WO2008014610A1

WO2008014610A1 - Drug delivery compositions and methods of forming and using same

Info

Publication number: WO2008014610A1
Application number: PCT/CA2007/001354
Authority: WO
Inventors: Dean-Mo Liu; Dorna Hakimi-Mehr; Mao-Jung Maurice Lien; Doug Smith; Wladyslaw Budzynski
Original assignee: Miv Therapeutics Inc.
Priority date: 2006-08-04
Filing date: 2007-08-01
Publication date: 2008-02-07

Abstract

This application relates to a drug delivery composition comprising a nonpolymeric, solidified matrix and a drug dispersed in the matrix. The matrix material comprises an organic metal salt or silica or titania, or a combination thereof. In one embodiment the drug is substantially uniformly dispersed in the matrix in a particulate form. The matrix material encapsulates the drug particles and controls its release in vivo. Optionally a biodegradable lipid layer may be applied to the matrix. The drug delivery composition may be applied to the surface of a medical device, such as a cardiovascular stent, or may be formulated as a pharmaceutical preparation suitable for other means of administration. Methods of forming the composition are described which enable in situ encapsulation of both water-insoluble and water-soluble drugs.

Description

DRUG DELIVERY COMPOSITIONS AND METHODS OF FORMING AND

USING SAME

RELATED APPLICATION

[01] This application claims the benefit of priority under 35 U. S. C. § 119(e) of U.S. Provisional Application No. 60/821 ,530, filed August 4, 2006, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

[02] This application relates to compositions formulated for delivery of drugs. This application also relates to methods of forming the compositions and using the compositions for drug delivery.

BACKGROUND

[03] The use of polymeric materials for drug delivery has been widely reported for years, especially in the field of cardiovascular drug eluting stents. Some prior art approaches are described in EP1652539, W02005112570 and W02005097224, for example. Polymers by nature have the potential to cause inflammatory reactions in vivo and their stability may diminish over time. Therefore alternatives to polymeric drug delivery systems have been investigated. Drug delivery systems including lipid- based, oil-based, and ceramic materials are known in the prior art. However, in the field of drug eluting cardiovascular stents, lipids and oils have shown problems with mechanical integrity, resulting in loss of the incorporated therapeutic agent. The properties of lipid and oil-based systems must therefore be improved before reliable drug delivery can be achieved in stent applications. Recently, a number of reports have addressed the use of ceramic-based drug delivery systems for stents, such as W02004024201 which discloses the use of calcium phosphate as a drug carrier.

[04] In W02005082277 a mesoporous oxide film is used in order to act as a reservoir for the release of drug and also to improve adhesion between organic coatings and inorganic substrates. In this approach silica or titania sol-gel are mixed with an organic (triblock copolymers) template and are deposited on a substrate, such as a cardiovascular stent. The organic template and the solvents are further removed, resulting in a mesoporous structure having a pore size between 2 to 20 nm. In this approach the mesoporous coating is impregnated with the therapeutic agent, namely paclitaxel or sirolimus, by dip coating in the drug solution or by spraying the drug solution onto the coating. This patent does not refer to in-situ incorporation of the drug into the mesoporous oxide.

[05] W02005089825 describes the application of a ceramic porous coating on the surface of a medical device, namely a stent. The porous coating acts as a reservoir for the drug and a polyelectrolyte multilayer, deposited on the surface of the porous coating, regulates the release of drug. The therapeutic agent can also be encapsulated within the multilayer coating. [06] A poly(dimethylsiloxane)-silica, organic-inorganic, composite coating was prepared by Gao et al (Gao Z, Nahrup JS, Mark JE, Sakr A., Journal of Applied Polymer Science; 2005, 96: 494-501 ) for the controlled delivery of drugs. The composite is mixed with channeling agents such as poly( ethylene glycol) in order to produce porosity for the drug release. The final composition is further deposited on the surface of drug tablets to control the release of drugs.

[07] EP1319416 discloses the use of a porous metallic stent with the porous surface coated with a ceramic material in order to improve the stability of the stent. A pharmaceutical agent is further deposited in the porous surface and is covered by a polymer barrier layer to control the drug diffusion. The polymer coating may also contain drugs which are released in a controlled manner.

