BRPI1014272B1 - COMPOSITION AND PHARMACEUTICAL COMPOSITION COMPRISING DICLOFENAC ACID PARTICLES - Google Patents

Abstract

DICLOFENAC FORMULATION The present invention relates to methods for producing diclofenac particles using dry milling processes, as well as compositions comprising diclofenac, medicaments produced using diclofenac in particle form and/or compositions, and methods of treating an animal, including humans, using a therapeutically effective amount of diclofenac administered by means of said medicaments.

Description

FIELD OF THE INVENTION

The present invention relates to methods for producing diclofenac particles using dry milling processes, as well as compositions comprising diclofenac, medicaments produced using diclofenac in particle form and/or compositions, and to methods of treating an animal, including humans, using a therapeutically effective amount of diclofenac administered by means of said medicaments.

FOUNDATION

Poor bioavailability is a significant problem encountered in the development of compositions in the therapeutic, cosmetic, agricultural, and food industries, especially those materials containing a biologically active material that is poorly soluble in water at physiological pH. The bioavailability of an active material is the degree to which the active material becomes available to the target tissue in the body or other medium after systemic administration via, for example, oral or intravenous routes. Many factors affect bioavailability, including the dosage form and the solubility and dissolution rate of the active material.

In therapeutic applications, poorly and slowly water-soluble materials tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation. Furthermore, poorly soluble active agents tend to be unfavorable or even dangerous for intravenous administration due to the risk of agent particles blocking blood flow through the capillaries.

It is known that the dissolution rate of a particulate drug increases with increasing surface area. One way to increase surface area is to decrease particle size. Consequently, methods for making finely divided or sysized drugs have been studied with the aim of controlling the size and size range of drug particles for pharmaceutical compositions.

For example, dry milling techniques have been used to reduce particle size and thus influence drug absorption. However, in conventional dry milling, the fineness limit is reached, generally in the region of about 100 microns (100,000 nm), at which point the material becomes cake in the milling chamber and prevents any further reduction in particle size. Alternatively, wet milling can be employed to reduce particle size, but flocculation restricts the lower particle size limit to about 10 microns (10,000 nm). The wet milling process, however, is susceptible to contamination, leading to a trend in the pharmaceutical art against wet milling. Another alternative milling technique, commercial air jet milling, has provided particles ranging in average size from at least about 1 to about 50 microns (1,000–50,000 nm).

There are several approaches currently used to formulate poorly soluble active agents. One approach is to prepare the active agent as a soluble salt. Where this approach cannot be employed, alternative (usually physical) approaches are used to improve the solubility of the active agent. Alternative approaches generally subject the active agent to physical conditions that change the physical and/or chemical properties of the agent to improve its solubility. These include process technologies such as micronization, crystal structure modification or polymorphism, development of oil-based solutions, use of co-solvents, surface stabilizers or complexing agents, microemulsions, supercritical fluid, and production of dispersions or solid solutions. More than one of these processes may be used in combination to improve the formulation of a given therapeutic material. Many of these approaches commonly convert a drug into an amorphous state, which generally leads to a higher dissolution rate. However, formulation approaches that result in the production of amorphous material are not common in commercial formulations due to concerns related to stability and the potential for the material to recrystallize.

These techniques for preparing such pharmaceutical compositions tend to be complex. For example, a major technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomers or initiators (which may have undesirable levels of toxicity), at the end of the manufacturing process.

Another method of delivering reduced particle size is the formation of pharmaceutical drug microcapsules; such techniques include micronization, polymerization, and co-dispersion. However, these techniques suffer from a number of disadvantages, including at least the inability to produce sufficiently small particles, such as those obtained by milling, and the presence of co-solvents and/or contaminants such as toxic monomers that are difficult to remove, leading to expensive manufacturing processes.

Over the last decade, intense scientific research has been conducted to improve the solubility of active agents by converting them into ultrafine powders using methods such as grinding and milling. These techniques can be used to increase the dissolution rate of a particulate solid by increasing the total surface area and decreasing the average particle size.

US Patent 6,634,576 discloses examples of wet milling of a solid substrate, such as a pharmaceutically active compound, to produce a "synergistic co-mixture".

International Patent Application PCT/AU2005/001977 (Nanoparticle Composition(s) and Method for Synthesis thereof) describes, among other things, a method comprising the step of contacting a precursor compound with a co-reagent under mechanochemical synthesis conditions, wherein a solid-state chemical reaction between the precursor compound and the co-reagent produces therapeutically active nanoparticles dispersed in a carrier matrix. Mechanochemical synthesis, as discussed in International Patent Application PCT/AU2005/001977, refers to the use of mechanical energy to activate, initiate or promote a chemical reaction, a crystal structure transformation or a phase change in a material or a mixture of materials, for example, by stirring a reaction mixture in the presence of a grinding medium to transfer mechanical energy to the reaction mixture, and includes, without limitation, "mechanochemical activation", "mechanochemical processing", "reactive grinding" and related processes.

International Patent Application PCT/AU2007/000910 (Methods for the preparation of biologically active compounds in nanoparticulate form) describes, among other things, a method for the dry milling of raloxifene with lactose and NaCl that produced nanoparticulate raloxifene without significant aggregation problems.

One limitation of many prior art processes is that they are not suitable for commercial-scale grinding. The present invention provides methods for overcoming problems identified by the prior art by providing a grinding process that yields particles with increased surface area, which can also be scaled up to a commercial scale.

An example of a therapeutic area where this technology could be applied is the area of acute pain management. Many pain medications such as diclofenac are commonly prescribed as pain relief for chronic pain. As a result, they are commonly taken on a daily basis to maintain an effective therapeutic level. Diclofenac is a poorly water-soluble drug, so dissolution and absorption into the body is slow. Thus, a method such as that of the present invention, which provides enhanced dissolution, will likely provide much faster absorption, resulting in a quicker onset of the therapeutic effect. By using a method such as that of the present invention, which provides faster absorption, a drug such as diclofenac could be used more readily to treat acute as well as chronic pain.

Although the context of the present invention is discussed in the context of improving the bioavailability of materials that are poorly or slowly soluble in water, the applications of the methods of the present invention are not limited to this, as is evident from the following description of the invention.

Furthermore, although the basis of the present invention is widely discussed in the context of improving the bioavailability of therapeutic or pharmaceutical compounds, the applications of the methods of the present invention are clearly not limited to this. For example, as is evident from the following description, the applications of the methods of the present invention include, but are not limited to: nutraceutical and nutritional compounds, complementary medicinal compounds, veterinary therapeutic applications, and applications of agricultural chemicals such as pesticides, fungicides, or herbicides.

Furthermore, an application of the present invention would be to materials containing a biologically active compound, such as, but not limited to, a therapeutic or pharmaceutical compound, a nutraceutical or nutrient, a complementary medicinal product, as active components in plant or other naturally occurring material, a veterinary therapeutic compound, or an agricultural compound such as a pesticide, fungicide, or herbicide. Specific examples would be turmeric, which contains the active compound curcumin, or flaxseed, which contains the nutrient ALA, an omega-3 fatty acid. As these specific examples indicate, this invention can be applied to, but is not limited to, a range of natural products, such as seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant or food materials containing a biologically active compound. Applying this invention to these types of materials would allow for greater availability of the active compound in the materials when used in the relevant application. For example, when the material subject to this invention is ingested orally, the active compound would be more bioavailable.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed towards the unexpected discovery that particles of a biologically active material can be produced by dry milling processes on a commercial scale. In a surprising aspect, the particle size produced by the process is equal to or less than 2000 nm. In another surprising aspect, the particle size produced by the process is equal to or less than 1000 nm. In yet another surprising aspect, the crystallinity of the active material is unchanged or not substantially altered. In a preferred embodiment, the present invention is directed towards the unexpected discovery that diclofenac particles can be produced by dry milling processes on a commercial scale.

Thus, in a first aspect, the invention comprises a method for producing a composition, comprising the steps of dry grinding a solid biologically active material and a grindable grinding matrix in a mill comprising a plurality of grinding media, for a period of time sufficient to produce particles of the biologically active material dispersed in at least one partially ground grinding material.

In a preferred embodiment, the average particle size, determined on a particle number basis, is equal to or smaller than a size selected from the group consisting of 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm. Preferably, the average particle size is equal to or greater than 25 nm.

In another preferred embodiment, the particles have an average particle size, determined on a particle volume basis, equal to or smaller than a size selected from the group consisting of 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm. Preferably, the average particle size is equal to or greater than 25 nm. Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% smaller than 2000nm (% < 2000 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% smaller than 1000nm (% < 1000 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 500nm (% < 500 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 300nm (% < 300 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 200nm (% < 200 nm). Preferably, the Dx of the particle size distribution, as measured on a particle volume basis, is selected from the group consisting of less than or equal to 10,000 nm, 5,000 nm, 3,000 nm, 2,000 nm, 1,900 nm, 1,800 nm, 1,700 nm, 1,600 nm, 1,500 nm, 1,400 nm, 1,300 nm, 1,200 nm, 1,100 nm, 1,000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm; where x is greater than or equal to 90.

In another preferred embodiment, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline, and at least 98% of the biologically active material is crystalline. More preferably, the crystallinity profile of the biologically active material is substantially the same as the crystallinity profile of the biologically active material before the material is subjected to the method as described herein.

In another preferred embodiment, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous, and less than 2% of the biologically active material is amorphous. Preferably, the biologically active material does not have a significant increase in amorphous content after the material is subjected to the method as described herein.

In another preferred embodiment, the grinding time period is a range selected from the group consisting of: between 10 minutes and 2 hours, between 10 minutes and 90 minutes, between 10 minutes and 1 hour, between 10 minutes and 45 minutes, between 10 minutes and 30 minutes, between 5 minutes and 30 minutes, between 5 minutes and 20 minutes, between 2 minutes and 10 minutes, between 2 minutes and 5 minutes, between 1 minute and 20 minutes, between 1 minute and 10 minutes, and between 1 minute and 5 minutes.

In another preferred embodiment, the grinding medium is selected from the group consisting of: ceramics, glasses, polymers, ferromagnetics, and metals. Preferably, the grinding medium is steel balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm, and between 3 and 10 mm. In another preferred embodiment, the grinding medium is zirconium oxide balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm, and between 3 and 10 mm. Preferably, the dry grinding apparatus is a mill selected from the group consisting of: attrition mills (horizontal or vertical), nutation mills, tower mills, pearl mills, planetary mills, vibratory mills, eccentric vibratory mills, gravity-dependent ball mills, rod mills, roller mills, and crushing mills. Preferably, the grinding medium within the grinding apparatus is mechanically agitated by 1, 2, or 3 rotating axes. Preferably, the method is configured to produce the biologically active material in a continuous manner.

Preferably, the total combined quantity of biologically active material and grinding matrix in the mill at any given time is equal to or greater than a mass selected from the group consisting of: 200 grams, 500 grams, 1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg, 75 kg, 100 kg, 150 kg, 200 kg. Preferably, the total combined quantity of biologically active material and grinding matrix is less than 2000 kg.

Preferably, the biologically active material is selected from the group consisting of: diclofenac or a derivative or salt thereof.

In another preferred embodiment, the grinding matrix is a single material or a mixture of two or more materials in any proportion. Preferably, the single material or a mixture of two or more materials is selected from the group consisting of: mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, maltodextrin, dextrin, inulin, dextrates, polydextrose, starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches, milk powder, skimmed milk powder, other milk solids and other derivatives, soy flour, soy bran or other soy products, cellulose, microcrystalline cellulose, materials based on microcrystalline cellulose, pregelatinized (or partially) starch, HPMC, CMC, HPC, citric acid, tartaric acid, malic acid, maleic acid, maleic acid fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, sodium acetate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulfite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potassium alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay-based or aluminum silicate-based materials, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, sodium N-lauroylsarcosine salt, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl castor oil 35, polyoxyl castor oil 40, polyoxyl castor oil 60, polyoxyl castor oil 100, polyoxyl castor oil 200, hydrogenated polyoxyl 40 castor oil, hydrogenated polyoxyl 60 castor oil, hydrogenated polyoxyl 100 castor oil, polyoxyl 200 castor oil hydrogenated, cetostearyl alcohol, macrogel hydroxystearate 15, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycocholic acid, sodium glycolate, cholic acid, sodium cholate, sodium deoxycholate, deoxyglycolate, cholic acid, sodium cholate, sodium deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic acid, sodium taurodeoxycholate, taurocholic acid, sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/lignosulfonate mixture, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Calcium Dodecylbenzene Sulfonate Diisopropyl, Sodium Dodecylbenzene Sulfonate, diisopropyl naphthalenesulfonate, erythritol distearate, naphthalene sulfonate condensate, nonylphenol ethoxylate (poe-30), tristyrylphenol ethoxylate, polyoxyethylene (15) seboalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, sodium methyl naphthalene formaldehyde sulfonate, sodium n-butyl naphthalene sulfonate, alcohol Ethoxylated tridecyl (poe-18), triethanolamine isodecanol phosphate ester, triethanolamine tristyrylphosphate ester, ethoxylated tristyrylphenol sulfate, bis(2-hydroxyethyl)seboalkylamines. Preferably, the concentration of the single (or first) material is selected from the group consisting of: 5 - 99% w/w, 10 - 95% w/w, 15 - 85% w/w, 20 - 80% w/w, 25 - 75% w/w, 30 - 60% w/w, 40 - 50% w/w. Preferably, the concentration of the second or subsequent material is selected from the group consisting of: 5-50% w/w, 5-40% w/w, 5-30% w/w, 5-20% w/w, 10-40% w/w, 10-30% w/w, 10-20% w/w, 20-40% w/w, or 20-30% w/w; or if the second or subsequent material is a water-soluble surfactant or polymer, the concentration is selected from 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2%. w/w, 0.5 - 1.5%, 0.5 -1% w/w, 0.75 - 1.25% w/w, 0.75 -1% and 1% w/w.

Preferably, the milling matrix is selected from the group consisting of: (a) lactose monohydrate or lactose monohydrate combined with at least one material selected from the group consisting of: xylitol; anhydrous lactose; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972; colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl)seboalkylamines (b) anhydrous lactose or anhydrous lactose combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972; colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl) seboalkylamines. (c) mannitol or mannitol combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972; colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl) seboalkylamines. (d) Sucrose or sucrose combined with at least one material selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972; colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl) seboalkylamines. (e) Glucose or glucose combined with at least one material selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972; colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl) seboalkylamines. (f) Sodium chloride or sodium chloride combined with at least one material selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972; colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl) seboalkylamines. (g) xylitol or xylitol combined with at least one material selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972; colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl) seboalkylamines. (h) Tartaric acid or tartaric acid combined with at least one material selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972; colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl) seboalkylamines. (i) microcrystalline cellulose or microcrystalline cellulose combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; mannitol; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972 colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonic acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters, ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl)seboalkylamines. (j) Kaolin combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972 colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters; ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl)seboalkylamines. (k) Talc combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium N-lauroyl sacrosin; lecithin; sodium docusate; polyoxyl-40-stearate; Aerosil R972 colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate mixture; calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; Linear and branched dodecylbenzene sulfonate acids; condensed formaldehyde naphthalene sulfonate; nonylphenol ethoxylate, POE-30; phosphate esters; ethoxylated tristyrylphenol, free acid; polyoxyethylene (15) seboalkylamines; sodium alkyl naphthalene sulfonate; condensed sodium alkyl naphthalene sulfonate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; sodium salt of n-butyl naphthalene sulfonate; ethoxylated tridecyl alcohol, POE-18; triethanolamine isodecanol phosphate ester; triethanolamine tristyrylphosphate ester; ethoxylated tristyrylphenol sulfate; bis(2-hydroxyethyl) seboalkylamines

Preferably, the grinding matrix is selected from the group consisting of: a material considered to be Generally Considered Safe (GRAS) for pharmaceutical products; a material considered acceptable for use in an agricultural formulation; and a material considered acceptable for use in a veterinary formulation.

In another preferred embodiment, a grinding aid or combination of grinding aids is used. Preferably, the grinding aid is selected from the group consisting of: colloidal silica, a surfactant, a polymer, stearic acid, and derivatives thereof. Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine-based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, polyalkyl and aryl ether sulfates and other sulfate surfactants, trimethylammonium-based surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters, alkylbenzene sulfonic acids, alkyl ether carboxylic acids, esters of Alkyl and Aryl Phosphate, Alkyl and Aryl Sulfate Esters, Alkyl and Aryl Sulphonic Acids, Alkyl Phenol Phosphate Esters, Alkyl Phenol Sulfate Esters, Alkyl and Aryl Phosphates, Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl Sulfonate Formaldehyde Condensates Naphthalene, Sulfosuccinates, lignosulfonates, Keto-Oleyl Alcohol Ethoxylates, Condensed Naphthalene Sulfonates, Dialkyl and Alkyl Naphthalene Sulfonates, Di-alkyl Sulfosuccinates, Ethoxylated Noniphenols, Ethylene Glycol Esters, Fatty Alcohol Alkoxylates, Tallowalkylamines hydrogenated, Mono-alkyl Sulfosuccinates, Nonylphenol Ethoxylates, Sodium N-methyl oleyl taurate, Tallowalkylamines, linear or branched dodecylbenzene sulfonic acids.

Preferably, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, sodium salt of N-lauroylsarcosine, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407, polyoxyl 2-stearyl ether, polyoxyl stearyl ether 100, polyoxyl stearyl ether 20, polyoxyl stearyl ether 10, polyoxyl cetyl ether 20, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl castor oil 35, polyoxyl castor oil 40, polyoxyl castor oil 60, polyoxyl castor oil 100, polyoxyl castor oil 200, polyoxyl hydrogenated castor oil 40, polyoxyl hydrogenated castor oil 60, polyoxyl hydrogenated castor oil 100, polyoxyl hydrogenated castor oil 200, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmate, Sorbitan monostearate, sorbitan trioleate, sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycolic acid, sodium glycolate, cholic acid, sodium cholate, sodium deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic acid, sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate/lignosulfonate condensate mixture, calcium dodecylbenzene sulfonate, sodium dodecylbenzene sulfonate, naphthaenesulfonate Diisopropyl, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, Nonylphenol Ethoxylate (POE-30), Tristyrylphenol Ethoxylate, Polyoxyethylene Tallowalkylamines (15), Sodium Alkyl Naphthalene Sulfonate, Sodium Alkyl Naphthalene Sulfonate Condensate, Sodium Alkylbenzene Condensate, Sodium Isopropyl Naphthalene Sulfonate, Sodium Methyl Naphthalene Sulfonate, Sodium n-Butyl Naphthalene Sulfonate, Tridecyl Alcohol Ethoxylate (POE-18), Trieranolamine Isodecanol Phosphate Ester, Trieranolamine Tristyryl Phosphate Ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.

