Raloxifene HCl Research Articles

Synthesis, biological evaluation, and stability studies of raloxifene mono- and bis-sulfamates as dual-targeting agents

All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8–9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC50 of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating activities of 7–9 showed generally lower affinities compared to Raloxifene HCl, diethylstilbestrol and other known ligands, with mono-sulfamate 8 being the best ligand (Ki of 1.5 nM) for ERα binding, although 7 had a Ki of 13 nM and both showed desirable antagonist activity. The antiproliferative activities of the sulfamate derivatives against the T-47D breast cancer cell line showed 7 as most potent (GI50 = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI50 of 1.34 µM against MDA-MB-231 breast cancer cells. Stability testing of 7–9 showed that bis-sulfamate 7 hydrolyzed by desulfamoylation at a surprisingly rapid rate, initially leading selectively to 8 and finally to Raloxifene 3 without formation of 9. The mechanisms of these hydrolysis reactions could be extensively rationalized. Conversion of Raloxifene (3) into its bis-sulfamate (7) thus produced a promising drug lead with nanomolar dual activity as an STS inhibitor and ERα antagonist, as a potential candidate for treatment of estrogen-dependent breast cancer.

Specific gene module pair-based target identification and drug discovery.

Identification of the biological targets of a compound is of paramount importance for the exploration of the mechanism of action of drugs and for the development of novel drugs. A concept of the Connectivity Map (CMap) was previously proposed to connect genes, drugs, and disease states based on the common gene-expression signatures. For a new query compound, the CMap-based method can infer its potential targets by searching similar drugs with known targets (reference drugs) and measuring the similarities into their specific transcriptional responses between the query compound and those reference drugs. However, the available methods are often inefficient due to the requirement of the reference drugs as a medium to link the query agent and targets. Here, we developed a general procedure to extract target-induced consensus gene modules from the transcriptional profiles induced by the treatment of perturbagens of a target. A specific transcriptional gene module pair (GMP) was automatically identified for each target and could be used as a direct target signature. Based on the GMPs, we built the target network and identified some target gene clusters with similar biological mechanisms. Moreover, a gene module pair-based target identification (GMPTI) approach was proposed to predict novel compound-target interactions. Using this method, we have discovered novel inhibitors for three PI3K pathway proteins PI3Kα/β/δ, including PU-H71, alvespimycin, reversine, astemizole, raloxifene HCl, and tamoxifen.

Raloxifene HCl – quercetin co-amorphous system: preparation, characterization, and investigation of its behavior in phosphate buffer

Purpose Raloxifene HCl (RLX), a practically insoluble drug used in the treatment of osteoporosis in post-menopausal women; was modified at its molecular level to enhance its solubility using co-amorphous technology. Methods In this study, RLX was co-amorphized with Quercetin (QCT; a nutraceutical flavonoid) using solvent evaporation (SE), quench cooling (QC), and ball milling (BM) techniques. The prepared co-amorphous systems (CAMs) were characterized using XRD, DSC, and FT-IR. For the simultaneous analysis of RLX and QCT, an RP-HPLC method was developed to quantify the drugs in the prepared systems. Behavior in aqueous media was investigated by studying amorphous and equilibrium solubility, and drug release of RLX using USP phosphate buffer pH 6.8. Results Solvent evaporation (RQ(SE)) was able to produce a homogeneous system, where quench cooling showed thermal degradation of the drug, and ball milling was not able to amorphize the blend. From the DSC results, it was found that RQ(SE) was able to increase the glass transition temperature by 40 °C. It was observed that the solubility of RLX reduced, as RLX formed phosphate aggregates in the buffer media which further formed complexes with QCT; this was determined by investigating the residual particles from solubility studies. Though the solubility was reduced, drug release of RQ(SE) exhibited improvement in concentration by 2.3 times. Conclusions RQ(SE) formed a stable CAM; though the solubility of RLX in presence of QCT reduced, from the drug release study, it was apparent that the co-amorphous technique improved the concentration of RLX.

