Research progress of ionizable lipid nanoparticles for siRNA delivery / 药学学报

Small interfering RNA (siRNA) is the initiator of RNA interference and inhibits gene expression by targeted degradation of specific messenger RNA. siRNA-mediated gene regulation has high efficiency and specificity and exhibits great significance in the treatment of diseases. However, the naked or unmodified siRNA has poor stability, easy to degrade by nuclease, short half-life, and low intracellular delivery. As an emerging non-viral nucleic acid delivery system, ionizable lipid nanoparticles play an important role in improving the druggability of siRNA. At present, one siRNA drug based on ionizable lipid nanoparticles has been approved for the treatment of rare disease. This review introduces the research progress in ionizable lipid nanoparticles for siRNA delivery, focusing on the effect of each component of lipid nanoparticles on the efficiency of siRNA-mediated gene silencing, which provides new references for the studies on ionizable lipid nanocarriers for siRNA delivery.

Avaliação do tratamento quimioterápico paliativo com o esquema LDE- paclitaxel em pacientes portadores de metástases ósseas por neoplasia maligna / Evaluation of palliative chemotherapy treatment with the LDEpaclitaxel regimen in patients with bone metastases from malignant neoplas

Introdução: Pacientes com câncer em estádios avançados e metástases ósseas frequentemente não apresentam condições clínicas para a realização de esquemas quimioterápicos convencionais subsequentes, restringindo as opções de tratamento. Anteriormente, demonstramos que nanopartículas artificiais lipídicas (LDE), semelhantes à lipoproteína de baixa densidade (LDL) rica em colesterol, são captadas por tecidos malignos, e quando associadas aos quimioterápicos, após injeção pela via endovenosa, reduz drasticamente a toxicidade do tratamento. Os objetivos deste presente estudo foram avaliar a resposta clínica ao tratamento quimioterápico com paclitaxel (PTX) associado à LDE; avaliar as toxicidades clínicas e laboratorial, e a capacidade da associação LDE-PTX em reduzir a dor oncológica relacionada às metástases ósseas em pacientes com carcinoma de mama, próstata e pulmão, previamente tratados e não elegíveis para tratamento quimioterápico convencional subsequente. Métodos: Dezoito pacientes (8 com câncer de mama, 5 de próstata e 5 de pulmão) com metástases ósseas foram incluídos. O tratamento consistiu no esquema LDE-PTX na dose convencional do PTX (175 mg/m2 de superfície corpórea de 3/3 semanas) e os pacientes foram avaliados por resposta clínica, redução da dor óssea, uso de medicamentos opióides, e ocorrência de fraturas ósseas patológicas. Resultados: No total, 104 ciclos de quimioterapia foram realizados, e nenhum paciente apresentou toxicidade clínica, laboratorial, assim como não houve fraturas patológicas. Dos 18 pacientes incluídos, 9 tiveram sobrevida livre de progressão de doença 6 meses. Houve em todos os pacientes redução da dor óssea, permitindo substituição da medicação opióide por analgésico não opióide. Conclusão: A melhora significativa na dor óssea sem que tenha ocorrido toxicidade do tratamento, e o tempo de não progressão de doença 6 meses na metade dos pacientes sugere que esses pacientes tenham se beneficiado consistentemente do tratamento com a LDE-PTX. Portanto, a LDE-PTX pode tornar- se uma opção terapêutica interessante em pacientes com carcinomas de próstata, mama ou pulmão em estágios avançados e sem condições clínicas de se submeterem a outros esquemas quimioterápicos convencionais

