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1.
PLoS One ; 14(12): e0226639, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31881053

RESUMO

Raloxifene is commonly used for breast cancer protection. The low bioavailability of raloxifene (2%) is the result of its low solubility and intestinal glucuronidation. The nano-lipid carriers are characterized by small particle size, biocompatibility, and sustainable properties that improve cellular uptake of the loaded drug. The aim of this study was the improvement of raloxifene bioavailability by enhancing its solubility and cellular penetration through formulation of D-α-tocopheryl polyethylene glycol 1000 succinate based transferosomes and augmenting their effect with the cationic cell-penetrating peptide transactivator of transcription of the human immunodeficiency virus. Particle size, zeta potential, and transmission electron microscope investigation of the formed nanocarriers were carried out. Ex vivo raloxifene permeation through rat skin and cell viability studies was investigated. The results of D-α-tocopheryl polyethylene glycol 1000 succinate- transactivator of transcription of the human immunodeficiency virus transferosomes showed an average vesicle size of 96.05 nm with positively charged vesicles 39.4 mV of zeta potential value. The results revealed significant (p < 0.05) enhancement of raloxifene permeation from raloxifene transferosomes- loaded film when compared with raw raloxifene film. IC50 results showed significant improvement of formulated raloxifene cytotoxicity by 1.42-fold in comparison with raw raloxifene against MCF-7 cell lines. The developed raloxifene-transferosomes are considered promising nano-lipid carriers for the enhancement delivery of raloxifene.


Assuntos
Portadores de Fármacos/metabolismo , Cloridrato de Raloxifeno/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Vitamina E/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Administração Cutânea , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacocinética , Anticarcinógenos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Células MCF-7 , Cloridrato de Raloxifeno/farmacocinética , Cloridrato de Raloxifeno/farmacologia , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Absorção Cutânea
2.
Int J Pharm ; 571: 118703, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31536761

RESUMO

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.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Portadores de Fármacos/química , Implantes de Medicamento/administração & dosagem , Fraturas por Osteoporose/tratamento farmacológico , Cloridrato de Raloxifeno/administração & dosagem , Animais , Conservadores da Densidade Óssea/farmacocinética , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/lesões , Química Farmacêutica , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos , Humanos , Injeções Intralesionais , Masculino , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Porosidade , Cloridrato de Raloxifeno/farmacocinética , Ratos , Propriedades de Superfície
4.
IET Nanobiotechnol ; 13(4): 392-399, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31171744

RESUMO

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.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Cloridrato de Raloxifeno/farmacocinética , Dióxido de Silício/química , Administração Oral , Animais , Disponibilidade Biológica , Masculino , Tamanho da Partícula , Porosidade , Cloridrato de Raloxifeno/administração & dosagem , Cloridrato de Raloxifeno/química , Ratos , Ratos Wistar , Solubilidade
5.
Drug Dev Ind Pharm ; 45(4): 587-602, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30633575

RESUMO

In the present work, MCM-41 and MCM-48 type of nanoparticles were successfully engineered. Effect of nanosize and amine functionalization on drug release, in vitro intestinal absorption and in vivo pharmacokinetic behavior was investigated in a comprehensive manner. The tailor-made bare and surface decorated MCM-41 and MCM-48 were synthesized and evaluated for their mesoporous skeleton, pore size, particle size, surface area, zeta potential, etc. by nitrogen sorption, DLS, TEM, etc. Incorporation of raloxifene (RLF) was affirmed using optimized immersion-solvent evaporation technique and its success confirmed by DSC, IR, and XRD analysis. TGA analysis revealed higher %grafting of amine groups on the exterior and larger RLF encapsulation into mesoporous derivate. The detailed in vitro release study revealed SGF to be the most compatible media for RLF showing an initial burst release from pristine nanoparticles and a delayed release from surface coated nanoparticles. Furthermore, release kinetics model data demonstrated Weibull and Higuchi as the best fit models for bare and amine-functionalized nanoparticles respectively. Moreover, an in vitro permeability study on Caco-2 cell line revealed higher absorption by engineered nanoparticle as compared to pure RLF and its marketed formulation. The supremacy in the in vivo pharmacokinetic parameters of RLF-41 and RLF-48 was demonstrated with 3.33 and 3.50 times enhancement in the bioavailability of RLF with respect to RLF suspension. To sum up, the results obtained were superior and promising for synthesized nanoparticles and more precisely for MCM-48 amongst them.


