Drug In Solid Lipid Nanoparticles Research Articles

Donepezil Base: Physicochemical Characterization, HPLC Method Development, Validation and its Application for the Determination of Shelf Life in Developed Solid Lipid Nanoparticles

Background/Objectives: Donepezil (DPL) is available as the hydrochloride salt (DPL-HCL) which is highly water-soluble, prompting leakage of the drug into water phase during solid lipid nanoparticles (SLNs) preparation which leads to reduce the entrapment efficiency as well as drug content. So, the drug was converted into its base form i.e. donepezil base (DPL base). The main objective of the work was to study the physicochemical characterization and identification of DPL base and to compare it with parent DPL-HCL, to develop a High-Performance Liquid Chromatography (HPLC) method for the detection of DPL base in SLNs. The develop method was used for the determination of shelf life of drug in SLNs. Methods: DPL-HCL was converted into DPL base simply by alkalization of DPL- HCL with NaOH and then extracted into dichloromethane (DCM) followed by drying to obtain DPL base. The HPLC method was developed and validated to quantify the DPL base for the determination of its shelf life in SLNs. The drug content in the developed SLNs was determined by extracting the DPL base using methanol as a solvent. The method was validated for linearity, precision, accuracy, reproducibility, limit of detection (LOD) and limit of quantification (LOQ). Results: DPL-HCL was successfully converted into DPL base with a yield value of 88.61%. The optimized mobile phase was comprised of 0.02 M phosphate buffer (pH 7.4), methanol and Acetonitrile (ACN) (40:50:10 v/v/v). The pH of mobile phase was adjusted with o-phosphoric acid. The linearity range of the developed method was found to be 0.5-80 µg/mL with LOD and LOQ value 0.086 and 0.263 µg/ml respectively. The shelf life of the DPL base in SLNs was found to be 2.29 years. Conclusion: The HPLC method for donepezil base was successfully developed and validated. RSD values for validated parameters were < 2, indicating the authenticity of the developed method. The method was successfully used for the determination of shelf life of the drug in SLNs.

Encapsulation challenges, the substantial issue in solid lipid nanoparticles characterization.

Solid lipid nanoparticles (SLNs), as alternative colloidal carriers, have been used for the sustained release of lipophilic drugs with poor water solubility. One of the most important parameters in the characterization of SLNs is entrapment efficiency (EE). Despite the importance of this factor in estimating the drug loading capacity, EE does not always represent the exact percentage of the entrapped drug. Several variables such as the stirring speed and duration, and concentration of surfactant, emulsifier, and drug play important roles in determining the final EE. In addition, EE is mainly affected by the type and concentration of the lipid. There are two major methods for the measurement of EE are in which the encapsulated drug in SLNs is either directly measured (direct method) or the amount of unencapsulated drug in the supernatant is measured (indirect method). Accuracy of drug analysis is the main challenge for EE calculation, and is either performed in the separated aqueous medium or the particles. In this review, we aimed to introduce the available methods for EE determination in SLNs and discuss the advantages and shortcomings of each method.

Development and Validation of a RP-HPLC Method for Simultaneous Estimation of Antitubercular Drugs in Solid Lipid Nanoparticles

A new simple, rapid and sensitive reversed-phase high-performance liquid chromatography method was developed and validated as per International Conference on Harmonization guidelines, Q2 R1, for simultaneous estimation of isoniazid, pyrazinamide and rifampicin in solid lipid nanoparticles. Separation was achieved on a 250×4.6 mm, 5 μm, C-18 column using a linear gradient flow rate of 1.5 ml/min. Isoniazid, pyrazinamide and rifampicin were identified based on their retention times as compared to standards and confirmed with characteristic spectra on a spectrophotometer at 238 nm and eluted at 3.787, 4.173 and 11.273 min, respectively, achieved within 20 min. This method was linear, precise with % RSD values of 0.18 % for isoniazid, 0.15 % for pyrazinamide and 0.47 % for rifampicin, accurate with mean recovery yields of 101.312 % for isoniazid, 99.910 % for pyrazinamide and 99.767 % for rifampicin and selective over the concentration range of 10-150 % for all the three drugs. This method is suitable due to its simplicity and accuracy for routine quality control and stability analysis of antitubercular drugs-loaded solid lipid nanoparticles.