Introduction: Patients with advanced cancer and bone metastases usually do not have clinical conditions to perform additional conventional chemotherapy regimens, restricting treatment options. Previously, we showed that lipid core nanoparticles (LDE), similar to cholesterol-rich low-density lipoprotein (LDL), are taken up by malignant tissues, and when associated to chemotherapy, after endovenous injection, it drastically decreases the toxicity of the treatment. The objectives of this study were to evaluate the clinical response to chemotherapy treatment with paclitaxel (PTX) associated with LDE; to evaluate the clinical and laboratorial toxicities, and the ability of the LDE-PTX to reduce cancer pain related to bone metastases in patients with breast, prostate or lung carcinoma, previously treated and not eligible for subsequent conventional chemotherapy treatment. Methods: Eighteen patients (8 with breast cancer, 5 with prostate and 5 with lung) with bone metastases were included. Treatment consisted of the LDE-PTX regimen at a conventional dose of PTX (175 mg/m2 body surface area, 3/3 weeks) and patients were evaluated for clinical response, reduction in bone pain, use of opioid medications, and the occurrence of pathological bone fractures. Results: In total, 104 chemotherapy cycles were performed, and none of the patients showed clinical or laboratorial toxicities, as well as there were no pathological fractures. Of the 18 patients evaluated, 9 had progression-fee survival 6 months. Patients had decrease in bone pain allowing replacement of opioid medication by another non-opioid analgesic. Conclusion: Significant improvement in bone pain without treatment toxicity, and time to disease progression of 6 months in half of the patients suggest that these patients have consistently benefited with LDE-PTX treatment. Therefore, LDE-PTX may become an interesting therapeutic option in patients with advanced stage of prostate, breast or lung carcinomas and without clinical conditions to undergo other conventional chemotherapy regimens

Tailoring combinatorial lipid nanoparticles for intracellular delivery of nucleic acids, proteins, and drugs

Lipid nanoparticle (LNP)-based drug delivery systems have become the most clinically advanced non-viral delivery technology. LNPs can encapsulate and deliver a wide variety of bioactive agents, including the small molecule drugs, proteins and peptides, and nucleic acids. However, as the physicochemical properties of small- and macromolecular cargos can vary drastically, every LNP carrier system needs to be carefully tailored in order to deliver the cargo molecules in a safe and efficient manner. Our group applied the combinatorial library synthesis approach and in vitro and in vivo screening strategy for the development of LNP delivery systems for drug delivery. In this Review, we highlight our recent progress in the design, synthesis, characterization, evaluation, and optimization of combinatorial LNPs with novel structures and properties for the delivery of small- and macromolecular therapeutics both in vitro and in vivo. These delivery systems have enormous potentials for cancer therapy, antimicrobial applications, gene silencing, genome editing, and more. We also discuss the key challenges to the mechanistic study and clinical translation of new LNP-enabled therapeutics.

Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm

Lipid nanoparticle (LNP) is commonly used to deliver mRNA vaccines. Currently, LNP optimization primarily relies on screening ionizable lipids by traditional experiments which consumes intensive cost and time. Current study attempts to apply computational methods to accelerate the LNP development for mRNA vaccines. Firstly, 325 data samples of mRNA vaccine LNP formulations with IgG titer were collected. The machine learning algorithm, lightGBM, was used to build a prediction model with good performance (R 2 > 0.87). More importantly, the critical substructures of ionizable lipids in LNPs were identified by the algorithm, which well agreed with published results. The animal experimental results showed that LNP using DLin-MC3-DMA (MC3) as ionizable lipid with an N/P ratio at 6:1 induced higher efficiency in mice than LNP with SM-102, which was consistent with the model prediction. Molecular dynamic modeling further investigated the molecular mechanism of LNPs used in the experiment. The result showed that the lipid molecules aggregated to form LNPs, and mRNA molecules twined around the LNPs. In summary, the machine learning predictive model for LNP-based mRNA vaccines was first developed, validated by experiments, and further integrated with molecular modeling. The prediction model can be used for virtual screening of LNP formulations in the future.