Assuntos
Portadores de Fármacos/química , Antagonistas de Estrogênios/farmacocinética , Cloridrato de Raloxifeno/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Células CACO-2 , Engenharia Química/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas de Estrogênios/administração & dosagem , Feminino , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Nanopartículas/química , Osteoporose/tratamento farmacológico , Permeabilidade , Cloridrato de Raloxifeno/administração & dosagem , Dióxido de Silício/química
6.
Braz. J. Pharm. Sci. (Online) ; 55: e18052, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1039069

RESUMO

A specific, precise, and accurate LC-UV method was developed and validated to assay raloxifene hydrochloride in rat plasma. Raloxifene was analyzed after liquid-liquid extraction and quantified by reversed phase liquid chromatography (C18 column) using acetonitrile and ammonium acetate buffer 0.05 M (pH 4.0) as mobile phase at a flow rate of 1 mL.min-1 and UV detection at 287 nm. Retention times of raloxifene and internal standard (dexamethasone) were approximately 11 min and 14 min, respectively. Linearity was checked for a concentration range between 25 ng.mL-1 and 1000 ng.mL-1. Intra- and inter-day precision had relative standard deviation lower than 10% and 15%, respectively. Recovery from plasma was higher than 90%. Accuracy values were 98.21%, 99.70%, and 102.70% for lower, medium, and upper limits of quantification, respectively. Limit of quantification was 25 ng.mL-1. Drug stability was analyzed at room temperature using plasma kept in a freezer at -80 °C for 45 days after processing for 6 h and three freeze-thaw cycles. The advantages of the method developed include stability under different conditions and low limit of quantification. Its applicability was confirmed by the analysis of raloxifene levels in plasma samples in a designed pharmacokinetic study in rats after intravenous administration (5 mg.kg-1).


Assuntos
Animais , Masculino , Ratos , Plasma/efeitos dos fármacos , Cloridrato de Raloxifeno/farmacocinética , Cromatografia de Fase Reversa/métodos , Disponibilidade Biológica
7.
Int J Nanomedicine ; 13: 6325-6335, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349253

RESUMO

Background: Raloxifene hydrochloride (RLX) is approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis, in addition to reducing the risk of breast cancer in postmenopausal women. RLX has the disadvantages of low aqueous solubility, extensive presystemic intestinal glucuronidation, and first-pass metabolism, resulting in a limited bio-availability of only 2%. The aim of this work was to enhance the bioavailability of RLX via the formulation of an in situ nasal matrix (misemgel) comprising micelles made of vitamin E and D-α-tocopheryl polyethylene glycol 1000 succinate and nanosized self-emulsifying systems (NSEMS). Materials and methods: Optimization of the RLX-loaded NSEMS was performed using a mixture design. The formulations were characterized by particle size and then incorporated into an in situ nasal gel. Transmission electron microscopy, bovine nasal mucosa ex vivo permeation, and visualization using a fluorescence laser microscope were carried out on the RLX in situ misemgel comparing with raw RLX in situ gel. In addition, the in vivo performance was studied in rats. Results: The results revealed improved permeation parameters for RLX misemgel compared with control gel, with an enhancement factor of 2.4. In vivo studies revealed a 4.79- and 13.42-fold increased bioavailability for RLX in situ misemgel compared with control RLX in situ gel and commercially available tablets, respectively. The obtained results highlighted the efficacy of combining two different formulations to enhance drug delivery and the benefits of utilizing different possible paths for drug absorption. Conclusion: The developed in situ misemgel matrix could be considered as a promising multifunctional platform for nasal delivery which works based on a dual-absorption mechanism.


