Bioadhesive Microspheres for Bioavailability Enhancement of Raloxifene Hydrochloride: Formulation and Pharmacokinetic Evaluation

Jha, Ram K.; Tiwari, Sanjay; Mishra, Brahmeshwar

doi:10.1208/s12249-011-9619-9

Cited by 44 publications

(15 citation statements)

References 32 publications

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“…Even though, 60% of raloxifene is absorbed orally, the absolute plasma bioavailability is only 2% because of its poor aqueous solubility (0.25 mg/lit in water) and extensive first pass metabolism by glucuronide conjugation [4]. RL-HCL comes under class II (low solubility and high permeability) of biopharmaceutical classification system (BCS) with lesser bioavailability [5]. …”

Section: Introductionmentioning

confidence: 99%

“…Even though several research works are being carried out to enhance the solubility and bioavailability of raloxifene by formulating it as tablets [19], microemulsions [20], microspheres [5], transdermal patch [21], and polymeric nanoparticles [22], still it is required to design the formulation having combined advantages like sustained release and avoiding first pass metabolism of RL-HCL. Therefore, the aim of the present work is to improve the bioavailability of RL-HCL by formulating it as SLN.…”

Section: Introductionmentioning

confidence: 99%

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Development and Evaluation of Solid Lipid Nanoparticles of Raloxifene Hydrochloride for Enhanced Bioavailability

Kushwaha

Vuddanda²,

Kumari³

et al. 2013

BioMed Research International

157

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Raloxifene hydrochloride (RL-HCL) is an orally selective estrogen receptor modulator (SERM) with poor bioavailability of nearly 2% due to its poor aqueous solubility and extensive first pass metabolism. In order to improve the oral bioavailability of raloxifene, raloxifene loaded solid lipid nanoparticles (SLN) have been developed using Compritol 888 ATO as lipid carrier and Pluronic F68 as surfactant. Raloxifene loaded SLN were prepared by solvent emulsification/evaporation method, and different concentrations of surfactant, and homogenization speed were taken as process variables for optimization. SLN were characterized for particle size, zeta potential, entrapment efficiency, surface morphology, and crystallinity of lipid and drug. In vitro drug release studies were performed in phosphate buffer of pH 6.8 using dialysis bag diffusion technique. Particle sizes of all the formulations were in the range of 250 to 1406 nm, and the entrapment efficiency ranges from 55 to 66%. FTIR and DSC studies indicated no interaction between drug and lipid, and the XRD spectrum showed that RL-HCL is in amorphous form in the formulation. In vitro release profiles were biphasic in nature and followed Higuchi model of release kinetics. Pharmacokinetics of raloxifene loaded solid lipid nanoparticles after oral administration to Wistar rats was studied. Bioavailability of RL-HCL loaded SLN was nearly five times than that of pure RL-HCL.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development and Evaluation of Solid Lipid Nanoparticles of Raloxifene Hydrochloride for Enhanced Bioavailability

Kushwaha

Vuddanda²,

Kumari³

et al. 2013

BioMed Research International

157

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“…it has low solubility and high permeability. But the bioavailability of raloxifene is very low, only 2%, due to a high first-pass metabolism in the liver by glucuronidation and enterohepatic cycling (Jha et al, 2011). So it would be advantageous to increase the solubility of the molecule.…”

Section: Introductionmentioning

confidence: 99%

“…So it would be advantageous to increase the solubility of the molecule. Raloxifene is available in HCl salt form as raloxifene (RLX; Rai et al, 2010;Jha et al, 2011). This drug is poorly absorbed from the gastrointestinal (GI) tract.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of solubility and dissolution rate of poorly water soluble raloxifene using microwave induced fusion method

Patil

Belgamwar

Patil

et al. 2013

Braz. J. Pharm. Sci.

