Ibandronate sodium

Ibandronate is a highly potent nitrogen-containing bisphosphonate used for the treatment of osteoporosis.

Phase I clinical study to select a novel oral formulation for ibandronate containing the excipient sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC).[Pubmed:22530305]

Pharmazie. 2012 Mar;67(3):233-41.

The aim of this study was to select a novel oral formulation for ibandronate (IBN, CAS number: 13892619). In four cohorts of 28, 21, 19 and 29 healthy volunteers, the impact of the carrier molecule sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC, CAS number: 203787-91-1) on the bioavailability of IBN was investigated. Within each cohort different oral formulations with one dose of ibandronate (30 mg) and three different ratios of IBN:SNAC (1:5, 1:10 and 1:20) were compared to the approved oral IBN tablet formulations (150 and 50 mg IBN) in a 4-way cross-over design and a one week washout between the administrations. The highest mean IBN exposure was achieved with a capsule formulation containing drug-coated beadlets and an IBN:SNAC ratio of 1:5. AUC(last) and C(max) of IBN were approximately 1.3- and 2.2-fold higher compared to the reference treatment (150 mg IBN without SNAC). Increasing the post-dose fasting duration from 15 to 30 min resulted in a more than 2-fold increase in AUC(last), while superimposable IBN serum concentration-time profiles were achieved after a 30 and 60 min fast. The tolerability of the IBN/SNAC treatments in all cohorts was similar to that in the IBN reference groups and most adverse events (AEs) were of mild to moderate intensity.

Impurity profiling of ibandronate sodium by HPLC-CAD.[Pubmed:26092222]

J Pharm Biomed Anal. 2015 Oct 10;114:254-64.

The modern bisphosphonate drug Ibandronate sodium, a challenging candidate for impurity profiling, was analyzed using high performance liquid chromatography (HPLC) combined with corona charged aerosol detection (CAD). Separation was achieved on a mixed mode column combining hydrophobic C18 and strong anion exchange retention mechanisms using a mass spectrometer compatible volatile mobile phase consisting of trifluoroacetic acid and acetonitrile while gradient elution was applied. The method was validated following the ICH guideline Q2(R1) and found suitable for the assessment of ibandronate's related substances. The observed CAD-response for all identified impurities was linear (R(2)>0.995) over a small concentration range (0.05-0.25) and a quantification limit of at least 0.03% was found. Four batches of two different manufacturers were tested by means of the method. None of the batches contained a single impurity above 0.05%. The major impurities of all batches were the synthesis by-products N-desmethyl- and N-despentyl ibandronate as well as N,N-dimethyl pamidronate.

Effects of ibandronate sodium, a nitrogen-containing bisphosphonate, on intermediate-conductance calcium-activated potassium channels in osteoclast precursor cells (RAW 264.7).[Pubmed:25362532]

J Membr Biol. 2015 Feb;248(1):103-15.

Ibanonate sodium (Iban), a nitrogen-containing bisphosphonate, is recognized to reduce skeletal complications through an inhibition of osteoclast-mediated bone resorption. However, how this drug interacts with ion channels in osteoclasts and creates anti-osteoclastic activity remains largely unclear. In this study, we investigated the possible effects of Iban and other related compounds on ionic currents in the osteoclast precursor RAW 264.7 cells. Iban suppressed the amplitude of whole-cell K(+) currents (I K) in a concentration-dependent manner with an IC50 value of 28.9 muM. The I K amplitude was sensitive to block by TRAM-34 and Iban-mediated inhibition of I K was reversed by further addition of DCEBIO, an activator of intermediate-conductance Ca(2+)-activated K(+) (IKCa) channels. Intracellular dialysis with Iban diminished I K amplitude and further addition of ionomycin reversed its inhibition. In 17beta-estradiol-treated cells, Iban-mediated inhibition of I K remained effective. In cell-attached current recordings, Iban applied to bath did not modify single-channel conductance of IKCa channels; however, it did reduce channel activity. Iban-induced inhibition of IKCa channels was voltage-dependent. As IKCa-channel activity was suppressed by KN-93, subsequent addition of Iban did not further decrease the channel open probability. Iban could not exert any effect on inwardly rectifying K(+) current in RAW 264.7 cells. Under current-clamp recordings, Iban depolarized the membrane of RAW 264.7 cells and DCEBIO reversed Iban-induced depolarization. Iban also suppressed lipopolysaccharide-stimulated migration of RAW 264.7 cells in a concentration-dependent manner. Therefore, the inhibition by Iban of IKCa channels would be an important mechanism underlying its actions on the functional activity of osteoclasts occurring in vivo.

In vitro osteoclast-suppressing effect of sodium ibandronate.[Pubmed:23422201]

Chin Med J (Engl). 2013 Feb;126(4):751-5.

BACKGROUND: Bisphosphonates (BPs) have been reported to reduce local recurrence in giant cell tumor (GCT) of bone because of their osteoclast-suppressing effect; however, the optimal mode of delivery and the dose and duration of treatment of BPs remain to be established. To address these issues, it is first necessary to clarify the manner of action of BPs on osteoclasts. We herein evaluated the osteoclast-suppressing effect of sodium ibandronate in vitro. METHODS: Mouse osteoclasts (OCLs) were generated in vitro using mouse bone marrow mononuclear cells. First, various concentrations of sodium ibandronate and equal amounts of phosphate-buffered saline were added to cell culture media. The number of multinucleated cells (over three nuclei) was recorded in each group, OCL formation was compared, and the most effective concentration of sodium ibandronate was determined. Then, high concentrations of sodium ibandronate were added to the experimental cell culture media; no ibandronate was given in the control group. Comparisons were made between the two groups in terms of OCL adhesion, migration, and bone resorption. RESULTS: OCL formation was suppressed by sodium ibandronate in vitro; the most pronounced effect was observed at the concentration of 10(-5) mol/L. OCL migration and bone resorption were significantly suppressed at this concentration, though there was no effect on OCL adhesion. CONCLUSIONS: Sodium ibandronate was effective in suppressing OCLs and decreasing resorption in GCT. The strong anti-OCL effectiveness at a high concentration in vitro indicates a topical mode of application.