Preparation of mitochondrial targeted calcium arsenite/doxorubicin lipid nanoparticles and the in vitro study in reversing tumor drug resistance / 药学学报

This study aims at the critical role of P-glycoprotein (P-gp) in tumor drug resistance, taking advantage of the adenosine triphosphate (ATP) dependence of P-gp mediated drug transport and efflux across the cell membrane. Mitochondrial targeted calcium arsenite/doxorubicin (DOX) lipid nanoparticles were constructed via hydrothermal method and thin-film dispersion method for reversing tumor drug resistance. The results showed that the lipid nanoparticles were uniform in size and well dispersed with a mean particle size of (261 ± 7) nm, zeta potential of (-9.6 ± 1.3) mV. The DOX loading efficiency and encapsulation efficiency were 22.6% and 84.0%. The in vitro drug release profile was pH-dependent; the drug accumulation at mitochondria was significantly increased, which then caused overload of calcium and inhibition of P-gp and ATP, thereby reversing tumor drug resistance. The simultaneously released arsenite ion and DOX could synergistically kill the tumor cells. In summary, the lipid nanoparticles prepared in this study have uniform particle size, high drug loading efficiency and encapsulation efficiency, excellent colloidal stability, pH responsiveness, and impressive ability to reverse tumor drug resistance, which may hold great potential in further clinical applications.

Efficient drug and gene delivery to liver fibrosis: rationale, recent advances, and perspectives

Liver fibrosis results from chronic damages together with an accumulation of extracellular matrix, and no specific medical therapy is approved for that until now. Due to liver metabolic capacity for drugs, the fragility of drugs, and the presence of insurmountable physiological obstacles in the way of targeting, the development of efficient drug delivery systems for anti-fibrotics seems vital. We have explored articles with a different perspective on liver fibrosis over the two decades, then collected and summarized the information by providing corresponding  and  cases. We have discussed the mechanism of hepatic fibrogenesis with different ways of fibrosis induction in animals. Furthermore, the critical chemical and herbal anti-fibrotics, biological molecules such as micro-RNAs, siRNAs, and growth factors, which can affect cell division and differentiation, are mentioned. Likewise, drug and gene delivery and therapeutic systems on  and  models are summarized in the data tables. This review article enlightens recent advances in emerging drugs and nanocarriers and represents perspectives on targeting strategies employed in liver fibrosis treatment.

Determination of Encapsulation Efficiency of Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates by Mini-Column Centrifugation Method / 中国药学杂志

OBJECTIVE: To establish a mini-column centrifugation method to determine the encapsulation efficiency (EE) of novel solid lipid nanoparticles containing oleic acid-CAT3 conjugates (OA-CAT3-SLN) and normal CAT3 SLN (CAT3-SLN). METHODS: Sephadex G-50 mini-columns were used to separate the encapsulated drug and free drug in the solid lipid nanoparticles (SLN) with the help of centrifugation. The boundary point of the elution between the encapsulated drug and free drug was established by the elution curve. The encapsulated drug in the SLN was eluted with 1 mL water for three times. Then 2 mL of ethanol was used to elute the separated free drug for three times. The eluted CAT3 was quantified by the verified HPLC-UV method and used to calculate the EE. The method was verified with the recovery and repeatability test. Finally, the EE of three batches of OA-CAT3-SLN and CAT3-SLN were determined. RESULTS: The mini-column centrifugation method could effectively separate the free drug from the encapsulated drug in SLN. The column recovery was (99.64±1.97)% (n=9), and the result of EE repeatability test of OA-CAT3-SLN was (83.71±0.70)% (n=5). The EE of OA-CAT3-SLN and CAT3-SLN were (86.26±2.65)% and (72.22±4.52)%, respectively (n=3). CONCLUSION: The established separation method is simple and reliable, with high recovery and good repeatability, and can distinguish different preparation processes.