Fabrication and optimization of raloxifene loaded spanlastics vesicle for transdermal delivery

This research work is envisioned for the development and optimization of Raloxifene HCL loaded spanlastics. Raloxifene HCL, a selective estrogen receptor modulator (SERM), is active for the deterrence and management of postmenopausal osteoporosis. Spanlastics nanocarrier was prepared by ethanol injection method and optimized for independent variables by using Box Behnken design. The independent variables used in the experiment were concentration of Span 60, Tween 80 as an edge activator, and sonication time. The individual and joined impacts of independent variables were assessed on vesicle size, polydispersity index (PDI), and encapsulation efficiency (EE). Raloxifene HCL and formulation were analyzed by FT-IR, DSC and XRD. Raloxifene HCL loaded spanlastics were characterized for particle size, PDI, EE, and in-vitro drug release. Ex vivo skin permeation and stability studies were performed for the optimized formulation. The optimized spanlastics vesicle showed a particle size of 275.4 nm with PDI, 0.267 which was suitable for permeation through skin layers. TEM image illustrated well-dispersed nanocarrier with spherical shape. The % cumulative drug release and transdermal flux for the optimized spanlastics formulation were found to be 85% (Approx. after 24 h) and 4.24 μg/cm2/hr respectively. The enhanced permeation across the skin layers was proposed to be due to the presence of ethanol which will increase the lipid fluidity of the stratum corneum and will help to penetrate the drug. Later the skin penetration ability was determined by confocal laser scanning microscopy (CLSM) and showed that rhodamine loaded spanlastics formulation penetrated to the depth of 54.9 μm while rhodamine suspension limited to 20 μm in the skin. We can conclude that raloxifene HCL loaded spanlastics could serve as a better approach to deliver drug in deeper layers of the skin.

Assessing the viability of carbamoylethyl pullulan-g-stearic acid based smart polymeric micelles for tumor targeting of raloxifene

The present investigation entails the synthesis of smart pullulan polymeric micelles for evaluating its tumor targeting potential. For this purpose, two step polymerization synthesis reactions were conducted. In the first step, carbamoylethylation occurs by reaction of the free alcoholic moieties at 6th position of glucopyranose unit of pullulan with acrylamide in presence of alkali to obtain carbamoylethyl pullulan (CmP). In the second step, CmP undergoes graft polymerization with stearic acid (SA) to obtain CmP-g-stearic acid diblock co-polymer (CmP-g-SA) as evident from FTIR and NMR analysis. The XpRD spectra showed crystalline nature that was further confirmed by SEM indicating rough and poly-porous morphology. The QbD based optimized formulations of raloxifene HCl (RLX) loaded polymeric micelles (RLX PMs) exhibited pH-dependent release profile with added advantage of 1.2 times reduction in percentage hemolysis giving substantial compatibility with erythrocytes. In vivo pharmacokinetic performance of RLX PMs suggested enhanced mean residence time and volume of distribution. Besides, the biodistribution study of RLX PMs manifested enhanced entry of RLX in mammary carcinoma tissues as compared to normal tissues suggested that CmP-g-SA based micelles enhanced the anti-tumor activity of RLX. Overall, the findings pointed toward the biocompatibility of CmP-g-SA as a potential carrier system for the delivery of RLX.

Calcium-Enriched Nanofibrillated Cellulose/Poloxamer in-situ Forming Hydrogel Scaffolds as a Controlled Delivery System of Raloxifene HCl for Bone Engineering [Retraction

[This retracts the article DOI: 10.2147/IJN.S323974.].

Calcium-Enriched Nanofibrillated Cellulose/Poloxamer in-situ Forming Hydrogel Scaffolds as a Controlled Delivery System of Raloxifene HCl for Bone Engineering.

