Antti Yli-Urpo

Silica xerogel as an implantable carrier for controlled drug delivery : evaluation of drug distribution and tissue effects after implantation

The purpose of the present study was to examine controlled delivery of toremifene citrate from subcutaneously implanted silica xerogel carrier and to evaluate silica xerogel related tissue effects after implantation. Toremifene citrate was incorporated into hydrolyzed silica sol in a room temperature process. Toremifene citrate treated silica xerogel implants were tested both in vitro and in vivo using healthy mice. Silica xerogel with tritium-labelled toremifene was implanted subcutaneously in mice for 42 d. To determine the amount of tritiated toremifene remaining in the silica discs at the implantation site, the discs were excised periodically and radioactivity measured. The amount of tritiated toremifene in the implant after 42 d was still about 16% and the amount of silica xerogel about 25%. In a histopathological study silica xerogel did not show any tissue irritation at the site of the implantation. A fibrotic capsule was formed around the implant. No silica xerogel related histological changes in liver, kidney, lymph nodes and uterus were observed during the implantation period. The silica xerogel discs showed a sustained release of toremifene citrate over 42 d. Histologically, toremifene-related changes in the uterus were also detectable at all studied time points. These findings suggest that silica xerogel is a promising carrier material for implantable controlled drug delivery system.

Compositional dependence of bioactivity of glasses in the system Na2O-K2O-MgO-CaO-B2O3-P2O5-SiO2

The bioactivity, i.e., bone-bonding ability, of 26 glasses in the system Na2O-K2O-MgO-CaO-B2O3-P2O5-SiO2 was studied in vivo. This investigation of bioactivity was performed to establish the compositional dependence of bioactivity, and enabled a model to be developed that describes the relation between reactions in vivo and glass composition. Reactions in vivo were investigated by inserting glass implants into rabbit tibia for 8 weeks. The glasses and the surrounding tissue were examined using scanning electron microscopy (SEM), light microscopy, and energy-dispersive X-ray analysis (EDXA). For most of the glasses containing < 59 mol % SiO2, SEM and EDXA showed two distinct layers at the glass surface after implantation, one silica-rich and another containing calcium phosphate. The build-up of these layers in vivo was taken as a sign of bioactivity. The in vivo experiments showed that glasses in the investigated system are bioactive when they contain 14-30 mol % alkali oxides, 14-30 mol % alkaline earth oxides, and < 59 mol % SiO2. Glasses containing potassium and magnesium bonded to bone in a similar way as bioactive glasses developed so far.

Calcium phosphate induction by sol-gel-derived titania coatings on titanium substrates in vitro

Titanium and its alloys are used widely in the manufacture of orthopedic and dental implants. Sol-gel-prepared titania is able to stimulate bone-like apatite formation in in vitro and in vivo cultures. These materials can be used, for example, as coatings on dental and orthopedic implants. However, the processes that lead to apatite formation are not fully understood. In this study different kinds of titania coatings on commercially pure titanium (c.p. Ti) were tested for apatite-forming ability. The rate of apatite formation is considered to be descriptive of a materials bioactive (bone-bonding) potential. Apatite-forming tests were done in simulated body fluid (SBF). Apatite-forming ability was highest with the addition of valeric acid to sol (600 degrees C) or with sintering sol-gel coatings at 450 degrees-550 degrees C. At that temperature range calcium phosphate forms on the coatings in 1 week. Calcium phosphate forming is observed in 1 day on standard coatings sintered at 500 degrees C.

Silica xerogel carrier material for controlled release of toremifene citrate

Sol-gel processed silica xerogel was used as a carrier material for toremifene citrate in order to develop an implantable controlled release formulation which could be localised to a desired site providing targeted and long-lasting disease control and resulting in a reduced amount of drug needed. Toremifene citrate, an anti-estrogenic compound, was incorporated into silica xerogel matrixes during polycondensation of organic silicate, tetraethyl ortho silicate (TEOS). The effects of drug amount, drying temperature and polyethylene glycol (PEG) on the release rate of toremifene citrate and degradation of the silica xerogel matrixes were investigated. Addition of PEG (M(w) 4600/10000) decreased the specific surface area of the matrix and lowered the release rate of the drug. Reducing the amount of drug in the matrix also decreased the release rate of toremifene citrate. However, drying temperature did not affect the release rate of silica or toremifene citrate. The release profiles of toremifene citrate were according to zero order kinetics, suggesting that drug release was controlled by erosion of the silica xerogel matrix. These results suggest that the toremifene citrate release rate can be controlled to some extent by adding (PEG) or by varying the amount of drug in the silica xerogel matrix.

Calcium phosphate formation on porous sol-gel-derived SiO2 and CaO-P2O5-SiO2 substrates in vitro.