Preferably, the polymer is selected from the list of: polyvinylpyrrolidones (PVP), polyvinyl alcohols, acrylic acid-based polymers, and acrylic acid copolymers.

Preferably, the grinding aid has a concentration selected from the group consisting of: 0.1 - 10% w/w, 0.1 - 5% w/w, 0.1 - 2.5% w/w, 0.1 - 2% w/w, 0.1 - 1%, 0.5 - 5% w/w, 0.5 - 3% w/w, 0.5 - 2% w/w, 0.5 - 1.5%, 0.5 - 1% w/w, 0.75 - 1.25% w/w, 0.75 - 1% and 1% w/w.

In another preferred embodiment of the invention, a facilitating agent is used or a combination of facilitating agents is used. Preferably, the facilitating agent is selected from the group consisting of: surfactants, polymers, binding agents, fillers, lubricants, sweeteners, flavoring agents, preservatives, buffers, humectants, disintegrants, effervescent agents, agents that may form part of a medicament, including a solid dose form or a dry powder inhalation formulation, and other material necessary for specific drug delivery. Preferably, the facilitating agent is added during dry grinding. Preferably, the facilitating agent is added to dry milling at a time selected from the group consisting of: with 1-5% of the total milling time remaining, with 1-10% of the total milling time remaining, with 1-20% of the total milling time remaining, with 1-30% of the total milling time remaining, with 2-5% of the total milling time remaining, with 2-10% of the total milling time remaining, with 5-20% of the total milling time remaining, and with 5-20% of the total milling time remaining. Preferably, the disintegrant is selected from the group consisting of: crosslinked PVP, crosslinked carmellose, and sodium starch glycolate. Preferably, the facilitating agent is added to the milled biologically active material and milling matrix and further processed in a mechanofusion process. Mechanofusion milling causes mechanical energy to be applied to powders or particle mixtures in the micrometer and nanometer range.

Reasons for including facilitating agents include, but are not limited to, providing better dispersibility, agglomeration control, and the release or retention of active particles from the delivery matrix. Examples of facilitating agents include, but are not limited to, cross-linked PVP (crospovidone), cross-linked carmellose (croscarmellose), sodium starch glycolate, Povidone (PVP), Povidone K12, Povidone K17, Povidone K25, Povidone K29/32 and Povidone K30, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, sodium stearate or lithium stearate, other fatty acids in solid form such as oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid, or derivatives (such as esters and salts), amino acids such as leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspartame or acesulfame K. In a preferred aspect of manufacturing this formulation, the facilitating agent is added to the mixture. The biologically active material and grinding co-matrix are ground and further processed in another grinding device such as mechanofusion, cyclomixture, or impact grinding such as ball grinding, jet grinding, or grinding using a high-pressure homogenizer, or combinations thereof. In a highly preferred aspect, the facilitating agent is added to the grinding mixture of biologically active material and grinding co-matrix some time before the end of the grinding process.

In another preferred embodiment, diclofenac is milled with lactose monohydrate and alkyl sulfates. Preferably, diclofenac is milled with lactose monohydrate and sodium lauryl sulfate. Preferably, diclofenac is milled with lactose monohydrate and sodium octadecyl sulfate. In another preferred embodiment, diclofenac is milled with lactose monohydrate, alkyl sulfates, and another surfactant or polymer. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and polyether sulfates. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and polyethylene glycol 40 stearate. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and polyethylene glycol 100 stearate. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and a poloxamer. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and poloxamer 407. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and poloxamer 338. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and poloxamer 188. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and a solid polyethylene glycol. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and polyethylene glycol 6000. Preferably, diclofenac is milled with lactose monohydrate, sodium lauryl sulfate, and polyethylene glycol 3000. In another preferred embodiment, diclofenac is milled with lactose monohydrate and polyether sulfates. Preferably, diclofenac is milled with lactose monohydrate and polyethylene glycol 40 stearate. Preferably, diclofenac is milled with lactose monohydrate and polyethylene glycol 100 stearate. In another preferred embodiment, diclofenac is milled with lactose monohydrate and polyvinylpyrrolidine. Preferably, diclofenac is milled with lactose monohydrate and polyvinylpyrrolidone with an approximate molecular weight of 30,000-40,000. In another preferred embodiment, diclofenac is milled with lactose monohydrate and alkyl sulfonates. Preferably, diclofenac is milled with lactose monohydrate and sodium docusate. In another preferred embodiment, diclofenac is milled with lactose monohydrate and a surfactant. Preferably, diclofenac is milled with lactose monohydrate and lecithin. Preferably, diclofenac is milled with lactose monohydrate and sodium n-lauroyl sarcosine. Preferably, diclofenac is milled with lactose monohydrate and polyethylene alkyl ether surfactants. Preferably, diclofenac is milled with lactose monohydrate and PEG 6000. In another preferred formulation, diclofenac is milled with lactose monohydrate and silica. Preferably, diclofenac is milled with lactose monohydrate and colloidal silica Aerosil R972. In another preferred embodiment, diclofenac is milled with lactose monohydrate, tartaric acid, and sodium lauryl sulfate. In another preferred embodiment, diclofenac is milled with lactose monohydrate, sodium bicarbonate, and sodium lauryl sulfate. In another preferred embodiment, diclofenac is milled with lactose monohydrate, potassium bicarbonate, and sodium lauryl sulfate. In another preferred embodiment, diclofenac is milled with mannitol and alkyl sulfates. Preferably, diclofenac is milled with mannitol and sodium lauryl sulfate. Preferably, diclofenac is milled with mannitol and sodium octadecyl sulfate. In another preferred embodiment, diclofenac is milled with mannitol, alkyl sulfates, and another surfactant or polymer. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and polyether sulfates. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and polyethylene glycol 40 stearate. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and polyethylene glycol 100 stearate. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and a poloxamer. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and poloxamer 407. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and poloxamer 338. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and poloxamer 188. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and a solid polyethylene glycol. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and polyethylene glycol 6000. Preferably, diclofenac is milled with mannitol, sodium lauryl sulfate, and polyethylene glycol 3000. In another preferred embodiment, diclofenac is milled with mannitol and polyether sulfates. Preferably, diclofenac is milled with mannitol and polyethylene glycol stearate 40. Preferably, diclofenac is milled with mannitol and polyethylene glycol stearate 100. In another preferred embodiment, diclofenac is milled with mannitol and polyvinylpyrrolidine. Preferably, diclofenac is milled with mannitol and polyvinylpyrrolidone with an approximate molecular weight of 30,000-40,000. In another preferred embodiment, diclofenac is milled with mannitol and alkyl sulfonates. Preferably, diclofenac is milled with mannitol and sodium docusate. In another preferred embodiment, diclofenac is milled with mannitol and a surfactant. Preferably, diclofenac is milled with mannitol and lecithin. Preferably, diclofenac is milled with mannitol and sodium n-lauroyl sarcosine. Preferably, diclofenac is milled with mannitol and polyethylene alkyl ether surfactants. Preferably, diclofenac is milled with mannitol and PEG 6000. In another preferred formulation, diclofenac is milled with mannitol and silica. Preferably, diclofenac is milled with mannitol and colloidal silica Aerosil R972. In another preferred embodiment, diclofenac is milled with mannitol, tartaric acid, and sodium lauryl sulfate. In another preferred embodiment, diclofenac is milled with mannitol, sodium bicarbonate, and sodium lauryl sulfate. In another preferred embodiment, diclofenac is milled with mannitol, potassium bicarbonate, and sodium lauryl sulfate.

In a second aspect, the invention comprises a biologically active material produced by the method described herein and a composition comprising the biologically active material as described herein. Preferably, the average particle size, determined on a particle number basis, is equal to or smaller than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm. Preferably, the average particle size is equal to or greater than 25 nm. Preferably, the particles have an average particle size, determined on a particle volume basis, equal to or smaller than a size selected from the group consisting of: 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm. Preferably, the average particle size is equal to or greater than 25 nm. Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% smaller than 2000nm (% < 2000 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% smaller than 1000nm (% < 1000 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 500nm (% < 500 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 300nm (% < 300 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 200nm (% < 200 nm). Preferably, the Dx of the particle size distribution, as measured on a particle volume basis, is selected from the group consisting of less than or equal to 10,000 nm, 5,000 nm, 3,000 nm, 2,000 nm, 1,900 nm, 1,800 nm, 1,700 nm, 1,600 nm, 1,500 nm, 1,400 nm, 1,300 nm, 1,200 nm, 1,100 nm, 1,000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm; where x is greater than or equal to 90. Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of at least 50% crystalline material, at least 60% crystalline material, at least 70% crystalline material, at least 75% crystalline material, at least 85% crystalline material, at least 90% crystalline material, at least 95% crystalline material, and at least 98% crystalline material. Preferably, the crystallinity profile of the biologically active material is substantially the same as the crystallinity profile of the biologically active material before the material is subjected to the method described herein. Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous, and less than 2% of the biologically active material is amorphous. Preferably, the biologically active material did not have any significant increase in amorphous content after subjecting the material to the method as described herein.

In a preferred embodiment, the invention comprises compositions comprising the biologically active ingredient together with the grinding matrix, a mixture of grinding matrix materials, grinding aids, mixtures of grinding aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.

In a third aspect, the invention comprises a pharmaceutical composition comprising a biologically active material produced by the method described herein and compositions described herein. Preferably, the invention comprises pharmaceutical compositions comprising the biologically active ingredient together with the grinding matrix, a mixture of grinding matrix materials, grinding aids, mixtures of grinding aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention. Preferably, the average particle size of the biologically active material, determined on a particle number basis, is equal to or smaller than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm. Preferably, the average particle size is equal to or greater than 25 nm. Preferably, the particles have an average particle size, determined on a particle volume basis, equal to or smaller than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm. Preferably, the average particle size is equal to or greater than 25 nm. Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: less than 2000nm (% < 2000 nm) is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100%; less than 1000nm (% < 1000 nm) is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100%; less than 500nm (% < 500 nm) is selected from the group 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100%; Less than 300 nm (% < 300 nm) is selected from the group 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100%; and less than 200 nm (% < 200 nm) is selected from the group 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100%. Preferably, the composition has a lower Tmax than that of the equivalent conventional composition administered at the same dose, wherein the composition comprises diclofenac. Preferably, the composition has a higher Cmax than that of the equivalent conventional composition administered at the same dose, wherein the composition comprises diclofenac. Preferably, the composition has a higher AUC than that of the equivalent conventional composition administered at the same dose, wherein the composition comprises diclofenac.

In a fourth aspect, the invention comprises a method of treating a human in need of such treatment, comprising the step of administering to the human an effective amount of a pharmaceutical composition as described herein.

In a fifth aspect, the invention comprises the use of the pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of a human being in need of such treatment.

A sixth aspect of the invention comprises a method for manufacturing a pharmaceutical composition as described herein comprising the step of combining a therapeutically effective amount of a biologically active material prepared by a method described herein or a composition as described herein, together with a pharmaceutically acceptable carrier to produce a pharmaceutically acceptable dose form.

A seventh aspect of the invention comprises a method for manufacturing a veterinary product comprising the step of combining a therapeutically effective amount of the biologically active material prepared by a method as described herein or a composition as described herein, together with an acceptable excipient to produce a dose form acceptable for veterinary use.

In an eighth aspect, the invention comprises a method for manufacturing a pharmaceutical formulation comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation that can deliver a therapeutically effective amount of the active ingredient to the pulmonary or nasal area. Such a formulation could be, but is not limited to, a dry powder formulation for oral inhalation into the lungs or a formulation for nasal inhalation. Preferably, the method for manufacturing such a formulation uses lactose, mannitol, sucrose, sorbitol, xylitol, or other sugars or polyols as the milling co-matrix along with surfactants such as, but not limited to, lecithin, DPPC (dipalmitoyl phosphatidylcholine), PG (phosphatidylglycerol), dipalmitoyl phosphatidyl ethanolamine (DPPE), dipalmitoyl phosphatidylinositol (DPPI), or other phospholipids. The particle size of the material produced by the invention disclosed herein results in the materials being readily aerosolized and suitable for delivery methods to an individual in need thereof, including pulmonary and nasal delivery methods.

While the method of the present invention has particular application in the preparation of biologically active materials that are poorly soluble in water, the scope of the invention is not limited to this. For example, the method of the present invention allows the production of biologically active materials that are highly soluble in water. These materials may offer advantages over conventional materials through, for example, faster therapeutic action or a lower dose. In contrast, wet milling techniques using water (or other comparatively polar solvents) are inapplicable to such materials, as the particles dissolve significantly in the solvent.

Other aspects and advantages of the invention will become apparent to those skilled in the art upon reviewing the subsequent description.

Brief Description of the Drawings

Figure 1A. Powder charge composition and particle size distribution of the material ground in a SPEX mill, examples A to S.

Figure 1B. Powder charge composition and particle size distribution of material ground in a SPEX mill, examples T to AL.

Figure 1C. Powder charge composition and particle size distribution of material ground in a SPEX mill, examples AM to BE.

Figure 1D. Powder charge composition and particle size distribution of material ground in a SPEX mill, examples BF to BX.

Figure 1E. Powder charge composition and particle size distribution of material ground in a SPEX mill, examples BY to CQ.

Figure 1F. Powder charge composition and particle size distribution of material ground in a SPEX mill, examples CR to DJ.

Figure 1G. Powder charge composition and particle size distribution of material ground in a SPEX mill, examples DK to EC.

Figure 1H. The figure shows the X-ray diffraction patterns: (A) after grinding sodium naproxen in tartaric acid; (B) unground sodium naproxen and (C) unground naproxen acid.

Figure 2A. Powder charge composition and particle size distribution of the material ground in a 110mL HD01 friction mill, examples A to F.

Figure 3A. Powder filler composition and particle size distribution of the material containing a mixture of 2 matrices, ground in the SPEX mill, examples A to E.

Figure 4A. Powder charge composition and particle size distribution of the material ground in a 1L HD01 friction mill, examples A to G.

Figure 5A. Powder charge composition and particle size distribution of material ground in a 750mL 1S attrition mill, examples A to F.

Figure 6A. Powder charge composition and particle size distribution of material ground in a 1S % Gallon Friction mill, examples A to R.

Figure 6B. Powder charge composition and particle size distribution of material ground in a 1S % Gallon Friction Mill, examples S to AK.

Figure 6C. Powder charge composition and particle size distribution of material ground in a 1S Friction Mill of % Gallon, examples AL to AU.

Figure 7A. Powder feed composition and particle size distribution of Metaxalone milled in a variety of mills, examples A to O.

Figure 8A. Powder charge composition and particle size distribution of the material ground in a HICOM mill, examples A to P.

Figure 9A. Powder charge composition and particle size distribution of material ground in a 1% Gallon 1S Friction Mill, examples A to S.

Figure 9B. Powder charge composition and particle size distribution of material ground in a 1% Gallon 1S Friction Mill, examples T to AL.

Figure 10A. Powder charge composition and particle size distribution of the ground material in a variety of large-scale mills, examples A to F.

Figure 11A. Powder charge composition and particle size distribution of Naproxen Acid milled in Mannitol in a 1S % Gallon attrition mill, examples A to M.

Figure 12A. Powder feed composition and particle size distribution of Naproxen Acid milled in the SPEX mill and particle size distribution after filtration, examples A to L.

Detailed Description of the Invention General

Those skilled in the art will appreciate that the invention described herein is susceptible to modifications and variations beyond those specifically described. It should be understood that the invention includes all such modifications and variations. The invention also includes all steps, features, compositions, and materials referred to or indicated in the specification, individually or collectively, and any and all combinations of, or any two or more of, such steps or features.

The present invention should not be limited in scope by the specific embodiments described in this document, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein.

The invention described herein may include one or more ranges of values (e.g., size, concentration, etc.). A range of values shall be understood to include all values within the interval, including the values that define the range, and values adjacent to the range that lead to the same or substantially the same result as the values immediately adjacent to that value that defines the limit for the range.

The full disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited in this document are incorporated herein by reference. Inclusion does not constitute an admission that any of the references constitute prior art or are part of the common general knowledge of people working in the field to which this invention relates.

In all this specification, unless otherwise indicated, the word "comprises" or variations such as "comprises" or "comprising" shall be understood to suggest the inclusion of a stated whole number, or group of whole numbers, but not the exclusion of any other whole number or group of whole numbers. Note also that in this disclosure, and particularly in the claims and/or paragraphs, terms such as "comprises," "comprises," "comprising," and the like may have the meaning ascribed to them in U.S. Patent Law; for example, they may mean "includes," "included," "including," and so forth. "Therapeutically effective quantity," as used herein with respect to methods of treatment and in particular to drug dosage, shall mean the dose that provides the specific pharmacological response for which the drug is administered in a significant number of individuals in need of such treatment. It is emphasized that a "therapeutically effective amount" administered to a given individual in a specific case will not always be effective in treating the diseases described in this document, even if such a dose is considered a "therapeutically effective amount" by those skilled in the art. It should also be understood that drug doses are, in special cases, measured as oral doses, or with reference to drug levels as measured in the blood.

The term "inhibit" is defined to include its generally accepted meaning, which includes prohibition, prevention, immobilization, and reduction, halting or reversal of progression or severity, and such action on a resulting symptom. As such, the present invention includes both therapeutic and prophylactic medical administration, as appropriate.