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The objective of the present work was to enhance the solubility and dissolution rate of the drug raloxifene HCl (RLX), which is poorly soluble in water. The solubility of RLX was observed to increase with increasing concentration of hydroxypropyl methylcellulose (HPMC E5 LV). The optimized ratio for preparing a solid dispersion (SD) of RLX with HPMC E5 LV using the microwave-induced fusion method was 1:5 w/w. Microwave energy was used to prepare SDs. HPMC E5 LV was used as a hydrophilic carrier to enhance the solubility and dissolution rate of RLX. After microwave treatment, the drug and hydrophilic polymer are fused together, and the drug is converted from the crystalline form into an amorphous form. This was confirmed through scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies. These results suggested that the microwave method is a simple and efficient method of preparing SDs. The solubility and dissolution rate of the SDs were increased significantly compared with pure RLX due to the surfactant and wetting properties of HPMC E5 LV and the formation of molecular dispersions of the drug in HPMC E5 LV. It was concluded that the solubility and dissolution rate of RLX are increased significantly when an SD of the drug is prepared using the microwave-induced fusion method.Uniterms: Raloxifene HCl. Microwave-induced fusion method. Solid dispersion. Solubility enhancement. HPMC E5 LV.O objetivo do presente trabalho foi aumentar a solubilidade e taxa de dissolução do cloridrato de raloxifeno (RLX), que é pouco solúvel em água. A solubilidade do RLX aumentou com o aumento da concentração de hidroxipropilmetilcelulose (HPMC E5 LV). A proporção otimizada para a preparação de uma dispersão sólida (DS) de RLX com HPMC E5 LV utilizando o método de fusão induzida por microondas foi de 1:5 (p/p). A energia do microondas foi usada para preparar DS. O HPMC E5 LV foi utilizado como veículo hidrofílico para aumentar a solubilidade e a taxa de dissolução de RLX. Após o tratamento por microondas, o polímero hidrofílico e o fármaco são fundidos em conjunto, sendo o fármaco convertido da forma cristalina para a amorfa. Confirmou-se por meio de microscopia eletrônica de varredura (MEV), calorimetria exploratória diferencial (DSC) e difração de raios X do pó (PXRD). Estes resultados sugerem que o método de microondas é simples e eficiente para a preparação de DS. A solubilidade e taxa de dissolução de DS foram aumentadas, significativamente, em comparação com RLX puro devido às propriedades tensoativas e umectantes de HPMC E5 LV e à formação de dispersões moleculares do fármaco em HPMC E5 LV. Concluiu-se que a solubilidade e a taxa de dissolução de RLX foram significativamente aumentadas quando a DS do fármaco é preparada utilizando o método de fusão induzida por microondas.

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“…Trials encompassed use of hydrophilic binders, 9 cogrinding technique, 10 cyclodextrin complexation, 8 and use of mucoadhesive microspheres of the complex to give a controlled release pattern. 11 Although the reported permeability of RLX as class II drug is high, one attempt has adopted enhancing in vitro intestinal permeability of drug via microemulsion technique and a water titration method. 12 Nevertheless, the authors recommended that their in vitro assumptions could only be confirmed after in vivo animal experimentation, which they did not perform.…”

Section: Introductionmentioning

confidence: 99%

Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal

Elsheikh¹,

Elnaggar²,

Gohar³

et al. 2012

IJN

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Raloxifene hydrochloride (RLX) is a selective estrogen-receptor modulator for treatment of osteoporosis and prevention of breast and endometrial cancer. By virtue of extensive presystemic clearance, RLX bioavailability is only 2%. The current study aimed to tailor and characterize RLX-loaded self-nanoemulsifying drug-delivery systems (SNEDDS) using bioactive excipients affecting drug metabolism. The potential of oral nanocarriers to enhance RLX delivery to endocrine target organs was assessed in fasted and fed female Wistar rats using high-performance liquid chromatography. RLX was loaded in the dissolved and dispersed status in the alkalinized (A-SNEDDS) and nonalkalinized (NA-SNEDDS) systems, respectively. Optimization and assessment relied on solubility studies, emulsification efficiency, phase diagrams, dilution robustness, cloud point, particle size, zeta potential (ZP), polydispersity index (PDI), and transmission electron microscopy. In vitro release was assessed using dialysis bag versus dissolution cup methods. NA-SNEDDS were developed with suitable globule size (38.49 ± 4.30 nm), ZP (31.70 ± 3.58 mV), PDI (0.31 ± 0.02), and cloud point (85°C). A-SNEDDS exhibited good globule size (35 ± 2.80 nm), adequate PDI (0.28 ± 0.06), and lower ZP magnitude (−21.20 ± 3.46 mV). Transmission electron microscopy revealed spherical globules and contended data of size analysis. Release studies demonstrated a nonsignificant enhancement of RLX release from NA-SNEDDS compared to drug suspension with the lowest release shown by A-SNEDDS. A conflicting result was elucidated from in vivo trial. A significant enhancement in RLX uptake by endocrine organs was observed after nanocarrier administration compared to RLX suspension. In vivo studies reflected a poor in vitro/in vivo correlation, recommended nanocarrier administration before meals, and did not reveal any advantage for drug loading in the solubilized form (A-SNEDDS). To conclude, NA-SNEDDS possessed superior in vitro characteristics to A-SNEDDS, with equal in vivo potential. NA-SNEDDS elaborated in this work could successfully double RLX delivery to endocrine target organs, with promising consequences of lower dose and side effects of the drug.

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Bioadhesive Microspheres for Bioavailability Enhancement of Raloxifene Hydrochloride: Formulation and Pharmacokinetic Evaluation

Cited by 44 publications

References 32 publications

Development and Evaluation of Solid Lipid Nanoparticles of Raloxifene Hydrochloride for Enhanced Bioavailability

Development and Evaluation of Solid Lipid Nanoparticles of Raloxifene Hydrochloride for Enhanced Bioavailability

Enhancement of solubility and dissolution rate of poorly water soluble raloxifene using microwave induced fusion method

Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal

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