[08] W09952471 describes the use of thin film iridium oxide on a stent. The oxide film is thin enough to be able to undergo significant stress during stent crimping and expansion. A biodegradable coating may be applied on the oxide layer in order to deliver drugs. [09] While various drug eluting systems are known in the prior art, there is a continuing need for improved non-polymeric drug delivery systems and methods, particularly systems capable of reliably achieving controlled release of both water-insoluble and water-soluble drugs.

SUMMARY OF INVENTION

[10] In accordance with the invention, a drug delivery composition is provided comprising a non-polymeric, solidified matrix comprising matrix material selected from an organic metal salt and silica; and a drug dispersed in the matrix. Alternatively or additionally, the matrix may also include titania. [11] The invention also relates to medical devices and pharmaceutical preparations comprising the composition and methods of formulating and using the composition to achieve gradual drug elution.

[12] One embodiment provides a method of forming a drug delivery composition comprising: (a) providing a drug;

(b) formulating a matrix solution comprising a matrix material selected from an organic metal salt and a silica precursor; and

(c) mixing said drug with said matrix solution to disperse said drug in said matrix material.

[13] Another embodiment provides a drug delivery composition comprising:

(a) a non-polymeric, solidified matrix comprising material selected from an organic metal salt; and (b) a drug dispersed in said matrix.

BRIEF DESCRIPTION OF DRAWINGS

[14] In drawings which illustrate embodiments of the invention, but which should not be construed as restricting the spirit or scope of the invention in any way, - A -

[15] Figure 1 is a schematic view showing a drug delivery composition coating an implantable medical device, in accordance with one embodiment of the invention;

[16] Figure 2 is a flowchart illustrating a multi-step procedure for formulating a drug delivery composition in accordance with one embodiment of the invention;

[17] Figure 3 are photographs of (A) an aqueous matrix solution comprising a dispersing agent and a matrix material, and (B) a solution comprising paclitaxel drug dispersed in the matrix solution; [18] Figure 4 is a is a flowchart illustrating a multi-step procedure for formulating a drug delivery composition in accordance with one embodiment of the invention;

[19] Figure 5 is a is a flowchart illustrating a multi-step procedure for formulating a drug delivery composition in accordance with one embodiment of the invention;

[20] Figure 6 is a scanning electron micrograph of paclitaxel drug nanoparticles embedded within a silica matrix; the drug particles have a spherical geometry and are each within a size range of approximately 100 nm - 200 run in diameter; [21] Figure 7 is a scanning electron micrograph of paclitaxel drug nanoparticles embedded within an organic salt matrix; the drug particles have an acicular geometry and are each within a size range of approximately 50 nm - 300 nm in length and approximately 100 nm - 200 nm in diameter; and [22] FIG. 8 is a graph of cumulative release of paclitaxel (μg, y-axis) versus time (min., x-axis).

DESCRIPTION

[23] Throughout the following description, specific details are set forth in order to provide a more thorough understanding of the invention. However, the invention may be practiced without these particulars. In other instances, well known elements have not been shown or described in detail to avoid unnecessarily obscuring the invention. Accordingly, the specification and drawings are to be regarded in an illustrative, rather than a restrictive, sense.

[24] This application relates to a drug delivery composition 10 and methods of formulating and using the composition to achieve controlled drug delivery. As shown in Figure 1 , composition 10 includes a solid non- polymeric matrix 12. As described further below, matrix 12 is composed of a matrix material comprising an organic metal salt or silica, or a combination thereof. Matrix 12 may also include a plurality of different organic metal salts in one embodiment. Alternatively or additionally, matrix 12 may also include titania. A therapeutic agent such as a drug 14 is dispersed in matrix 12 in particulate or molecular (i.e. fully dissolved) form. The matrix material may encapsulate or physically entrap each particle of drug 14. In one embodiment, drug 14 may be dispersed relatively uniformly in matrix 12. Optionally, a lipid layer 16 (topcoat) may be applied to matrix 12. In the embodiment shown in Figure 1 , composition 10 may be applied as a coating on a substrate 18, such as an implantable medical device. Substrate 18 may include a biocompatible layer 20 on an outer surface thereof. In other embodiments, composition 10 may be deployed as a pharmaceutical preparation adapted for oral, injection, inhalation or topical administration.