Assuntos
Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Géis/química , Nanopartículas/administração & dosagem , Mucosa Nasal/metabolismo , Cloridrato de Raloxifeno/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Administração Intranasal , Animais , Disponibilidade Biológica , Bovinos , Portadores de Fármacos/química , Emulsões , Masculino , Micelas , Nanopartículas/química , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacocinética , Ratos , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Distribuição Tecidual
8.
Int J Nanomedicine ; 13: 5215-5229, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233182

RESUMO

Purpose: In the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy. Methods: Raloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Results: The mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat. Conclusion: We prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These trans-dermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat.


Assuntos
Nanopartículas/administração & dosagem , Osteoporose/tratamento farmacológico , Cloridrato de Raloxifeno/administração & dosagem , Administração Cutânea , Animais , Disponibilidade Biológica , Peso Corporal , Cálcio/análise , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Endocitose , Masculino , Mentol/farmacologia , Ovariectomia , Tamanho da Partícula , Cloridrato de Raloxifeno/sangue , Cloridrato de Raloxifeno/farmacocinética , Ratos Wistar , Absorção Cutânea/efeitos dos fármacos , Solubilidade
9.
Drug Deliv Transl Res ; 8(3): 670-692, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29589250

RESUMO

The work describes systematic development of nanomicellar cationic supersaturable self-nanoemulsifying drug delivery systems (CS-SNEDDS) for augmenting oral biopharmaceutical performance of raloxifene hydrochloride. Plain SNEDDS formulation containing Capryol 90, Cremophor RH 40, and Transcutol HP was optimized using D-optimal mixture design. SNEDDS were characterized for emulsification time, globule size, in vitro drug release, and ex vivo permeation. The CS-SNEDDS formulation was prepared from the optimized SNEDDS by adding oleylamine as the cationic charge inducer and HPMC as the polymeric precipitation inhibitor. Evaluation of CS-SNEDDS was carried out through in vitro cell line studies on Caco-2 and MCF-7 cells, in situ perfusion, and in vivo pharmacokinetic studies, which indicated significant improvement in biopharmaceutical attributes of the drug from CS-SNEDDS over plain drug.


Assuntos
Sistemas de Liberação de Medicamentos , Antagonistas de Estrogênios/administração & dosagem , Etilenoglicóis/administração & dosagem , Nanopartículas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polímeros/administração & dosagem , Propilenoglicóis/administração & dosagem , Cloridrato de Raloxifeno/administração & dosagem , Animais , Transporte Biológico , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Liberação Controlada de Fármacos , Emulsões , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacocinética , Etilenoglicóis/química , Etilenoglicóis/farmacocinética , Humanos , Derivados da Hipromelose/química , Mucosa Intestinal/metabolismo , Células MCF-7 , Micelas , Modelos Biológicos , Nanopartículas/química , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polímeros/química , Polímeros/farmacocinética , Propilenoglicóis/química , Propilenoglicóis/farmacocinética , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacocinética , Ratos Sprague-Dawley
10.
Int J Pharm ; 542(1-2): 36-46, 2018 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-29501737

RESUMO

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 ±â€¯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.


Assuntos
Etanol/administração & dosagem , Cloridrato de Raloxifeno/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Administração Cutânea , Animais , Disponibilidade Biológica , Etanol/química , Etanol/farmacocinética , Lipossomos , Cloridrato de Raloxifeno/sangue , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacocinética , Ratos Sprague-Dawley , Moduladores Seletivos de Receptor Estrogênico/sangue , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Pele/metabolismo , Absorção Cutânea
11.
AAPS PharmSciTech ; 19(3): 1105-1115, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29181706