Towards better modelling of drug-loading in solid lipid nanoparticles: Molecular dynamics, docking experiments and Gaussian Processes machine learning

This study represents one of the series applying computer-oriented processes and tools in digging for information, analysing data and finally extracting correlations and meaningful outcomes. In this context, binding energies could be used to model and predict the mass of loaded drugs in solid lipid nanoparticles after molecular docking of literature-gathered drugs using MOE® software package on molecularly simulated tripalmitin matrices using GROMACS®. Consequently, Gaussian processes as a supervised machine learning artificial intelligence technique were used to correlate the drugs’ descriptors (e.g. M.W., xLogP, TPSA and fragment complexity) with their molecular docking binding energies. Lower percentage bias was obtained compared to previous studies which allows the accurate estimation of the loaded mass of any drug in the investigated solid lipid nanoparticles by just projecting its chemical structure to its main features (descriptors).

Self-reporter shikonin-Act-loaded solid lipid nanoparticle: Formulation, physicochemical characterization and geno/cytotoxicity evaluation

Shikonin and some of its derivative have approved apoptotic potential in different human cancer cell lines, and moreover have a dominant fluorescent emission at ∼600nm. Here, to enhance shikonin-Act anti-proliferation properties, it was successfully incorporated in Solid Lipid Nanoparticles (SLNs) by the hot homogenization and entrapment efficiency (EE) of drug in SLNs was determined by ultrafiltration method. Scanning electron microscopy (SEM), laser diffractometry and zeta-sizer indicated that shikonin-Act-SLN were spherical and regular particles in the range of 70–120nm with polydispersity index (PI) of less than 0.10. The physical stability of shikonin-Act-loaded SLN in aqueous dispersion was evaluated in terms of size, PI, EE and drug leakage and the results showed that SLNs were stable upon storing three month. Long term in vitro release of the shikonin-Act was also approved. Cellular uptake of the shikonin-Act-SLN was examined by the in vitro fluorescent microscopy and facs flow cytometry analyses. In vivo rat imaging approved the penetrating capability of shikonin-Act-SLN emission through living tissues. In vitro anti-proliferation and genotoxicity evaluation by MTT and comet assay confirmed that shikonin-Act-SLN showed higher cytotoxic/antitumor potential than intact shikonin in terms of IC50 and DNA damage. This work provide sufficient information about improving of the therapeutic efficacy of the shikonin-Act, and also using of the shikonin-Act-SLN in bio-distribution studies during drug delivery investigation by incorporating in lipidic and colloidal drug delivery particles such as SLNs.

The effective encapsulation of a hydrophobic lipid-insoluble drug in solid lipid nanoparticles using a modified double emulsion solvent evaporation method

Raloxifene HCl (RH), a selective estrogen receptor modulator (SERM), is indicated for the prophylaxis or treatment of postmenopausal osteoporosis. RH shows extremely poor bioavailability due to limited solubility and an extensive intestinal/hepatic first-pass metabolism. Solid lipid nanoparticles (SLNs) are valuable carriers that can enhance drug bioavailability. However, in the case of RH, the encapsulation of the drug in SLNs remains a challenge because of its poor solubility in both water and lipids. In this study, a series of RH-containing SLNs (RH-SLNs) were generated using a modified double emulsion solvent evaporation (DESE) method. Briefly, RH with various drug/lipid ratios was solubilized in the inner core of a double emulsion using different water/organic solvent mixtures. Our best formulation was achieved with the formation of negatively charged nanoparticles, 180nm in diameter, with an encapsulation and loading efficiency of 85% and 4.5%, respectively. It also showed a Fickian mechanism of the drug release in the basic dissolution media. Thermal analysis revealed a distinct decrease in the crystallinity of lipids and RH in comparison with the unprocessed materials. The results of a cell viability assay also showed a better antiproliferative effect of the drug-loaded SLNs versus the free drug solution. Thus, these results indicated that the modified DESE method could be proposed for the effective encapsulation of RH in SLNs with appropriate physicochemical and biological properties.