[25] One embodiment for formulating composition 10 is shown schematically in Figure 2. In this embodiment the drug to be delivered is water-insoluble. For example, many anti-thrombosis, anti-proliferative and anti-cancer drugs are water-insoluble. One particular example of a water- insoluble drug is paclitaxel. The first step in the process is to dissolve the water-insoluble drug in a solvent to form a drug solution 22. In this example the solvent may be immiscible or only slightly miscible in water. Example of suitable solvents include methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, and xylenes. In particular examples, the amount of drug dissolved in solution 22 may vary between about 5 - 20 weight percent. [26] In the embodiment of Figure 2, after the drug solution 22 is prepared, it is further mixed with a water-based solution 24 which includes a dispersing agent. Examples of suitable dispersing agents include polysorbates, chitosan, didodecyldimethylammonium bromide (DMAB), dextranes, and mixtures thereof. A typical amount of the dispersing agent that is effective for achieving a stable drug suspension can be in the range of 0.1 to 50 weight percent of the drug. The amount of the dispersing agent may vary depending upon the size of drug particles required. A higher amount of the dispersing agent is typically required for drug particles less than 2 micrometers in diameter. In particular embodiments of the invention the drug particles are within the range of about 1 nm - 3000 nm in diameter.

[27] Solutions 22 and 24 may be mixed in a high-speed homogenizer or other homogenization device for a time period long enough to completely remove the solvent by natural or forced evaporation. In the case of forced evaporation, a mild heating or vacuum can be applied. As shown in Figure 2, the homogenization process yields a drug colloidal suspension 26.

[28] After drug suspension 26 is prepared, it is mixed with a matrix solution 28. In one embodiment matrix solution 28 is prepared by dissolving organic metal salt(s) or silica precursor(s) or a combination thereof in an aqueous solvent. Additionally or alternatively titania precursors) may be dissolved in the aqueous solvent. Optionally solution 28 may contain a mixture of water and alcohol. Typically the concentration of the alcohol is at or below 30 weight percent of matrix solution 28 and more particularly below 20 weight percent. The concentration of the organic metal salts, silica precursor(s), or titania precursor(s) in matrix solution 28 can vary within a range from 0% to 100%. Suitable organic metal salts include calcium gluconate anhydrate, magnesium gluconate anhydrate, magnesium gluconate dihydrate, calcium lactate gluconate, calcium gluconate monohydrate, calcium saccharate tetrahydrate, calcium folinate, tricalcium citrate tetrahydrate, ferrous gluconate anhydrate, ferrous gluconate dehydrate, and monosodium citrate anhydrate. In particular embodiments of the invention organic metal salts may be selected that are weakly soluble in water at physiological temperatures. As used in this patent application, "weakly soluble" means that the organic metal salt has less than 10% solubility in water at physiological temperatures. In one embodiment the solubility of the salt in water is less than 5% and more preferably less than 3%. As will be apparent to a person skilled in the art, salt ionic species should be selected that will not likely cause significant adverse effects when composition 10 is administered to humans. For example, aluminum ions should be avoided. The salt ionic species may include both monovalent and divalent forms acceptable for administration to humans. In different embodiments the organic metal salts may be in monomeric and oligomeric forms.

[29] Suitable silica precursors for inclusion in matrix solution 28 include silicon alkoxides, such as tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), or silanols such as monomethyl silane triol, dimethyl silane diol, trimethyl silanes, ethyl silane triol, and diethyl silane diol. The term silica precursors can also include other precursors or derivatives such as silicates, e.g. sodium silicate, colloidal silica, or a combination thereof. In one example, the silica precursors can form more than 50 weight percent of matrix solution 28.

