Sustained release of simvastatin from premixed injectable calcium phosphate cement

Abstract

Locally applied simvastatin is known to promote bone regeneration; however, the lack of suitable delivery systems has restricted its clinical use. In this study we demonstrate for the first time the use of premixed acidic calcium phosphate cement (CPC) as a delivery system for water-solubilized simvastatin. Freeze-dried simvastatin β-hydroxy acid (SVA) was added to the premixed cement paste in four different doses (1, 0.5, 0.25, and 0 mg SVA/g cement). The addition of the drug did not alter the cement setting time (38 min), compression strength (5.54 MPa), or diametral tensile strength (2.62 MPa). In a release study conducted in phosphate buffered saline at 37°C, a diffusion-controlled release was observed for over a week. Furthermore, the osteogenic effect of the released SVA was demonstrated in vitro. Cell proliferation, alkaline phosphatase activity, and mineralization were assayed after incubation with cement extracts. The lower doses of SVA (0.5 and 0.25 mg SVA/g cement) showed an approximately fourfold increase in mineralization as compared to the control. In conclusion, our findings suggest that premixed acidic CPC is a good option for local delivery of SVA, due to its ability of slowly releasing the drug, leading to a prolonged stimulation of osteogenesis.

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

“…In the current work, the unaltered handling properties of the paste: cohesion (Figure 2), setting times (Table 1) and injectability ( Figure 3) suggested that the addition of simvastatin did not modify the workability of the paste, as suggested elsewhere [23]. Although simvastatin did not prevent the transformation of the reagents into rhombohedric crystals of brushite ( Interestingly, s-C-3m showed the highest porosity and the lowest tortuosity factor of all (Figure 7b).…”

“…In a previous study using premixed brushite cement as carrier of simvastatin (a similar amount, of 0.25 mg simvastatin/g cement) [23] a slow drug release was observed and almost all drug was released after 7 days. The drug release pattern for the premixed brushite cement was similar to the one observed for the aqueous brushite cement s-C-15h, which could indicate a high tortuosity factor of the premixed cement.…”

“…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].…”

“…Although the importance of monitoring the drug release from fresh cement has been highlighted [7], to the best of the authors' knowledge, no previous studies have evaluated the drug release of a fresh, recently prepared cement paste. A previous study in our research group evaluated the release of simvastatin from premixed brushite cement during setting [23]. However, that study was performed on premixed cement, where the cement powder is mixed with glycerol and the setting reaction does not start until the mixture is put in contact with an aqueous solution, hence giving rise to a very different setting situation and drug release conditions than the aqueous mixtures commonly used.…”

PNIPAAM modified mesoporous hydroxyapatite for sustained osteogenic drug release and promoting cell attachment

“…Therefore, to overcome this problem, polymers such as poly(β-amino ester) (PBAE) [18], polyethylene glycol (PEG) [19], and poly(L-lactic acid) (PLLA) [20] were added to adjust the release profile of the drug. Inorganic porous materials were also used as bone substitutes, such as α-tricalcium phosphate (α-TCP) [21], β-tricalcium phosphate (β-TCP) [22–24], and hydroxyapatite (HA) [18]. SIM was also mixed with these materials to be drug delivery scaffolds.…”