Preparation, Characterization and In-Vivo Evaluation of Raloxifene Hydrochloride Solid Lipid Nanoparticles

Raloxifene hydrochloride is a relatively new selective estrogen receptor modulator. Clinical studies revealed that absolute bioavailability of raloxifene in humans is 2%. The major problems that have limited the therapeutic efficacy of raloxifene as an oral dosage form are its low solubility in physiological pH conditions, extensive first pass metabolism, high inter-individual and intra-individual variability (30%) following oral administration. The objective of the present investigational study was to improve the bioavailability and minimize variability of raloxifene hydrochloride by preparing solid lipid nanoparticles (SLN) using Tristearin (TS), Trimyristin (TM) and Tripalmitin (TP), by hot homogenization technique. Formulation and process variables were studied and evaluated. Particle size and zeta potential were measured by photon correlation spectroscopy using Malvern Zetasizer (ZS-90). The solid state properties of the drug in SLN’s were characterized by DSC and X-ray powder diffraction (XRPD) analysis. In-vitro release studies were performed in physiologically relevant media using modified franz diffusion cell. Systemic exposure of nanoparticle formulation was evaluated in male Wistar rats for increase in the rate and extent of drug absorption. The results demonstrated that stable raloxifene SLN formulations having a mean size range of 154 to 175 nm with a zeta potential range of –17 to –22 mV were developed. The entrapment efficiency of drug was more than 98% indicating homogeneous dispersion of drug in the lipid matrix. The in-vitro release studies showed that SLN (TM) formulation has significantly higher rate of drug dissolution as compared to other SLN formulations. Systemic exposure studies in rats indicated a significant increase in the rate and extent of drug absorption. Keywords: Solid lipid nanoparticles, Lymphatic transport, Bioavailability, First-pass metabolism.

Preparation, Characterization and In-Vivo Evaluation of Raloxifene Hydrochloride Solid Lipid Nanoparticles

Raloxifene hydrochloride is a relatively new selective estrogen receptor modulator. Clinical studies revealed that absolute bioavailability of raloxifene in humans is 2%. The major problems that have limited the therapeutic efficacy of raloxifene as an oral dosage form are its low solubility in physiological pH conditions, extensive first pass metabolism, high inter-individual and intra-individual variability (30%) following oral administration. The objective of the present in- vestigational study was to improve the bioavailability and minimize variability of raloxifene hydrochloride by preparing solid lipid nanoparticles (SLN) using Tristearin (TS), Trimyristin (TM) and Tripalmitin (TP), by hot homogenization technique. Formulation and process variables were studied and evaluated. Particle size and zeta potential were measured by photon correlation spectroscopy using Malvern Zetasizer (ZS-90). The solid state properties of the drug in SLN's were characterized by DSC and X-ray powder diffraction (XRPD) analysis. In-vitro release studies were performed in physio- logically relevant media using modified franz diffusion cell. Systemic exposure of nanoparticle formulation was evaluated in male Wistar rats for increase in the rate and extent of drug absorption. The results demonstrated that stable raloxifene SLN formulations having a mean size range of 154 to 175 nm with a zeta potential range of -17 to -22 mV were devel- oped. The entrapment efficiency of drug was more than 98% indicating homogeneous dispersion of drug in the lipid ma- trix. The in-vitro release studies showed that SLN (TM) formulation has significantly higher rate of drug dissolution as compared to other SLN formulations. Systemic exposure studies in rats indicated a significant increase in the rate and ex- tent of drug absorption.

Design and In Vitro Evaluation of Solid-Lipid Nanoparticle Drug Delivery for Aceclofenac

Solid-lipid nanoparticles (SLNs) are an interesting nanoparticulate delivery system. The present work was carried out with the aim to develop a prolonged release solid-lipid nanoparticulate system for the drug using aceclofenac. Aceclofenac-loaded solid-lipid nanoparticles (ACSLNs) was prepared by hot high pressure homogenization technique. Tripalmitin was used as the lipid core. Surfactants (Poloxamer 188, Tween 80, and soya lecithin) and co-surfactant (sodium tauro glycholate) were used in the formulations. The prepared ACSLN formulations were characterized for encapsulation efficiency (EE), photon correlation spectroscopy (PCS), scanning electron microscopy (SEM), and x-ray diffraction (XRD). From these studies, mean particle diameter of the formulation prepared with combination of surfactants (Poloxmer 188 and Tween 80) was about 200 nm with spherical morphology and amorphous nature. Higher EE was obtained with SLNs prepared using combination of soya lecithin and poloxmer 188. The organization and distribution of the ingredients in the nanoparticulate system were studied by differential scanning calorimetry (DSC) and the results showed that the drug is incorporated into the solid matrix. The prepared formulations demonstrated favorable in vitro prolonged release characteristics. Experimental in vitro release data were substituted in available mathematical models to establish the release kinetics of ACSLNs and it was found to follow first-order kinetics and Higuchi diffusion mechanism. Our results suggest that these SLN formulations could constitute a promising approach for the drug delivery of aceclofenac.