The term "biologically active material" is defined to mean a biologically active compound or a substance comprising a biologically active compound. In this definition, a compound is generally taken to mean a distinct chemical entity where a chemical formula or formulas can be used to describe the substance. Such compounds are usually, but not necessarily, identified in the literature by a single classification system such as a CAS number. Some compounds may be more complex and have a mixed chemical structure. For such compounds, they may only have an empirical formula or be qualitatively identified. A compound would generally be a pure material, although it would be expected that up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the substance could be other impurities and the like. Examples of biologically active compounds are, but are not limited to, pharmaceutical actives, and analogues, homologues, and first-order derivatives thereof. A substance containing a biologically active compound is any substance that has as one of its components a biologically active compound. Examples of substances containing biologically active compounds include, but are not limited to, pharmaceutical formulations and products.

Any of the terms, "biologically active", "active", "active material" have the same meaning as biologically active material.

The term "grinding matrix" is defined as any inert substance that a biologically active material can or is combined with and ground. The terms "co-grinding matrix" and "matrix" are interchangeable with "grinding matrix".

Particle size

There is a wide variety of techniques that can be used to characterize the particle size of a material. Those versed in the technique also understand that almost all of these techniques do not physically measure the actual size of the particles, as one might measure something with a ruler, but rather measure a physical phenomenon, which is interpreted to indicate a particle size. As part of the interpretation process, some assumptions need to be made to allow the mathematical calculations to be performed. These assumptions yield results such as an equivalent spherical particle size, or a hydrodynamic radius.

Among these various methods, two types of measurements are most commonly used. Photon correlation spectroscopy (PCS), also known as "dynamic light scattering" (DLS), is commonly used to measure particles smaller than 10 microns. Typically, this measurement produces an equivalent hydrodynamic radius, often expressed as the average size of a distribution of numbers. The other common particle size measurement is laser diffraction, which is commonly used to measure the size of particles from 100 nm to 2000 microns. This technique calculates an equivalent volume distribution of spherical particles that can be expressed using descriptors such as the average particle size or the % of particles under a given size.

Those skilled in the art recognize that different characterization techniques such as photon correlation spectroscopy and laser diffraction measure different properties of a set of particles. As a result, various techniques will give various answers to the question: "what is the particle size?". In theory, one can convert and compare the various parameters that each technique measures; however, for real-world particle systems, this is not practical. As a result, the particle size used to describe this invention will be given as two different sets of values, each relating to these two common measurement techniques, such that measurements can be made with either technique and then evaluated against the description of this invention.

For measurements made using a photo-correlation spectroscopy instrument, or an equivalent method known in the art, the term "average particle size number" is defined as the average particle diameter, as determined on a number basis.

For measurements made with a laser diffraction apparatus, or an equivalent method known in the art, the term "average particle size" is defined as the average particle diameter as determined on a basis of equivalent spherical particle volume. Where the term average is used, it is understood to describe the particle size that divides the population in half such that 50% of the population is larger or smaller than this size. The average particle size is often written as D50, D(0.50) or D[0.5] or similar. As used herein, D50, D(0.50) or D[0.5] or similar should be taken to mean "average particle size".

The term "Dx of particle size distribution" refers to the xth percentile of the distribution; thus, D90 refers to the 90th percentile, D95 refers to the 95th percentile, and so on. Taking D90 as an example, this can often be written as D(0,90) or D[0,9] or similar. With respect to average particle size and Dx, an uppercase D or lowercase d are interchangeable and have the same meaning.

Another commonly used way to describe a particle size distribution measured by laser diffraction, or an equivalent method known in the art, is to describe what percentage of a distribution is under or above the indicated size. The term "percent less than," also written as "%<," is defined as the percentage, by volume, of a particle size distribution with a named size, for example, % < 1000 nm. The term "percent greater than," also written as "%>," is defined as the percentage, by volume, of a particle size distribution along a named size, for example, % > 1000 nm.

The particle size used to describe this invention should be understood as the size of the particles, measured at or shortly before the time of use. For example, the particle size is measured two months after the material is subjected to the grinding method of this invention. In a preferred embodiment, the particle size is measured at a time selected from the group consisting of: 1 day after grinding, 2 days after grinding, 5 days after grinding, 1 month after grinding, 2 months after grinding, 3 months after grinding, 4 months after grinding, 5 months after grinding, 6 months after grinding, 1 year after grinding, 2 years after grinding, 5 years after grinding.

For many of the materials subjected to the methods of this invention, the particle size can be easily measured. Where the active material has low water solubility and the matrix is ground into a powder with good water solubility, the powder can simply be dispersed in an aqueous solvent. In this scenario, the matrix dissolves, leaving the active material dispersed in the solvent. This suspension can be measured by techniques such as PCS or laser diffraction.

Suitable methods for measuring precise particle size where the active material has substantial water solubility or the matrix has low solubility in a water-based dispersant are described below. 1. In circumstances where the insoluble matrix, such as microcrystalline cellulose, impedes measurement, active material separation techniques such as filtration or centrifugation could be used to separate the insoluble matrix from the active material particles. Other auxiliary techniques would also be necessary to determine if any active material was removed by the separation technique so that this can be taken into account. 2. In cases where the active material is highly soluble in water, other solvents can be evaluated for particle size measurement. Where a solvent could be found that the active material is poorly soluble in, but is a good solvent for the matrix, a measurement would be relatively straightforward. If such a solvent is difficult to find, another approach would be to measure the matrix and active material together in a solvent (such as isooctanes) that are both insoluble. Then the powder would be measured in another solvent, where the active material is soluble, but the matrix is not. Thus, with a measurement of the particle size of the matrix and a measurement of the size of the matrix and active material together, an understanding of the particle size of the active material can be obtained. 3. In some circumstances, image analysis could be used to obtain information about the particle size distribution of the active material. Suitable image measurement techniques may include transmission electron microscopy (TEM), scanning electron microscopy (SEM), optical microscopy, and confocal microscopy. In addition to these standard techniques, some additional technique would need to be used in parallel to differentiate the active material and matrix particles. Depending on the chemical composition of the materials involved, possible techniques could be elemental analysis, Raman spectroscopy, FTIR spectroscopy, and fluorescence spectroscopy.

Other definitions

Throughout this specification, unless the context requires otherwise, the phrase "dry mill" or variations such as "dry grinding" should be understood to refer to grinding in at least the substantial absence of liquids. If liquids are present, they are present in quantities such that the contents of the mill retain the characteristics of a dry powder.

"Flowable" means a powder with physical characteristics that make it suitable for further processing using typical equipment used for the manufacture of pharmaceutical compositions and formulations.

Other definitions for the selected term used herein can be found in the detailed description of the invention and apply throughout the document. Unless otherwise indicated, all other scientific and technical terms used herein have the same meaning as commonly understood by a person skilled in the art to which the invention pertains.

The term "millable" means that the grinding matrix is capable of being physically degraded under the dry grinding conditions of the invention method. In one embodiment of the invention, the ground grinding matrix is of a particle size similar to the biologically active material. In another embodiment of the invention, the particle size of the matrix is substantially reduced, but not as small as the biologically active material.

Other definitions for the selected terms used herein can be found in the detailed description of the invention and applied throughout the document. Unless otherwise indicated, all other scientific and technical terms used herein have the same meaning as commonly understood by a person skilled in the art to which the invention pertains.

Specific

In one embodiment, the present invention is directed to a method for producing a composition, comprising the steps of: dry grinding a solid biologically active material and a grindable grinding matrix in a mill comprising a plurality of grinding media, for a period of time sufficient to produce particles of the biologically active material dispensed in at least one partially ground grinding material.

The mixture of active material and matrix can then be separated from the grinding media and removed from the mill.

In one aspect, the mixture of active material and matrix is then further processed. In another aspect, the milled matrix is separated from the particles of the biologically active material. In a further aspect, at least a portion of the milled matrix is separated from the particulate biologically active material.

Grinding media are essentially resistant to fracture and erosion in the dry grinding process. The quality of the grinding matrix, in relation to the amount of biologically active material in particulate form, and the grinding extent of the grinding matrix, is sufficient to inhibit the re-agglomeration of the active material particles.

The present invention also relates to biologically active materials produced by said methods, to medicaments produced using said biologically active material, and to methods of treating an animal, including humans, using the therapeutically effective amount of said biologically active material administered by means of said medicaments.

Commercial Scale

The present invention relates to the unexpected discovery that particles of a biologically active material can be produced by dry milling processes as described herein on a commercial scale. In one surprising aspect, the particle size produced by the process is equal to or less than 2000 nm. In another surprising aspect, the particle size produced by the process is equal to or less than 1000 nm. This can result in a more efficient and cost-effective process.

One of the main objectives in reducing manufacturing costs is encapsulating nanoparticles in materials that do not need to be removed. This allows for a simple manufacturing process where conventional formulation technologies can be used to progress the encapsulated matrix nanoparticles directly into a final product. In order to do this, the material used within the matrix must be acceptable to industry regulators. In some cases, materials may be acceptable for use, but only in limited quantities. Another aspect of matrix choice is functionality. Some matrices that produce good encapsulated nanoparticles may be acceptable from a safety standpoint, but these materials may limit the manufacturing of a dosage form such as a tablet.

Improved dissolution profile

The process results in biologically active material having an improved dissolution profile. An improved dissolution profile has significant advantages, including improved bioavailability of the biologically active material in vivo. Preferably, the improved dissolution profile is observed in vitro. Alternatively, the improved dissolution profile is observed in vivo by observing a better bioavailability profile. Standard methods for determining the dissolution profile of a material in vitro are available in the art. A suitable method for determining an improved dissolution profile in vitro might include determining a concentration of the sample material in a solution over a period of time and comparing the results from the sample material to a control sample. An observation that the peak solution concentration for the sample material was reached in less time than the control sample would indicate (assuming it is statistically significant) that the sample material has an improved dissolution profile. The measurement sample is defined here as the mixture of the biologically active material with the milling matrix and/or other additives, which have been subjected to the invention processes described herein. A control sample is defined here as a physical mixture (not subjected to the processes described in the present invention) of the components in the measurement sample with the same relative proportions of actives, matrix and/or additive as the measurement sample. For dissolution testing purposes, a prototype formulation of the measurement sample may also be used. In this case, the control sample would be formulated in the same way. Standard methods for determining the enhanced dissolution profile of a material in vivo are available in the art. A suitable method for determining an enhanced dissolution profile in a human may be, after delivering the dose, to measure the absorption rate of the active material by measuring the plasma concentration of the sample compound over a period of time and comparing the results from the sample compound to a control. An observation that the peak plasma concentration for the sample compound was reached in less time than the control could indicate (assuming it is statistically significant) that the sample compound has improved bioavailability and an improved dissolution profile. Preferably, the improved dissolution profile is observed at a gastrointestinally relevant pH when observed in vitro. Preferably, the improved dissolution profile is observed at a pH that is favorable to indicating improvements in dissolution when compared to the measurement sample for the control compound. Suitable methods for quantifying the concentration of a compound in an in vitro or in vivo sample are widely available in the art. Suitable methods could include the use of spectroscopy or radioisotope labeling. In a preferred embodiment, the method of quantifying dissolution is determined in a solution with a pH selected from the group consisting of: pH 1, pH 2, pH 3, pH 4, pH 5, pH 6, pH 7, pH 7.3, pH 7.4, pH 8, pH 9, pH 10, pH 11, pH 12, pH 13, pH 14 or a pH with 0.5 of a pH unit from any of these groups.

Crystallization Profile

Methods for determining the crystallinity profile of biologically active material are widely available in the art. Suitable methods may include X-ray diffraction, differential scanning calorimetry, Raman or IR spectroscopy.

Profile of Amorficity

Methods for determining the amorphous content of biologically active material are widely available in the art. Suitable methods may include X-ray diffraction, differential scanning calorimetry, Raman or IR spectroscopy.

Grinding die

As will be described later, the selection of a suitable grinding die offers advantageous applications of the method of the present invention.

A highly advantageous application of the invention's method is the use of a water-soluble grinding matrix in conjunction with a poorly water-soluble biologically active material. This provides at least two advantages. The first is that when the powdered biologically active materials are placed in water – such as ingestion of the powder as part of an oral medication – the matrix dissolves, releasing the active particulate material in such a way that there is maximum surface area exposed to a solution, thus allowing rapid dissolution of the active compound. The second key advantage is the ability, if necessary, to remove or partially remove the matrix before further processing or formulation.

Another advantageous application of the invention's method is the use of a water-insoluble grinding matrix, especially in the area of agricultural use, where a biologically active material such as a fungicide is commonly delivered as part of a dry powder or suspension. The presence of a water-insoluble matrix will provide benefits such as increased rain resistance.

Without wishing to commit to the theory, it is believed that the physical degradation (including, but not limited to, a reduction in particle size) of the moifiable grinding matrix offers the advantage of an invention, acting as a more effective diluent than a grinding matrix of a large particle size.

Once again, as will be described later, a highly advantageous aspect of the present invention is that certain grinding matrices suitable for use in the method of an invention are also suitable for use in a medicament. The present invention encompasses methods for producing a medicament incorporating both the biologically active material and the grinding matrix or, in some cases, a biologically active material and a portion of the grinding matrix, the medicaments produced, and methods of treating an animal, including humans, using a therapeutically effective amount of said biologically active material by means of said medicaments.

Similarly, as will be described subsequently, a highly advantageous aspect of the present invention is that certain grinding matrices suitable for use in the method of the invention are also suitable for use in a carrier for an agricultural chemical, such as a pesticide, fungicide, or herbicide. The present invention encompasses methods for producing an agricultural chemical composition incorporating both the biologically active material in particulate form and the grinding matrix, or in some cases the biologically active material and a portion of the grinding matrix, and agricultural chemical compositions thus produced. The medicament may include only the biologically active material together with the ground grinding matrix or, more preferably, the biologically active material and the ground grinding matrix may be combined with one or more pharmaceutically acceptable carriers, as well as any desired excipient or other similar agents commonly used in the preparation of medicaments.

Similarly, the agricultural chemical composition may include only the biologically active material along with the ground matrix or, more preferably, the biologically active material and the ground matrix may be combined with one or more carriers, as well as any desired excipient or other similar agents commonly used in the preparation of agricultural chemical compositions.

In a particular embodiment of the invention, a grinding matrix is suitable for use in a medicament and easily separable from the biologically active material by methods that do not depend on particle size. Such grinding matrices are described in the following detailed description of the invention. Such grinding matrices are highly advantageous insofar as they offer significant flexibility in that a grinding matrix can be incorporated into the biologically active materials in a medicament.

In a highly preferred form, a grinding matrix is harder than the biologically active material, and is thus able to reduce the particle size of the active material under the dry grinding conditions of the invention. Again, without wishing to commit to theory, under these circumstances, it is believed that the moifiable grinding matrix offers the advantage of the present invention through a second route, with the smaller particles of the grinding matrix produced under dry grinding conditions allowing for greater interaction with biologically active materials.

The quality of the grinding matrix in relation to the quantity of biologically active material, and the extent of physical degradation of the grinding matrix, is sufficient to inhibit the re-agglomeration of the active material particles. Preferably, the quality of the grinding matrix in relation to the quantity of biologically active material, and the extent of physical degradation of the grinding matrix, is sufficient to inhibit the re-agglomeration of the active material particles in nanoparticulate form. The grinding matrix is generally not selected to be chemically reactive with the biologically active material under the grinding conditions of the invention, except, for example, where the matrix is deliberately chosen to undergo a mechanochemical reaction. Such a reaction may be the conversion of a free base or acid to a salt or vice versa.

As stated above, the method of the present invention requires that a grinding matrix be ground with biologically active materials, i.e., a grinding matrix physically degrade under the dry grinding conditions of the invention to facilitate the retention and formation of particulates of the biologically active material with reduced particle size. The precise extent of degradation required will depend on certain properties of a grinding matrix and the biologically active material, the ratio of biologically active material to grinding matrix, and the particle size distribution of the particles comprising the biologically active material.

The physical properties of a grinding matrix required to achieve the necessary degradation are dependent on the precise grinding conditions. For example, a harder grinding matrix may degrade sufficiently provided it is subjected to more vigorous dry grinding conditions.

The physical properties of a grinding matrix relevant to the extent that the agent will degrade under dry grinding conditions include hardness, friability, as measured by indicators such as hardness, fracture toughness, and brittleness index.

A low hardness (typically a Mohs hardness less than 7) of the biologically active material is desirable to ensure particle fracture during processing, so that composite microstructures develop during grinding. Preferably, the hardness is less than 3, as determined using the Mohs hardness scale.

Ideally, a grinding matrix should have low abrasiveness. Low abrasiveness is desirable to minimize contamination of the biologically active material mixture in a grinding matrix by the grinding media and/or grinding chamber of the mill medium. An indirect indication of abrasiveness can be obtained by measuring the level of contaminants based on grinding.

Ideally, a grinding matrix has a low tendency to agglomerate during dry grinding. While it is difficult to objectively quantify the tendency to agglomerate during grinding, it is possible to obtain a subjective measure by observing the level of "agglomeration" of a grinding matrix in the grinding bodies and grinding chamber of the middle of the mill as dry grinding progresses.

The grinding matrix can be an organic or inorganic substance.