RESUMO

Raloxifene (RLX) has been strongly recommended for postmenopausal women at high risk of invasive breast cancer and for prevention of osteoporosis. However, low aqueous solubility and reduced bioavailability hinder its clinical application. The objective of this study was to explore the potential of RLX loaded mixed micelles (RLX-MM) using Pluronic F68 and Gelucire 44/14 for enhanced bioavailability and improved anticancer activity on human breast cancer cell line (MCF-7). RLX-MM were prepared by solvent evaporation method and optimized using 32 factorial design. The average size, entrapment efficiency and zeta potential of the optimized formulation were found to be 190 ± 3.3 nm, 79 ± 1.3%, 13 ± 0.8 mV, respectively. In vitro study demonstrated 74.68% drug release from RLX-MM in comparison to 42.49% drug release from RLX dispersion. According to the in vitro cytotoxicity assay, GI50 values on MCF-7 breast cancer cell line for RLX-MM and free RLX were found to be 22.5 and 94.71 µg/mL, respectively. Significant improvement (P < 0.05) in the anticancer activity on MCF-7 cell line was observed in RLX-MM over RLX pure drug. Additionally, oral bioavailability of RLX-MM was improved by 1.5-fold over free RLX when administered in female Wistar rats. Incorporation of RLX in the hydrophobic core and improved solubility of the drug due to hydrophilic shell attributed to the enhanced cytotoxicity and bioavailability of RLX-MM. This research establishes the potential of RLX loaded mixed micelles of Pluronic F68 and Gelucire 44/14 for improved bioavailability and anticancer activity on MCF-7 cell line.


Assuntos
Antineoplásicos/administração & dosagem , Cloridrato de Raloxifeno/administração & dosagem , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Neoplasias da Mama/tratamento farmacológico , Citotoxinas/administração & dosagem , Citotoxinas/farmacocinética , Citotoxinas/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Micelas , Poloxâmero/química , Polietilenoglicóis/química , Cloridrato de Raloxifeno/farmacocinética , Cloridrato de Raloxifeno/uso terapêutico , Ratos , Ratos Wistar , Solubilidade
12.
Drug Dev Ind Pharm ; 44(4): 687-696, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29168671

RESUMO

The objective of this work was to utilize a potential of microemulsion for the improvement in oral bioavailability of raloxifene hydrochloride, a BCS class-II drug with 2% bioavailability. Drug-loaded microemulsion was prepared by water titration method using Capmul MCM C8, Tween 20, and Polyethylene glycol 400 as oil, surfactant, and co-surfactant respectively. The pseudo-ternary phase diagram was constructed between oil and surfactants mixture to obtain appropriate components and their concentration ranges that result in large existence area of microemulsion. D-optimal mixture design was utilized as a statistical tool for optimization of microemulsion considering oil, Smix, and water as independent variables with percentage transmittance and globule size as dependent variables. The optimized formulation showed 100 ± 0.1% transmittance and 17.85 ± 2.78 nm globule size which was identically equal with the predicted values of dependent variables given by the design expert software. The optimized microemulsion showed pronounced enhancement in release rate compared to plain drug suspension following diffusion controlled release mechanism by the Higuchi model. The formulation showed zeta potential of value -5.88 ± 1.14 mV that imparts good stability to drug loaded microemulsion dispersion. Surface morphology study with transmission electron microscope showed discrete spherical nano sized globules with smooth surface. In-vivo pharmacokinetic study of optimized microemulsion formulation in Wistar rats showed 4.29-fold enhancements in bioavailability. Stability study showed adequate results for various parameters checked up to six months. These results reveal the potential of microemulsion for significant improvement in oral bioavailability of poorly soluble raloxifene hydrochloride.


Assuntos
Cloridrato de Raloxifeno/administração & dosagem , Cloridrato de Raloxifeno/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Animais , Disponibilidade Biológica , Preparações de Ação Retardada , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Emulsões , Excipientes , Tamanho da Partícula , Cloridrato de Raloxifeno/química , Ratos , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/química , Solubilidade , Tensoativos , Viscosidade
13.
Eur J Pharm Sci ; 112: 195-206, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29196024

RESUMO

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.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Maleatos/administração & dosagem , Nanopartículas/administração & dosagem , Osteoporose/tratamento farmacológico , Polietilenos/administração & dosagem , Cloridrato de Raloxifeno/administração & dosagem , Administração Oral , Fosfatase Alcalina/sangue , Animais , Disponibilidade Biológica , Conservadores da Densidade Óssea/sangue , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacocinética , Cálcio/sangue , Feminino , Maleatos/química , Maleatos/farmacocinética , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanopartículas/ultraestrutura , Osteoporose/sangue , Ovariectomia , Fósforo/sangue , Polietilenos/química , Polietilenos/farmacocinética , Cloridrato de Raloxifeno/sangue , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacocinética , Ratos Wistar , Solubilidade , Tecnologia Farmacêutica
14.
AAPS PharmSciTech ; 18(7): 2529-2540, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28224392