Construction of Matrine Solid Lipid Nanoparticle and Determination of the Entrapment Efficiency / 中国药学杂志

OBJECTIVE: To prepare matrine solid lipoid nanoparticle,establish preparating method and determine the encapshlation efficiency. METHODS: Matrine solid lipoid nanoparticle was prepared by microemulsion-probe ultrasonic method and its quality was evaluated by particle size, Zeta potential, microscopic morphology and in vitro release. The encapsulation efficiency of the carrier was measured by different methods and their effect was compared. RESULTS: The diameter of matrine solid lipoid nanoparticle was (116.7±2.6) nm and its Zeta potential was (-45±1.7)mV. Transmission electron micrographs showed that the solid lipoid nanoparticle was uniform in size and spherical. The in vitro release result suggested the carrier exhibited control release character. Dextran gel microcolumn centrifugation can effectively separate free drugs and carriers, and the measured encapsulation efficiency data has little difference in stability. CONCLUSION: Matrine solid lipoid nanoparticle is successfully prepared and their particle size, Zeta potential and in vitro release quality are evaluated.Dextran gel microcolumn method is effective in the measurement of matrine solid lipoid nanoparticle, providing a reliable reference for the determination of water-soluble drug encapsulation efficiency.

Optimization of Formulation of Econazole Solid Lipid Nanoparticles Based on Pseudo-ternary Phase Diagrams and Central Composite Design-Response Surface Methodology / 中国药学杂志

OBJECTIVE: To optimize the formulation of econazole solid lipid nanoparticles(E-SLN) by combining pseudo-ternary phase diagrams and central composite design-response surface methodology (CCD-RSM). METHODS: Econazole solubility in different solid lipids and the capacity of lipid emulsion were tested. The microemulsion region was obtained by the pseudo-ternary phase diagrams. Then the E-SLN were prepared by microemulsion method. Drug/lipid (X1), lipid/surfactant (X2) and surfactant/cosurfactant (X3) were taken as individual factors, the encapsulation efficiency (Y1), particle size (Y2), Zeta potential (Y3) were taken as the dependent factors. The possible optimum formulation was predicted by CCD-RSM and validated. RESULTS: Econazole could be dissolved in tripalmitic acid glyceride (TAG), monostearic acid glyceride, stearic acid and lauric acid glyceride. TAG had a good capacity of emulsion. The optimized formulation was econazole 0.06 g, glyceryl palmitate 0.48 g, Tween-80 1.194 g, glycerol 0.274 g and added water to 30 mL by CCD-RSM. According to the optimized formulation, the encapsulation efficiency, particle size and Zeta potential were (94.06±1.54)%, (18.88±0.38)nm and (3.53±0.01)mV, respectively. The deviation was less than 5%. CONCLUSION: The stable and ultra-small size E-SLN with high encapsulation efficiency could be obtained by combining pseudo-ternary phase diagrams and CCD-RSM.

Inhibitory effects of down-regulation of JNK enzymatic activity on growth of human prostate cancer cells, hepatocellular carcinoma cells and breast cancer cells / 吉林大学学报(医学版)

Objective: To discuss the role for down-regulation of JNK enzymatic activity in the tumor treatments by interrupting JNK gene expression with JNK inhibitor SP600125 and JNK-siRNA encapsulated by lipid nanoparticles in vivo and in vitro. Methods: In vitro experiments, the experiment was divided into siRNA group and inhibitor SP600125 group. In siRNA group, JNK-siRNA and NC-siRNA were transfected into the human prostate cancer cells (PC cells), human hepatocellular carcinoma cells (SMMC-7721 cells) and human breast cancer cells (MCF cells), respectively. In inhibitor SP600125 group, SP600125 was delivered to human hepatocellular carcinoma cells. The expression levels of JNK or p-JNK proteins in human prostate cancer cells, human hepatocellular carcinoma cells, and human breast cancer cells after transfected with JNK-siRNA and inhibitor SP600125 were detected by Western blotting method. The cell viabilities of tumor cells in various groups were examined by WST-1 proliferation assay. In vivo experiments, the human hepatocellular carcinoma SMMC-7721 cells were used to establish the subcutaneous hepatocellular carcinoma xenograft tumor models by subcutaneous injection. The eight mice were fed until the tumors were generated to 3 mm× 3 mm. They were randomly divided into inhibitor SP600125 group and negative control group, JNK-siRNA group and NC-siRNA control group. Each mouse in various groups was injected intratumorally with 5 nmol SP600125, negative control solution, lipid nanoparticles-mediated JNK-siRNA and NC-siRNA negative control. The volumes of tumors of the mice in various groups were observed. The expressions of JNK or p-JNK proteins in tumor tissue were examined by immunohistochemical staining. Results: In vitro experiments, compared with NC-siRNA control group, the expression level of JNK protein in human prostate cancer cells, human hepatocellular carcinoma cells and human breast cancer cells in JNK-siRNA group were decreased (P<0. 01); the expression level of p-JNK protein in human hepatocellular carcinoma cells in inhibitor SP600125 group was significantly increased compared with its negative control group (P<0. 01). Invivo experiment, the human hepatocellular carcinoma cells were taken as an example, the volume of tumor of the mice in inhibitor SP600125 group was significantly reduced compared with negative control group, whereas the change of tumor volume in JNK-siRNAs group was not significant compared with NC-siRNA control group. The immunohistochemical staining results showed that compared with their negative control groups, the expression amount of p-JNK protein in tumor tissue of the mice in SP600125 group and the expression amount of JNK protein in tumor tissue of the mice in JNK-siRNA group were decreased (P< 0.01). Conclusion: Down-regulation of enzymatic activity of JNK can decrease the expression level of JNK gene and then inhibit the tumor growth both in vivo and in vitro.