In one embodiment, the milling matrix is selected from the following, either as a single substance or a combination of two or more substances: Polyols (sugar alcohols) for example (but not limited to) mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol; monosaccharides for example (but not limited to) glucose, fructose, mannose, galactose; disaccharides and trisaccharides for example (but not limited to) anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose; polysaccharides for example (but not limited to) maltodextrins, dextrin, inulin, dextrates, polydextrose; other carbohydrates for example (but not limited to) starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, flours and other starches, soy flour, soy bran or other soy products, cellulose, microcrystalline cellulose, co-mixed excipients based on microcrystalline cellulose, chemically modified excipients such as pre-gelatinized (or partially) starch, modified cellulose such as HPMC, CMC, HPC, enteric polymer coatings such as hypromellose phthalate, cellulose acetate phthalate (Aquacoat®), polyvinyl acetate phthalate (Sureteric®), hypromellose acetate succinate (AQOAT®), and polymethacrylates (Eudragit® and Acryl-EZE®), milk products for example (but not limited to) milk powders, skimmed milk powders, other milk solids and dehydrated milk, other functional excipients, organic acids for example (but not limited to) citric acid, tartaric acid, malic acid, fumaric acid, acid maleic acid, ascorbic acid, succinic acid, conjugate salts of organic acids, for example (but not limited to) sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, potassium ascorbate, inorganic acids such as sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, and... dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulfite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potassium alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates, alkali metal hydrogen carbonates of pharmaceutically acceptable products, such as, but not limited to, sodium, potassium, lithium, calcium, barium and ammonium salts (or volatile amine salts), for example (but not limited to) ammonium chloride, methylamine hydrochloride, ammonium bromide, other inorganics for example (but not limited to), thermal silica, chalk, mica, silica, alumina, titanium dioxide, talc, kaolin, bentonite, hectorite, trisilicate of magnesium, clay or other clay derivatives or aluminum silicates, a surfactant, for example (but not limited to) sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, sodium salt of N-lauroylsarcosine, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, stearyl polyoxyl ether 100, stearyl polyoxyl ether 20, stearyl polyoxyl ether 10, cetyl polyoxyl ether 20, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl castor oil 35, polyoxyl castor oil 40, polyoxyl castor oil 60, polyoxyl castor oil 100, polyoxyl castor oil 200, hydrogenated polyoxyl castor oil 40, hydrogenated polyoxyl castor oil 60, hydrogenated polyoxyl castor oil 100, hydrogenated polyoxyl castor oil 200, cetostearyl alcohol, macrogel 15 hydroxystearate, Sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycolic acid, sodium glycolate, cholic acid, sodium cholate, sodium deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic acid, sodium taurodeoxycholate, deoxycholic tauroacid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate/lignosulfonate condensate mixture, calcium dodecylbenzene sulfonate, sulfonate Sodium Dodecylbenzene, Diisopropyl Naphthalenesulfonate, Erythritol Distearate, Naphthalene Sulfonate Formaldehyde Condensate, Nonylphenol Ethoxylate (POE-30), Tristyrylphenol Ethoxylate, Polyoxyethylene Tallowalkylamines (15), Sodium Alkyl Naphthalene Sulfonate, Sodium Alkyl Naphthalene Sulfonate Condensate, Sodium Alkylbenzene Condensate, Sodium Isopropyl Naphthalene Sulfonate, Sodium Methyl Naphthalene Sulfonate, Sodium n-Butyl Naphthalene Sulfonate, Tridecyl Alcohol Ethoxylate (POE-18), Trieranolamine Isodecanol Phosphate Ester, Trieranolamine Tristyryl Phosphate Ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2- hydroxyethyl)tallowalkylamines.

In a preferred embodiment, the grinding matrix is a matrix that is considered GRAS (Generally Recognized as Safe) by persons skilled in pharmaceutical techniques.

In another preferred aspect, a combination of two or more suitable matrices, such as those listed above, can be used as a milling matrix to provide improved properties, such as reduced clumping and greater improvement in the dissolution profile. The combination of matrices can also be advantageous when the matrices have different solubilities, allowing the removal or partial removal of one matrix, leaving the other or part of the other to provide encapsulation or partial encapsulation of the biologically active material.

Another highly preferred aspect of the method is the inclusion of a suitable grinding aid in the die to improve grinding performance. Improvements in grinding performance would include, but are not limited to, a reduction in clumping or superior powder recovery from the mill. Examples of suitable grinding aids include surfactants, polymers, inorganics such as silica (including colloidal silicas), aluminum silicates, and clays.

There is a wide range of surfactants that will make suitable grinding aids. The highly preferred form is where the surfactant is a solid, or can be manufactured into a solid. Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine-based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, polyalkyl and aryl ether sulfates and other sulfate surfactants, trimethylammonium-based surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters, alkylbenzene sulfonic acids, alkyl ether carboxylic acids, esters of Alkyl and Aryl Phosphate, Alkyl and Aryl Sulfate Esters, Alkyl and Aryl Sulphonic Acids, Alkyl Phenol Phosphate Esters, Alkyl Phenol Sulfate Esters, Alkyl and Aryl Phosphates, Alkyl Polysaccharides, Alkylamine Ethoxylates, Formaldehyde Condensates of Alkyl Phenol Sulfonates Alkyl-Naphthalene, Sulfosuccinates, lignosulfonates, Keto-Oleyl Alcohol Ethoxylates, Condensed Naphthalene Sulfonates, Dialkyl and Alkyl Naphthalene Sulfonates, Di-alkyl Sulfosuccinates, Ethoxylated Noniphenols, Ethylene Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated tallowalkylamines, Mono-alkyl Sulfosuccinates, Nonylphenol Ethoxylates, Sodium N-methyl oleyl taurate, Tallowalkylamines, linear or branched dodecylbenzene sulfonic acids.

Preferably, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, sodium salt of N-lauroylsarcosine, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407, polyoxyl 2 stearyl ether, stearyl ether polyoxyl 100, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, monopalmiate of Sorbitan, sorbitan monostearate, sorbitan trioleate, sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycolic acid, sodium glycolate, cholic acid, sodium cholate, sodium deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic acid, sodium taurodeoxycholate, deoxycholic tauroacid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate/lignosulfonate condensate mixture, calcium dodecylbenzene sulfonate, dodecylbenzene sulfonate Sodium, Diisopropyl Naphthalenesulfonate, Erythritol Distearate, Naphthalene Sulfonate Formaldehyde Condensate, Nonylphenol Ethoxylate (POE-30), Tristyrylphenol Ethoxylate, Polyoxyethylene Tallowalkylamines (15), Sodium Alkyl Naphthalene Sulfonate, Sodium Alkyl Naphthalene Sulfonate Condensate, Sodium Alkylbenzene Condensate, Sodium Isopropyl Naphthalene Sulfonate, Sodium Methyl Naphthalene Sulfonate, Sodium n-Butyl Naphthalene Sulfonate, Tridecyl Alcohol Ethoxylate (POE-18), Trieranolamine Isodecanol Phosphate Ester, Trieranolamine Tristyryl Phosphate Ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2- hydroxyethyl)tallowalkylamines.

Preferably, the polymer is selected from the list of: polyvinylpyrrolidones (PVP), polyvinyl alcohols, acrylic acid-based polymers, and acrylic acid copolymers.

Preferably, the grinding aid has a concentration selected from the group consisting of: 0.1 - 10% w/w, 0.1 - 5% w/w, 0.1 - 2.5% w/w, of 0.1 - 2% w/w, 0.1 - 1%, 0.5 - 5% w/w, 0.5 - 3% w/w, 0.5 - 2% w/w, 0.5 - 1.5%, 0.5 - 1% w/w, of 0.75 - 1.25% w/w, 0.75 - 1% and 1% w/w.

Grinding bodies

In the method of the present invention, the grinding media are preferably chemically inert and rigid. The term "chemically inert," as used herein, means that the grinding media do not react chemically with the biologically active material or a grinding matrix.

As described above, grinding media are essentially resistant to fracture and erosion during the grinding process.

Grinding bodies are desirably provided in the form of bodies that may have any of a variety of smooth, regular shapes, flat or curved surfaces, and without sharp or raised edges. For example, suitable grinding bodies may be in the form of bodies having ellipsoidal, ovoid, spherical, or right cylindrical shapes. Preferably, grinding bodies are provided in the form of one or more beads, balls, spheres, rods, right cylinders, drums, or right end-radius cylinders (i.e., right cylinders having hemispherical bases with the same radius as the cylinder).

Depending on the nature of the biologically active material and grinding matrix, the grinding media bodies desirably have an effective average particle diameter (i.e., "Particle size") between about 0.1 and 30 mm, more preferably between about 1 and about 15 mm, even more preferably between about 3 and 10 mm.

Grinding media can include various substances, such as ceramics, glass, metal, or polymeric compositions, in particle form. Suitable metal grinding media are typically spherical and generally have good hardness (i.e., RHC 60-70), circularity, high wear resistance, and a narrow size distribution. They may include, for example, balls manufactured from type 52100 chrome steel, or type 316 or 440C stainless steel, or type 1065 high carbon steel.

Preferred ceramics, for example, can be selected from a wide range of ceramics desirably having sufficient hardness and fracture resistance to prevent chipping or crushing during grinding, and also having sufficiently high densities. Suitable densities for grinding media can range from about 1-15 g/cm3, preferably from about 1-8 g/cm3. Preferred ceramics can be selected from steatite, aluminum oxide, zirconium oxide, zirconia-silica, yttrium-stabilized zirconium oxide, magnesium-stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, and the like, as well as mixtures thereof.

Preferred glass grinding media are spherical (e.g., beads), have a narrow size distribution, are durable, and include, for example, lead-free soda-lime glass and borosilicate glass. Polymeric grinding media are preferably and substantially spherical and can be selected from a wide range of polymeric resins having sufficient hardness and friability to enable them to avoid chipping or crushing during grinding, abrasion resistance to minimize friction resulting in product contamination, and freedom from impurities such as metals, solvents, and residual monomers.

Preferred polymeric resins, for example, can be selected from cross-linked polystyrenes, such as polystyrene cross-linked with divinylbenzene, styrene copolymers, polyacrylates such as polymethyl methacrylate, polycarbonates, polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides, high-density polyethylenes, polypropylenes, and so forth. The use of polymeric grinding media to grind the materials to a very small particle size (as opposed to mechanochemical synthesis) is disclosed, for example, in U.S. patents 5,478,705 and 5,500,331. Polymeric resins typically have densities ranging from about 0.8 to 3.0 g/cm3. Polymeric resins of higher densities are preferred.

Alternatively, the grinding medium may be composite particles comprising core particles having a polymeric resin bonded thereto. The core particles may be selected from substances known to be useful as grinding media, for example, glass, alumina, zirconia silica, zirconium oxide, stainless steel, and the like. Preferred core substances have densities greater than about 2.5 g/cm3.

In one embodiment of the invention, the grinding medium is formed from a ferromagnetic substance, thus facilitating the removal of contaminants resulting from wear of the grinding medium through the use of magnetic separation techniques.

Each type of grinding media has its own advantages. For example, metals have the highest specific gravity, which increases grinding efficiency due to higher impact energy. Metal costs range from low to high, but metal contamination of the final product can be a problem. Glasses are advantageous from the point of view of low cost and the availability of beads as small as 0.004 mm. However, the specific gravity of glasses is lower than other media and significantly more grinding time is required. Finally, ceramics are advantageous from the point of view of low wear and contamination, ease of cleaning, and high hardness.

Dry Milling

In the dry grinding process of the present invention, the biologically active material and grinding matrix, in the form of crystals, powders, or the like, are combined in suitable proportions with a plurality of grinding media in a grinding chamber that is mechanically agitated (i.e., with or without agitation) for a predetermined period of time at a predetermined agitation intensity. Typically, a grinding apparatus is used to impart motion to the grinding media by the external application of agitation, wherein various translational, rotational, or inversional motions, or combinations thereof, are applied to the grinding chamber and its contents, or by the internal application of agitation through a rotating shaft terminating in a blade, rotor propeller, or paddle, or by a combination of both actions.

During grinding, the motion transmitted to the grinding media can result in the application of shear forces, as well as multiple impacts or collisions with significant intensity between the grinding media and the particles of the biologically active material and the grinding matrix. The intensity and nature of the forces applied by the grinding media to the biologically active material and the grinding matrix are influenced by a wide variety of processing parameters, including: the type of grinding apparatus, the intensity of the forces generated, the kinematic aspects of the process, the size, density, shape and composition of the grinding media, the weight ratio of the biologically active material and grinding matrix mixture to the grinding media; the duration of grinding; the physical properties of both the biologically active materials and the grinding matrix, the atmosphere present during activation, and others.

Advantageously, the grinding media is capable of repeatedly or continuously applying mechanical compression forces and shear stress to the biologically active material and grinding matrix. Suitable grinding media include, but are not limited to, the following: high-energy ball mills, sand, bead or pearl mills, basket mills, planetary mills, vibratory action ball mills, multi-axial agitator/mixer, stirred ball mill, horizontal small media mill, multi-ring pulverizing mill, and the like, including small grinding media. The grinding apparatus may also contain one or more rotating shafts.

In a preferred embodiment of the invention, dry grinding is performed in a ball mill. Throughout the remainder of the specification, reference will be made to dry grinding being performed by means of a ball mill. Examples of this type of mill are attrition mills, nutation mills, tower mills, planetary mills, vibratory mills, and gravity-dependent ball mills. It will be appreciated that dry grinding with the second method of the invention can also be achieved by any suitable means other than ball grinding. For example, dry grinding can also be achieved using jet mills, rod mills, roller mills, or crusher mills.

Biologically active material

Biologically active material includes active compounds, including compounds for veterinary and human use such as, but not limited to, pharmaceutical actives, and the like.

Biologically active material is commonly a material for which a person skilled in the art desires enhanced dissolution properties. Biologically active material can be a conventional active agent or drug, although the process of the invention can be employed in formulations or agents that have already reduced particle size compared to conventional forms. Suitable biologically active materials for use in the invention include diclofenac.

As discussed in the background of the invention, biologically active materials that are poorly soluble in water at gastrointestinal pH will especially benefit from being prepared, and the method of the present invention is particularly advantageously applied to materials that are poorly soluble in water at gastrointestinal pH.

Conveniently, the biologically active material is able to withstand temperatures that are typical in uncooled dry milling, which can exceed 80°C. Therefore, materials with melting points of around 80°C or higher are highly suitable. For biologically active materials with lower melting points, the milling medium can be cooled, allowing materials with significantly lower melting temperatures to be processed according to the method of an invention. For example, a simple water-cooled mill will maintain the temperature below 50°C, or chilled water could be used to further reduce the milling temperature. Those skilled in the art will understand that a high-energy ball mill could be designed to run at any temperature between the aforementioned -30 to 200°C. For some biologically active materials, this can be advantageous for controlling the milling temperature at temperatures significantly below the melting point of the biologically active material.

The biologically active material is obtained conventionally commercially and/or prepared using techniques known in the state of the art.

It is preferable, but not essential, that the particle size of the biologically active material be less than about 1,000 μm, as determined by particle size analysis. If the coarse particle size of the biologically active material is greater than about 1,000 μm, then it is preferred that the substrate of the biologically active material particles be reduced in size to less than 1,000 μm using another standard grinding method.

Processed biologically active material

Preferably, the biologically active materials that have been subjected to the methods of the invention comprise particles of the biologically active material with an average particle size, determined on a particle number basis, equal to or less than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm.

Preferably, the biologically active materials that have been subjected to the methods of the invention comprise particles of the biologically active material with an average particle size, determined on a particle volume basis, equal to or smaller than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm.

Preferably, the biologically active materials that have been subjected to the methods of the invention comprise particles of biologically active material wherein the Dx of the particle size distribution, as measured on a particle volume basis, is selected from the group consisting of being less than or equal to 10,000nm, 5,000nm, 3,000nm, 2,000nm, 1,900nm, 1,800nm, 1,700nm, 1,600nm, 1,500nm, 1,400nm, 1,300nm, 1,200nm, 1,100nm, 1,000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, 300nm, 200nm and 100nm; where x is greater than or equal to 90.

These sizes refer to particles that are either fully dispersed or partially agglomerated.

Clusters of biologically active material after processing

The agglomerates comprising the particles of the biologically active material, said particles having a particle size within the limits specified above, shall be understood to fall within the scope of the present invention, regardless of whether the agglomerates exceed the limits specified above.

The agglomerates comprising the particles of the biologically active material, said agglomerates having a total agglomerate size within the limits specified above, shall be understood to fall within the scope of the present invention.

Agglomerates comprising particles of the biologically active material shall be understood to fall within the scope of the present invention if, at the time of use or further treatment, the particle size of the agglomerate is within the limits specified above.

The agglomerates comprising the particles of the biologically active material, said particles having a particle size within the limits specified above, at the time of use, or for further treatment, shall be understood to fall within the scope of the present invention, regardless of whether the agglomerates exceed the ranges specified above.

Processing Time

Ideally, the biologically active material and the grinding matrix are dry-ground for the shortest time necessary to form a mixture of the biologically active material in a grinding matrix so that the active material improves dissolution to minimize any possible contamination of the mill media and/or the plurality of grinding bodies. This time varies greatly depending on the biologically active material and grinding matrix, and can range from as short as 1 minute to several hours. Dry-grinding times exceeding 2 hours can lead to degradation of the biologically active material and an increase in the level of undesirable contaminants.

Appropriate agitation rates and total grinding times are adjusted for the size and type of grinding apparatus as well as the grinding medium, the weight ratio of the biologically active material and the grinding matrix mixture for the plurality of grinding bodies, the physicochemical properties of the biologically active material and the grinding matrix, and other parameters that can be empirically optimized.

Inclusion of a grinding matrix with the biologically active material and separation of the grinding matrix from the biologically active material.

In a preferred aspect, the grinding matrix is not separated from the biologically active material but is retained with the biologically active material in the final product. Preferably, the grinding matrix is considered to be Generally Considered Safe (GRAS) for pharmaceutical products.

In an alternative aspect, the grinding matrix is separated from the biologically active material. In another aspect, where the grinding matrix is not completely ground, the unground grinding matrix is separated from the biologically active material. In a further aspect, at least a portion of the ground grinding matrix is separated from the biologically active material.

Any portion of the grinding matrix may be removed, including but not limited to 10%, 25%, 50%, 75%, or substantially the entire grinding matrix.

In some embodiments of the invention, a significant portion of the ground matrix may comprise particles of a similar size to and/or smaller than the particles comprising the biologically active material. Where the portion of the ground matrix to be separated from the particles of the biologically active material comprises particles of a similar size to and/or smaller than the particles comprising the biologically active material, separation techniques based on size distribution are inapplicable.

Under these circumstances, the method of the present invention may involve separating at least a portion of the ground matrix from the biologically active material by means of techniques including but not limited to electrostatic separation, magnetic separation, centrifugation (density separation), hydrodynamic separation, flotation.

Advantageously, the step of removing at least a portion of the ground matrix of biologically active material can be accomplished through means such as selective dissolution, washing, or sublimation.

One advantageous aspect of the invention would be the use of a grinding matrix that has two or more components, where at least one component is water-soluble and at least one component has low water solubility. In this case, washing can be used to remove the water-soluble matrix component, leaving the biologically active material encapsulated in the remaining matrix components. In a highly advantageous aspect of the invention, the matrix with low solubility is a functional excipient.