[30] In the embodiment of Figure 2, the next step in the formulation process in this example is to mix drug colloidal suspension 26 with matrix solution 28 to thereby form a liquid precursor solution 30 of composition 10 (see Figure 1 ). Precursor solution 30 comprises drug 14 dispersed in matrix solution 28 as discussed above. This process is sometimes referred to herein as in situ encapsulation. For example, if drug 14 is nanoparticulate, nanoparticles of drug 14 may become physically entrapped or encapsulated in the matrix material during this mixing step.

[31] For example, Figure 3A illustrates a matrix solution 28 of dispersing agent (e.g., didodecyldimethylammonium bromide) and precursor (e.g., calcium gluconate anhydrate). Figure 3B illustrates the matrix solution mixed with the drug colloidal suspension 26 to yield precursor solution 30. In this example the drug 14, namely 1 weight percent paclitaxel, remains stably suspended in precursor solution 30 in nanoparticulate form for greater than 24 hours.

[32] Precursor solution 30 may be applied as a coating to a substrate 18 in a liquid form and allowed to dry to form a solidified composition 10. In one embodiment, the solidified matrix is porous. In one embodiment, the porous matrix is nanoporous, having pores ranging fromi nm to 1000 nm, e.g., from 1 nm to 500 nm.

[33] As shown in Figure 1 , substrate 18 may be an implantable medical device, such as a stent. In some applications the coating may be applied to an outer biocompatible layer 20 of substrate 18 (Figure 1 ). As will be apparent to a person skilled in the art, liquid precursor 30 may be deployed in many other alternative means. For example, precursor solution 30 may optionally be combined with a pharmaceutically acceptable carrier to formulate a drug delivery product suitable for therapeutic or prophylactic administration.

[34] Optionally, composition 10 may include a lipid layer 16 applied to matrix 12 once it has solidified as shown in Figures 1 and 2. Lipid layer 16 may serve to soften and lubricate the surface of matrix 12 to facilitate intravascular or other means of in vivo administration. For example, lipid layer 16 may serve to protect drug 14 from degradation by digestive acids. The lipid forming lipid layer 16 may be a small molecule rather than a macromolecular lipid or polymeric lipid. Suitable lipids include oleic acid, vegetable oils, stearic acid, beeswax, 12-hydroxystearic acid, glycerol behenate, hydrogenated castor oil, hydrogenated soybean oils, phospholipids, soybean lecithin, and mixtures thereof. Lipid layer 16 may be water-insoluble, biocompatible and enzymatically biodegradable in vivo to enable gradual exposure of matrix 12 and hence release of drug 14 as described further below. The thickness of layer 16 may vary depending upon the degradation rate and the length of time the coating is required. For example, layer 16 may vary in thickness between about a few hundred nanometers and a few micrometers. [35] The physical characteristics of composition 10, such as the size, morphology and distribution of the nanoparticles of drug 14, may be varied or "tuned" depending the particular make-up of matrix 12. This feature is illustrated in Figure 6 and 7 which show drug 14, namely paclitaxel nanoparticles, substantially uniformly distributed in a matrix 12 of silica, which was prepared in a manner similar to the method of Example 1 , below. Figure 6 is an SEM picture of a resulting silica matrix containing paclitaxel. Figure 7 is an SEM picture of matrix comprising organic metal salts, e.g., calcium gluconate anhydrate, with a dispersing agent (e.g., didodecyldimethylammonium bromide) and precursor (e.g., calcium gluconate anhydrate) and further containing paclitaxel. The size and morphology of the dispersed drug may be altered by adjusting the relative amounts of organic metal salts and silica forming the matrix composite. [36] The amount and distribution of drug 14 within matrix 12 of composition 10 may also be readily controlled by varying other process parameters including the concentration of the matrix material within matrix solution 28, the drying rate (natural or forced), and the particular coating process employed (e.g. dipping, spinning, or spraying). In different embodiments of the invention the particle size of drug 14 may be manipulated to range between about 1 run to 3,000 run, or more particularly between about 10 run to 2,000 nm. The concentration of drug 14 may vary depending upon the process parameters selected and the particular application. In one example the concentration of drug 14 may be increased up to about 80 weight percent of matrix 12 when in the solidified form. [37] Figure 4 illustrates an alternative process for manufacturing a composition 10 where drug 14 is incorporated in matrix 12 in a molecular (i.e. fully dissolved form) rather than a particulate form. The process of Figure 4 is generally similar to the process of Figure 2 except that the drug 14 is water-insoluble and the formation of a drug colloidal suspension 28 in the presence of water is not required. Combining drug solution 22 with