Preparation and Characterization of Syringopicroside Solid Lipid Nanoparticles / 中国药房

OBJECTIVE： To prepare Syringopicroside solid lipid nanoparticles （SYR-SLN）， and optimize the formula and characterize SYR-SLN. METHODS： SYR-SLN were prepared by emulsion evaporation method. Using entrapment efficiency as index， based on single factor， orthogonal design was adopted to optimize the mass ratio of lecithin-monoglyceride， volume ratio of organ phase to water phase， poloxamer 188 （F68） concentration and drug dosage. The optimal formula technology was established to investigate entrapment efficiency， drug-loading amount， morphology， particle size， Zeta potential， stability， etc. RESULTS： The mass ratio of lecithin-monoglyceride was 3 ∶ 1； the volume ratio of organic phase to water phase was 1 ∶ 2； the concentration of F68 was 0.4％； drug dosage was 10 mg. The optimal formula included that monoglyceride 80 mg， lecithin 240 mg， 0.4％ F68， syringopicroside 10 mg， absolute ethyl alcohol 5 mL， distilled water 10 mL， emulsification temperature at 65℃ and stirring at 600 r/min. Encapsulation efficiency of SYR-SLN was （42.35±0.60）％ （n＝3）； drug-loading amount was （5.33±0.03）％ （n＝3）； SYR-SLN had a spherical morphology and was evenly distributed. The average particle size was （180.30±5.31） nm with Zeta potential of （－41.9±0.8） mV， and the SYR-SLN could maintain stable for 15 days at 4℃. CONCLUSIONS： SYR-SLN is prepared successfully， and the technology is simple with high encapsulation efficiency.

Absorption Mechanism of Baicalin and Its Solid Lipid Nanoparticles on Caco-2 Cells / 中国药学杂志

OBJECTIVE: To study the absorption mechanism of baicalin (BA) and baicalin solid lipid nanoparticles (BA SLN) by establishing an in vitro Caco-2 cell model. METHODS: A Caco-2 cell model was established. The appropriate concentration of BA and BA SLN in Caco-2 cell monolayer model was screened by CCK-8 method and LDH method. The content of BA was determined by high performance liquid chromatography, and the effects of time, concentration, temperature and endocytosis inhibitor on the uptake of BA and BA SLN were studied by this model. The transport of BA and BA SLN in the presence or absence of efflux inhibitors was also investigated. The expression of efflux protein was detected by Western blot. RESULTS: At 50-150 μg·mL-1, the uptake of BA and BA SLN was concentration-dependent; at 4 to 37 ℃, the uptake of BA and BA SLN increased with increasing temperature; endocytosis inhibitor influenced the cellular uptake of BA SLN; multidrug resistance-associated protein 2 (MRP2) inhibitors and breast cancer resistance protein (BCRP) inhibitors significantly reduced BA efflux, but did not affect BA SLN efflux; blank SLN and BA SLN can reduce the expression of MRP2 and BCRP in cells. CONCLUSION: BA is taken up and transported by small intestinal epithelial cells in a passive manner, and may be accompanied by energy dependence, which is related to MRP2 and BCRP efflux. BA SLN can significantly increase the uptake of drugs in the Caco-2 cell model, which may be related to the increase of endocytic pathway uptake and inhibition of extracellular repressor expression inhibition drug efflux.