A highly advantageous aspect of the present invention is that certain grinding matrices suitable for use in the method of the invention (wherein they physically degrade to the desired extent under dry grinding conditions) are also pharmaceutically acceptable and therefore appropriate for use in a medicament. Where the method of the present invention does not involve the complete separation of a grinding matrix from the biologically active material, the present invention encompasses methods for producing a medicament incorporating both biologically active material and at least a portion of the ground grinding matrix, the medicaments thus produced, and methods of treating an animal, including humans, using a therapeutically effective amount of said biologically active material by means of said medicaments.

The medicament may include only the biologically active material and the milling matrix or, more preferably, the biologically active material and milling matrix may be combined with one or more pharmaceutically acceptable carriers, as well as any desired excipient or other similar agents commonly used in the preparation of medicaments.

Similarly, a highly advantageous aspect of the present invention is that certain grinding matrices suitable for use in the method of the invention (in which they physically degrade to a desired extent under dry grinding conditions) are also suitable for use in an agricultural chemical composition. Where the method of the present invention does not involve the complete separation of a grinding matrix from the biologically active material, the present invention encompasses methods for producing the agricultural chemical composition incorporating both the biologically active material and at least a portion of the ground grinding matrix, the agricultural chemical composition thus produced, and methods of using such compositions.

The composition of an agricultural chemical product may include only the biologically active material and the grinding matrix or, more preferably, the biologically active material and grinding matrix may be combined with one or more acceptable carriers, as well as any desired excipient or other similar agents commonly used in the preparation of agricultural chemical product compositions.

In a particular embodiment of the invention, a grinding matrix is suitable for use in a medicament and easily separable from the biologically active material by methods that do not depend on particle size. Such grinding matrices are described in the following detailed description of the invention. Such grinding matrices are highly advantageous insofar as they offer significant flexibility in that a grinding matrix can be incorporated with biologically active materials in a medicament.

The mixture of biologically active material and grinding matrix can then be separated from the grinding media and removed from the mill.

In one embodiment, the grinding matrix is separated from the mixture of the biologically active material and grinding matrix. Where the grinding matrix is not completely ground, the unground grinding matrix is separated from the biologically active material. In a further aspect, at least a portion of the ground grinding matrix is separated from the biologically active material.

The grinding media are essentially resistant to fracture and erosion in the dry grinding process.

The quality of the grinding matrix in relation to the quantity of biologically active material, and the grinding extent of the grinding matrix, is sufficient to provide a reduced particle size of the biologically active material.

The grinding matrix is neither chemically nor mechanically reactive with the pharmaceutical material under the dry grinding conditions of the invention method, except, for example, where the matrix is deliberately chosen to undergo a medico-chemical reaction. Such a reaction could be the conversion of a free base or acid to a salt or vice versa.

Preferably, the medication is in a solid dose form; however, other dose forms may be prepared by those skilled in the art.

In one embodiment, after the step of separating said mixture of biologically active material and grinding matrix from the plurality of grinding bodies, and before the step of using said mixture of biologically active material and grinding matrix in the manufacture of a medicament, the method may comprise the step of: removing a portion of a grinding matrix from said mixture of biologically active material and grinding matrix to provide a mixture enriched in the biologically active material; and a step of using said mixture of biologically active material and grinding matrix in the manufacture of a medicament, more particularly comprising the step of using the mixture of biologically active material and enriched grinding matrix in the form of the biologically active material in the manufacture of a medicament.

The present invention includes medicaments manufactured by said methods, and methods for treating an animal, including humans, by administering a therapeutically effective amount of biologically active material by means of said medicaments.

In another embodiment of the invention, a facilitating agent or a combination of facilitating agents is also included in the mixture to be ground. Such facilitating agents suitable for use in the invention include diluents, surfactants, polymers, binding agents, fillers, lubricants, sweeteners, flavoring agents, preservatives, buffers, humectants, disintegrants, effervescent agents, and agents that may form part of a medicament, including a solid dose form, or other excipients necessary for another specific drug delivery, such as the agents and means listed below under the heading Medicaments and Pharmaceutical Composition, or any combination thereof.

Biologically active materials and compositions

The present invention encompasses pharmaceutically acceptable materials produced according to the methods of the present invention, compositions including such materials, including compositions comprising such materials together with the grinding die with or without grinding aids, facilitating agents, with at least a portion of a grinding die or separate from the grinding die.

The pharmaceutically acceptable materials within the compositions of the invention are present at a concentration of between about 0.1% and about 99.0% by weight. Preferably, the concentration of the pharmaceutically acceptable materials within the compositions will be from about 5% to about 80% by weight, while concentrations of 10% to about 50% by weight are highly preferred. Ideally, the concentration will be in the range of approximately 10 to 15% by weight, 15 to 20% by weight, 20 to 25% by weight, 25 to 30% by weight, 30 to 35% by weight, 35 to 40% by weight, 40 to 45% by weight, 45 to 50% by weight, 50 to 55% by weight, 55 to 60% by weight, 60 to 65% by weight, 65 to 70% by weight, 70 to 75% by weight, or 75 to 80% by weight for the composition before any further removal (if desired) of any portion of the grinding matrix. Where part or all of the grinding matrix has been removed, the relative concentration of pharmaceutically acceptable materials in the composition may be considerably higher depending on the amount of grinding matrix that is removed. For example, if all the grinding matrix is removed, the particle concentration in the preparation can reach 100% by weight (when subjected to the presence of facilitating agents).

The compositions produced according to the present invention are not limited to the inclusion of a single species of pharmaceutically acceptable materials. More than one species of pharmaceutically acceptable materials may therefore be present in the composition. Where more than one species of pharmaceutically acceptable materials are present, the composition thus formed may either be prepared in a dry milling step, or the pharmaceutically acceptable materials may be prepared separately and then combined to form a single composition.

Medications

The medicaments of the present invention may include pharmaceutically acceptable material, optionally together with the grinding matrix or at least a portion of a grinding matrix, with or without grinding aids, facilitating agents, combined with one or more pharmaceutically acceptable carriers, as well as other agents commonly used in the preparation of pharmaceutically acceptable compositions.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for parenteral, intravenous, intraperitoneal, intramuscular, sublingual, pulmonary, transdermal, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or sterile powders and dispersions for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of these agents and media for the manufacture of medicaments is well known in the art. Except to the extent that any conventional media or agent is incompatible with the pharmaceutically acceptable material, its use in the manufacture of a pharmaceutical composition according to an invention is contemplated.

Acceptable pharmaceutical carriers according to the invention may include one or more of the following examples: (1) surfactants and polymers include, but are not limited to, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol, povidone, polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose derivatives, hydroxypropylmethylcellulose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropylmethylcellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols and their polymers, emulsifiers, sugar gums, starch, organic acids and their salts, vinylpyrrolidone and vinyl acetate; (2) linking agents, such as different celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and/or (3) filling agents, such as lactose monohydrate, anhydrous lactose, microcrystalline cellulose and different starches; and/or (4) lubricating agents such as agents that act on the fluidity of the powder to be compacted, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel; and/or (5) sweeteners, such as any natural or artificial sweetener, including sucrose, xylitol, sodium saccharin, cyclamate, aspartame and acesulfame K; and/or (6) flavoring agents; and/or (7) preservatives, such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid, such as butylparaben, alcohols, such as ethyl or benzyl alcohol, phenolic chemicals, such as phenol, or quaternary compounds, such as benzalkonium chloride; and/or (8) buffers; and/or (9) diluents, such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides and/or mixtures thereof; and/or (10) wetting agents, such as corn starch, potato starch, starch and modified starches, croscarmellose sodium, cross-linked povidone, sodium starch glycolate and mixtures thereof; and/or (11) disintegrants; and/or (12) effervescent agents, such as effervescent pairs, such as an organic acid (for example, citric, tartaric, malic, adipic, fumaric, succinic and alginic acids and anhydrides and acid salts), or a carbonate (for example, sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate) or bicarbonate (for example, sodium bicarbonate, or potassium bicarbonate); and/or (13) other pharmaceutically acceptable excipients.

The medicinal products of the invention suitable for use in animals and in particular in humans should normally be stable under the manufacturing and storage conditions. The medicinal products of the invention comprising the biologically active material may be formulated as a solid, a solution, a microemulsion, a liposome, or other ordered structures suitable for high drug concentrations. The actual dosage levels of the biologically active material in the medicinal product of the invention may be altered in accordance with the nature of the biologically active material, as well as the potential increase in efficacy due to the advantages of delivering and administering the biologically active material (e.g., increased solubility, faster dissolution, larger surface area of the biologically active material, etc.). Thus, as used herein, “therapeutically effective amount” will refer to the amount of biologically active material required to effect a therapeutic response in an animal. Effective amounts for this use will depend on: the desired therapeutic effect; the route of administration; the potency of the biologically active material; the desired duration of treatment; The stage and severity of the disease being treated; the patient's weight and general state of health; and the judgment of the prescribing physician.

In another embodiment, the biologically active material, optionally together with the milling matrix or at least a portion of a milling matrix, of the invention can be combined in a medicament with another biologically active material, or even the same biologically active material. In the latter embodiment, a medicament can be achieved that provides different release characteristics – early release of the biologically active material, and subsequent release of a biologically active material of larger average size.

Pharmacokinetic Properties of Diclofenac Compositions

Suitable animal models for determining pharmacokinetic parameters are described in the prior art, such as the beagle dog model described in U.S. Patent No. 7,101,576.

Quick Start Activity

The diclofenac compositions of the invention exhibit faster therapeutic effects.

In one example, after administration, the diclofenac compositions of the invention comprising diclofenac have a Tmax of less than about 5 hours, less than about 4.5 hours, less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.75 hours, less than about 2.5 hours, less than about 2.25 hours, less than about 2 hours, less than about 1.75 hours, less than about 1.5 hours, less than about 1.25 hours, less than about 1.0 hour, less than about 50 minutes, less than about 40 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, less than about 5 minutes, or less than about 1 minute.

High Bioavailability

The diclofenac compositions of the invention preferably exhibit high bioavailability (AUC) and require lower doses compared to previous conventional compositions administered at the same dose. Any drug composition can have adverse side effects. Thus, lower doses of drugs that can achieve the same or better therapeutic effects as those observed with higher doses of conventional compositions are desired. Such lower doses can be achieved with the compositions of the invention because the higher bioavailability observed with the compositions compared to conventional drug formulations means that lower doses of the drug are required to obtain the desired therapeutic effect.

The pharmacokinetic profiles of the compositions of the invention are not substantially affected by the fed or fasting state of the individual ingesting the compositions.

The invention comprises diclofenac compositions in which the pharmacokinetic profile of the composition is not substantially affected by the fed or fasting state of an individual ingesting the composition. This means that there is no significant difference in the amount of composition or rate of absorption of the composition when the compositions are administered in the fed versus fasting state. Thus, the compositions of the invention substantially eliminate the effect of food on the pharmacokinetics of the composition.

The difference in absorption of the diclofenac composition of the invention, when administered in a fed versus fasted state, is less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%. This is a particularly important feature for treating patients who have difficulty maintaining a fasting state.

Furthermore, preferably the difference in the absorption rate (i.e., Tmax) of the diclofenac compositions of the invention, when administered in the fed versus fasted state, is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, or essentially no difference. The benefits of a dosage form that substantially eliminates the effect of food include an increase in individual convenience, thus increasing individual compliance, since the individual does not need to ensure that they are taking a dose with or without food.

Preferably, the Tmax of an administered dose of a diclofenac composition of the invention is lower than that of a conventional active drug composition administered at the same dosage.

A preferred diclofenac composition of the invention exhibits, in comparative pharmacokinetic tests with a standard conventional drug active composition in the form of an oral suspension, capsule, or tablet, a Tmax that is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10% of the Tmax exhibited by the standard conventional drug active composition. Furthermore, preferably the Cmax of a diclofenac composition of the invention is greater than the Cmax of a conventional drug active composition administered at the same dosage. A preferred diclofenac composition of the invention exhibits, in pharmacokinetic tests compared with a standard conventional drug active composition in the form of an oral suspension, capsule, or tablet, a Cmax that is greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, or greater than about 150% of the Cmax exhibited by the standard conventional drug active composition.

Furthermore, the diclofenac composition preferably has a higher AUC than that of the equivalent conventional composition administered at the same dosage. A preferred diclofenac composition of the invention exhibits, in pharmacokinetic tests compared with a standard conventional drug active composition in the form of an oral suspension, capsule, or tablet, an AUC that is greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, or greater than about 150% of the AUC exhibited by the standard conventional drug active composition.

Any standard pharmacokinetic protocol can be used to determine the blood plasma concentration profile in humans after administration of a composition, and thus establish whether the composition satisfies the pharmacokinetic criteria set forth herein. For example, a randomized single-dose crossover study can be conducted using a group of healthy adult human subjects. The number of subjects should be sufficient to provide adequate control of variation in a statistical analysis, and is generally about 10 or more, although for certain purposes a smaller group may be sufficient. Each subject receives, via oral administration at time zero, a single dose (e.g., 300 mg) of a test formulation of the composition, typically around 8 a.m. after an overnight fast. The subject remains fasting and upright for approximately 4 hours after administration of the composition. Blood samples are collected from each subject before administration (e.g., 15 minutes) and at several intervals after administration. For the present purpose, it is preferable to take several samples in the first hour, and to take samples less frequently thereafter. For example, blood samples can be collected at 15, 30, 45, 60, and 90 minutes after administration, then every hour for 2 to 10 hours after administration. Additional blood samples can also be taken later, for example, 12 and 24 hours after administration. If the same individuals are to be used for a study of a second test formulation, a period of at least 7 days should elapse before administration of the second formulation. Plasma is separated from blood samples by centrifugation, and the separated plasma is analyzed for composition by a validated high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry procedure. The plasma concentrations of the composition referred to here mean the total concentrations including both free and bound composition.

Any formulation providing the appropriate pharmacokinetic profile is suitable for administration according to the present methods. Examples of formulation types that provide such profiles are liquid dispersions and solid dose forms of the composition. If the liquid dispersion medium is one in which the composition has very low solubility, the particles will be present as suspended particles. The smaller the particles, the greater the likelihood that the formulation will exhibit the desired pharmacokinetic profile.

Thus, a diclofenac composition of the invention, after administration to an individual, provides improved pharmacokinetic and/or pharmacodynamic properties compared to a standard reference diclofenac composition as measured by at least one of absorption rate, dosage potency, efficacy, and safety.

Methods of administering medications comprising biologically active materials.

The medicinal products of the invention can be administered to animals, including humans, in any pharmaceutically acceptable manner, such as orally, rectally, pulmonaryly, intravaginally, topically (powders, ointments, or drops), transdermally, parenterally, intravenously, intraperitoneally, intramuscularly, sublingually, or as a buccal or nasal spray.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets, and granules. Furthermore, by incorporating any of the commonly used excipients, such as those listed above, and generally 5 to 95% of the biologically active agent, and more preferably at a concentration of 10% to 75%, a pharmaceutically acceptable non-toxic oral composition will be formed.

The medicinal products of the invention can be administered parenterally as a solution of the biologically active agent suspended in an acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, for example, water, buffered water, 0.4% saline, 0.3% glycine, hyaluronic acid, and the like. These compositions can be sterilized by well-known conventional sterilization techniques, or they can be sterilely filtered. The resulting aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution before administration.

For aerosol administration, the medicinal products of the invention are preferably supplied together with a surfactant or propellant polymer. The surfactant or polymer should, of course, be non-toxic and preferably soluble in the propellant. Representatives of these agents are esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with a polyhydric aliphatic alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides, may be employed. The surfactant or polymer may constitute 0.1%-20% by weight of the composition, preferably 0.25-5%. The balance of the composition is ordinarily propellant. A carrier may also be included, as desired, as is the case with, for example, lecithin for intranasal release.

The medicinal products of the invention can also be administered via liposomes, which serve to target the active agent to a specific tissue, such as lymphoid tissue, or selectively target cells. Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers, and the like. In these preparations, the compound microstructure composition is incorporated as part of a liposome, alone or in conjunction with a molecule that binds to other therapeutic or immunogenic compositions.

As described above, the biologically active material can be formulated in a solid dosage form (e.g., for oral administration, or suppository), along with the milling matrix, or at least a part of it. In this case, there may be little or no need to add stabilizing agents, since the milling matrix can effectively act as a solid-state stabilizer.

However, if the biologically active material is to be used in a liquid suspension, the particles made up of the biologically active material may require additional stabilization, since the solid carrier has been substantially removed to ensure the elimination, or at least the minimization, of particle agglomeration.

Therapeutic uses

Therapeutic uses of the medicines of the invention include pain relief, anti-inflammatory effects, migraine, asthma, and other disorders that require the active agent to be administered with high bioavailability.

One of the main areas where rapid bioavailability of a biologically active material is required is in pain relief. Minor analgesics, such as cyclooxygenase inhibitors (aspirin-related drugs), can be prepared as medicaments according to the present invention.

The invented medicines can also be used for the treatment of eye disorders. That is, the biologically active material can be formulated for administration to the eyes as an aqueous suspension in physiological saline, or a gel. Furthermore, the biologically active material can be prepared in powder form for administration through the nose for rapid penetration into the central nervous system.

The treatment of cardiovascular diseases can also benefit from biologically active materials according to the invention, such as the treatment of angina pectoris, and in particular, molsidomine can benefit from improved bioavailability.

Other therapeutic uses of the drugs of the present invention include the treatment of hair loss, sexual dysfunction, or the cutaneous treatment of psoriasis.

The present invention will now be described with reference to the following non-limiting examples. The description of the examples is not limiting in the preceding paragraphs of this descriptive report, but is provided for the sake of illustrating the methods and compositions of the invention.

Examples

It will become evident to those skilled in milling and pharmaceutical techniques that numerous modifications and improvements can be made to the processes described above without departing from the basic inventive concepts. For example, in some applications the biologically active material can be pre-treated and supplied to the process in pre-treated form. All such improvements and modifications are considered to be within the scope of the present invention, the nature of which should be determined from the above description and the appended claims. Furthermore, the following examples are provided for illustrative purposes only and are not intended to limit the scope of the processes or compositions of the invention.

