Raloxifene HCl

Raloxifene HCl（LY139481）is a potent and selective of estrogen receptor (ER) with the IC50 value of 2.9~5.7nM [1].

Raloxifene HCl（LY139481）is a selective and uncompetitive of estrogen receptor (ER) with the IC50 value of 2.9~5.7nM for phthalazine oxidase in human liver cytosol. In addition, Raloxifene has been found to be a potent inhibitor for the three oxidation reactions with the Ki values of 0.87nM, 1.2nM and 1.4nM for phthalazine oxidation, vanillin oxidation and nicotine-△1’(5‘)-iminium ion oxidation, respectively. And the inhibition of Raloxifene HCl is not time-dependent fashion. Apart from these, Raloxifene HCl has been reported to noncompetitively inhibit the aldehyde oxidase-catalyzed reduction reaction with the Ki value of 52nM [1].

References:
[1] Obach RS.Potent inhibition of human liver aldehyde oxidase by raloxifene.

Drug Metab Dispos. 2004 Jan;32(1):89-97.

Solid state interaction of raloxifene HCl with different hydrophilic carriers during co-grinding and its effect on dissolution rate.[Pubmed:19048425]

Drug Dev Ind Pharm. 2009 Apr;35(4):455-70.

This study investigated the effects of different classes of hydrophilic carriers (poly vinyl pyrrolidones [PVPs] [Plasdone K-25 and Plasdone S-630], cellulosic polymers [hydroxypropyl methyl cellulose and hydroxy propyl cellulose], and Sodium Alginate) on the solid state and dissolution rate of Raloxifene hydrochloride (R-HCl). Solid state characterizations of co-ground mixtures and physical mixtures in 1:1 and 1:2 ratios of drug to polymer were performed by employing laser diffractometer for particle size and differential scanning calorimetry (DSC) for solid state interactions. The results of particle size studies showed that only co-grinding with PVPs was more effective in the reduction of particle size than the milling of drug alone. DSC study indicated that the crystalline nature of the drug was reduced after co-grinding with PVPs when compared with their corresponding physical mixtures. The hydrophilic carriers other than PVPs did not reduce the crystalline nature of the drug significantly. X-ray diffraction and scanning electron microscopy were carried out for selected batches to confirm DSC results. Significant enhancement in dissolution rate and extent was observed with co-ground mixtures of drug and PVPs. Plasdone S-630 was found to be a better carrier for R-HCl in terms of achieving improvement in dissolution. In vitro dissolution data can be described by Hixson-Crowell model, indicating the drug release mechanism predominated by erosion.

Novel biodegradable polyesters. Synthesis and application as drug carriers for the preparation of raloxifene HCl loaded nanoparticles.[Pubmed:19633613]

Molecules. 2009 Jul 7;14(7):2410-30.

Raloxifene HCl is a drug with poor bioavailability and poor water solubility. Furthermore nomicron pharmaceutically acceptable organic solvent has been reported before to dilute the drug. It was observed that Raloxifene HCl can be diluted in a solvent mixture of acetone/water or ethanol/water. The aim of this study was to use biodegradable polymers in order to prepare Raloxifene HCl nanoparticles. For this purpose a series of novel biodegradable poly(ethylene succinate-co-propylene adipate) P(ESu-co-PAd) polyesters were synthesized following the polycondensation method and further, poly(ethylene succinate) (PESu) and poly(propylene adipate) (PPAd) were used. The prepared polyesters were characterized by intrinsic viscosity measurements, end group analysis, enzymatic hydrolysis, Nuclear Magnetic Resonance Spectroscopy ((1H)-NMR and (13)C-NMR) and Wide-angle X-ray Diffractometry (WAXD). The drug nanoparticles have been prepared by a variation of the co-precipitation method and were studied by Wide-angle X-ray Diffractometry (WAXD), FTIR spectrometry, light scattering size distribution, Scanning Electron Microscopy (SEM) and release behavior measurements. The interactions between the polymers and the drug seem to be limited, so the drug occurs in crystalline form in all nanoparticles. The size of the nanoparticles seems to be in the range of 150-350 nm, depending on the polymer that was used. The drug release depends on the melting point and degree of crystallinity of the polyesters used. An initial high release rate was recorded followed by very slow rates of controlled release.

Effectiveness of various drug carriers in controlled release formulations of raloxifene HCl prepared by melt mixing.[Pubmed:19751201]

Curr Drug Deliv. 2009 Oct;6(5):425-36.

In the present study solid dispersions of Raloxifene HCl were prepared by melt mixing. As drug carriers, biodegradable/biocompatible aliphatic polyesters were used. These formulations were compared to those based on extensively used drug carriers such as PEG and Gelucire 50/13. The used aliphatic polyesters namely poly(propylene succinate) (PPSu) and poly(propylene adipate) (PPAd) were prepared by melt polycondensation. The polyesters have melting points close to human body temperature and were used for first time as drug carries. Polymer cytocompatibility based on HUVEC cells viability in the presence of increasing concentrations of polymer was investigated and it was found that PPSu and PPAd exhibit comparable cytocompatibility with poly(dl-lactide). The physical state of solid dispersions was evaluated by FTIR, SEM and XRD techniques. In all cases the interactions between drug and carriers are limited and thus the dispersed drug was mainly in the crystalline state. SEM revealed that the particles size of the dispersed drug increases with increasing the drug amount. The release behavior of the drug is affected from both the drug amount and the kind of the used carrier. The drug is released almost immediately from PEG formulations while Gelucire results in sustained release. In formulations that polyesters were used as drug carriers the release is slower.

