Solid Lipid Nanoparticles Formulations Research Articles

Effect of lipid types on physicochemical characteristics, stability and antioxidant activity of gamma-oryzanol-loaded lipid nanoparticles

In the present study gamma-oryzanol, an antioxidant, was incorporated into three different types of solid lipid: wax, triglycerides, a mixture of glycerides as solid lipid nanoparticles (SLN) and liquid lipid (Miglyol 812) as nanoemulsion (NE). Instability was found only from NE due to its significant increase in particle size and decreased entrapment efficiency (%EE) at a storage temperature of 45°C. Solid lipid type in SLN plays an important role only on %EE, but not chemical stability. A decrease in crystallinity of SLN was observed with the incorporation of gamma-oryzanol and low recrystallization index were found with two glycerides-based SLN. The in vitro release studies demonstrated that a biphasic release pattern fitted well with the Higuchi model of SLN formulations. In comparison, nearly constant release was observed in NE comprised of similar composition. Wax-based SLN demonstrated the lowest cytotoxicity. NE, wax-based SLN and a mixture of glycerides-based SLN were considered to enhance the antioxidant activity of gamma-oryzanol.

Membrane-assisted production of S1P loaded SLNs for the treatment of acne vulgaris

The incorporation of the sparingly soluble drug sphingosine-1-phosphate (S1P) into solid lipid nanoparticle (SLN) formulations using a ceramic membrane-assisted emulsification technique was investigated. SLNs have been used as an alternative to emulsions and liposomes in cosmetic and pharmaceutical preparations for the last two decades. They were prepared by replacing the liquid lipid part of the emulsions with a lipid part, which is solid at room temperature and/or at body temperature. The influence of a number of parameters on the particle size and size distribution of formulation and on the lipid flux were issued here. The chosen experiment parameters were: Lipid concentration varied from 5 to 20% w/w at various trans-membrane pressures (4–6 bar) and at aqueous phase cross-flow velocities varied from 2 to 12.5 m/s. A mono-channel ceramic membrane with a pore size of 0.2 µm and a 0.4 µm 19-channel membrane were used. It was shown that the investigated membrane system allows the preparation of SLNs with a mean particle size between 0.2 and 1 µm. The advantages of using a membrane-supported process are excellent scaling-up abilities and the control of the particle size through an appropriate selection of process parameters such as aqueous phase cross-flow velocity, lipid phase pressure and membrane properties.

Development of Solid Lipid Nanoparticles of Lamivudine for Brain Targeting

The objective of present investigation was to enhance brain penetration of Lamivudine, one of the most widely used drugs for the treatment of AIDS. This was achieved through incorporating the drug into solid lipid nanoparticles (SLN) prepared by using emulsion solvent diffusion technique. The formulations were characterized for surface morphology, size and size distribution, percent drug entrapment and drug release. The optimum rotation speed, resulting into better drug entrapment and percent yield, was in the range of 1000-1250 r/min. In vitro cumulative % drug release from optimized SLN formulation was found 40-50 % in PBS (pH-7.4) and SGF (pH-1.2) respectively for 10 h. After 24 h more than 65 % of the drug was released from all formulations in both mediums meeting the requirement for drug delivery for prolong period of time.

Rheological and morphological characterizations on physical stability of gamma-oryzanol-loaded solid lipid nanoparticles (SLNs)

In the present study, gamma-oryzanol was incorporated into glycerol behenate (Compritol 888 ATO) nanoparticles (SLNs) at 5 and 10% (w/w) of lipid phase. Increasing lipid phase concentration resulted in increased consistency and particle diameter of SLNs. Upon storage over 60 days at 4, 25 and 40 °C, the instability was observed by rheological analysis for all samples due to the formation of gelation. Rheological measurement revealed the increase in storage modulus and critical stress during storage at all temperatures. However, at 40 °C, the pronounced instability was observed from the highest increase in storage modulus and a formation of rod-like network structure from scanning electron micrographs. An increase in crystallinity, determined by differential scanning calorimetry, was also found during storage at all temperatures, confirming the instability of SLNs. Particle diameters and zeta potentials of both concentrations at all storage conditions failed to explain the observed instability. These investigations may help to develop formulations of solid lipid nanoparticles, which are optimized with respect to the desired rheological properties.