The following materials were used in the examples.

Active pharmaceutical ingredients were purchased from commercial suppliers, excipients from commercial suppliers such as Sigma-Aldrich or retailers, while food ingredients were purchased from retailers.

The following mills were used for the grinding experiments. Spex-type mill:

Small-scale grinding experiments were performed using a Spex 8000D vibratory mixer/mill. Twelve 3/8” stainless steel balls were used as the grinding medium. The powder charge and grinding medium were loaded into a hardened steel flask with an internal volume of approximately 75 mL. After grinding, the ground material was dispensed from the flask and sieved to remove the grinding medium.

Attritor-type mill:

Small-scale attrition grinding experiments were performed using a Union Process 1HD attrition mill with a 110 mL grinding chamber. The grinding medium consisted of 330 g of 5/16” stainless steel spheres. The mill was loaded through the loading port with dry materials initially added, followed by the grinding medium. The grinding process was carried out with the casing cooled to 10-20°C and the shaft rotating at 500 rpm. Upon completion of grinding, the ground material was discharged from the mill and sieved to remove the grinding medium.

Medium-scale attritor grinding experiments were performed using a Union Process 1HD attritor mill with a 1 L grinding chamber or a Union Process 1S attritor mill with a 750 mL grinding chamber. The grinding medium consisted of 3 kg of 5/16” stainless steel balls or 1.5 kg of 3/8” stainless steel balls for the 1S attritor. The 1HD mill was loaded through the loading port, with dry materials initially added, followed by the grinding medium, while in the 1S attritor mill, the grinding medium was initially added, followed by dry materials. The grinding process was carried out with the casing cooled to 1020°C with the shaft rotating at 350 rpm in the 1HD attritor or 550 rpm in the 1S attritor. Upon completion of grinding, the ground material was discharged from the mill and sieved to remove the grinding medium.

Medium to large-scale attritor grinding experiments were performed using a Union Process 1S attritor mill with a 1/4 gallon grinding chamber. The grinding medium consisted of 7 kg of 3/8” stainless steel balls. The mill was loaded through the loading door, with the grinding medium initially added, followed by dry powders. The grinding process was carried out with the casing cooled to 18°C and the shaft rotating at 550-555 rpm. Upon completion of grinding, the ground powder was discharged from the mill through the bottom discharge door at 77 rpm for 5 min.

Large-scale attrition grinding experiments were performed using a Union Process 1S attrition mill with a 1/4 gallon grinding chamber. The grinding medium consisted of 20 kg of 3/8” stainless steel balls. The mill was loaded through the loading door, with the grinding medium initially added, followed by the dry powders. The grinding process was carried out with the casing cooled to ambient temperature and the shaft rotating at 300 rpm. Upon completion of grinding, the ground powder was discharged from the mill through the bottom discharge door at 77 rpm for 5 min.

Larger-scale attrition grinding was performed in a Union Process 30S mill with a 25-gallon grinding chamber (Union Process, Akron, OH, USA). The grinding medium consisted of 454 kg of 3/8” stainless steel balls. The mill was loaded through its split top cover, with the grinding medium initially added, followed by the dry powder (25 kg). The grinding process was carried out with the casing cooled to 10°C and the shaft rotating at 130 rpm. Upon completion of grinding, the ground powder was discharged from the mill through the bottom discharge port at 77 rpm for 5 min.

Siebtechnik Mill

Medium-scale grinding experiments were also carried out on a Siebtechnik GSM06 (Siebtechnik GmbH, Germany) with two 1L grinding chambers. Each chamber was filled with 2.7 kg of stainless steel media with a diameter of 3/8”. The media and powder were loaded without a lid. The mill was operated at ambient temperature. The vibration speed was that of the standard mill settings. Upon completion of grinding, the media was separated from the powder by sieving.

Simoloyer Mill

Medium-scale grinding experiments were carried out in a Simoloyer CM01 (ZOZ GmbH, Germany) with a 2L grinding chamber. The grinding medium consisted of 2.5 kg of stainless steel media with a diameter of 5 mm. The media was loaded through the loading port followed by dry materials. The grinding vessel was cooled using water to a temperature of approximately 18°C. The mill speed was operated in cycle mode: at 1300 rpm for two minutes and at 500 rpm for 0.5 min, and so on. Upon completion of grinding, the media was discharged from the mill using a graduated valve to retain the grinding media.

Large-scale grinding experiments were carried out in a Simoloyer CM100 (ZOZ GmbH, Germany) with a 100 L grinding chamber. The grinding medium consisted of 100 kg of stainless steel media with a diameter of 3/16”. The powder charge (11 kg) was added to the grinding chamber, which already contained the grinding medium, through a loading port. The grinding chamber was cooled to 18°C and the powder was ground for a total of 20 minutes using a cycling mode equivalent to a tip speed of 1300/500 rpm for 2/0.5 min in the CM-01 type mill. Upon completion of grinding, the mill was discharged by suction of the powder into a cyclone.

Hicom Mill

The grinding operations performed in a Hicom nutation mill used 14 kg of stainless steel and 0.25” grinding medium along with a 480 g powder charge. The mill was loaded by premixing the medium and powder, then by adding the mixture to the grinding chamber through the loading port at the top of the mill. Grinding was carried out at 1000 rpm and the mill was discharged by inverting the mill and emptying it through the loading port. The recovered material was sieved to separate the grinding medium from the powder.

The variations for the grinding conditions defined above are indicated in the variations column in the data tables. The key to these variations is shown in Table A.

Particle Size Measurement:

Particle size distribution (PSD) was determined using the Malvern Mastersizer 2000 fitted with a Malvern Hydro 2000S pump unit. Measurement settings used: Measurement time: 12 seconds, Measurement cycles: 3. The final result was generated by averaging the three measurements. Samples were prepared by adding 200 mg of ground material to 5.0 mL of 1% PVP in 10 mM hydrochloric acid (HCl), vortication for 1 min, and then sonication. From this suspension, sufficient dispersant (10 mM HCl) was added to achieve a desired level of obscuration. If necessary, a further 1-2 minutes of sonication was applied using the internal sonication probe in the measuring cell. The refractive index of the active ingredient to be measured was in the range of 1.49-1.73. Any variations to this general method are summarized in Table B.

XRD Analysis:

Powder X-ray diffraction (XRD) patterns were measured using a Kristalloflex D 5000 diffractometer (Siemens). The measurement range was 5-18 degrees 2-Theta. The slit width was set to 2 mm and the cathode ray tube was operated at 40 kV and 35 mA. Measurements were recorded at room temperature. The recorded traces were subsequently processed using Bruker EVA software to obtain the diffraction pattern. Table A. Variations for grinding conditions. Only the conditions reported in the table have been modified compared to the conditions reported above. Table B. Variations for particle size measurement conditions. Abbreviations: HCl: Hydrochloric acid 5 Nap: Naproxen acid PSD: Particle size distribution PVP: Polyvinylpyrrolidone RI: Refractive index Rpm: Revolutions per minute 10 SLS: Sodium lauryl sulfate SSB: Stainless steel spheres XRD: X-ray diffraction

Other abbreviations used in the data tables are listed below in Table C (for assets), Table D (for matrices), and Table E (for surfactants).

In the data tables, the single letter with sample number abbreviations has been used to identify specific sample numbers within the table. The data tables show in the figures the use of surfactant; the matrix is interchangeable and does not necessarily define the nature of that material. Table C. Abbreviations used for active pharmaceutical ingredients. Table D. Abbreviations used for excipients. Table E. Abbreviations used for surfactants

Example 1: Spex Grinding

A range of active ingredients, matrices, and surfactants, in a variety of combinations, were milled using a Spex mill. Details of these millings are shown in Figures 1A-1G, along with the particle size distributions of the milled active ingredients.

These grindings demonstrate that adding a small amount of surfactant to the grinding matrix results in a smaller particle size compared to grindings with only one active ingredient and a single matrix. Some examples of this are samples Z and AA compared to sample Y; sample AB compared to sample AC; sample AE compared to sample AD; sample AG compared to sample AF; sample AP compared to sample AO; sample AR compared to sample AQ; sample AT compared to sample AS; samples AX, AY, and AZ compared to sample AW; sample BC compared to sample BD; sample BI compared to sample BH; samples BL-BR compared to sample BK; samples CS-DB compared to sample DC. This last example is particularly noteworthy, as these grindings were performed at 45% v/v. This demonstrates the wide applicability of this invention. Some other examples demonstrating that the addition of surfactants is beneficial for size reduction are samples DD-DI, DG, and DK compared to sample DH; Sample DM compared to sample DL. Other samples, such as samples DY-CE compared to sample DX; sample AV compared to sample UA; samples BH compared to sample A and samples KM compared to sample J, demonstrate that this conclusion is also true when particle size statistics, such as % <1 micron, are used.

Note that this also applies to mechanochemical matrix milling. This is demonstrated by sample BI, where sodium naproxen is milled with tartaric acid and converts to acid naproxen. Figure 1H shows the X-ray diffraction data demonstrating the transformation.

Other samples, such as CB-CR, show examples where surfactants suitable for use with IV formulations can be used to manufacture very small particles.

It is also worth noting that the DS and DT samples can be sized using a saturated solution of the active ingredient (salbutamol), demonstrating that highly water-soluble active ingredients can be measured, provided care is taken when measuring the size.

Two datasets, samples N-Q and samples R-U, also demonstrate that the invention described herein is unique. In these samples, the active ingredient is milled with a matrix and a surfactant, producing small particles. When milled with the matrix alone, the particle sizes are larger; in the case of sample Q, they are not even nanoparticles. When the active ingredient is milled with only 1% surfactant, the resulting particle size is very large. Even when an 80% surfactant is used, the particle size is large.

Example 2: 110ml Attritor

A range of active ingredients, matrices, and surfactants, in a variety of combinations, were milled using the 110 ml agitated attrition mill. Details of these millings are shown in Figure 2A, along with the particle size distributions of the active ingredients that were milled.

These millings also demonstrate that adding a small amount of surfactant to the milling matrix results in a smaller particle size compared to milling with only one active ingredient and a single matrix in a small-scale agitated mill, as well as in the Spex vibratory mill. Sample F also demonstrates that small particles can be obtained at a high percentage of active ingredients when a surfactant is present. Samples D and E also show that the addition of surfactant also increased the powder yield from the mill.

Example 3: Secondary Matrix

In this example, naproxen was milled with a mixture of two matrices using the Spex mill. Details of these millings are shown in Figure 3A, along with the particle size distributions of the milled actives. Samples A and B were milled in a primary matrix of lactose monohydrate and 20% of a second matrix. The particle size of these millings is smaller than the particle size from milling with lactose monohydrate alone (see example 1, sample AH, Figure 1B). The particle size is also smaller than naproxen milled in the secondary matrices (see example 1, samples AI and AJ, Figure 1B). This demonstrates that the matrix mixtures have synergy when combined.

Samples C-E were milled in anhydrous lactose with 20% of a second matrix. All of these samples had a much smaller particle size than naproxen milled in anhydrous lactose alone (see example 1, sample AK, Figure 1B).

These grinding results demonstrate that adding a second matrix to the primary grinding matrix provides a smaller particle size compared to grinding with only a single matrix.

Example 4: Attritor 1L

Two active ingredients with various combinations of lactose and SDS were milled using a 1L stirred attrition mill. Details of these millings are shown in Figure 4A, along with the particle size distributions of the milled active ingredients.

Samples A and B are 20% meloxicam millings. While sample B has a slightly smaller particle size than sample A, there is a dramatic difference in the amount of material recovered from milling. Sample A, milled with 3% SDS, has a high yield of 90%, while sample B, without surfactant, has virtually no yield with all the powder hardened in the mill.

In samples C-F, milling with 13% diclofenac shows that the use of a second matrix (tartaric acid) in combination with 1% SDS offers the best result in terms of good particle size and high yield. Sample D, which only has the mixed matrix, has a very good particle size but a low yield.

These results show that adding a small amount of surfactant improves grinding performance.

Example 5: Attritor 750mL

Two active ingredients with various surfactant combinations were milled using a 750 ml stirred attrition mill. Details of these millings are shown in Figure 5A, along with the particle size distributions of the milled active ingredients.

In samples A-C, three naproxen millings are shown. Sample A has only 1% SDS as a surfactant. Samples B and C have a second surfactant, and these samples have a smaller particle size measured by % <500 nm, <% 1000 nm, and % <2000 nm.

Samples D-F show three diclofenac millings. Sample D has only 1% SDS as a surfactant. Samples E and F have a second surfactant and these samples have a smaller particle size compared to sample D.

These examples demonstrate that using a combination of surfactants can be useful for achieving a better reduction in particle size.

Example 6: 1/2 Gallon 1S

A range of active ingredients, matrices, and surfactants, in a variety of combinations, were milled using the 1S gallon % mill. Details of these millings are shown in Figures 6A-C, along with the particle size distributions of the active ingredients that were milled.

The following examples demonstrate that a higher yield is obtained when an active ingredient is milled in a 1S gallon mill with the use of a surfactant, compared with the use of no surfactant, where all other parameters being identical. Samples C and D (Figure 6A) show Naproxen acid milled in Mannitol, with yields of 92% and 23%, with and without surfactant. Samples S and AL (Figures 6B and C) show the same for glyphosate, with yields of 95% and 26%, respectively. Samples AI and AJ (Figure 6B) show yields of ciprofloxacin of 94% and 37% with and without surfactant, while samples AM and AN (Figure 6C) show yields of Celecoxib of 86% and 57% with and without surfactants. Finally, samples AP and AQ (Figure 6C) show that grinding Mancozeb with or without surfactants resulted in yields of 90% and 56%, respectively.

The following examples illustrate that grinding an asset in a 1S gallon mill with a surfactant, compared with one without a surfactant, where all other parameters are identical, leads to the smallest particle size after grinding. Samples C and D (Figure 6A) show a D(0.5) of 0.181 and 0.319, with or without surfactant, while samples AM and AN (Figure 6C) show D(0.5) of 0.205 and 4.775 with and without surfactants.

The Q-S series of samples are taken over a single glyphosate milling cycle. The data demonstrate that the size of the active ingredients decreases with milling time.

Other samples, such as V-AA, show examples where surfactants suitable for use with IV formulations can be used to manufacture very small particles.

Some of the particle size data in Figures 6A-C were converted to an average particle size and are shown in the tables. This number was calculated as follows. The volume distribution was transformed into a numerical distribution using the Malvern Mastersizer software. For each batch size, the batch size was multiplied by the % of particles in the batch. These numbers were summed and divided by 100 to give the average particle size number.

Example 7: Metaxalone

Metaxalone was milled with various combinations of matrices and surfactants using a variety of mills. Details of these millings are shown in Figure 7A, along with the particle size distributions of the milled actives. Samples A, B, E, G, H, and I were milled in a Spex mill. Samples C, D, and F were milled in a 750 ml atrittor. The remaining samples were milled in a 1S gallon % mill.

Sample A compared with sample B and sample H compared with sample G demonstrate that the addition of one or more surfactants allows the production of small active particles. Other millings, such as samples C-F, show that Metaxalone can be finely milled at high active ingredient loads. Sample I shows that disintegrants can be added during milling without resulting in the production of small active particles. Note that the particle size in sample I is obtained after filtration through a 10-micron filter. Sample N shows an alternative method for manufacturing a formulation with small particles and disintegrants. In this example, the powder from sample M was left in the mill, and a wetting agent (PVP) and disintegrant were added. The powder was milled for another 2 minutes and then discharged, obtaining a very high yield of 97%.

The J-M sample series were taken from a single grinding process. The data demonstrate that the size of the assets decreases with grinding time.

Example 8: Hicom

A range of active ingredients, matrices, and surfactants in a variety of combinations were milled using a Hicom mill. Details of these millings are shown in Figure 8A, along with the particle size distributions of the active ingredients that were milled.

The data show that the invention described here can be used with the Hicom mill with its nutation action. The data in Figure 8A show that a variety of assets can be finely ground in very short times and with good yields on a scale of 500 grams.

Samples N and O show that cocoa powder can be reduced to very fine sizes in short times using the invention described in combination with the Hicom nutation mill. Similarly, sample P shows that this also applies to cocoa nibs.

Example 9: 1.5 Gallon 1S

A range of active ingredients, matrices, and surfactants in a variety of combinations were milled using the 1.5 Gallon 1S mill. Details of these millings are shown in Figures 9A-B, along with the particle size distributions of the active ingredients that were milled.

The following examples demonstrate the higher yield obtained when grinding an asset in a 1.5 gallon 1S attrition mill with a surfactant, compared to no surfactant, where all other parameters are identical. Samples J and N (Figure 9A) show yields of 51% and 80%, with and without surfactant. Samples K and P (Figure 9A) show yields of 27% and 80%, with and without surfactant, while sample L (Figure 9A) shows a yield of 94% with surfactant and the control without surfactant (sample M, Figure 9A) resulted in no yield due to clumping within the mill.

The following examples illustrate that grinding an asset in a 1.5 gallon 1S attrition mill with a surfactant, compared with one without a surfactant, where all other parameters are identical, leads to a smaller particle size after grinding. Samples F and G (Figure 9A) show a D(0.5) of 0.137 and 4.94, with or without surfactant, while samples K and P (Figure 9A) show D(0.5) of 0.242 and 0.152, with and without surfactants.

The AI-AL sample series are taken over a single milling of meloxicam. The data demonstrate that the size of the active ingredients decreases with milling time.

Other samples, such as A-E, show examples that surfactants suitable for use with IV formulations can be used to manufacture very small particles.

Sample M was a meloxicam mill in lactose monohydrate without surfactant. After 3 minutes of milling, the mill refused to rotate. Milling was suspended and restarted, but only ran for another 3 minutes before stopping again. At this point, the mill disassembled and no evidence of clumping was found. However, the powder had a rough and stagnant appearance, making it impossible to rotate. The medium was weighed and found to contain 150 grams of powder, indicating that it was stuck together and difficult to move. At this point, the mill was reassembled and the powder and medium were put back together. 30.4 grams of SDS were included in the mill, making it similar to mill L. After the addition of surfactant, the mill was run for another 14 minutes (giving a total of 20 minutes) without any incident. After unloading the powder, the medium was weighed, and the weight of powder in the medium was only 40.5 grams. This indicates that the addition of the surfactant improved the grinding performance and the ability to grind the powder.