Surface modification of PGP for a neutrophil-nanoparticle co-vehicle to enhance the anti-depressant effect of baicalein

Exploiting cells as vehicles combined with nanoparticles combined with therapy has attracted increasing attention in the world recently. Red blood cells, leukocytes and stem cells have been used for tumor immunotherapy, tissue regeneration and inflammatory disorders, and it is known that neutrophils can accumulate in brain lesions in many brain diseases including depression. -Acetyl Pro-Gly-Pro (PGP) peptide shows high specific binding affinity to neutrophils through the CXCR2 receptor. In this study, PGP was used to modify baicalein-loaded solid lipid nanoparticles (PGP-SLNs) to facilitate binding to neutrophils . Brain-targeted delivery to the basolateral amygdala (BLA) was demonstrated by enhanced concentration of baicalein in the BLA. An enhanced anti-depressant effect was observed and The mechanism involved inhibition of apoptosis and a decrease in lactate dehydrogenase release. Behavioral evaluation carried out with rats demonstrated that anti-depression outcomes were achieved. The results indicate that PGP-SLNs decrease immobility time, increase swimming time and climbing time and attenuate locomotion in olfactory-bulbectomized (OB) rats. In conclusion, PGP modification is a strategy for targeting the brain with a cell-nanoparticle delivery system for depression therapy.

Pharmacokinetics and bioequivalence of evodiamine butyryl derivative-loaded lipid nanoparticles in rats / 中草药

Objective To study the pharmacokinetic characteristics and bioequivalence of evodiamine butyryl derivative (EAB) and evodiamine butyryl derivative-loaded lipid nanoparticles (EABLN) in rats. Methods EABLN were prepared by a film ultrasound method, 16 male SD rats were randomly divided into two groups, and their blood were extracted from eye socket after they were intragastric administrated EAB or EABLN (100 mg/kg) for a given time period. Plasma concentration of EAB was determined by HPLC, then pharmacokinetic data, bioequivalence between EAB and EABLN were analyzed by DAS software. Results The main pharmacokinetic parameters of EABLN were listed, AUC(0-72 h), Cmax, and tmax were (11 535.39 ± 261.08) μg∙h/L, (886.73 ± 15.40) μg/L, and (2.00 ± 0.17) h, respectively. Relative bioavailability of EABLN to EAB was 143%, the bioequivalence of AUC(0-72 h) and Cmax in EAB and EABLN were eligible, but bioequivalence of tmax was not eligible. Conclusion EABLN improved the pharmacokinetics of EAB in rats, meanwhile, oral bioavailability of EAB was significantly increased, and there was not bioequivalence between EABLN and EAB.

Preparation and characterization of non-viral gene delivery systems with pEGFP-C1 Plasmid DNA

ABSTRACT In recent years, non-viral delivery systems for plasmid DNA have become particularly important. They can overcome the disadvantages of viral systems such as insertional mutagenesis and unpredicted immunogenicity. Some additional advantages of non-viral gene delivery systems are; good stability, low cost, targetability, delivery of a high amount of genetic materials. The aim of the study was to develop novel non-viral nanosystems suitable for gene delivery. Two formulations were developed for this purpose: water-in-oil microemulsion (ME) and solid lipid nanoparticles (SLN). The microemulsion was composed of Peceol, Tween 80, Plurol oleique, ethanol and water. The SLN was consisting of Precirol, Esterquat-1 (EQ1), Tween 80, Lecithin, ethanol and water. Characterization studies were carried out by measuring particle size, zeta potential, viscosity and pH. TEM imaging was performed on SLN formulations. Protection against DNase I degradation was examined. Cytotoxicity and transfection efficacy of selected formulations were tested on L929 mouse fibroblast cells. Particle sizes of complexes were below 100 nm and with high positive zeta potential. TEM images revealed that SLNs are spherical. The SLN:DNA complexes have low toxicity and good transfection ability. All results showed that the developed SLN formulations can be considered as suitable non-viral gene delivery systems.