PurposeTEMPO-oxidized nanofibrillated cellulose (TONFC) originating from an agricultural waste (sugar cane) was utilized to prepare injectable in-situ forming hydrogel scaffolds (IHS) for regenerative medicine.MethodsTONFC was prepared and characterized for its morphology and chemical structure using TEM and FT-IR, respectively. The cold method was applied to prepare hydrogels. Various concentrations of poloxamer 407 were added to the prepared TONFC (0.5%w/w). Different sources of calcium, Fujicalin® (DCP) or hydroxyapatite (TCP), were used to formulate the aimed calcium-enriched raloxifene hydrochloride-loaded IHS. Gelation temperature, drug content, injectability and in-vitro drug release were evaluated along with the morphological characters. Cytocompatibility studies and tissue regeneration properties were assessed on Saos-2 cells.ResultsTEM photograph of TONFC showed fibrous nanostructure. The selected formulation “Ca-IHS4” composed of TONFC+15% P407+10% TCP showed the most prolonged release pattern for 12 days with the least burst effect (about 25% within 24 h). SEM micro-photographs of the in-situ formed scaffolds showed a highly porous 3D structure. Cytocompatibility studies of formulation “Ca-IHS4” revealed the biocompatibility as well as improved cell adhesion, alkaline phosphatase enzyme activity and calcium ion deposition.ConclusionThe outcomes suggest that Ca-IHS4 presents a simple, safe-line and non-invasive strategy for bone regeneration.

In-vitro Release and Stability Studies of Raloxifene Loaded Solid-Lipid Nanoparticle

Objective: Raloxifene HCl (RLX) show a low oral bioavailability (<2%) in human due to its poor solubility and extensive (>90%) first-pass metabolism. To overcome these limitations, the present investigation deals with the development of Compritol 888 ATO based optimized RLX-loaded solid lipid nanoparticle (SLN) .
 Methods: Compritol 888 ATO-based RLX-loaded optimized solid lipid nanoparticle (SLN) were formulated using oil in water microemulsion method. Drug-excipients compatibility was confirmed through a powder X-ray diffraction study. The optimized SLN was characterized for particle size and drug release.
 Results: Drug-excipients compatibility was confirmed powder X-ray diffraction study. As per the desirability function value (0.959) the optimized formulation has the size and EE of 168.97 nm and 93.14%. In-vitro study showed a sustained release of RLX from the optimized SLNs. The optimized formulation was found stable for 180 days.
 Conclusion: The high biocompatibility, biodegradability, ability to protect drug in GIT and sustained release properties make SLNs an ideal candidate to resolve poor oral bioavailability challenges.

FABRICATION AND CHARACTERIZATION OF RALOXIFENE LOADED SOLID-LIPID NANOPARTICLES

Objective: The poor water solubility of the drug presents a great challenge for the formulation development and results in low oral bioavailability. The oral bioavailability of Raloxifene HCl (RLX) is very low (<2%) in humans due to its poor solubility. The objective of the present study was to develop RLX loaded solid-liquid nanoparticles for effective drug delivery.
 Methods: Compritol 888 ATO-based RLX-loaded solid lipid nanoparticles (SLNs) were formulated using the oil in water microemulsion method. Drug-excipients compatibility was confirmed through Fourier transform infrared spectroscopy, Differential scanning calorimetry methods. The SLN was characterized for particle size, surface morphology, entrapment efficiency.
 Results: A total of seventeen formulations (SLN1-SLN17) were developed as per the 3 levels 3 factor Box–Behnken design. The model used for the analysis was statistically analyzed using ANOVA and the goodness of fit was evaluated using diagnostic plots. As per the response-surface plots, the amount of lipid, poloxamer 407, and ultrasonication time have a significant effect on the particle size and entrapment efficiency (%EE). The developed RLX-loaded SLNs have the size and %EE in the range of 165.63±2.62 nm to 315.33±4.87 nm and 75.21±2.32% to 95.32±2.11%. The TEM analysis showed that the developed RLX-loaded SLNs were almost spherical and has a small size range.
 Conclusion: The high biocompatibility, biodegradability, ability to protect drugs in GIT, and sustained release properties make SLNs an ideal candidate to resolve poor oral bioavailability challenges.