Some of the particle size data in Figures 9A-B were converted to an average particle size and are shown in the tables. This number was calculated as follows. The volume distribution was transformed into a number distribution using the Malvern Mastersizer software. For each size batch, the batch size was multiplied by the % of particles in the batch. These numbers were summed and divided by 100 to give the average particle size number.

Example 10: Large scale 25/11kg

Sample A (Figure 10A) was ground in a Siebtechnik mill for 15 minutes. After this time, the powder was completely hardened on the walls of the mill and the medium. No powder could be removed to measure particle size. At this point, 0.25 g (1% w/w) of SLS was added to the mill chamber and grinding was then carried out for another 15 minutes. After the second grinding period in the presence of SLS, the powder was no longer agglomerated in the medium and some free powder was also present. Observations made before and after the addition of SLS demonstrate that the addition of the surfactant reduces the problem of agglomeration. With the addition of the surfactant, the agglomerated material could be recovered to become free powder again, with a small particle size.

Sample B-E was ground in horizontal Simoloyer mills. Details of these grindings are shown in Figure 10A, along with the particle size distributions of the active ingredients that were ground.

The data show that the invention described here can be used with Simoloyer mills with their horizontal attritor action. We highlight example E, which was ground on a scale of 11 kg. This demonstrates that the invention described here is suitable for grinding on a commercial scale.

Sample F was ground in a vertical attrition mill (União S-30 Process). Details of this grinding are shown in Figure 10A, along with the particle size distribution of the ground active ingredient.

The data shows that the invention described here can be used with S-30 mills with their vertical attritor action. It is important to highlight that this grinding was carried out on a 25kg scale. This demonstrates that the invention described here is suitable for grinding on a commercial scale.

Example 11: Naproxen

Naproxen was milled in mannitol with a range of surfactants using the % GallonIS mill. Details of these millings are shown in Figures 11A, along with the particle size distributions of the active ingredients that were milled.

Naproxen acid milled in mannitol with a surfactant (Sample A, D-J, in Figure 11A) leads to higher yields compared to naproxen acid milled in mannitol without surfactant (Sample K, Figure 11A). Naproxen acid milled in mannitol and microcrystalline cellulose or the primellose disintegrant (sample L or M, Figure 11A) leads to a small particle size with D(0.5) around 0.25 in both cases.

Example 12: Filtering

Some matrices, auxiliary mills, or facilitating agents used in this invention are not water-soluble. Examples include microcrystalline cellulose and disintegrants such as croscarmellose and sodium starch glycolate. In order to more easily characterize the particle size of the active ingredient after milling with these materials, filtration methods can be used to remove them, allowing for better characterization of the active ingredients. In the following examples, naproxen was milled with lactose and microcrystalline cellulose (MCC). The particle size was characterized before and after filtration, and the ability of the filters to allow naproxen to pass through was demonstrated using HPLC tests. The milling and particle size details are shown in Figure 12a. Note that in this table, the particle sizes with milling details are unfiltered. The particle sizes in the rows without milling details are after filtration. The sample that was filtered is indicated in the active ingredient section. HPLC assays were performed on samples, before and after filtration, through 10-micron poroplast filters. The collected samples were diluted to obtain a nominal concentration of 100 mcg/ml. The HPLC assay data are shown in Table 12.

The sample was milled with 5% MCC. Before filtration, the D50 was 2.5 mM; after filtration (sample B), the D50 was 183 nm. When sample B was analyzed, the concentration was 94 mg/ml, indicating that the filtration process retained little naproxen. The second milling (sample C) was performed without MCC. The D50 was 160 nm, as expected. After filtration (sample D), the particle size was not altered, indicating that if the filtration process removed any naproxen, it was removed continuously. Some of the C samples were then milled with MCC for 1 minute. This is sufficient time to incorporate the MCC into the powder, but not enough to affect the particle size distribution. Two millings were performed. Sample E incorporated 5% w/w of MCC into the powder, and sample F 9% w/w. After incorporating MCC, the particle size increased dramatically. These samples were then filtered (samples E and F) and the size re-evaluated. After filtration, the particle size was the same as sample C, which was the starting material. The assay of samples E-H indicates that filtration does not significantly remove any naproxen. The combination of particle size and assay data clearly shows that the material, such as MCC, can be easily and successfully removed, allowing the actual particle size of the active ingredient to be measured.

Samples I and J were milled with 10% and 20% w/w MCC. The particle size after filtration is shown for samples K and L. Again, filtration resulted in a reduction in particle size due to the removal of the MCC component. And, once again, the HPLC assay for samples I-L shows that little naproxen was lost during filtration.

This data also demonstrates that the MCC can be successfully used as a co-matrix in the invention disclosed herein. Table 12: HPLC assay of naproxen, before and after filtration of samples. Example 13: Fabrication of Diclofenac Nanoformulation Capsules Example 13(a): 18 mg Diclofenac ground powder (666.2 g, from Example 9, Sample W) was placed in the bowl of a KG-5 high shear granulator. Separately, a 30% w/w povidone K30 solution was prepared by dissolving 60.0 g of povidone K30 in 140.0 g of purified water. The granulator was operated at a pulser speed of 250 rpm and an impeller speed of 2500 rpm. A portion of the povidone solution (88.6 g) was introduced into the granulation over a period of approximately 9 minutes using a peristaltic pump. An additional 30 g of water was then added to the granulation.

The wet granules were dispersed onto lined paper trays and dried in an oven at 70°C for 2 hours.

They were then subjected to manual sieving through a 10-mesh manual sieve. After approximately 2.25 hours of drying time, the drying loss was determined to be 0.559%.

The dry granules were processed in a CoMill frame adapted with a 200 mesh sieve and 0.225 inch spacer, operated at 1265 rpm. The process yielded 539.0 g of dry, ground granules.

The granules were filled into white opaque rigid gelatin capsules of size 4 using an IN-CAP® automatic capsule filling machine (Dott. Bonapace & C., Milan, Italy). The machine was configured with size 4 change parts and a 10 mm dosing disc. The target filling weight was 124.8 mg, and the average weight of an empty capsule shell was 38 mg. The machine was operated at speed setting #2. The #4 block pin was set to 21 mm; all other block pin settings were N/A.

The filled capsules were polished in a capsule polishing machine, and the net yield of filled capsules was 480.2 g (approximately 2,910 capsules). Example 13(b): 35 mg

Two separate granulation sub-batches were used for the manufacture of 35 mg Diclofenac Nanoformulation Capsules. Granulation sub-batch A: 642.7 g of milled diclofenac powder (Example 9, Sample X) was placed in the bowl of a KG-5 high-shear granulator. Separately, a 30% w/w povidone K30 solution was prepared by dissolving 60.0 g of povidone K30 in 140.0 g of purified water. The granulator was operated at an impeller speed of 250 rpm and a pulser speed of 2500 rpm. A portion of the binder solution (85.5 g) was introduced into the granulation over a period of approximately 8.5 minutes via a peristaltic pump. An additional 30 g of purified water was then added to the granulation at the same rate. The wet granules were dispersed in paper trays lined to a thickness of approximately %”.

Granulation sub-batch B: 519.6 g of ground diclofenac powder (Example 9, Sample Y) was placed in the bowl of a KG-5 high-shear granulator. Separately, a 30% povidone solution was prepared by dissolving 60.0 g of povidone K30 in 140.0 g of purified water. The granulator was operated at an impeller speed and a pulser speed of 2500 rpm. A portion of the povidone solution (69.1 g) was added to the granulation over a period of approximately 6.5 minutes. An additional 30 g of water was then added at the same rate. The wetted granules were dispersed onto paper trays lined to a thickness of approximately %”.

The wet granules from sub-lots A and B were dried in an oven at 70°C for approximately 2 hours. They were then subjected to manual sieving through a 10-mesh manual sieve and tested for loss on drying. The LOD result was 0.316%.

The dry granules were ground in a CoMill frame fitted with a 200 mesh sieve and 0.225 inch spacer, operated at 2500 rpm. The ground granules were placed in an 8 qt V-mixer and mixed for 5 minutes, yielding 1020.2 granules.

The granules were filled into white opaque rigid gelatin capsules of size 3 using a MiniCap Capsule Filling Machine equipped with size-change parts 3. The target filling weight was 242.7 mg and the average weight of an empty capsule shell was 47 mg. The granules were filled into the capsule shells manually using a scraper. Vibration and obstruction were adjusted to achieve the target filling weight. The filled capsules were polished on a capsule polishing machine, yielding 1149.2 g of filled capsules (approximately 3,922 capsules).

Example 14: Dissolution rate of ground diclofenac

In this example, the dissolution rate is compared between 18 mg and 35 mg of nanoformulations of the invention (Example 13(a) and 13(b)), and Voltarol Dispersible Tablets of commercial reference diclofenac 50 mg (Novartis, UK) containing 46.5 mg of free diclofenac acid, equivalent to 50 mg of diclofenac sodium. The dissolution method used was Slide I (baskets) according to USP <711> with a stirring speed of 100 rpm. The dissolution media were 0.05% sodium lauryl sulfate and citric acid solution buffered at pH 5.75. The dissolution volume was 900 mL and the dissolution medium temperature was 37°C. Samples were tested at 15, 30, 45 and 60 minutes and at infinity. Infinity was defined as an additional 15 minutes at a higher rotation speed. A 1 ml sample was taken at each time point, filtered, and analyzed by HPLC with the detection wavelength set at 290 nm. The data in Table 14a below report the dissolved percentage of the active quantity in each test article, for the specified time points.

Table 14a. Dissolution profiles for Voltarol® 50 mg Dispersible Tablets, Diclofenac 18 mg Nanoformulation Capsules and Diclofenac 35 mg Nanoformulation Capsules.

The results demonstrate that ground diclofenac capsules dissolve more rapidly and completely than commercial reference diclofenac. Those skilled in the art will readily appreciate the advantages conferred by faster dissolution—more active agent is available at any given time point. Put another way, an equal amount of dissolved diclofenac can be obtained with a smaller initial dose of ground diclofenac, as opposed to the larger initial dose required for reference diclofenac to achieve the same amount of dissolved diclofenac. Additionally, as the results make clear, reference diclofenac does not achieve complete dissolution even by the final time point, while ground diclofenac achieves approximately 90% dissolution within 15 minutes. Again, a smaller dose of ground diclofenac yields an amount of dissolved diclofenac that a larger dose of reference diclofenac might otherwise be required to match.

Example 15: Bioavailability of ground diclofenac.

This example describes a five-pathway, single-dose relative bioavailability study of diclofenac 18 mg and 35 mg capsules and Caraflam® 50 mg tablets in healthy subjects under fed and fasted conditions.

The pharmacokinetic study described in this example uses 18 mg and 35 mg Diclofenac Nanoformulation Capsules manufactured as described in Examples 13(a) and 13(b). OBJECTIVES 1) To determine the relative bioavailability of diclofenac from a 35 mg test capsule versus a 50 mg reference tablet when administered to healthy subjects under fed conditions. 2) To determine the effect of food on the rate and extent of absorption of a single dose of the 35 mg diclofenac nanoformulation test capsule formulation administered to healthy subjects under fasted and fed conditions. 3) To determine the effect of food on the rate and extent of absorption of a single dose of the 50 mg potassium diclofenac reference tablet formulation administered to healthy subjects under fasted and fed conditions. 4) To evaluate the dose proportionality between 18 mg and 35 mg test capsule formulations of diclofenac nanoformulation administered to healthy individuals under fed conditions.

Methodology:

This was a single-center, single-sequence, 5-treatment, 5-period, open-label, randomized, single-dose crossover study investigating the relative bioavailability and dose proportionality of the test product (i.e., 18 mg and 35 mg diclofenac acid nanoformulation capsules) vs. the reference product (50 mg diclofenac potassium immediate-release tablet [Cataflam]) administered under fasting and fed conditions. Forty (40) male and female subjects who met all study eligibility criteria were randomized equally on a 1:1:1:1:1 basis to one of 10 treatment administration sequences. Each subject received 5 treatments in order of their assigned sequence according to the randomization code. Subjects entered the clinic on Day 1 of Treatment Period 1 and spent the night fasting. On the morning of Day 1, subjects received the test or reference products in a fasted state or 30 minutes after the start of an FDA High-Fat Breakfast (depending on the study treatment). Blood samples for pharmacokinetic (PK) assessment of diclofenac plasma concentrations were obtained before and 12 hours after dosing. Subjects were then discharged and returned to the clinic after a 7-day washout interval to continue the treatment sequence for periods 2, 3, 4, and 5. A blood sample for safety assessments was collected with the last PK sample in Treatment Period 5. Information on adverse effects (AEs) obtained during confinement or reported in outpatient visits was reviewed and documented. Number of Individuals (Planned and Analyzed): Number of individuals planned for recruitment: up to 40 Number of individuals recruited in the study: 40 Number of individuals completing the study: 38 Number of individuals bioanalytically analyzed: 30 Number of individuals analytically analyzed: 30 Diagnosis and Main Inclusion Criteria:

Male and female individuals who provided written informed consent were at least 18 years of age, weighed at least 110 kilograms and had a body mass index (BMI) between 18 and 30 kg/m2, and were healthy based on medical history, physical examination, electrocardiogram (ECG), and clinical laboratory test results. All female individuals were not pregnant or breastfeeding; women of childbearing age agreed to take precautions to avoid pregnancy. Eligibility criteria required individuals to demonstrate negative test results for hepatitis B, hepatitis C, and human immunodeficiency virus, as well as a negative urine sweep for addictive drugs and a breathalyzer test for alcohol.

Product Test, Dosage and Method of Administration:

The test products were nanoformulation capsules of diclofenac acid in concentrations of 18 mg and 35 mg.

The 18 mg test product was administered as Treatment A. Individuals assigned to Treatment A received a single 18 mg capsule orally with 240 mL of water after an overnight fast.

The 35 mg test product was administered as Treatments B and C. Subjects assigned to Treatment B received a single 35 mg capsule orally with 240 mL of water after an overnight fast. Subjects assigned to Treatment C received a single 35 mg capsule orally with 240 mL of water 30 minutes after the start of an FDA-approved high-fat breakfast.

Treatment Duration:

The treatment duration was a single dose in each period. Reference Therapy, Administration Method and Batch Number

The reference product was 50 mg Cataflam (diclofenac potassium) tablets, manufactured by Patheon Inc., Whitby Operations and distributed by Novartis Pharmaceutical Corporation. A single lot of the reference product was used in this study (Lot Number C7C02722). The reference product was administered as Treatments D and E. Subjects assigned to Treatment D received a single 50 mg tablet orally with 240 mL of water after an overnight fast. Subjects assigned to Treatment E received a single 50 mg tablet orally with 240 mL of water 30 minutes after the start of an FDA high-fat breakfast.

Evaluation Criteria: Pharmacokinetics:

Blood samples for measuring diclofenac plasma concentrations were collected pre-dose and at 0.083, 0.167, 0.25, 0.33, 0.50, 0.67, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.67, 4, 4.5, 5, 6, 8, 10, and 12 hours post-dose. Primary PK variables included: area under the concentration-time curve from time zero to the time of the last sample with a quantifiable concentration (AUC0-t); area under the concentration-time curve from time zero extrapolated to infinity (AUCo-~); and maximum measured concentrations (Cmax). Secondary PK variables included: time to reach maximum concentration (Tmax); terminal elimination rate constant (Ke); and terminal elimination half-life (T1/2).

Security:

A physical examination, serological testing for HIV, hepatitis B, and hepatitis C, as well as a urine drug screening were performed at the Screening Visit. Samples for general clinical laboratory tests were collected, 12-lead ECG scans were obtained, vital signs were measured, and pregnancy tests (for female subjects) were performed at the Screening Visit and at specified time points. Throughout the study, individuals were monitored for laboratory and clinical evidence of adverse events.

Statistical Methods: Pharmacokinetics:

Statistical analyses were performed using the mixed model procedure of the SAS® statistical program (PC Version 9.1.3) in a Windows XP Professional environment. Pharmacokinetic parameter estimates were evaluated using mixed model analysis (PROC MIXED). The model included fixed effects for sequence, period, and treatment; and random effects for individuals nested within the sequence. Least squares means and standard error values from these analyses were used to construct 90% confidence intervals for relative bioavailability assessments according to FDA recommended procedures. Normalized dose AUC and Cmax values for the 18 mg and 35 mg test products were untransformed and compared by Analysis of Variance (ANOVA). As specified in the protocol, dose proportionality should be conducted if the overall treatment effect was not significant at the 5% level, or if the 90% confidence intervals for the geometric mean ratios contained the value “1.00”.

Security:

Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) and listed by system organ class (SOC) and preferred timeframe (PT). Treatment-emergent AEs were summarized by incidence, relationship to the study drug, and severity.

SUMMARY - RESULTS DEMOGRAPHIC CHARACTERISTICS OF INDIVIDUALS:

Forty (40) individuals were randomized to treatment, and 38 (thirty-eight) individuals (95%) completed all 5 study periods. Two individuals voluntarily withdrew consent before dosing in Period 2. The 40 individuals who received at least one dose of the study drug were included in the complete analysis set and ranged in age from 21 to 56 years, with a mean age of 34.6 years. There were 27 male individuals (67.5%) and 13 female individuals (32.5%). Regarding race/ethnicity, 32 individuals (80.0%) were Black, 6 individuals (15.0%) were Caucasian, and 2 individuals (5.0%) were Hispanic. The mean height was 172.9 cm, with a range of 151 to 189 cm. The mean body weight was 77.4 kg, with a range of 52.9 to 104.8 kg. The average BMI was 25.8 kg/m2, with a range of 20.0 to 29.7 kg/m2. The demographic findings reflected a healthy adult population.