The effect of glycolic acid monomer ratio on the emulsifying activity of PLGA in preparation of protein-loaded SLN

Our previous work demonstrated that lactic/glycolic acid copolymer (PLGA) was an efficient emulsifier for the primary w/o emulsion in the formulation of protein-loaded solid lipid nanoparticles (SLN) by w/o/w double emulsion-solvent evaporation technique. In this work, the effect of PLGA composition on the emulsifying activity was studied with PLGA of different lactic/glycolic acid ratios (90/10, 75/25, 50/50). The results demonstrated that the glycolic acid monomer ratio significantly affected the emulsifying activity of PLGA. Increasing the glycolic acid monomer ratio from 10% to 50% decreased the minimum PLGA content needed to produce stable w/o emulsions. With same PLGA contents, increase of the glycolic acid monomer ratio increased the stable time of the w/o emulsion, yielded smaller and narrower-distributed SLN, and enhanced the encapsulation efficiency and loading capacity.

Formulation and Evaluation of Lidocaine Lipid Nanosystems for Dermal Delivery

The objective of the present investigation was to formulate solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for improving the dermal delivery of a local anesthetic agent lidocaine (LID). SLN and NLC were characterized for particle size distribution, polydispersity index, entrapment efficiency, X-ray powder diffraction pattern (XRD), thermal behavior by differential scanning colorimeter (DSC) and surface morphology by transmission electron microscopy (TEM). LID-loaded SLN and NLC were formulated into hydrogels for topical application. The in vitro permeation profiles of LID SLN gel, LID NLC gel, and a marketed LID formulation (Xylocaine gel) were evaluated by using guinea pig skin. The in vivo efficacy of LID SLN gel, LID NLC gel, and a marketed LID formulation (Xylocaine gel) gel was evaluated on guinea pig using pinprick test. LID SLN showed a particle size of 78.1 nm with a polydispersity index of 0.556, whereas LID NLC showed a particle size of 72.8 nm with a polydispersity index of 0.463. The entrapment efficiency of LID in both SLN and NLC was 97% and 95.9%, respectively. The TEM studies revealed the almost spherical nature of LID SLN and NLC formulations. The XRD and DSC studies of LID SLN suggested amorphization of drug in the carrier system. The SLN formulation was stable with respect to particle size, polydispersity, and entrapment efficiency for 6 months at 40 degrees C/75% relative humidity (RH). Negligible leakage was observed for the NLC formulation when stored for 1 month at 40 degrees C/75% RH. In vitro permeation studies indicated that LID SLN gel and LID NLC gel significantly sustained the LID release compared to that of Xylocaine gel. The in vivo efficacy results supported the results of the in vitro permeation studies wherein the LID SLN gel and LID NLC gel resulted in fivefold and sixfold increase in duration of anesthesia, respectively, compared to that of Xylocaine gel.

Formation of ion pairing as an alternative to improve encapsulation and stability and to reduce skin irritation of retinoic acid loaded in solid lipid nanoparticles

This work aims to investigate the influence of the formation of ion pairing between all- trans retinoic acid (RA) and a lipophilic amine (stearylamine; STE) on the drug encapsulation efficiency (EE) and stability of solid lipid nanoparticles (SLNs). The SLNs were characterized for EE and size. The EE and particle size were significantly improved and reduced, respectively, when the surfactant or co-surfactant concentration increased. However, while the formulation without STE allowed only 13% of RA encapsulation, the EE for RA–STE-loaded SLNs was 94%. The stability studies showed a significant decrease in EE for the SLNs without STE, while, for SLNs loaded with RA and STE, the EE remained constant after 360 days. The interactions among ion pairing components and the lipid matrix were investigated through small-angle X-ray scattering (SAXS). The SAXS analysis revealed the presence of RA in the crystalline form in SLNs without ion pairing, while crystalline RA was not observed in SLNs loaded with RA/amine. Skin irritation studies showed that the SLNs loaded with the ion pairing were significantly less irritating when compared to the marketed RA-cream. This novel SLN formulation represents a promising alternative for topical treatment of acne with RA.