(precursor) matrix solution 28 forms a clear solution rather than a suspension (since drug 14 is in molecular form). For example, the water-insoluble drug can be dissolved in an alcohol and/or another organic solvent such as tetrahydrofuran or methylene chloride to form drug solution 22. In this example the dispersing agent may or may not be added to matrix solution 28. As described above, suitable dispersing agents include polysorbates, chitosan, didodecyldimethylammonium bromide (DMAB), dextranes, and mixtures thereof. Matrix solution 28 may be prepared from silica precursors such as, but not limited to, tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), monomethyl silane triol, dimethyl silane diol, trimethyl silanes, ethyl silane triol, and diethyl silane diol in acid water, and may be hydrolyzed before or after addition of drug solution 22. The molar ratio of the silanols to water may vary, in one embodiment, between about 1 :4 to 1 :8 to minimize the amount of water and thereby inhibit precipitation of the drug. Matrix solution 28 can be further diluted in alcohol or a solvent miscible with water such as ethyl alcohol or tetrahydrofuran. An organic metal salt may then be optionally added to the hydrolyzed silanol. The matrix solution 28 thus formed is permitted to age for about one day or more. The aging process can ensure that all hydrolysis and condensation reactions are fully completed (this process may occur either before or after drug 14 is added). [38] In this example, the drug solution 22 and matrix solution 28 are then mixed directly together to form coating 30 containing the drug in molecular rather than particulate form. The ratio of solvent/alcohol to water may be adjusted to ensure the solubility of drug 14 in precursor solution 30 (e.g. 20:1 ). Coating 30 may be a liquid or solid and may be further aged before application as a coating on a medical device or spray application of matrix particles for drug delivery.

[39] As in the example described above, the physical microstructure of the silica matrix 12 and the entrapment of the drug inside the nanoporous structure of the matrix 12 will limit the crystallization of the drug. Thus the size of drug nanoparticles will not exceed that of the tiny voids of the silica matrix. The relative hydrophilicity and hydrophobicity of matrix 12 can be adjusted by changing the molar ratios of the components. For example, ethyl trimethoxysilane, methyl triethoxysilane, trimethylethoxy silane, triethylethoxy silane can be used in combination with TMOS and/or TEOS in the ratio range of 1-4:1 in order to produce the matrix 12. Replacing TMOS or TEOS with the above-mentioned compounds can directly modify the chemistry of the pore-walls and can impart hydrophobic properties to the otherwise hydrophilic silica matrix 12.

[40] A further alternative process for manufacturing a composition 10 incorporates drug 14 in matrix 12 in molecular rather than particulate form. In this case the drug is water soluble. The water-soluble drug can be directly added into the matrix solution 28 for a subsequent shape-forming process (not shown), or, as shown in Figure 5, it may be dissolved in water first to form an aqueous drug solution 22A and then added to matrix solution 28. No non-aqueous solvent is used in this example. The water-soluble drug can be physically encapsulated into the final salts or silica matrix 12 (see Figure 1) in molecular form or in form of small drug particles produced by recrystallization of drug within the microstructure of matrix 12 after water is removed. A coating 30 is then formed

[41] In use, composition 10 may be deployed to a target location in vivo. For example, composition 10 may be coated on a stent substrate 18 and delivered to a target intravascular location. Aqueous body fluids at the target location will penetrate the porous structure of matrix 12 and cause gradual release of drug 14. If a lipid layer 16 is present, then the body fluids (e.g. containing enzymes) may first gradually degrade the lipid layer 16. As described further below, since drug 14 is dispersed within matrix 14 in particulate or molecular form, there is a high surface area of drug 14 in contact with the body fluids, allowing the controlled release of the drug via inward-diffusion (of body fluid) and outward-diffusion (of dissolved drug molecules). Thus the mechanism of release of drug 14 from matrix 12 is governed by the diffusion of water or other aqueous media into the pores of the matrix 12 and subsequent dissolution and diffusion of drug 14 to the surface. The relative hydrophilic and hydrophobic properties of matrix 12 will affect the diffusion rate of water into the porous structure and therefore influence the rate of release of drug 14. The chemistry of the matrix material or precursors thereof will also influence the microstructure of the matrix 12, (e.g. pore size and volume) which will further affect the size, morphology, and crystallization of drug 14.

