. J. Pharm. Sci. Res 2:77-84

[29] Costa P, Lobo JMS) 2001 (Modeling and comparison of dissolution profiles. Eur. J. Pharm. Biopharm 13:123-133
https://doi.org/10.1016/S0928-0987(01)00095-1

[30] Barzegar-Jalali M, Adibkia K, Valizadeh H, Shadbad, A. Nokhodchi MRS, Omidi Y, Somayeh H, Nezhadi Gh, Hasan M,) 2008( Kinetic analysis of drug release from nanoparticles. Int. J. Pharm. Pharm. Sci 11:167-177‏
https://doi.org/10.18433/J3D59T

[31] Varelas CG, Dixon DG, Steiner CA )1995( Zero-order release from biphasic polymer hydrogels. J. Control. Release 34:185-192‏
https://doi.org/10.1016/0168-3659(94)00085-9

[32] Li X, Lin X, Zheng L, Yu L, Lv F, Zhang Q, Liu W (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 317:352-359
https://doi.org/10.1016/j.colsurfa.2007.11.011

[33] Li X, Lin X, Zheng L, Yu L, Lv F, Zhang Q, Liu W (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 Physicochem Eng Asp, 317: 352-359
https://doi.org/10.1016/j.colsurfa.2007.11.011

[34] Ramalingam P, Ko YT (2016) Improved oral delivery of resveratrol from N-trimethyl chitosan-g-palmitic acid surface-modified solid lipid nanoparticles. Colloids Surf B Biointerfaces 139:52-61‏
https://doi.org/10.1016/j.colsurfb.2015.11.050

[35] Zhang N, Ping QN, Huang GH, Xu WF ) 2005( Investigation of lectin-modified insulin liposomes as carriers for oral administration. Int. J. Pharm 294:247-259‏
https://doi.org/10.1016/j.ijpharm.2005.01.018

[36] Kashanian S, Azandaryani AH, Derakhshandeh K ) 2011 (New surface-modified solid lipid nanoparticles using N-glutaryl phosphatidylethanolamine as the outer shell. Int. J. Nanomed 6:2393
https://doi.org/10.2147/IJN.S20849

[37] Jani P, Halbert GW, LangrIdge J, Florence AT Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size dependency. J. Pharm. Pharmacol 42:821-826
https://doi.org/10.1111/j.2042-7158.1990.tb07033.x

[38] Lu X, Howard MD, Mazik M, Eldridge J, Rinehart JJ, Jay M, Leggas M (2008) Nanoparticles containing anti-inflammatory agents as chemotherapy adjuvants: optimization and in vitro characterization. AAPS J 10:133-140
https://doi.org/10.1208/s12248-008-9013-z

[39] Liu W, Hu M, Liu W, Xue C, Xu H, Yang X (2008) Investigation of the carbopol gel of solid lipid nanoparticles for the transdermal iontophoretic delivery of triamcinolone acetonide acetate. Int. J. Pharm 364:135-141‏
https://doi.org/10.1016/j.ijpharm.2008.08.013