RESUMO

Bioenhancers can increase the bioavailability of metabolism susceptible drugs. The present study was designed to understand the impact of bioenhancer on permeability and bioavailability of a biopharmaceutical drug disposition classification system (BDDCS) class II drug raloxifene (RLX). RLX undergoes extensive first pass metabolism by UGT enzymes in gastrointestinal tract (GIT) and has an oral bioavailability of about 2%. Self-emulsifying drug delivery system (SEDDS) of RLX was developed using a designed approach and this formulation was loaded with reported bioenhancers: quercetin and piperine. These formulations were tested for improvement in permeability and bioavailability of the RLX. The apparent permeability using everted gut sac (P app) for SEDDS (5.26 ± 1.10 × 10-8 cm/s) was found to be similar to that of SEDDS with bioenhancers (5.11 ± 1.05 × 10-8 cm/s). In oral bioavailability study in rat, SEDDS demonstrated a 4-fold and 2.5-fold higher AUC0-∞ than RLX suspension (control) and marketed product, respectively. No additional improvement in permeability and bioavailability was offered by inclusion of piperine and quercetin (bioenhancers) in the SEDDS.


Assuntos
Sistemas de Liberação de Medicamentos , Cloridrato de Raloxifeno/administração & dosagem , Animais , Disponibilidade Biológica , Química Farmacêutica , Liberação Controlada de Fármacos , Emulsões , Feminino , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacocinética , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química
15.
Mol Cell Endocrinol ; 440: 34-43, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27832985

RESUMO

INTRODUCTION: The deleterious effects of letrozole, an aromatase inhibitor, used in the adjuvant treatment of breast cancer in postmenopausal women, on bone are well-documented and represent a major drawback to its clinical use. Raloxifene, a selective estrogen receptor modulator and a clinically approved anti-osteoporotic drug, has been recently demonstrated to be efficacious in women with breast cancer. The present study evaluated the effects of preventive and curative treatment with raloxifene on letrozole-induced alterations of bone microarchitecture and turnover markers in a chemically-induced menopause model in mice. METHOD: Swiss strain albino female mice were made menopausal by inducing ovotoxicity using vinyl cyclohexene di epoxide (VCD, 160 mg/kg for 15 days followed by 30 days drug-free period) confirmed by ovarian histology and serum estradiol levels. Effects on femoral and lumbar bones were evaluated by micro CT determination of bone volume, trabecular number, separation, thickness, connective density and trabecular pattern factor and bone turnover markers including ALP, TRAP5b, hydroxyproline and RANKL. In addition to these, markers of Wnt signaling (sclerostin and dickkopf-1) were also evaluated. To rule out the involvement of pharmacokinetic interaction, plasma levels of letrozole and raloxifene were measured following drugs alone and in combination. RESULTS: Though bone loss was observed in VCD treated mice (as indicated by micro CT measurements), it was further enhanced with letrozole administration (1 mg/kg) for one month particularly in epiphysis of femoral bones. Raloxifene (15 mg/kg), whether administered concurrently or post-letrozole was able to revert the structural alterations and changes in turnover markers caused by letrozole to varying degrees (p < 0.01 or p < 0.001). Further, estrogen deficiency following letrozole treatment in ovotoxic mice was associated with significant increase in sclerostin and dickkopf-1 in both lumbar and femur bones (p < 0.001) which was attenuated with preventive and curative treatment with raloxifene (p < 0.05). The plasma levels of letrozole remained unaffected by raloxifene administration and vice versa. CONCLUSIONS: Our study indicates the potential of raloxifene in preventing and attenuating letrozole-induced bone loss. Further, these effects were found to be independent of a pharmacokinetic interaction between the two drugs.