Preparation and characterization of chloroaluminum phthalocyanine-loaded solid lipid nanoparticles by thermal analysis and powder X-ray diffraction techniques

Solid lipid nanoparticles (SLN) without drug and SLN loaded with chloroaluminum phthalocyanine (AlClPc) were prepared by solvent diffusion method in aqueous system and characterized by thermal analyses and X-ray diffraction (XRD) in this study. Determination of particle size, zeta potential (ZP), and encapsulation efficiency were also evaluated. SLN containing AlClPc of nanometer size with high encapsulation efficiency and ZP were obtained. The results indicated that the size of SLN loaded with AlClPc is larger than that of the inert particle, but ZP is not changed significantly with incorporation of the drug. In differential scanning calorimetry (DSC) curves, it was observed that the melting point of stearic acid (SA) isolated and in SLN occurred at 55 and 64 °C, respectively, suggesting the presence of different polymorphs. DSC also shows that the crystallinity state of SLN was much less than that of SA isolated. The incorporation of drug in SLN may have been favored by this lower crystallinity degree of the samples. XRD techniques corroborated with the thermal analytic techniques, suggesting the polymorphic modifications of stearic acid.

Solid lipid nanoparticles and nanosuspension formulation of Saquinavir: preparation, characterization, pharmacokinetics and biodistribution studies

Solid lipid nanoparticles (SLNs) and nanosuspensions (NSs) have shown great promise for improving bioavailability of poorly water-soluble drugs. This study was aimed to develop SLNs and NS of Saquinavir (SQ) for improvement in bioavailability. These formulations were characterized and their pharmacokinetics and biodistribution in mice were evaluated. Saquinavir-loaded SLNs (SQSLNs) showed particle size 215 ± 9 nm and entrapment efficiency 79.24 ± 1.53%, while solid-state studies (differential scanning calorimetry and X-ray diffraction) indicated entrapment of the drug in SLNs. Saquinavir NS (SNS) showed particle size 344 ± 16 nm with fourfold increase in saturation solubility and its solid-state studies showed reduction in crystallinity. Pharmacokinetics and biodistribution studies of orally administered SQSLN and SNS in mice exhibited higher plasma level concentration compared to saquinavir microsuspension (SMS). The relative bioavailabilities for SNS and SQSLN were 37.39% and 66.53%, respectively, compared to 18.87% bioavailability obtained after administration of SMS, indicating suitability of nanoparticulate formulations for improving bioavailability.

Current View on Nanosized Solid Lipid Carriers for Drug Delivery to the Skin

Drug delivery into the skin is problematic because, as a natural barrier, it has a very low permeation rate. Several approaches have been made to increase the latter. Current advances in materials science and nanotechnology promise the development of new generations of drug carriers for therapeutic, diagnostic and protective purposes. We have reviewed various lipid drug delivery systems to the skin, with the main focus on solid lipid nanoparticles (SLNs). Further the article concerns possible variants in formulation of SLNs, the selection of lipid compounds and safe stabilizers, and the influence of the physicochemical properties of the drugs on distribution after loading into SLNs. In the last part the advantages of delivery into keratinocytes by SLNs over that of the free drug is addressed, focusing on decreased cytotoxicity of the incorporated drug in SLNs and controlled drug delivery to the subcellular compartments. This knowledge is important in the design and production of advanced solid lipid drug carriers. Additionally, the need for novel approaches or devices to improving permeation is also discussed in the context of moving the nanocarriers to targets deeper in the skin.

Formulation and Evaluation of Solid Lipid Nanoparticles of a Water Soluble Drug: Zidovudine

The present investigation was undertaken to develop solid lipid nanoparticles (SLN) of a hydrophilic drug Zidovudine (an anti-human immunodeficiency viral agent) and improve the entrapment efficiency of the drug in SLN. The SLN were prepared with stearic acid by process of w/o/w double-emulsion solvent-evaporation method using 3(2) factorial design. Different triglycerides alone and in different combinations, with/without stearic acid were used to prepare SLN using similar procedure. Two operating variables, polyvinyl alcohol concentration and amount of lipid were found to have significant effect on the particle size and entrapment efficiency (EE) of the SLN. The maximum EE was found to be ca. 27% with particle size of 621 nm which was significantly higher than that reported earlier. The optimized batch was also analyzed for its morphological, physiochemical and drug release properties. EE of batches with triglycerides were significantly less than that achieved with stearic acid alone. This work indicates the possible advantage of fatty acids over triglycerides in the entrapment of hydrophilic drugs in SLN.