Formulation and In Vitro Characterization of Raloxifene Nanostructured Lipid Carriers For Oral Delivery With Full Factorial Design-Based Studies Using Quality By Design (QbD) Approach

The main aim of the present study is to improve the dissolution rate of Raloxifene Hydrochloride by formulating nanostructured lipid carriers (NLC) using Quality by Design (QbD) approach. The formulations of NLC-RH were prepared by the ultrasonication method using stearic acid as solid lipid, medium-chain triglyceride as the liquid lipid and polysorbate 80 as the surface-active agent. Two most critical quality attributes (CQAs) for NLC-RH were particle size and entrapment efficiency. The other attributes of medium influence identified includes dissolution rate, zeta potential and particle size didtribution. The Critical Material Attributes (CMAs) identified were solid lipid/liquid lipid ratio and surfactant concentration. The time required for ultrasonication was selected as a Critical Process Parameter (CPP). The 23 full factorial design was used to evaluate the relationship between the CMAs and CPPs variable. Based on the experiments, the composition of the optimal formulation is achieved with solid lipid/liquid lipid ratio of 7:3 and 7 % of surfactant concentration with 15 min of ultrasonication time. The optimized formulation of NLC-RH was found to be with a mean particle size of 146 nm with narrow particle size distributions. From the above results, it is concluded that a promising Raloxifene HCl loaded NLC could give a novel and potential therapy for osteoporosis.

Ethosomes: A Novel Drug Delivery System And Their Therapeutic Applications -A Review

“Ethosomes” are soft vesicles made up of Phospholipids, Ethanol and water. They are “novel carrier system” used for delivery of drugs having low penetration through biological membrane i.e., Skin “Transdermal delivery of drugs” plays a major role in the Ethosomes. In this review we are going to discuss about various applications of ethosomes i.e. Delivery of antibiotic, Delivery of NSAIDS, Anti-cancer, Anti-fungal, Skin cancer, Anti-Acne etc. Ethosomes are loaded with drugs like Indomethacin (NSAIDS), Clotrimazole (Anti-fungal), Raloxifene HCl (Anti-cancer), Fluconazole (Antibiotic) etc. This review explains about the preparation methods used in the preparation of ethosomes such as cold method, Hot method, Injection method, Mechanical dispersion method and Classic methods. Evaluation tests performed in the ethosomes are Drug entrapment efficiency, permeation characteristics, Assay of HPLC, FT-IR studies, stability studies, size analysis, zeta potential etc. Various Penetrtion enhancers like Labrasol, Transcutol, and Terpenes were used in the formulation of ethososmes. Improve the penetration of both lipophilic and hydrophilic drugs through stratum corneum [SC] into deeper layers of the skin very effectively when compared with liposomes. Ethosomes can act as a carrier for large and diverse group of drugs with different physicochemical properties and found a number of applications in pharmaceutical, biotechnological and cosmetic fields. Enhanced delivery of bioactive molecules through the skin and cellular membranes by means of an ethosomal transporter opens numerous confronts and prospects for the research and future development of novel improved therapies. The formulation of ethosomes possesses promising future in effective dermal or transdermal delivery of bioactive agents.