Ethosomal Hydrogel of Raloxifene HCl: Statistical Optimization & Ex Vivo Permeability Evaluation Across Microporated Pig Ear Skin.[Pubmed:26787414]

Curr Drug Deliv. 2016;13(7):1111-1122.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 mug/cm2/h through the intact pig ear skin which was further enhanced through the microporated skin (transdermal flux, 6.194 mug/cm2/h) with a 3.87 fold rise when compared to drug permeation from plain solution applied over intact skin (transdermal flux, 1.6 mug/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. CONCLUSION: In a nutshell, the developed system was found efficient, safe and stable and seems promising for transdermal use.

Tamoxifen and raloxifene suppress the proliferation of estrogen receptor-negative cells through inhibition of glutamine uptake.[Pubmed:20383709]

Cancer Chemother Pharmacol. 2011 Feb;67(2):285-91.

PURPOSE: Modulation of estrogen receptor (ER) plays a central role in selective estrogen receptor modulators (SERMs) molecular mechanism of action, although studies have indicated that additional, non-ER-mediated mechanisms exist. It has been suggested that the induction of oxidative stress by SERM could be one of the non-ER-mediated mechanisms held responsible for their pro-apoptotic role in ER-negative cells. Tumor cells are known for their high requirement of glutamine (Gln) that serves multiple functions within the cells, including nutritional and energy source, as well as one of the precursors for the synthesis of natural antioxidant glutathione (GSH). We hypothesized that one of the mechanisms responsible for ER-independent anti-neoplastic properties of SERMs and also for their adverse side effects could be dependent on the inhibition of Gln uptake. METHODS: Human ER-negative MDA-MB231 breast cancer cells were treated with different doses of Tam and Ral. Gln uptake was monitored by using [(3)H]Gln assay. The effect of Tam and Ral on Gln transporter ASCT2 expression, glutathione (GSH) levels and cellular proliferation was determined. RESULTS: Tam and Ral inhibited Gln uptake in a dose-dependent manner through inhibition of ASCT2 Gln transporter. This effect of the anti-estrogens was associated with inhibition of GSH production and apoptosis. Treatment of cells with N-acetyl L-cysteine and 17 beta-estradiol 2 reversed the effects of Ral and Tam. CONCLUSIONS: Our results indicate that one of the mechanisms of action (and possibly some of the side effects) of TAM and RAL is associated with inhibition of cellular Gln uptake, oxidative stress and induction of apoptosis.

Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulation.[Pubmed:11704975]

Rev Endocr Metab Disord. 2001 Jan;2(1):129-38.

Raloxifene possesses a complex pharmacology with tissue-selective estrogen agonist and antagonist effects. At the center of these effects resides the high affinity interaction of raloxifene with the ER. The ability of raloxifene to compete with estrogen for ER binding accounts for the estrogen antagonist effects of raloxifene in uterine and mammary tissue. Since the precise mechanism for the agonist effect of estrogen on the skeleton remains uncertain, it is difficult to unequivocally cite a single estrogen-like mechanism for raloxifene in bone. However, multiple lines of evidence clearly indicate that the estrogen agonist effect of raloxifene on bone is also mediated via an interaction with ER. The data showing non-additivity of raloxifene and estrogen effects in bone, and those showing the requirement for a pituitary hormone in the anti-estrogenic action of raloxifene and estrogen are particularly important. Thus, global evaluation of the similarities and parallel responses of raloxifene and estrogen in bone and the cardiovascular system, as summarized above, strongly support a similar mechanistic basis for the agonist effects of these agents on the skeleton.

Effect of estrogen agonists and antagonists on induction of progesterone receptor in a rat hypothalamic cell line.[Pubmed:10465261]

Endocrinology. 1999 Sep;140(9):3928-37.

Estrogen is essential in the hypothalamus for the central regulation of reproduction. To understand the molecular mechanism(s) of estrogen action in the hypothalamus, immortalized rat embryonic hypothalamic cell lines were characterized for steroid receptors and subcloned. Scatchard analysis of the D12 subclone demonstrated one high affinity estrogen receptor-binding site (Kd = 31.3+/-1.9 pM) with a Bmax of 30.8+/-0.8 fmol/mg. Estrogen receptor-alpha protein was identified by Western blot and gel shift analyses. Treatment with estradiol (48 h) stimulated progesterone receptor (PR) messenger RNA expression and binding to [3H]R5020, a synthetic progestin. Because the agonist or antagonist activity of estrogen mimetics can be cell type dependent, the activities of various estrogen mimetics were determined in D12 cells. ICI 182,780 (IC50 = 0.63 nM), raloxifene (IC50 = 1 nM), enclomiphene (IC50 = 77 nM), and tamoxifen (IC50 = 174 nM) inhibited the induction of PR by estradiol, and none of these compounds significantly stimulated PR when given alone. In contrast, 17alpha-ethynyl estradiol (EC50 = 0.014 nM), zuclomiphene (EC50 = 100 nM), and genistein (EC50 = 17.5 nM) functioned as estrogen agonists in these cells. In addition, the estrogen-induced progesterone receptor activated a progesterone response element reporter construct in response to progestins. Thus, the D12 rat hypothalamic cell line provides a useful model for characterizing tissue-selective estrogenic compounds, identifying estrogen- and progesterone-regulated hypothalamic genes, and understanding the molecular mechanisms of steroid action in various physiological processes mediated by the hypothalamus.

Raloxifene hydrochloride (LY156758 hydrochloride; LY139481 hydrochloride) is a second generation selective and orally active estrogen receptor modulator. Raloxifene hydrochloride produces estrogen-agonistic effects on bone and lipid metabolism and estrogen-antagonistic effects on uterine endometrium and breast tissue.

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