Assuntos
Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/patologia , Menopausa/efeitos dos fármacos , Cloridrato de Raloxifeno/uso terapêutico , Animais , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Cicloexenos , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Letrozol , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Vértebras Lombares/fisiopatologia , Camundongos , Nitrilos/sangue , Nitrilos/farmacocinética , Cloridrato de Raloxifeno/sangue , Cloridrato de Raloxifeno/farmacocinética , Cloridrato de Raloxifeno/farmacologia , Triazóis/sangue , Triazóis/farmacocinética , Compostos de Vinila
16.
Pharmazie ; 70(12): 791-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26817276

RESUMO

This study aimed to develop a dry suspension formulation of raloxifene (RLX) using its HP-ß-cyclodextrin inclusion complexes to enhance the oral bioavailability. Dry suspensions loading RLX/HP-ß-cyclodextrin inclusion complexes (RLX-HICs) were prepared by solvent evaporation followed by a standard wet granulation process. The inclusion complexes were characterized by scanning electron microscopy, differential scanning calorimetry, and Fourier transform infrared spectroscopy. The features of dry suspensions such as dispersibility, flowability and dissolution were compared with conventional suspensions. Dry suspensions containing RLX-HICs dramatically increased the dissolution of RLX. Pharmacokinetic studies in rats showed that dry suspensions with RLX-HICs significantly enhanced the oral bioavailabilities of RLX. The absolute and relative bioavailabilities were up to 13.04% and 413.97% compared with the solution formulation (i.v.) and conventional suspensions (i.g.), respectively. The bioavailability improvement for dry suspensions with RLX-HICs can be attributed to improved dissolution and physiochemical properties of RLX, by which the overall absorption was enhanced. Dry suspensions prepared from RLX-HICs may be an attractive formulation for the oral delivery of RLX.


Assuntos
Cloridrato de Raloxifeno/administração & dosagem , Cloridrato de Raloxifeno/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Microscopia Eletrônica de Varredura , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Suspensões , beta-Ciclodextrinas/química
17.
Drug Deliv ; 22(6): 823-36, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24725026

RESUMO

CONTEXT: Osteoporosis (OP) is a disease of skeletal system and is associated with fragility fracture at the hip, spine and wrist. Various drugs have been used to treat OP. One of them is raloxifene hydrochloride (RLX), a second-generation selective estrogen receptor modulator (SERM) approved by the USFDA. RLX possesses only 2% absolute bioavailability (BA) by oral route due to its extensive first-pass metabolism. OBJECTIVE: The purpose of the current research work was to develop and evaluate RLX-loaded chitosan nanoparticles (CS-NPs) for treatment of OP with enhanced BA. MATERIALS AND METHODS: The RLX-loaded CS-NPs were prepared by gelation of CS with tripolyphosphate (TPP) by ionic cross-linking. Formulation was optimized and in vitro drug release and in vivo study were performed. RESULTS AND DISCUSSIONS: CS-NPs were formed by the ionic gelation method. The particle size, entrapment efficiency and loading efficiency varied from 216.65 to 1890 nm, 32.84 to 97.78% and 23.89 to 62.46%, respectively. Release kinetics showed diffusion-controlled and Fickian release pattern. In vivo study indicated higher plasma drug concentration with NPs administered intranasally as compared to drug suspension administered through oral route (p < 0.05). A significantly higher drug concentration in plasma was achieved in 10 min after nasal administration with respect to oral administration. CONCLUSION: The results suggest that RLX-loaded CS-NPs have better BA and would be a promising approach for intranasal (i.n.) delivery of RLX for the treatment of OP.


Assuntos
Quitosana/química , Nanopartículas/química , Cloridrato de Raloxifeno/administração & dosagem , Cloridrato de Raloxifeno/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Administração Intranasal , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Química Farmacêutica/métodos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Osteoporose Pós-Menopausa , Tamanho da Partícula , Ratos , Ratos Wistar
18.
Int J Nanomedicine ; 9: 4331-46, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25246789

RESUMO

Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon(®) 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a homogeneous distribution and low polydispersity index (0.08). They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 µg/cm(2)/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser scanning microscopy proved an enhanced permeation of coumarin-6-loaded transfersomes, to a depth of approximately160 µM, as compared with rigid liposomes. These ex vivo findings proved that a raloxifene hydrochloride-loaded transfersome formulation could be a superior alternative to oral delivery of the drug.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Nanoestruturas/química , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Animais , Portadores de Fármacos/farmacologia , Modelos Biológicos , Tamanho da Partícula , Fosfolipídeos , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Projetos de Pesquisa , Pele/química , Tensoativos
19.
Wien Klin Wochenschr ; 126(13-14): 403-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24842749