Sol-gel-derived SiO2 and CaO-P2O5-SiO2 have been shown to be bioactive and bone bonding. In this study bioactive sol-gel-derived SiO2 and CaO-P2O5-SiO2 systems were tested for in in vitro bioactivity. The calcined ceramic monoliths were immersed in a simulated body fluid and analyzed to follow the hydroxyapatite formation on the ceramic surface. Apatite-forming ability was investigated in terms of structural changes by changing the composition and the preparation method. The role of Ca and P dopants in the substrate structure is complicated, and careful characterization is needed. The composition and structure together determine the in vitro bioactivity. The pore structure was analyzed using N2-adsorption/desorption isotherms. The results indicate that a great mesopore volume and a wide mesopore size distribution favor hydroxycarbonate apatite nucleation and a great surface area is not needed. The performed preparation process for silica in a basic environment provides a convenient way to prepare a mesoporous material.

In vitro evaluation of poly(ε-caprolactone-co-dl-lactide)/ bioactive glass composites

In vitro bioactivity of composites of poly(e-caprolactone-co-DL-lactide) P(CL/DL-LA) containing different amounts (40, 60 and 70 wt%) of bioactive glass, S53P4, was evaluated. Two ranges of granule size of bioactive glass (<45 μm and 90–315 μm) were blended with P(CL/DL-LA) copolymer in a batch mixer. The composites were characterised by dynamic mechanical thermal analysis. The molecular weight and the melting temperature of the copolymer matrix were adjusted to enable the application of the composite material by injection below 50°C. Formation of Ca-P deposition on the surface of the composites after dissolution in simulated body fluid at 37°C was recorded by scanning electron microscopy. Degradation of the composite material was measured by water absorption and changes in the average molecular weights as a function of the dissolution time. In vitro bioactivity was found to be dependent on the weight fraction and granule size range of the bioactive glass used. The presence of the bioactive filler also accelerated the degradation compared with the neat polymer sample.

In vitro release of heparin from silica xerogels

Heparin, a powerful anticoagulant used for the prophylaxis of both surgical and medical thrombosis, was incorporated into a silica xerogel matrix during polycondensation of organic silicate. The influence of various chemical sol-gel parameters (the properties of reaction precursors, catalyst and final moisture content of the gel and heparin concentration) was studied. The release of heparin from the gel was according to zero order during the dissolution period and the release rate of heparin was proportional to the drug load in the concentration range between 6.8 and 13.6 wt%. It was found that the catalyst used for the preparation of the gel, the final moisture content and the chemical modification of silica xerogel network have an influence on the release rate of heparin. The released heparin from all the different xerogels studied retained about 90% of its biological activity.

In vitro evaluation of sol–gel processed spray dried silica gel microspheres as carrier in controlled drug delivery

The objective of this study was to evaluate sol-gel-derived spray dried silica gel microspheres as carrier material for dexmedetomidine HCl and toremifene citrate. The drug was dissolved in sol-gel processed silica sol before spray drying with Büchi laboratory scale equipment. Microspheres with a low specific surface area were spherical by shape with a smooth surface without pores on the external surface. The particle size distribution was quite narrow. The in vitro release of toremifene citrate and dexmedetomidine HCl showed a dose-dependent burst followed by a slower release phase, that was proportional to the drug concentration in the concentration range between 3.9 and 15.4 wt.%. The release period for toremifene citrate was approximately 10 days and for dexmedetomidine HCl between 7 and 50 days depending on drug concentration. Spray drying is a promising way to produce spherical silica gel particles with a narrow particle size range for controlled delivery of toremifene citrate and dexmedetomidine HCl.

Sol‐gel‐processed sintered silica xerogel as a carrier in controlled drug delivery

Sol-gel-processed sintered silica xerogel was studied as a controllable, dissolvable, implantable material. The erosion of the matrix and the release of the preadsorbed drug toremifene citrate was investigated both in vitro and in vivo using mice. In an in vitro dissolution study, 50 to 60% of the drug was released after 24 h, according to the square root of time kinetics, and the weight loss of the silica was 24 wt %. Silica xerogel with tritium-labeled toremifene was implanted subcutaneously in mice for 56 days. To determine the amount of tritiated drug remaining in the silica disks at the implantation site, the disks were excised periodically and the radioactivity measured. About 40% of the radioactivity was released during the first 4 days and all of it within 28 days. Radioactivity also was measured in the liver, lungs, kidneys, uterus, and blood. The radioactivity reached a maximum level after 4 days in the liver, kidneys, and lungs and slowly decreased until all of the drug had been released from the matrix after 28 days. After release of the drug (28 days) the amount of remaining silica xerogel implant was 45 wt %, and at the end of the study (56 days) it was 24 wt %. In the histopathological study, sintered silica xerogel did not show any tissue toxicity at the site of the implantation, in the liver, or in the kidneys. It was concluded that sintered silica xerogel is a biocompatible and controllably resorbable material and therefore is a promising matrix for use in the sustained delivery of drugs.

BIOACTIVE GLASS S53P4 IN FRONTAL SINUS OBLITERATION: A LONG-TERM CLINICAL EXPERIENCE

Synthetic, osteoconductive, and antimicrobial bioactive glass (BAG) has been used in many surgical applications.