Controlled Release of Simvastatin Acid Using Cyclodextrin Inclusion System

Yoshinari, Masao; Matsuzaka, Kenichi; Hashimoto, Sadamitsu; Ishihara, Kazuyuki; Inoue, Takashi; Oda, Yutaka; Ide, Takaharu; Takano, Teruo

doi:10.4012/dmj.26.451

Cited by 27 publications

(25 citation statements)

References 22 publications

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“…Brushite cements have a high ionic concentration and an acidic setting reaction, properties that could reduce or inhibit the action of certain drugs [7]. Nevertheless, a previous study concluded that the therapeutic action of simvastatin was not altered after being released by a brushite cement [23], which could be partially explained by the stability of simvastatin in acidic pHs [31].…”

Section: Discussionmentioning

confidence: 99%

“…n. 79902-63-9, USA) was used as the model drug. Whereas lipophilic molecules of simvastatin (lactone) are metabolized in the liver for the reduction of cholesterol, a more hydrophilic form (hydroxyacid) is needed in hard tissues applications to potentiate its pharmacological effect [30,31]. The simvastatin was therefore hydrolysed to convert its isolated β-hydroxyacid form into an open ring by adding the simvastatin in an alkaline solution of ethanol/NaOH 0.1 M and heating it at 50 ºC for 2 h [32].…”

Section: Cement Preparationmentioning

confidence: 99%

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Changes in the drug release pattern of fresh and set simvastatin-loaded brushite cement

Mestres

Kugiejko

Pastorino

et al. 2016

Materials Science and Engineering: C

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Calcium phosphate cements are synthetic bone graft substitutes able to set at physiological conditions. They can be applied by minimally invasive surgery and can also be used as drug delivery systems.Consequently, the drug release pattern from the cement paste (fresh cement) is of high clinical interest.However, previous studies have commonly evaluated the drug release using pre-set cements only.Therefore, the aim of this work was to determine if the time elapsed from cement preparation until immersion in the solution (3 min for fresh cements, and 1 h and 15 h for pre-set cements) had an influence on its physical properties, and correlating these to the drug release profile. Simvastatin was selected as a model drug, while brushite cement was used as drug carrier. This study quantified how the setting of a material reduces the accessibility of the release media to the material, thus preventing drug release. A shift in the drug release pattern was observed, from a burst-release for fresh cements to a sustained release for pre-set cements.

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Section: Discussionmentioning

confidence: 99%

Section: Cement Preparationmentioning

confidence: 99%

Changes in the drug release pattern of fresh and set simvastatin-loaded brushite cement

Mestres

Kugiejko

Pastorino

et al. 2016

Materials Science and Engineering: C

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“…Simvastatin is administered by gavage and requires hepatic conversion to metabolically active β-hydroxy acid to become medicinally active. Therefore, for local administration, simvastatin must first be hydrolyzed to form simvastatin acid 18,19) . The structure of fluvastatin is significantly different from those of previously used HMG-CoA reductase inhibitors such as the pravastatin and simvastatin metabolites, which are derived from fungi 20,21) .…”

Section: Discussionmentioning

confidence: 99%

Effect of Locally Applied Fluvastatin in Low-turnover Osteoporosis Model Mouse with Femur Bone Defect

Ohira

Koji

Sasaki

et al. 2015

J. Hard Tissue Biology.

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The aim of this study was to investigate the effects of local administration of fluvastatin-gelatin complex on the healing of bone defects in low-turnover osteoporosis mice. Gelatin was used as a carrier of the fluvastatin. A fluvastatin-gelatin complex solution was created by dissolving each concentration of fluvastatin in a 75mg/mL gelatin solution. The gelatin solution was mixed with air, then lyophilized for 1 day and crosslinked by dry heating to make a fluvastatin-gelatin complex sponge. After crosslinking, the complex sponge was cut into pieces 1 mm diameter × 1 mm high to fit the bone defect area. The amount of fluvastatin in the sponge was adjusted to control (0 nmol), 0.1 nmol, 0.2 nmol, and 0.4 nmol. Using 20-week-old low-turnover osteoporosis model mice (SAMP6) and normal model mice (SAMR1), cylindrical and bone defects were made in sites 1.0 mm in diameter and depth, 1 mm of 3 mm from both sides of the distal end of the femur. The complex sponge was then inserted into each site, and the wound was closed. Radiographic analysis and histologic examinations were then performed. In SAMP6, the bone volumes of the bone defect areas in the 0.1nmol and 0.2nmol groups were significantly higher compared with those of the control and 0.4nmol groups at 14 and 21 days. Histological observation showed that the volume of newly formed bone increased in the 0.1nmol and 0.2nmol groups compared to those in the control and 0.4nmol groups at 14 and 21 days. The bone volumes of newly formed bone in SAMR1 were higher than were those in SAMP6, and the optimum concentration of fluvastatin was different between SAMP6 and SAMR1. The present study suggests that local administration of a fluvastatin-gelatin complex sponge provides improvement in bone healing in low-turnover osteoporosis.

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“…23) Simvastatin is administered by gavage and requires hepatic conversion to metabolically active â-hydroxy acid to become medicinally active. Therefore, for local administration, simvastatin would first have to be hydrolyzed to simvastatin acid 24,25) . In this experiment, fluvastatin was used to investigate the effect of the local administration of statins.…”

Section: Discussionmentioning

confidence: 99%

Osteogenic Effect of Local Administration of Fluvastatin using a Fluvastatin-gelatin Complex in Senile Osteoporosis Model Rat

Yasuda

Koji

Satô

et al. 2014

J. Hard Tissue Biology.

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Statins, inhibitors of 3-hydroxy-2-methyl-glutaryl coenzyme A reductase, were recently reported to promote the differentiation of osteoblasts produced by the stimulation of bone morphogenetic protein-2 (BMP-2). The aim of this study was to investigate the osteogenic effect of a local administration of fluvastatin in senile osteoporosis model rats using a fluvastatin-gelatin complex. The gelatin-hydrogel was put into cylindrical titanium tubes 1.5 mm in diameter and 2.2 mm high. It was then crosslinked by ultraviolet irradiation, after which it was lyophilized. Subsequently, the carriers were placed in the fluvastatin solution (300 μM) for one day to bind the alkaline gelatin and acidic statin electrostatically (fluvastatin-gelatin complex; statin group). A control group consisted of the carriers immersed in sterilized water. Specimens of both the statin group and the control group were implanted into the femur of 15-week-old male senile osteoporosis model rats (SHRSP). Radiographic analysis, histologic examination, and immunohistochemical staining (BMP-2 and Runx2) were then performed. At 14 and 21 days, the bone volumes of the newly formed bone in the statin group was significantly higher compared to those of the control group (P<0.05). Histological observation showed that a high level of new bone formation was present in the statin group compared to that of the control group during all time periods. At 7 days, positive immune reactions with BMP-2 and Runx2 were seen in the statin group. The local administration of the fluvastatin-gelatin complex facilitated bone formation in senile osteoporosis model rats.

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Controlled Release of Simvastatin Acid Using Cyclodextrin Inclusion System

Cited by 27 publications

References 22 publications

Changes in the drug release pattern of fresh and set simvastatin-loaded brushite cement

Changes in the drug release pattern of fresh and set simvastatin-loaded brushite cement

Effect of Locally Applied Fluvastatin in Low-turnover Osteoporosis Model Mouse with Femur Bone Defect

Osteogenic Effect of Local Administration of Fluvastatin using a Fluvastatin-gelatin Complex in Senile Osteoporosis Model Rat

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