Development and validation of stability indicating RP-HPLC method for the determination of related substances in Raloxifene hydrochloride tablets dosage forms

This work is intended to thrive a stability-indicating high performance liquid chromatographic method for the analysis of Raloxifene HCl related compounds in pharmaceutical dosage forms. The separation was achieved Inertsil C8 (150 x 4.6 mm ID, 3.5μm)column using a gradient method. Mobile phase A is 0.01M KH2PO4 buffer (pH4.5), and mobile phase B is acetonitrile used in this work. 1.0 mL/ minute is the flow of rate and at 280nm noticed wavelength is monitored. For specificity, the limit of quantification, the limit of detection, linearity, accuracy, method precision, intermediate precision, robustness and stability this method is validated. The six injection impurities of standard solutions at the 4.0 µg/mL conjecture concentration were confirmed experimentally for LOQ values. The correlation coefficient of the impurities is more than 0.99. All impurities meet the criteria for linearity of both the impurities and raloxifene. The RSD recoveries obtained for impurities are not more than 10%. The achievement of this study demonstrated that the method is selective, linear, precise, rugged, robust and stability-indicating for the determination of related substances in raloxifene HCl tablet dosage form.

Long lasting in-situ forming implant loaded with raloxifene HCl: An injectable delivery system for treatment of bone injuries.

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.

Production of a new platform based on fumed and mesoporous silica nanoparticles for enhanced solubility and oral bioavailability of raloxifene HCl.

The purpose of the present study was to compare mesoporous and fumed silica nanoparticles (NPs) to enhance the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RH). Mesoporous silica NPs (MSNs) and fumed silica NPs were used by freeze-drying or spray-drying methods. MSNs were obtained with different ratios of cetyltrimethylammonium bromide. Saturation solubility of the NPs was compared with the pure drug. The optimised formulation was characterised by scanning electron microscopy (SEM), X-ray diffraction (XRD) and differential scanning calorimetry. The pharmacokinetic studies were done by oral administration of a single dose of 15 mg/kg of pure drug or fumed silica NPs of RH in Wistar rats. MSNs enhanced the solubility of RH from 19.88 ± 0.12 to 76.5 μg/ml. Freeze-dried fumed silica increased the solubility of the drug more than MSNs (140.17 ± 0.45 μg/ml). However, the spray-dried fumed silica caused about 26-fold enhancement in its solubility (525.7 ± 93.5 μg/ml). Increasing the ratio of silica NPs enhanced the drug solubility. The results of XRD and SEM analyses displayed RH were in the amorphous state in the NPs. Oral bioavailability of NPs showed 3.5-fold increase compared to the pure drug. The RH loaded fumed silica NPs prepared by spray-drying technique could more enhance the solubility and oral bioavailability of RH.

Transdermal delivery of raloxifene HCl via ethosomal system: Formulation, advanced characterizations and pharmacokinetic evaluation

Raloxifene HCl belongs to a class of selective estrogen receptor modulators (SERMs) which is used for the management of breast cancer. The major problem reported with raloxifene is its poor bioavailability which is only up to 2%. The main objective of the present work was to formulate raloxifene loaded ethosomal preparation for transdermal application and compare it with an oral formulation of the drug. Five ethosomal formulations with different concentrations of ethanol and a conventional liposomes formulation were prepared by rotary evaporation method. The prepared systems were characterised by high resolution transmission electron microscopy (HRTEM), force emission electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and 31P NMR study. All these advanced characterization study established that the ethosome formulation was well defined by its size, shape and its bilayer formation. Transdermal flux of the optimized ethosome formulation was 22.14 ± 0.83 µg/ml/cm2 which was 21 times higher when compared to the conventional liposomes. Confocal microscopy study revealed an enhanced permeation of coumarin-6 dye loaded ethosomes to much deeper layers of skin when compared with conventional liposomes. The gel was found to be pseudoplastic with elastic behaviour. In-vivo studies on rats showed a higher bioavailability of RXL (157% times) for ethosomal formulation when compared with the oral formulation. In conclusion, RXL loaded ethosomal formulation via transdermal route showed superior drug delivery properties as compared to oral formulation.