Excipient Formula Research of Nicotinate-Curcumin nanoparticles Prepared by Film Ultrasonic Method / 中国药学杂志

OBJECTIVE: To optimize the film-ultrasonic technique for preparing nicotinate-curcumin nanoparticles. METHODS: An HPLC method was established for determination of nicotinate-curcumin. Using the entrapment efficiency of nicotinate-curcumin as the evaluation indicator, the optimum excipient formula was selected through the Box-Bebnken reponse surface design of three factors (amounts of nicotinate-curcumin and lecithin and concentration of tween-80) at three levels. RESULTS: With the established optimal formula, ie 80 mg stearic acid, 150 mg lecithin and 20 mL tween-80 (0.6%), the entrapment efficiency of nicotinate-curcumin approached 65%. The mean particle size was 190 nm. CONCLUSION: The nicotinate-curcumin nanoparticles prepared by the film ultrasonic technique optimized by central composite design test have high entrapment efficiency, indicating that the technique is feasible.

Formulation and Evaluation of Solid Lipid Nanoparticle (SLN) Based Topical Gel of Etoricoxib.

The objective of present investigation was to prepare & evaluate solid lipid nanoparticle (SLN) based topical gel of non- steroidal anti-inflammatory drug (NSAID) etoricoxib for the treatment of arthritis which would attenuate the gastrointestinal related toxicities associated with oral administration. SLN were formulated by melt emulsification and solidification at low temperature method using stearic acid & tween 80. All the formulation were subjected to particle size, particle size distribution, zeta potential, scanning electron microscopy, crystallinity study by DSC and in-vitro release studies. It has been observed that, the high lipid concentration containing formulation have higher entrapment as compare to other two formulation. The SLN- dispersion shows 70.766% entrapment & zeta potential of the formulation were -25.6 which indicates the stability of formulation. The In Vitro drug release rate of gel was evaluated using Modified franz diffusion cell containing dialysis membrane with phosphate buffer pH 7.4 as the receptor medium. The in-vitro release was carried out in comparison with a carbopol gel & hydroxypropylmethylcellulose (HPMC) gel. The permeability parameters steady-state flux (Jss) was significantly increased in SLN-F3C (carbopol) formulation as compared with SLN-F3HPMC (hydroxypropyl methylcellulose) formulation. It was concluded that the Etoricoxib loaded SLN based gel formulation containing carbopol was suitable for topical application and shows much better result of anti-inflammatory activity.

Polyelectrolyte layer-by-layer assembled lipid nanoparticles for improving oral absorption of doxorubicin / 药学学报

