Sustained In-Vivo Release of Triptorelin Acetate from a Biodegradable Silica Depot: Comparison to Pamorelin® LA.

Triptorelin acetate was encapsulated into silica microparticles by spray-drying a mixture of colloidal silica sol and triptorelin acetate solution. The resulting microparticles were then combined with another silica sol containing silica nanoparticles, which together formed an injectable silica-triptorelin acetate depot. The particle size and surface morphology of the silica-triptorelin acetate microparticles were characterized together with the in vitro release of triptorelin, injectability and rheology of the final injectable silica-triptorelin acetate depot. In vivo pharmacokinetics and pharmacodynamics of the silica-triptorelin acetate depot and Pamorelin® were evaluated and compared in Sprague-Dawley male rats after subcutaneous administration. Serum samples up to 91 days were collected and the plasma concentrations of triptorelin and testosterone were analyzed with ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In vivo pharmacokinetics showed that injections of the silica-triptorelin acetate depot gave 5-fold lower Cmax values than the corresponding Pamorelin® injections. The depot also showed a comparable sustained triptorelin release and equivalent pharmacodynamic effect as the Pamorelin® injections. Detectable triptorelin plasma concentrations were seen with the depot after the 91-day study period and testosterone plasma concentrations remained below the human castration limit for the same period.

Hydroxyapatite coating of cellulose sponge does not improve its osteogenic potency in rat bone.

Regenerated cellulose sponges were coated biomimetically with hydroxyapatite to increase their osteogenic properties. Induction of apatite precipitation was carried out with bioactive glass in simulated body fluid (SBF) for 24 h and the final coating was carried out in 1.5 x concentrated SBF for 14 days. Biomimetically mineralized and non-mineralized sponges were then implanted into standard size femoral cortical defects of rats, and the invasion of bone into the implant was followed up to one year. The apatite coating did not improve the osteoconductive property of cellulose in this rat cortical defect model. In fact, it generated a strong and highly cellular inflammatory reaction and less osteoid tissue. The biomimetic implants contained more immunodetectable TGFbeta1 (a strong stimulator of fibroblast activity) than untreated implants, and also bound more TGFbeta1 in vitro, which could, at least in part, explain the fibrotic invasion of biomimetically mineralized sponges.

Intracranial biodegradable silica-based nimodipine drug release implant for treating vasospasm in subarachnoid hemorrhage in an experimental healthy pig and dog model.

Nimodipine is a widely used medication for treating delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. When administrated orally or intravenously, systemic hypotension is an undesirable side effect. Intracranial subarachnoid delivery of nimodipine during aneurysm clipping may be more efficient way of preventing vasospasm and DCI due to higher concentration of nimodipine in cerebrospinal fluid (CSF). The risk of systemic hypotension may also be decreased with intracranial delivery. We used animal models to evaluate the feasibility of surgically implanting a silica-based nimodipine releasing implant into the subarachnoid space through a frontotemporal craniotomy. Concentrations of released nimodipine were measured from plasma samples and CSF samples. Implant degradation was followed using CT imaging. After completing the recovery period, full histological examination was performed on the brain and meninges. The in vitro characteristics of the implant were determined. Our results show that the biodegradable silica-based implant can be used for an intracranial drug delivery system and no major histopathological foreign body reactions were observed. CT imaging is a feasible method for determining the degradation of silica implants in vivo. The sustained release profiles of nimodipine in CSF were achieved. Compared to a traditional treatment, higher nimodipine CSF/plasma ratios can be obtained with the implant.

Frontal sinus and skull bone defect obliteration with three synthetic bioactive materials. A comparative study.

Three synthetic bioactive materials were studied in an experimental model to compare their usability in a frontal sinus and a skull bone defect obliteration. Bioactive glass number 9 (BAG(1)), bioactive glass number 13 (BAG(2)), and hydroxyapatite (HA) granules were investigated. BAG(1) and HA granules have been previously tested clinically. The clinical usefulness of BAG(2) granules has not been tested. Upper bony walls of 45 Elco rabbits' frontal sinuses were drilled open from four separate holes with the use of a standard method. The skull bone defects and the sinuses in frontal bone were filled with BAG(1) or BAG(2) on one side, and with HA on the other side. Two parallel posterior defects were covered with a pedicled periosteum flap, and two anterior defects with a free flap. The resorption of materials, new bone, and fibrous-tissue formation were observed with a histomorphometric method at 1, 3, and 6 months postoperatively. Scanning-electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR) were done at 6 months. In histomorphometry, the new bone formation increased with all the investigated materials throughout the study (p < 0.001), but the results showed higher new bone formation in the defects filled with BAG(1) than in corresponding BAG(2)- or HA- filled defects. New bone formation and resorption of materials were faster in defects covered by pedicled than by free periosteum flaps (p < 0.001). Intimate contact between the used materials and new bone was confirmed by SEM. FTIR analysis of bone produced by BAG(1) and BAG(2) was of the same type as natural frontal bone. BAG(2) can be manufactured in various shapes, and thus, could possibly be used in clinical conditions requiring a special anatomical implant shape. However, more research is needed regarding this property of BAG(2).

Release of silica, calcium, phosphorus, and fluoride from glass ionomer cement containing bioactive glass.

The aim of this study was to examine the release of silica (Si), calcium (Ca), phosphorous (P), and fluoride (F) from conventional glass ionomer cement (GI) and resin-modified glass ionomer cement (LCGI), containing different quantities of bioactive glass (BAG). Further aim was to evaluate in vitro biomineralization of dentine. The release of Si increased with the increasing immersion time from the specimens containing BAG, whereas the amount of Ca and P decreased indicating in vitro bioactivity of the materials. LCGI with 30wt% of BAG showed highest bioactivity. It also showed CaP-like precipitation on both the surface of the test specimens and on the dentin discs immersed with the material. Within the limitations of this study, it can be concluded that a dental restorative material consisting of glass ionomer cements and BAG is bioactive and initiates biomineralization on dentin surface in vitro.

Mineralization of dentin induced by treatment with bioactive glass S53P4 in vitro.

Dentin hypersensitivity can be managed to occlude dentin tubules, but none of the agents used are components of natural dentin. Using a calcium phosphate precipitation (CPP) method, dentin tubules can be occluded with a calcium phosphate (CaP) layer similar to the major inorganic component of dentin. The CPP method utilizes acidic pH conditions, such as etching of dentin, over the course of several dental treatments. A gentler method can be used to produce a CaP layer on the surface of dentin. By treating with bioactive glass S53P4 (BAG), or regular commercial glass (CG), mineralization occurs in physiologically neutral solutions such as simulated body fluid (SBF) and remineralization solution (RMS). After a short period of immersion, silica is dissolved from both types of glass, but the amount of silica released is much greater from BAG than from CG. The dissolved silica is adsorbed on the surface of dentin during the pretreatment procedure and enhances the mineralization of dentin in SBF. After 14 days' mineralization the dentin is fully covered by the CaP layer, but after 14 days' immersion in RMS decalcification of the dentin occurs. Pretreatment with BAG decreases the degree of decalcification of dentin during the mineralization process. These findings suggest that bioactive glass S53P4 can be used as a therapeutic material for mineralization of dentin and its tubules in a physiological environment.