Enhanced solubility, oral bioavailability and anti-osteoporotic effects of raloxifene HCl in ovariectomized rats by Igepal CO-890 nanomicelles

The purpose of the present study was to enhance the bioavailability and anti-osteoporotic effects of raloxifene HCl (RH) by increasing its solubility and inhibition of the p-glycoprotein pump using surfactant micelles of Igepal CO-890. The micelles were prepared by the direct method and their critical micellar concentration, drug dissolution rate, saturated solubility, drug loading and surface morphology were defined. The cytotoxicity of Igepal CO-890 and its ability to inhibit the p-glycoprotein pump were studied on Caco-2 cells. The pharmacokinetic parameters were analyzed by oral administration of a single dose of 15 mg/kg in Wistar rats. Anti-osteoporotic effects were studied by measuring the calcium, phosphorous, and uterus weight of rats after one month of oral administration of 6 mg/kg/day of RH in ovariectomized rats. Igepal CO-890 micelles enhanced the RH solubility by about two-fold. The FT-IR and DSC studies indicated no interaction between the drug and the surfactant. XRD spectrum showed an amorphous state of RH in the micelles. The p-glycoprotein pump was inhibited by Igepal CO-890 in Caco-2 cells comparable to verapamil. Micelles increased the uterine weight and decreased the serum calcium and phosphorus significantly compared to the untreated drug. Oral bioavailability of RH increased about four-fold by nanomicelles.

Nano Transfersomes Vesicles of Raloxifene HCl with Sorbitan 80: Formulation and Characterization

Lipid vesicles in the nano range with ionic and nonionic surfactants are known as transfersomes. The presence of surfactant in the bilayer structure makes the vesicles very flexible in nature and helps them to permeate through the stratum corneum. The purpose of this research was to develop and characterize a transfersomal formulation of raloxifene HCl to deliver it into systemic circulation through the transdermal route. The transfersomal formulation was prepared by the rotary evaporation method with phospholipon 90G and sorbitan 80. The particle size, zeta potential and polydispersity index (PDI) of the formulation were measured. The drug entrapment efficiency (EE%) of the vesicles was determined by an indirect ultracentrifugation method. Differential scanning calorimetry (DSC), ex-vivo skin permeation study, field emission scanning electron microscope (FESEM), high resolution transmission electron microscope (HRTEM) and confocal laser scanning microscopy (CLSM) study were carried out as parts of advanced characterization of the developed formulation. The vesicles were found to have an average particle size of 95.1±1.05nm with a PDI value of 0.162±0.01 and zeta potential of +17.62±0.29 mV. EE% was recorded up to 90.9±1.15. Transdermal flux (J = 4.66±0.79 μg/cm2hr) of the developed formulation showed a favorable value required for the formulation efficacy. FESEM and TEM study results proved the spherical and round structures of the vesicles. DSC showed that the raloxifene was in the non-crystal form and was enclosed in the lipid bilayer. CLSM study proved the distribution of the drug in the stratum corneum, viable epidermis and dermis with high fluorescence intensity. The developed nano transfersomes of raloxifene HCl with sorbitan 80 showed encouraging results and can be further investigated for in vivo efficacy.

Poly(methyl vinyl ether-co-maleic acid) for enhancement of solubility, oral bioavailability and anti-osteoporotic effects of raloxifene hydrochloride