Polyelectrolyte layer-by-layer assembled lipid nanoparticles (NPs) were prepared to improve their stability against lipolysis in gastrointestinal tract, and efficiency of oral absorption of doxorubicin (DOX). The lipid NPs were prepared by hot melt-probe sonication method. The polyelectrolyte layer-by-layer assembled lipid NPs (DOX-NPs/CS/γ-PGA) was prepared by layer-by-layer self-assembling polyelectrolytes cationic chitosan (CS) and anionic poly (γ-glutamic acid) (γ-PGA) on the surface of lipid NPs based on electrostatic interaction. The particle size, polydispersity index (PDI) and zeta potential of lipid NPs and DOX-NPs/CS/γ-PGA were determined by dynamic light scattering (DLS). The in vitro drug release was determined in pH 1.2 HCl solution and pH 6.8 phosphate buffer solution (PBS). The stability of lipid NPs against lipolysis was evaluated in simulated gastrointestinal medium containing lipase. The cellular uptake of lipid NPs and DOX-NPs/CS/γ-PGA was evaluated in Caco-2 cell model. The pharmacokinetic of DOX after oral absorption was studied in SD rats. Results showed that the average particle size and zeta potential of DOX-NPs/CS/γ-PGA were 180.6±5.4 nm and -38.53±0.29 mV, respectively. The DOX-NPs/CS/γ-PGA effectively slowed down the release of DOX from nanoparticles, and decreased the lipolysis of lipid NPs in simulated gastrointestinal medium. The cell study showed that DOX-loaded lipid NPs and DOX-NPs/CS/γ-PGA remarkably enhanced the cell uptake in comparison with DOX solution. The DOX-NPs/CS/γ-PGA significantly improved oral absorption of DOX compared with DOX-loaded lipid NPs. The Cmax, tmax were 0.76±0.25 μg·mL-1 and 0.5 h, respectively; AUC0-24h was 3.02 folds and the relative bioavailability was 302.46% with DOX solution as reference. The stability of lipid NPs against lipolysis and drug release were significantly improved by layer-by-layer assembling, leading to an improved oral absorption.

Formulation Optimization of Indomethacin-loading Solid Lipid Nanoparticles by Box-Behnken Response Surface Methodology / 中国药房

OBJECTIVE:To optimize the formulation of indomethacin-loading solid lipid nanoparticle(SLN). METHODS:Us-ing indomethacin as model drug,glyceryl behenate as oil phase,poloxamer 188 and polyethylene glycol-12-hydroxystearic acid as emulsifier,with turbidity,entrapment efficiency and drug loading amount as index,Box-Behnken response surface methodology was used to optimize the amount of oil phase,emulsifier-oil phase ratio,drug-oil phase ratio. The physicochemical properties of SLNs were characterized by SEM and DSC. RESULTS:The optimal formulation was as follows as oil phase of 0.91%,emulsifier-oil ratio of 1∶1,drug-oil phase ratio of 1∶5. The turbidity,entrapment efficiency and drug loading amount of prepared nanoparticle were 1 025-1 030 NTU,98.94%-99.08%,2.43%-2.46%,respectively;particle size and polydispersity index(PDI)were 181.5-182.3 nm and 0.340-0.341(n=3). The results of DSC showed that indomethacin was not present in crystalline state dispersed into SLNs. CONCLUSIONS:The optimal formulation is screened successfully,and indomethacin-loaded SLNs have been prepared.

Quality Evaluation of Solid Lipid Nanoparticle of the Skin Extract of Bufobufo gargarizans / 中国药房

OBJECTIVE:To evaluate the quality of solid lipid nanoparticle of the skin extract of Bufobufo gargarzans. METH-ODS:The morphology of solid lipid nanoparticle of the skin extract of B. gargarzans was observed by TEM. The particle size was determined by laser scattering particle size analyzer. The contents of cinobufagin and resibufogenin, encapsulation efficiency, drug-loading amount and accumulative release rate of cinobufagin were determined by HPLC. The stability of nanoparticle was in-vestigated within 24 h at 60,25 and 4 ℃. RESULTS:The solid lipid nanoparticle of the skin extract of B. gargarzans were uni-form in particle size and showed round and spheroidicity shape;average particle size was(138.5±4.2)nm,The encapsulation effi-ciency of cinobufagin and resibufogenin were 90.60% and 91.51%,and drug-loading amount were 35.82% and 44.15%. The accu-mulative release rate of cinobufagin was 50%at 4 h and reached 88%at 48 h,which was in line with Weibull equation(r=0.9438). Under 3 kinds of temperature conditions,encapsulation efficiency decreased gradually as the holding time of nanoparticle pro-longed;the decrease degree was the smallest at 4 ℃.CONCLUSIONS:The quality evaluation results of solid lipid nanoparticle of the skin extract of B. gargarzans are in line with the standard,and prepared nanoparticles show sustained-release effects and should be kept under low temperature.