EXAMPLES

Example 1

[42] To 4 g TMOS (trimethylorthosilicate) in 4g ethanol, 2 g 0.005 N HCI solution was added at room temperature to form a solution. The solution was stirred overnight. To 1.6 g of the above solution, 2 ml_ of 2 wt% paclitaxel solution in ethanol was added. The final solution was stirred overnight.

Example 2

[43] The solution of Example 1 was spray coated on a stainless steel coronary stent to achieve a coating weight of about 100 μg.

Example 3 [44] The coated stents of Example 2 were placed in 9 ml_ PBS solution and were rotated at a speed of 20 rpm in a water bath at 37⁰C. Samples of the solution were taken at various time points and were analyzed using reverse phase high performance chromatography (HPLC). The system used is a Varian ProStar HPLC with dual pumps, uv detection and an autosampler. The stationary phase is an L43 PFP 250x4.3mm Taxsil column (Varian), kept at a temperature of 30⁰C. The mobile phase is acetonitrile:water (52:48), with an isocratic flow rate of 1 ml/min.

[45] FIG. 8 shows the release profile of paclitaxel from the coated stents as a graph of cumulative paclitaxel (μg, y-axis) versus time (min., x- axis). It can be seen that after an initial burst release, the drug is released steadily over time.

[46] As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof.

Claims

1. A method of forming a drug delivery composition comprising:

(a) providing a drug;

2. The method as defined in claim 1 , wherein the providing in (a) comprises dissolving a drug in a first solvent to form a drug solution, and the mixing in (c) comprises mixing said drug solution with said matrix solution.

3. The method as defined in claim 2, wherein said drug is water- insoluble and wherein said first solvent comprises an alcohol or an organic solvent selected from tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile and dioxane.

4. The method as defined in claim 3, wherein said matrix solution comprises water or a mixture of water and alcohols and wherein the molar ratio of said silica precursor to said water in said matrix solution is between about 1 :4 to 1 :8.

5. The method as defined in claim 2, wherein said drug is water- soluble and wherein said first solvent comprises water.

6. The method as defined in claim 1 , wherein: the providing in (a) comprises dissolving a water-insoluble drug in a first solvent to form a drug solution, followed by the step of mixing said drug solution with an aqueous solution comprising water and a dispersing agent to form a substantially homogenous drug colloidal suspension; and the mixing in (c) comprises mixing said drug colloidal suspension and said matrix solution to disperse said drug in said matrix material.

7. The method as defined in claim 6, wherein said first solvent is immiscible or slightly miscible in water and is selected from methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, and xylenes.

8. The method as defined in claim 6, wherein said first solvent substantially evaporates during said step of mixing said drug solution and said aqueous solution.

9. The method as defined in claim 6, wherein said dispersing agent is selected from polysorbates, chitosan, didodecyldimethylammonium bromide (DMAB), and dextranes.

10. The method as defined in claim 6, wherein the concentration of said dispersing agent in said aqueous solution ranges from 0.1 to 50 weight percent.

11. The method as defined in claim 6, wherein said step of formulating a matrix solution comprises dissolving said matrix material in a second solvent comprising a mixture of water and alcohol, wherein the concentration of said alcohol in said second solvent is less than 30 weight percent.

12. The method as defined in claim 11 , wherein the concentration of said alcohol in said second solvent is less than 20 weight percent.

13. The method as defined in claim 6, wherein said matrix material is hydrophilic.

14. The method as defined in claim 1 , wherein said organic metal salt is weakly soluble in water.

15. The method as defined in claim 1 , wherein said organic metal salt is selected from calcium gluconate anhydrate, magnesium gluconate anhydrate, magnesium gluconate dihydrate, calcium lactate gluconate, calcium gluconate monohydrate, calcium saccharate tetrahydrate, calcium folinate, tricalcium citrate tetrahydrate, ferrous gluconate anhydrate, ferrous gluconate dehydrate, and monosodium. citrate anhydrate.