Effect of poloxamer 188 on lymphatic uptake of carvedilol-loaded solid lipid nanoparticles for bioavailability enhancement

The present work aimed to investigate the effect of different concentrations of poloxamer 188, a surfactant, on lymphatic uptake of carvedilol-loaded solid lipid nanoparticles (SLNs) for oral bioavailability enhancement. Microemulsion technique was employed to prepare the SLN formulations having varying concentrations of poloxamer 188, which were subsequently subjected to various in vitro and in vivo evaluations to study their release pattern. On increasing the percentage concentration of poloxamer 188, the bioavailability decreased from 4.91- to 2.84-fold after intraduodenal administration in the male Wister rat. It could be attributed to the increase in particle size as well as reduction in hydrophobicity of SLNs. As indicated by pharmacokinetic data, the AUC(0–t) of all three (SLN) formulations (6.27 ± 0.24 μgh/mL with FZ-1, 4.13 ± 0.11 μgh/mL with FZ-2, and 3.63 ± 0.10 μgh/mL with FZ-3) were significantly higher (p < 0.05) than that of carvedilol suspension (1.27 ± 0.23 μgh/mL). These findings augur well with the possibility of enhancement of the oral bioavailability of drug, via the lymphatic system bypassing hepatic first pass metabolism.

Physicochemical Characteristics, Cytotoxicity, and Antioxidant Activity of Three Lipid Nanoparticulate Formulations of Alpha-lipoic Acid

Exogenously supplied alpha-lipoic acid (LA) has proven to be effective as an antioxidant. In an effort to develop a water-soluble formulation for topical administration, LA was formulated in the form of solid lipid nanoparticles (SLN), nanostructure lipid carriers (NLC), and nanoemulsion (NE) and characterized in terms of physical and biological properties. Mean particle size of 113, 110, and 121 nm were obtained for NE, NLC, and SLN, respectively, with narrow size distribution. Zeta potential was approximately in the range of -25 to -40 mV. Disc and spherical structures of nanoparticles were observed by cryo-scanning electron microscopy. Entrapment efficiency of LA in three formulations was found to be more than 70%. After 120 days of storage at 25 degrees C, physical stability of all formulations remained unchanged whereas the entrapment efficiency of SLN and NLC could be maintained, suggesting relative long-term stability. Prolonged release of LA formulation following the Higuchi model was found where a faster release was observed from NE compared with that of SLN and NLC. More than 80% of cell survivals were found up to 1 microM of LA concentrations. Antioxidant activity analysis demonstrated that all LA-loaded formulations expressed antioxidant activity at a similar magnitude as pure LA. These results suggest that chosen compositions of lipid nanoparticles play an important role on drug loading, stability, and biological activity of nanoparticles. Both SLN and NLC demonstrated their potential as alternative carriers for aqueous topical administration of LA.

Diazepam-Loaded Solid Lipid Nanoparticles: Design and Characterization

The aim of the present study was to investigate the feasibility of the inclusion of a water-insoluble drug (diazepam, DZ) into solid lipid nanoparticles (SLNs), which offer combined advantages of rapid onset and prolonged release of the drug. This work also describes a new approach to prepare suppositories containing DZ-loaded SLN dispersions, as potential drug carrier for the rectal route. Modified high-shear homogenization and ultrasound techniques were employed to prepare SLNs. The effect of incorporation of different concentrations of Compritol ATO 888 or Imwitor 900K and Poloxamer 188 or Tween 80 was investigated. Results showed that varying the type or concentration of lipid matrix or surfactant had a noticeable influence on the entrapment efficiencies, particle size, and release profiles of prepared SLNs. Differential scanning calorimetry and X-ray diffraction measurements showed that the majority of SLNs possessed less ordered arrangements of crystals than the corresponding bulk lipids, which was favorable for increasing the drug loading capacity. Transmission electron microscopy and laser diffractometry studies revealed that the prepared nanoparticles were round and homogeneous and 60% of the formulations were less than 500 nm. Additionally, SLN formulations showed significant (P < 0.05) prolonged release than DZ solution. The subsequent step encompassed the preparation and evaluation of SLN-based suppositories utilizing SLN formulations that illustrated optimal release profiles. The in vitro release of DZ from the suppositories prepared using DZ-loaded SLN dispersions (equivalent to 2 mg DZ) was significantly (P < 0.05) extended compared to suppositories containing 2 mg DZ free drug.