RESUMO

BACKGROUND: Raloxifene is a selective oestrogen receptor modulator with effects on bone and breast cancer and cardiovascular disease risk. The aim of this study was to examine the influence of raloxifene treatment on surrogate markers of atherosclerosis and the correlation of these markers with raloxifene serum concentrations. METHODS: A prospective clinical trial on 53 postmenopausal osteoporotic women treated with raloxifene was performed. Surrogate markers of atherosclerosis (flow-mediated vasodilatation, glyceryltrinitrate-induced vasodilatation of the brachial artery, carotid intima-media thickness (c-IMT), inter-cell adhesion molecule-1, vascular-cell adhesion molecule-1 and E-selectin) were measured before and after 6 months of treatment. Serum concentrations of raloxifene and raloxifene metabolites were assessed after 12 months of treatment. The tested markers were correlated with measured serum concentrations of raloxifene species. RESULTS: Among the tested surrogate markers of atherosclerosis c-IMT, E-selectin and ICAM changed significantly during treatment. A negative correlation of the non-metabolized raloxifene serum levels with the percentage change of c-IMT during treatment (r = - 0.315, p = 0.048) was found. Likewise, the sum of the levels of three raloxifene metabolites, raloxifene-6-b-glucuronide (M1), raloxifene-4'-b-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3) in serum showed a negative correlation with the percentage change of c-IMT during treatment (r = - 0.375, p = 0.017). For the other tested parameters, no correlation with raloxifene serum levels was found. CONCLUSIONS: To the best of our knowledge, this is the first study correlating raloxifene species serum concentrations with changes in the surrogate markers of atherosclerosis. A greater decrease of c-IMT in patients with higher raloxifene concentrations could contribute to a lower risk of cardiovascular events in these patients.


Assuntos
Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/induzido quimicamente , Osteoporose/sangue , Osteoporose/tratamento farmacológico , Cloridrato de Raloxifeno/efeitos adversos , Cloridrato de Raloxifeno/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia , Túnica Média/efeitos dos fármacos , Túnica Média/patologia , Adulto , Idoso , Biomarcadores , Selectina E/sangue , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Cloridrato de Raloxifeno/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Eslovênia , Estatística como Assunto , Molécula 1 de Adesão de Célula Vascular/sangue
20.
J Nanosci Nanotechnol ; 14(7): 4820-31, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24757949

RESUMO

The main aim of this study was to improve the oral bioavailability of raloxifene (RXF), a selective estrogen receptor modulator, by incorporation into solid lipid nanoparticles (SLN). RXF-loaded SLN was prepared by homogenization-sonication technique and characterized through physicochemical, pharmacokinetic, and cytotoxicity studies. The optimized SLN formulation exhibited a spherical shape with average size around 140 nm, easing its transport across the lymphatic system. Augmentation in the profiles of C(max) (308%) and AUC (270%) indicated a significant enhancement in the rate and extent of bioavailability by SLN formulations compared to free drug. In vitro cytotoxicity study performed in NIH-3T3 cells revealed that RXF-SLN was cytocompatible, and SLN remained unchanged during the freeze-drying process. Furthermore, the optimized formulation was quite stable at room temperature for more than two months, exemplifying its superior performance. In conclusion, SLN provides a promising platform for the pronounced enhancement of RXF bioavailability.


Assuntos
Lipídeos/química , Nanocápsulas/química , Cloridrato de Raloxifeno/administração & dosagem , Cloridrato de Raloxifeno/farmacocinética , Administração Oral , Animais , Difusão , Composição de Medicamentos/métodos , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacocinética , Substâncias Macromoleculares/química , Masculino , Teste de Materiais , Taxa de Depuração Metabólica , Conformação Molecular , Nanocápsulas/administração & dosagem , Tamanho da Partícula , Cloridrato de Raloxifeno/sangue , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície
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