16. The method as defined in claim 1 , wherein said silica precursor is selected from tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), monomethyl silane triol, dimethyl silane diol, trimethyl silanes, ethyl silane triol, diethyl silane diol, sodium silicate and colloidal silica.

17. The method as defined in claim 1 , further comprising allowing said matrix to solidify to form a drug delivery composition comprising: (a) a non-polymeric, solidified matrix comprising material selected from an organic metal salt and silica; and

(b) a drug dispersed in said matrix.

18. The method as defined in claim 17, wherein said solidified matrix is porous silica.

19. The method as defined in claim 17, wherein said drug is dispersed in said matrix in particulate form.

20. The method as defined in claim 19, wherein the particle size of said drug when in said particulate form is between about 1 nm - 3000 nm.

21. The method as defined in claim 19, wherein the particle size of said drug when in said particulate form is between about 10 nm - 2000 nm.

22. The method as defined in claim 17, wherein said drug is dispersed in said matrix in molecular form.

23. The method as defined in claim 17, wherein said matrix is hydrophilic.

24. The method as defined in claim 17, wherein said composition comprises a drug dispersing agent.

25. The method as defined in claim 24, wherein said dispersing agent is selected from polysorbates, chitosan, didodecyldimethylammonium. bromide (DMAB), and dextranes.

26. The method as defined in claim 17, comprising a lipid layer applied to said matrix.

27. The method as defined in claim 26, wherein said lipid is water- insoluble.

28. The method as defined in claim 27, wherein said lipid is selected from oleic acid, vegetable oils, stearic acid, beeswax, 12- hydroxystearic acid, glycerol behenate, hydrogenated castor oil, hydrogenated soybean oils, phospholipids, and soybean lecithin.

29. The method as defined in claim 17, wherein said matrix comprises a plurality of pores.

30. The method as defined in claim 29, wherein the size of said pores limits the growth of drug particles dispersed in said matrix.

31. The method as defined in claim 17, wherein said drug is physically encapsulated by said matrix material within said composition.

32. The method as defined by claim 1 , wherein said composition is a stable suspension of said drug in said matrix.

33. A method of releasing a drug at a target location comprising: (a) delivering the drug delivery composition of prepared by the method of claim 1 to said target location; and

(b) exposing said composition to an aqueous solution at said target location, wherein said aqueous solution penetrates said matrix and causes said drug to gradually elute from said composition.

34. The method as defined in claim 33, wherein aqueous solution is a bodily fluid.

35. The method as defined in claim 33, wherein said target location is located in vivo and wherein said drug delivery composition is delivered to said target location via a medical device.

36. The method as defined in claim 35, wherein said medical device is a stent.

37. The method as defined in claim 35, wherein said medical device has a biocompatible layer on at least a portion of the outer surface thereof and wherein said drug delivery composition is applied to said biocompatible layer.

38. The method as defined in claim 35, wherein multiple layers of said composition are applied to said medical device, wherein at least some of said multiple layers comprise different drugs.

39. A drug delivery composition comprising: (a) a non-polymeric, solidified matrix comprising material selected from an organic metal salt; and

(b) a drug dispersed in said matrix.

40. The composition as defined in claim 39, wherein said drug is substantially uniformly dispersed in said matrix.

41. The composition as defined in claim 39, wherein said matrix is porous.

42. The composition as defined in claim 39, wherein said organic metal salt is selected from calcium gluconate anhydrate, magnesium gluconate anhydrate, magnesium gluconate dihydrate, calcium lactate gluconate, calcium gluconate monohydrate, calcium saccharate tetrahydrate, calcium folinate, tricalcium citrate tetrahydrate, ferrous gluconate anhydrate, ferrous gluconate dehydrate, and monosodium citrate anhydrate.

43. The composition as defined in claim 39, wherein said organic metal salt is weakly soluble in water.

44. The composition as defined by claim 39, wherein said matrix comprises a plurality of organic metal salts.