Solid lipid nanoparticle (SLN) formulations as a potential tool for the reduction of cytotoxicity of saponins.

The present pilot study explored the potential of solid lipid nanoparticles (SLN) to entrap saponins and reduce the membrane toxicity of these compounds. SLN composed of different types of solid lipid were prepared by the cold homogenisation technique. Combinations of anionic, cationic and non-ionic stabilisers were selected in order to obtain negatively, positively and neutrally charged SLN. Mean particle size and zeta potential of blank and saponin-loaded formulations were measured by Dynamic Light Scattering (DLS), Electrophoretic Light Scattering (ELS) and in vitro cytotoxicity on MRC-5 SV2 and J774 cells was assessed using a resazurin-based assay. The type of solid lipid used for the formulation influenced the mean particle size, while the zeta potential mainly depended on the kind of surfactant utilised. Blank SLN composed of hard fat and anionic or non-ionic surfactants did not result in cytotoxicity. After loading with saponin, the anionic hard fat SLN was found to be the optimal formulation.

Recent Advances and Patents on Solid Lipid Nanoparticles

Solid Lipid Nanoparticles (SLNs) have attracted increasing scientific and commercial attention as colloidal drug carriers during the last decade. They have emerged as a potential alternative compared to other colloidal systems like polymeric nanoparticles, liposomes and fat emulsions, as they have been claimed to combine their advantages but successfully overcome their drawbacks. SLN formulations are extensively developed and characterized for their in vitro and in vivo applications by various routes like parenteral, oral, pulmonary, ocular, and dermal. SLNs are being widely investigated as carriers for delivery of macromolecules like proteins, oligonucleotides and DNA. SLNs have already been taken up for medium and large scale production using two of its reported production methods. In fact, the first SLN based product has recently been introduced in the Poland market as a topically applied moisturizer. Newer methods for production of SLNs and their applications are being reported and patented. Nanostructured lipid carriers (NLC) are mixture of solid lipid and liquid lipid while Lipid Drug Conjugates (LDC) are water insoluble lipid carrier for loading of poorly lipid soluble drugs. These new generation of lipid nanoparticles have been claimed to overcome the shortcomings of SLNs. This article reviews the formulation, characterization, applications, and patents on the advances and research on SLNs, NLC and LDC.

Characterization of a new solid lipid nanoparticle formulation containing retinoic acid for topical treatment of acne

Solid lipid nanoparticles (SLNs) were characterized by differential scanning calorimetry (DSC) and powder diffraction. The DSC thermograms showed a slight reduction in the melting point of lipid matrix and a broadening of its melting peak, indicating an increased number of lattice defects in SLNs. X-ray powder diffraction data also revealed a slightly broader reflection for SLNs and the presence of X-ray peaks of the all-trans retinoic acid (RA) crystals outside of the lipid matrix of SLNs without stearylamine (STE). These data suggest the presence of an extensive association of ion pairing components (RA and STE), and indicate that the utilization of some specific types of compounds containing amine groups is an interesting approach to improve the encapsulation efficiency of RA in SLNs. The formation of the ion pairing is an interesting alternative for RA encapsulation in SLNs, improving the benefits obtained by the drug incorporation in lipid matrix (increased stability, controlled release, and targeting effect), which are important for the topical treatment of acne.

Formulations of retinyl palmitate included in solid lipid nanoparticles: characterization and influence on light-induced vitamin degradation

The therapeutic use of retinoids is still limited because of adverse effects and their chemical instability due to moisture, oxygen, acids, metals and light exposure. The purpose of this research was to investigate particulate carrier systems such as solid lipid nanoparticles (SLNs) for formulation of vitamin A palmitate. SLN (Precirol ATO 5, Pluronic F68, sodium cholate) were obtained using the hot homogenization technique and sonication, and were characterized using freeze fracture microscopy, dynamic light scattering, for size and zeta potential measurements and DSC. SLN formulation was optimized by modifying surfactant mixture composition to obtain better SLN physical stability and better vitamin entrapment efficiency. Preferential vitamin disposition on particle surface was evaluated by DSC analyses and release studies. RetP stability studies were carried out using normal phase HPLC on samples exposed continuously, in a darkened room, to the light of a filament lamp (400 lux) and the influence of the inclusion in solid lipid nanoparticles on retinyl palmitate (RetP) light-induced degradation was evaluated in the presence and absence of conservative agent (BHA, 3-tert-butyl-4-idroxi-anisole). The Precirol ATO 5 SLN formulation of RetP offers high entrapment efficiency but does not offer the possibility of preventing photo-degradation of RetP. In the nanoparticulate structures analyzed, RetP is preferentially distributed to the surface of the particles and partially exposed to external aqueous phase, thus no protection from RetP degradation can be evidenced in comparison to reference RetP solution (THF:water 9:1 v:v).