Raloxifene HCl (RH) has poor water solubility and due to its extensive first pass metabolism; its bioavailability is only 2%. The purpose of the present study was to enhance the aqueous solubility, oral bioavailability and anti-osteoporotic effects of RH by electro-sprayed nanoparticles (NPs) in ovariectomized rats. NPs containing RH and different ratio of poly(methyl vinyl ether-co-maleic acid) (PMVEMA) were electrosprayed. The voltage, distance of needle to the collector, flow rate of the solution and polymeric percentage were optimized according to the size of NPs and drug solubility. The optimized formulation was characterized by SEM, XRD, DSC, and FTIR. The pharmacokinetic parameters were studies by oral administration of a single dose of 15mg/kg in Wistar rats. The anti-osteoporotic effects were studied in female ovariectomized rats. Animals were treated with 6mg/kg/day for 2months then serum calcium, phosphorous and alkaline phosphatase levels were measured. RH loaded electrosprayed NPs showed 10-fold enhanced solubility compared to the free drug. Moreover, the XRD and SEM tests displayed an amorphous state of drug in the NPs. FTIR and DSC tests revealed no interaction between the polymer and the drug. Serum calcium, phosphorous and alkaline phosphatase levels were significantly decreased in ovariectomized rats receiving oral RH NPs (P<0.05). No significant difference was detected between RH NPs and estradiol groups (P>0.05). Oral bioavailability of NPs showed 7.5-fold increase compared to the pure drug. The electrosprayed PMVEMA nanoparticles can enhance solubility, bioavailability and antiosteoporotic effects of RH.

Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling.

BackgroundInterleukin-6 (IL-6) is a multifunctional cytokine, which is involved in the regulation of differentiation and growth of certain types of tumor cells. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) induced by IL-6 is frequently detected in liver cancer and has emerged as a viable molecular target for liver cancer treatment. However, few inhibitors targeting up-streams of STAT3 are available for the therapy of liver cancer. We reported the discovery of EVISTA (Raloxifene HCl) as novel inhibitor of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Raloxifene in STAT3 signaling or liver cancer cells is still unclear.ResultsRaloxifene inhibited the P-STAT3 stimulated by IL-6, but not the induction of STAT1 and STAT6 phosphorylation by IFN-γ, IFN-α, and IL-4. Raloxifene inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell-lines. Raloxifene inhibited the targets of STAT3, such as Bcl-2, Bcl-xl and survivin and cell viability, cell migration, and colony formation in liver cancer cells. Further, daily administration of Raloxifene suppressed the Hep-G2 tumor growth in mice in vivo.Materials and MethodsThe inhibitory effect on STAT3 phosphorylation and activity as well as cell viability, migration, and colony forming ability by Raloxifene was examined in human liver cancer cells. Tumor growth was detected via mouse xenograft tumor mode.ConclusionsOur results suggest that Raloxifene is a potent IL-6/GP130 inhibitor and may be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling.

Ethosomal Hydrogel of Raloxifene HCl: Statistical Optimization & Ex Vivo Permeability Evaluation Across Microporated Pig Ear Skin.

The oral bioavailability of Raloxifene hydrochloride, an FDA approved selective estrogen receptor modulator, is severely limited due to its poor aqueous solubility and extensive first pass metabolism. The Present work focuses on the development of ethosomal hydrogel for transdermal delivery of Raloxifene HCl as an alternate way to solve aforementioned problem. The physical breaching of stratum corneum, the principal barrier, by microneedle treatment was also employed to potentiate its transdermal permeation. The influence of lipid and ethanol concentration on vesicle size and entrapment efficiency was extensively investigated using response surface methodology based on central composite design. The software based optimization was done and validated using check point analysis. Optimized batch was extensively evaluated for its safety, efficacy and stability. The optimized ethosomal batch possessed 403 nm size and 74.25% drug entrapment. Its zeta potential and in vitro drug release were also found favorable for transdermal permeation. The ex vivo skin permeation study revealed a transdermal flux of 4.621 μg/cm2/h through the intact pig ear skin which was further enhanced through the microporated skin (transdermal flux, 6.194 μg/cm2/h) with a 3.87 fold rise when compared to drug permeation from plain solution applied over intact skin (transdermal flux, 1.6 μg/cm2/h). Histopathological skin sections showed the non-irritant nature of the ethosomal hydrogel and microneedle treatment. The formulation was found stable under both refrigeration and room temperature conditions for 6 weeks. In a nutshell, the developed system was found efficient, safe and stable and seems promising for transdermal use.