Modified glycosides, compositions comprised thereof and methods of use thereof

Modified glycosides are provided which can be used to form a variety of materials including solid delivery systems, and optically clear colored devices or coatings. The solid delivery systems can be used for delivery and release of a variety of substances can be in the form of tablets for oral administration, or in the form of powders, microspheres or implants for intravenous, intradermal, transdermal, pulmonary or other route of administration. The modified glycosides may be processed to form a vitreous glass matrix having a substance, such as a therapeutic agent, or an optically active dye incorporated therein. In one embodiment, the vitreous glass matrix is provided in a solid dose form which is capable of releasing a therapeutic substance in situ at various controlled rates.

EXAMPLE 1 
 Synthesis and Characterization of Glycoside of Sugar Alcohol Derivates Acetyl derivatives of polyols were prepared, wherein the polyols were the following glycosides of sugar alcohols: lactitol, palatinit, and the individual sugar components of palatinit, as described below. 10 g of the polyol was dissolved in 40 mL of acetic anhydride containing 4 g of sodium acetate. When all the sugar had Dissolved, 100 mL of distilled water was added to the solution and the mixure extracted with dichloromethane to extract the derivatized polyol. The acetylated polyol was recovered by evaporating off the solvent and the derivative characterized by nuclear magnetic resonance spectroscopy (NMR) and differential scanning calorimetry (DSC). The products were obtained and characterized by NMR and DSC, for the acetyl derivatives of lactitol (4-O-&bgr;-D-galactopyranosyl-D-glucitol), palatinit &lsqb;a mixture of GPS (&agr;-D-glucopyranosyl-1→6-sorbitol) and GPM (&agr;-D-glucopyranosyl-1→6-mannitol)&rsqb;, and its individual sugar alcohol components GPS and GPM. Table 1 shows the melting points and Tgs (glass transition state temperatures) for the acetyl derivatives formed, lactitol nonaacetate, palatinit nonaacetate and GPS nonaacetate and GPM nonaacetate. The glasses showed a range of melt temperatures suitable for the incorporation of labile substances such as biologically active compounds, without thermal degradation, and Tgs above ambient. Tgs were obtained as the average of two runs. 1 TABLE 1 Melting Point Derivative (° C.) Tg (° C.) Lactitol nonaacetate 119 39.5 Palatinit nonaacetate 108 35.3 GPS nonaacetate 204 17.4 GPM nonaacetate 87 35 
 EXAMPLE 2 
 Formation of Glasses using Derivatives of Glycosides of Sugar Alcohols and Analysis of their Solvent Properties. Glasses are formed of the derivatives of glycosides of sugar alcohols prepared as described above in Example 1 by quenching from the melt according to the method described in PCT GB95/01861. Various dyes are added to the melts and then mixed before quenching to form glasses incorporating the dyes. Solubility of the dyes in the melt and in the quenched glass is assessed visually as an increase in dye intensity and the presence of particulate material. The results of the incorporation of various dyes in lactitol nonaacetate glasses is shown in Table 2; these glasses were also characterized by DSC. The glasses were found to be good solvents for poorly water soluble solutes. Surprisingly, the incorporation of such active substances showed little effect on the Tg of the glasses formed as assessed by DSC and no evidence of devitrification was observed even after 2 months at ambient temperature and humidity. The glasses are thus suitable for use as optically clear filter devices and for the encapsulation and controlled release of bioactive substances. 2 TABLE 2 Dye Water Solubility glass solubility Napthol green B ± ± Mordant blue 9 &plus; − Acid yellow 65 &plus;&plus; — Disperse red 1 — &plus;&plus;&plus; 
 EXAMPLE 3 
 Formation of Glassy Coating Containing Optically Active Molecules Dissolved in Modified Glycosides Disperse Red 1 and lactitol nonaacetate (ratio 0.1/100 g/g) were dissolved in dichloromethane and the solution was applied in a fine coat to a glass slide. The solvent was evaporated off in an air stream, leaving a thin coating of red colored lactitol nonaacetate glass. The colored glass formed was visually compared to glasses of trehalose and trehalose acetate encapsulating the dye. The glass color was more intense than an equivalent trehalose glass containing 10× more dye. Furthermore, the glass coating remained clear when exposed to ambient temperatures and humidities unlike glasses of trehalose octaacetate which became cloudy overnight. 
 EXAMPLE 4 
 Formation of Glassy Matrix of Modified Glycosides Containing Pharmaceutically Active Molecules for Controlled Release The hydrophobic drug Cyclosporin A and the hydrophilic drug Diltiazem HC 1 were both incorporated in a glass of lactitol nonaacetate (ratio of 10 g drug to 100 g modified glycoside) by either quenching from the melt or evaporation from solvent. For glass formation by quenching from the melt, 1 g of drug was dissolved in 10 g of lactitol nonaacetate melt at 120° C. and the mix quenched immediately after it went clear. For glass formation by solvent evaporation, 1 g of drug and 10 g of lactitol nonaacetate were dissolved in dichloromethane and the solvent was evaporated off in an air stream. Surprisingly, the glasses formed by both methods, and incorporating both drugs, were all optically clear and remained clear on storage at ambient temperatures and humidities for at least a month. Also surprisingly the Tgs of the glasses were all approx. 39° C. However, the glasses containing the different drugs showed different profiles of controlled release of incorporated drugs on immersion of the glasses in stirred saline solution. Addition of 0.1% detergent (Tween 20) to the saline solution also altered the rate of controlled release of incorporated drug. 
 EXAMPLE 5 
 Controlled Release of Active Molecules Dissolved in Modified Glycosides. Disperse Red 1 was incorporated as a model active in a glass of lactitol nonaacetate (ratio 0.1/100 g/g) by melt mixing. The release of model active from 0.5 mm and 3 mm thickness layers of glass, into either water or an aqueous solution of 5% Tween 20, was monitored by absorbance at 510 nm. No dissolution of either thickness glass was observed in water whereas complete release of active was observed in 12 and 72 hours, from the 0.5 mm and 3 mm thickness glasses respectively, in surfactant-containing media with constant agitation. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention, which is delineated by the appended claims.