Diclofenac sodium delivery to the eye: In vitro evaluation of novel solid lipid nanoparticle formulation using human cornea construct

Solid lipid nanoparticles (SLNs) were prepared with a combination of homolipid from goat (goat fat) and phospholipid, and evaluated for diclofenac sodium (DNa) delivery to the eye using bio-engineered human cornea, produced from immortalized human corneal endothelial cells (HENC), stromal fibroblasts and epithelial cells CEPI 17 CL 4. Encapsulation efficiency was high and sustained release of DNa and high permeation through the bio-engineered cornea were achieved. Results obtained in this work showed that permeation of DNa through the cornea construct was improved by formulation as SLN modified with phospholipid.

Injectable actarit-loaded solid lipid nanoparticles as passive targeting therapeutic agents for rheumatoid arthritis

This work systematically studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with actarit, a poor water soluble anti-rheumatic drug. The goal of this study was to design passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects such as nephrotoxicity and gastrointestinal disorders commonly associated with oral formulations of actarit. Based on the optimized results of single-factor and orthogonal design, actarit-loaded SLNs were prepared by a modified solvent diffusion–evaporation method. The formulated SLNs were found to be relatively uniform in size (241 ± 23 nm) with a negative zeta potential (−17.14 ± 1.6 mV). The average drug entrapment efficiency and loading were (50.87 ± 0.25)% and (8.48 ± 0.14)%, respectively. The actarit-loaded SLNs exhibited a longer mean retention time in vivo ( t 1/2(β), 9.373 h; MRT, 13.53 h) compared with the actarit 50% propylene glycol solution ( t 1/2(ke), 0.917 h; MRT, 1.323 h) after intravenous injection to New Zealand rabbits. The area under curve of plasma concentration–time (AUC) of actarit-loaded SLNs was 1.88 times greater than that of the actarit in 50% propylene glycol solution. The overall targeting efficiency (TE C ) of the actarit-loaded SLNs was enhanced from 6.31% to 16.29% in spleen while the renal distribution of actarit was significantly reduced as compared to that of the actarit solution after intravenous administration to mice. These results indicated that injectable actarit-loaded solid lipid nanoparticles were promising passive targeting therapeutic agents for rheumatoid arthritis.

Novel cationic solid lipid nanoparticles enhanced p53 gene transfer to lung cancer cells

Mutations in the p53 tumor suppressor gene are the most common molecular genetic abnormalities to be described in lung cancer. However, there have been few reports of nonviral vector-mediated p53 gene delivery in lung cancer. A new formulation of cationic solid lipid nanoparticles (SLNs) for gene delivery was produced by the melt homogenization method with slight modification, and the SLNs were formulated by mixing tricaprin (TC) as a core, 3β[ N-( N′, N′-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol), dioleoylphosphatidylethanolamine (DOPE) and Tween 80 in various ratios. Plasmid DNA (pp53-EGFP)/SLNs complexes were transfected into human non-small cell lung cancer cells (H1299 cells) and transfection efficiency was determined by FACS analysis. The gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The cellular growth inhibition and apoptosis of treated cells with pp53-EGFP/SLNs complexes were assessed by trypan blue exclusion assay and annexin V staining, respectively. In vivo biodistribution of plasmid DNA was investigated by PCR and RT-PCR. The transfection efficiency of SLN1 (TC:DC-Chol:DOPE:Tween 80 = 0.3:0.3:0.3:1), which showed the highest transfection efficiency among the SLN formulations, was higher than that of commercially available Lipofectin ®. The SLNs-mediated transfection of the p53 gene resulted in efficient high levels of wild-type p53 mRNA and protein expression levels in H1299 cells. The efficient reestablishment of wild-type p53 function in lung cancer cells restored the apoptotic pathway. Taken together, our results reveal that cationic SLN-mediated p53 gene delivery may have potential for clinical application as a nonviral vector-mediated lung cancer therapy due to its effective induction of apoptosis and tumor growth inhibition.