Formulation and optimization of solid lipid nanoparticles of buspirone HCl for enhancement of its oral bioavailability

Solid lipid nanoparticles (SLNs) of buspirone HCl as a water-soluble drug were prepared by emulsification-evaporation, followed by the sonification method. A preliminary screening of the most effective parameters on the production of nanoparticles by a Taguchi L8 orthogonal array showed that the lipid type, surfactant percentage, speed of homogenizer, and acetone:dichloromethane (DCM) ratio had a significant effect on particle size. In the next step, the lipid was fixed on cetyl alcohol, surfactant on Tween 20, lecithin:lipid weight ratio on 20:70, sonication time on 30 seconds, and the other effective, independent factors aforementioned were studied each at three levels by a three-factor, three-level Box-Behnken design. The percentage of drug entrapment, mean particle-size diameter, and zeta potential were studied as the responses. Contour plots were constructed to further elucidate the relationship between the independent and dependent variables. A pharmacokinetic study was conducted in male Wistar rats after oral administration of 15 mg.kg−1 buspirone in the form of free drug or SLNs. The optimized SLNs had aq particle size of 345.7 nm, loading efficiency of 32.8%, and zeta potential of −6.8 mV. Buspirone released about 90% during 4.5 hours in vitro. It was found that the relative bioavailability of the drug in SLNs was significantly increased, compared to that of the drug solution.

현탁된 고형지질나노입자 내로 친수성 약물의 봉입률을 증대시키기 위한 w/o/w 에멀션 가온용융유화법의 평가

Recently increasing attention has been focused on solid lipid nanoparticles (SLN) as a parenteral drug carrier due to its numerous advantages that can come from both polymeric particle and fat emulsions, together with the possibility of controlled release and increasing drug stability. Lipophilic drugs such as paclitaxel, cyclosporin A, and all-trans retinoic acid have been successfully entrapped in SLN but the incorporation of hydrophilic drugs in SLN is very limited because of their very low affinity to the lipid. Therefore, as a new approach to improve the loading of hydrophilic drugs, a w/o/w emulsion technique has been developed. The primary objective of the current study was to improve the loading efficiency of a model hydrophilic drug, glycine (Log P = -3.44) into SLN. The proposed preparation process is as follows: A heated aqueous phase consisting of 0.1 ml of glycine solution in water (100 mg/ml), and poloxamer 188 (5 mg) were then added to a molten oil phase containing precirol (100 mg) and lecithin (5 mg). This mixture was dispersed by sonicator, leading to a w/o emulsion. A double emulsion (w/o/w) was formed after the addition of 2% poloxamer solution to the above dispersed system. After cooling the double emulsion, solid lipid nanosuspensions were successfully formed. The lipid nanoparticles had the mean particle size of 441.25 nm, and the average zeta potential of -20.98 mV. The drug loading efficiency was measured to be 8.54% and the drug loading amount was measured to be 0.92%. The w/o/w emulsion method showed an increased loading efficiency compared to conventional o/w emulsion method.

Solid lipid nanoparticles (SLN) for controlled drug delivery

The lipid matrix material is melted, drug incorporation can be performed by dissolving the drug in the melted lipid. There are two basic production techniques for Solid Lipid Nanoparticles (SLN), homogenization of melted lipids at elevated temperature and homogenization of a suspension of solid lipids at room temperature or below. The maximum pay load of lipophilic drugs in SLN is determined by their solubility in the melted lipid. The toxicity is the governing factor deciding if a product has the chance to be introduced to the pharmaceutical market. Compared to liposomes the SLN possess the advantage of better protection of drugs against chemical degradation. In general, SLN can be potentially applied in all drug formulations in which polymeric nanoparticles or colloidal drug carriers are useful. The SLN might be used similarly to topical cosmetical products in dermatological pharmaceutical formulations. The SLN can act as a drug reservoir providing controlled drug release.