Effect of Solid Lipid Nanoparticles Formulation Compositions on Their Size, Zeta Potential and Potential for In Vitro pHIS-HIV-Hugag Transfection

This work was conducted to determine model equations describing the effect of solid lipid nanoparticles (SLN) formulation compositions on their size and zeta potential using the face-centered central composite design and to determine the effect of SLN formulation compositions on the potential for in vitro pHIS-HIV-hugag transfection. SLN were prepared by the hot high pressure homogenization technique using cetylpalmitate as lipid matrix at varying concentrations of Tween 80 and Span 85 mixture, dimethyldioctadecyl ammonium bromide (DDAB) and cholesterol. Size and zeta potential used as responses of the design were measured at pH 7.0. The model equations were accepted as statistical significance at p value of less than 0.05. Ability of SLN to form complex with pHIS-HIV-hugag was evaluated by electrophoretic mobility shift assay. In vitro cytotoxicity of SLN was studied in HeLa cells using alamar blue bioassay. The potential of SLN for in vitro pHIS-HIV-hugag transfection was also determined in HeLa cells by western blot technique. SLN possessed diameter in a range of 136-191 nm and zeta potential 11-61 mV depending on the concentrations of surfactant mixture, DDAB and cholesterol. The regression analysis showed that the model equations of responses fitted well with quadratic equations. The ability of SLN to form complex with pHIS-HIV-hugag was also affected by formulation compositions. In vitro cytotoxicity results demonstrated that HeLa cells were not well tolerant of high concentrations of SLN but still survived in a range of 100-200 microg/ml of SLN in culture medium. The results of transfection study showed ability of SLN to use as a vector for in vitro pHIS-HIV-hugag transfection. However, their potential for in vitro transfection was lower than the established transfection reagent. Size and zeta potential of SLN could be predicted from their quadratic model equations achieved by combination of three variables surfactant, DDAB and cholesterol concentrations. In addition, these variables also affected the potential of SLN as a vector for in vitro pHIS-HIV-hugag transfection. The results here provide the framework for further study involving the SLN formulation design for DNA delivery.

Development of a new solid lipid nanoparticle formulation containing retinoic acid for topical treatment of acne

The development of solid lipid nanoparticles (SLN) containing all-trans retinoic acid (RA) is an interesting approach to topical treatment of acne. SLN has potential for controlled release and follicular penetration, which can reduce adverse effects in comparison with conventional formulations. However, the encapsulation efficiency (EE) of RA in SLN is usually low, unless a high surfactant/lipid ratio is used. The aim of this work was to develop SLN with high EE using a low surfactant/lipid ratio. Different formulations of RA-loaded SLN were prepared using glyceryl behenate as lipid matrix. The particle size, EE, zeta potential and differential scanning calorimetry (DSC) were investigated. High EE in SLN was obtained with addition of amines. These results indicate that the utilization of amines is an interesting approach to improve the EE of RA in SLN using a low surfactant/lipid ratio.

Sunblocking efficiency of various TiO2‐loaded solid lipid nanoparticle formulations1

In this study, titanium dioxide (TiO(2)) was incorporated into solid lipid nanoparticle (SLN) formulations using both classical and novel preparation methods. The SLNs were investigated by evaluating their stabilities and physicochemical characteristics. UV-protection abilities of formulations were investigated using in vitro Transpore and Sun To See(TM) test methods. Results have been discussed by comparing the classical SLN formulation with the novel SLN, hybrid SLN (H-SLN) and the emulsion formulations. The results showed the superiority of the H-SLN formulations compared with the classical SLN; all SLN formulations were better when compared with the emulsion formulations considering the UV protection. Incorporation of TiO(2) as a sunscreen agent into SLN formulations gives opportunity to produce stable and safe formulations with reduced amount but high UV-protection ability.