Pharmacokinetic results:

According to the Statistical Analysis Plan, all available data from the first 30 of the 38 individuals who completed all 5 periods were used in the pharmacokinetic analyses. The results of statistical tests on pharmacokinetic parameters for diclofenac are summarized in Tables 15a-d below. Table 15a. B:D Treatments (35 mg test product vs. 50 mg reference product [fasting conditions])

The AUC(ot) and AUC(o-~) values for the test product (35 mg capsule) were approximately 20% lower than those observed for the reference product (50 mg tablet). Cmax for the reference product was only 7% higher than the test product and was not statistically significant (α = 0.05). The 35 mg test capsules and the 50 mg reference tablets (Cataflam) were not bioequivalent when administered to fasting subjects. Abbreviations: ANOVA (analysis of variance); AUC(0-t) (area under the concentration-time curve from zero to the last measurable concentration); AUC(0-~) (area under the concentration-time curve from zero to infinity); CI (confidence interval); Cmax (measured maximum plasma concentration); Ke (terminal elimination rate constant); T1/2 (terminal elimination half-life); Tmax (time to reach maximum concentration). Least squares geometric means for peak areas and concentrations. Least squares arithmetic means for other parameters. b. Ratio calculated as least squares mean of Fasting Test. c. Confidence interval on the test-to-reference ratio. d. Reported mean (median) for Tmax. * Comparisons were detected as statistically significant with α = 0.05. Table 15b. C:B Treatments [35 mg test product fed vs. fasted individuals] Food reduced AUC(ot) and AUC(o-~) values by 9% and 7%, respectively. Cmax decreased by 58%. All parameters were statistically significant (α = 0.05) indicating a food effect for the 35 mg test product. Abbreviations: ANOVA (analysis of variance); AUC(0-t) (area under the concentration-time curve from zero to the last measurable concentration); AUC(0-~) (area under the concentration-time curve from zero to infinity); CI (confidence interval); Cmax (measured maximum plasma concentration); Ke (terminal elimination rate constant); T1/2 (terminal elimination half-life); Tmax (time to reach maximum concentration). a. Least squares geometric means for peak areas and concentrations. a. Least squares arithmetic means for other parameters. b. Ratio calculated as least squares mean of Feeding Test divided by least squares mean of Fasting Test. c. Confidence interval for the Feeding Test-to-Fasting Test ratio. d. Reported mean (median) for Tmax. * Comparisons were detected as statistically significant by ANOVA, with α = 0.05. Table 15c. E:D Treatments (50 mg of reference product [fed vs. fasted individuals]) Food reduced AUC(ot) and AUC(o-~) by 9% and 8%, respectively. Cmax decreased by 27%. These PK parameters were statistically significant (α = 0.05), indicating a food effect for the reference product. Abbreviations: ANOVA (analysis of variance); AUC(0-t) (area under the concentration-time curve from zero to the last measurable concentration); AUC(0-~) (area under the concentration-time curve from zero to infinity); CI (confidence interval); Cmax (measured maximum plasma concentration); Ke (terminal elimination rate constant); T1/2 (terminal elimination half-life); Tmax (time to reach maximum concentration). a. Least squares geometric means for peak areas and concentrations. a. Least squares arithmetic means for other parameters. b. Ratio calculated as the least squares mean of Reference Feeding divided by the least squares mean of Reference Fasting. c. Confidence interval for the Reference Feeding-to-Reference Fasting ratio. d. Reported mean (median) for Tmax. * Comparisons were detected as statistically significant by ANOVA, with α = 0.05. Table 15d. Dose Proportionality for Treatments A:B (Test Product of 18 mg vs. 35 mg [Fasting Individuals]) Differences in dose-normalized Untransformed AUC(ot) and AUC(o-~) were statistically significant (α < 0.05), and the 90% confidence interval for their ratios did not contain the value “1.00”, thus these parameters failed the per-protocol dose-proportionality test. Alternatively, dose proportionality can still be concluded for the 18 mg and 35 mg test products since (1) the 90% confidence interval of the dose-normalized In-transformed ratios Cmax, AUC, and AUC was fully contained within the acceptance range of 0.800 and 1.250 for bioequivalence, and (2) the dose-normalized geometric mean ratios between the 18 mg and 35 mg test capsules were 0.996, 0.938, and 0.946, respectively for Cmax, AUC(0-t), and AUC(0-~). Abbreviations: ANOVA (analysis of variance); AUC(0-t) (area under the concentration-time curve from zero to the last measurable concentration); AUC(0-~) (area under the concentration-time curve from zero to infinity); CI (confidence interval); Cmax (measured maximum plasma concentration); Ke (terminal elimination rate constant); T1/2 (terminal elimination half-life); Tmax (time to reach maximum concentration). a. Least squares geometric means for peak areas and concentrations. Least squares arithmetic means for other parameters. AUC(0-t), AUC(0-~), and Cmax for 18 mg were dose-normalized by multiplying the ratio of 35 mg divided by 18 mg (equal to 1.944). b. The ratio calculated as the dose-normalized least squares mean for the 18 mg test product divided by the least squares mean for the 35 mg test product. c. Confidence interval for the dose-normalized-to-test ratio of 18 mg to 35 mg. d. Reported mean (median) for Tmax. * Comparisons were detected as statistically significant by ANOVA, with α = 0.05.

SAFETY RESULTS:

A total of 40 (100%) individuals were included in the safety population. 13 (thirteen) treatment-emergent adverse events (AEs) were experienced by 7 individuals (18.0%). 6 (six) treatment-emergent AEs were reported by 5 individuals (12.5%) who received the test product and 7 treatment-emergent AEs were reported by 2 individuals (5.0%) who received the reference product. 10 (ten) of the 13 treatment-emergent AEs (76.9%) were considered moderate in severity; 3 (23.0%) were considered moderate (i.e., vomiting and headache [Individual 15]) and none were considered life-threatening. Fatigue was the treatment-emergent AD with the highest overall incidence, i.e., reported by 3 individuals (8.0%) who received the test product (35 mg diclofenac nanoformulation capsule). Six (6) of 40 individuals (15.0%) reported nine treatment-emergent adverse events (AEs) that were determined to be at least possibly related to the administration of the study drug. No clinically significant changes in laboratory results or vital signs occurred, in the investigator's opinion. There were no deaths or other serious adverse events in this study.

CONCLUSIONS:

This was a 10-sequence, 5-treatment, 5-period, open-label, randomized, single-dose, single-center crossover study investigating the relative bioavailability and dose proportionality of the Test product (i.e., 18 mg and 35 mg diclofenac acid nanoformulation capsules) vs. the reference product (50 mg diclofenac potassium immediate-release tablet [Cataflam]) administered under fed and fasting conditions. Forty (40) healthy adult males and females were recruited for the study. Eligible subjects received 5 treatments in the order of their assigned sequence according to the randomization schedule. There was a 7-day washout interval between each Treatment Period. Thirty-eight (38; 95%) subjects completed all 5 study periods. Two (92; 5%) individuals voluntarily dropped out of the study before dosing in Period 2. Pharmacokinetic blood samples were obtained pre-dose and 12 hours post-dose. During the study, individuals were monitored for clinical and laboratory evidence of adverse events.

A single dose of diclofenac (18 mg, 35 mg, or 50 mg) was safe and well tolerated. Seven (7; 18.0%) individuals reported a total of 13 treatment-emergent AEs. Six (6; 15%) individuals reported 9 treatment-emergent AEs that were determined to be at least possibly related to the administration of the study drug. All treatment-emergent AEs were considered to be of moderate severity, with the exception of vomiting and 2 occurrences of headache experienced by Individual 15. No deaths or serious adverse events occurred.

All available data from the 30 individuals who completed all 5 study periods were used in the pharmacokinetic analyses. Conclusions based on statistical tests of diclofenac PK parameters are summarized below. 35 mg test product vs. 50 mg reference product (fasting individuals):

These two formulations were not bioequivalent under fasting conditions since the 90% confidence interval for the geometric mean and the peak concentration ratios for diclofenac were outside the range of 0.800 to 1.250. 35 mg test product (fed vs. fasted subjects):

Food decreased AUC(o-t) and AUC(o-~) values by 9% and 7%, respectively. Cmax was decreased by 58%. Conversely, Tmax was 22 minutes slower when the 35 mg test product was administered under fed conditions. 50 mg reference product (fed vs. fasting subjects):

Food decreased the AUC(o-t) and AUC(o-~) values by 9% and 8%, respectively. Cmax decreased by 27%. Conversely, Tmax was 58 minutes slower when the 50 mg reference product was administered under fed conditions. 35 mg test product vs. 50 mg reference product (fed subjects):

These two formulations were not bioequivalent under fed conditions since the 90% confidence interval for the geometric mean and peak concentration ratios was outside the range of 0.800 to 1.250. Dose proportionality assessment (18 mg vs. 35 mg test product in fasted subjects):

Although the 18 mg and 35 mg products were not identified as dose-proportional based on per-protocol analysis, dose proportionality can still be concluded since: (1) the 90% confidence interval for the dose-normalized In-transformed ratios Cmax, AUC(o-t), and AUC(o-~) was fully contained within the acceptance range of 0.800 and 1.250 for bioequivalence; and (2) the dose-normalized geometric mean ratios between the 18 mg and 35 mg test capsules were 0.996, 0.938, and 0.946 respectively for Cmax, AUC(o-t), and AUC(o-~).

Example 16: Efficacy and safety of ground diclofenac

This example describes a Phase 2, placebo-controlled, active, parallel-group, single-dose, double-blind, randomized, placebo-controlled diclofenac nanoformulation capsule study for the treatment of pain following surgical removal of third molars.

The Phase II efficacy study described in this example uses 18 mg and 35 mg Diclofenac Nanoformulation Capsules manufactured as described in Example 13(a) and (b). OBJECTIVES: The primary objective of this study is to evaluate the analgesic efficacy and safety of Diclofenac Nanoformulation Capsules compared with placebo in subjects with acute dental pain following third molar extraction. The secondary objective of this study is to evaluate the time to onset of analgesia for Diclofenac Nanoformulation Capsules compared with the standard celecoxib formulation. NUMBER OF SUBJECTS: Planned recruitment (and/or completion): Approximately 200 subjects (100 in each treatment group) will be recruited. SUBJECT POPULATION: Inclusion Criteria: An individual will be eligible to enter the study if all of the following inclusion criteria are met: 1. Male or female > 18 and < 50 years of age. 2. Requires extraction of 2 or more third molars. At least 1 of the third molars must be a mandibular molar completely or partially impacted by bone. If only 2 molars are removed, then they must be ipsilateral. 3. Experience moderate to severe pain intensity within 6 hours after surgery, as measured by a Visual Analogue Scale (VAS) rating of > 50 mm on a 100-mm scale. 4. Have a body weight of > 45 kg and a body mass index (BMI) of < 35 kg/m2. 5. If female and of childbearing age, non-lactating and not pregnant (negative pregnancy test in serum and urine on the day of dosing initiation). 6. If female, not of childbearing age (defined as post-menopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or practicing one of the following medically acceptable methods of birth control: a. Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 complete cycle (based on the individual's usual menstrual cycle length) before administration of the study drug. b. Total abstinence from sexual intercourse (since the last menstrual periods before administration of the study drug). c. Intrauterine device (IUD). d. Dual barrier method (condoms, diaphragm, or vaginal ring with spermicidal gels or creams). 7. Be in good health, in the investigator's opinion. 8. Be able to provide written informed consent to participate in the study and be able to understand the study procedures and requirements. 9. Must voluntarily sign and date an informed consent form (ICF) that is approved by an Institutional Review Board (IRB) before conducting any study procedure. 10. Be willing and able to comply with the study requirements (including diet and smoking restrictions), complete pain assessments, remain at the study site overnight, and return for follow-up 7 ± 2 days after surgery. Exclusion Criteria:

An individual will not be eligible to enter the study if any of the following exclusion criteria are not met: 1. Having a known history of clinically significant allergic reaction or intolerance to acetaminophen, aspirin, or any nonsteroidal anti-inflammatory drug (NSAIDs, including diclofenac and celecoxib); a history of NSAID-induced bronchospasm (individuals with the triad of asthma, nasal polyps, and chronic rhinitis are at higher risk for bronchospasm and should be carefully considered); or hypersensitivity, allergy, or significant reaction to sulfa drugs (including sulfonamides), ingredients of the study drug, or any other drug used in the study, including anesthetics and antibiotics that may be required on the day of surgery. 2. Testing positive on a urine drug screen or breathalyzer test for alcohol. Individuals who test positive on the screen and can obtain a prescription for the medication from their physician may be considered for recruitment to the study at the investigator's discretion. 3. Have a known or suspected history of alcoholism or drug abuse or misuse within a 2-year screening period, or evidence of tolerance or physical dependence prior to dosing with the study drug. 4. Have received or will require any medication (except hormonal contraceptives, vitamins, or nutritional supplements) within 5 half-lives (or, if the half-life is unknown, within 48 hours) prior to dosing with the study drug. 5. Have any clinically significant unstable cardiac, respiratory, neurological, immunological, hematological, or renal disease, or any other condition that, in the investigator's opinion, may compromise the individual's well-being, ability to communicate with study staff, or otherwise contraindicate participation in the study. 6. Have a history or current diagnosis of a significant psychiatric disorder that, in the investigator's opinion, would affect the individual's ability to meet the requirements of the study. 7. Are receiving systemic chemotherapy, have an active malignancy of any type, or have been diagnosed with cancer within the last 5 years of the scan (excluding squamous cell or basal cell carcinoma of the skin). 8. Have a history of a clinically significant gastrointestinal (GI) event (investigator's opinion) within 6 months prior to the scan or have any history of peptic or gastric ulcers or gastrointestinal bleeding. 9. Have a surgical or medical condition of the gastrointestinal or renal system that may significantly impair the absorption, distribution, or excretion of any drug substance. 10. Are considered by the investigator, for any reason (including, but not limited to, the risks described as precautions, warnings, and contraindications in the current version of the Investigator's Leaflet [IB] for Diclofenac Nanoformulation Capsules), to be an unsuitable candidate to receive the study drug. 11. Have a history of chronic use (defined as daily use for > 2 weeks) of NSAIDs, opioids, or glucocorticoids (except inhaled nasal steroids and topical corticosteroids) for any condition within 6 months prior to dosing with the study drug. Aspirin at a daily dose of < 325 mg is permitted for cardiovascular (CV) prophylaxis if the individual has been on a stable dosing regimen for > 30 days prior to the scan and has not experienced any significant medical problems. 12. Have significant renal or hepatic disease, as indicated by clinical laboratory evaluation (results > 3 times the upper limit of normal [ULN] for any liver function test, including aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase, or creatinine > 1.5 times the ULN) or have any clinically significant laboratory findings in the investigator's opinion that may contraindicate participation in the study. 13. Have significant difficulty swallowing capsules or are unable to tolerate oral medication. 14. Have previously participated in another Diclofenac Nanoformulation Capsules study, or have received any investigational drug or device or investigational therapy within 30 days prior to the screening.

PROJECT:

This is a phase II multicenter, randomized, double-blind, parallel-group, active- and placebo-controlled study to evaluate the efficacy and safety of Diclofenac Nanoformulation Capsules (18 mg and 35 mg) in individuals with postoperative dental pain. Eligible individuals will complete all screening procedures within 28 days prior to surgery.

During screening, individuals will provide written informed consent to participate in the study before any protocol-specified procedures or assessments are completed. On Day 1, individuals who remain eligible for study participation after completion of screening procedures and assessments will undergo extraction of 2 or more third molars. At least 1 of the third molars must be a mandibular molar that is completely or partially impacted by bone. If only 2 molars are removed, then they must be ipsilateral. All individuals will receive local anesthesia (2% lidocaine with 1:100,000 epinephrine). Nitrous oxide will be permitted at the investigator's discretion. Individuals who experienced moderate to severe pain intensity (a score of > 50 mm on a 100-mm VAS) within 6 hours after surgery and who continue to meet all study entry criteria will be randomized in a 1:1:1:1 ratio to receive 1 oral dose of Diclofenac Nanoformulation Capsules (18 mg or 35 mg), celecoxib capsules (400 mg), or placebo. The study drug will be administered by a non-mixed, third-party doser who will not perform any efficacy or safety assessments.

Individuals will assess their baseline pain intensity (VAS) before receiving the study drug (pre-dose, Time 0) and their pain intensity (VAS) and pain relief (5-point categorical scale) at the following appropriate time points: 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after Time 0 and immediately before the first dose of rescue medication. The 2-stopwatch method will be used to record the time to perceptible pain relief and time to significant relief, respectively. Individuals will complete a general assessment of the study drug 12 hours after Time 0 or immediately before the first dose of rescue medication (whichever occurs first). Vital signs will be recorded after the individual has been in a seated position for 5 minutes at the following times: before surgery, before time 0, 12 hours after time 0, and/or immediately before the first dose of rescue medication. Adverse events (AEs) will be monitored and recorded from the time of ICF signing until the Follow-up Visit (or Early Termination Visit). During the 12 hours following time 0, individuals will complete efficacy and safety assessments. Individuals will remain at the study site overnight and will be discharged on the morning of day 2. After discharge from the study site, individuals will be given a diary to record concomitant medications taken and AEs experienced after discharge.

Paracetamol (1000 mg) will be permitted as the initial rescue medication. Individuals will be encouraged to wait at least 60 minutes after receiving the study drug before taking the rescue medication. Additional analgesic rescue medication may be administered at the investigator's discretion if the rescue medication specified by the protocol is deemed inadequate. Individuals are not permitted to take any medications (except hormonal contraceptives, vitamins, nutritional supplements, and study medications) within 5 half-lives (or, if the half-life is unknown, within 48 hours) before taking the study medication until study discharge (day 2). Other restrictions include the following: alcohol use is prohibited from 24 hours before surgery until hospital discharge on day 2; nothing by mouth (NPO) from midnight before surgery until 1 hour after surgery; clear liquids are permitted only starting one hour after surgery until 1 hour after administration; 1 hour after administration, diet may be anticipated according to standard practice.

After discharge from the study site, individuals may be prescribed analgesics for home use according to standard practice in the study area. On Day 8 (± 2 days), individuals will return to the study site for a brief confirmatory physical assessment and concomitant medication and AE assessments. STUDY DRUG: Diclofenac Nanoformulation Capsules (18 mg and 35 mg) for oral administration REFERENCE PRODUCTS: Celecoxib 200-mg capsules administered as a 400-mg Placebo dose TREATMENT REGIMES

Eligible individuals meeting all study entry criteria will be randomized to receive one of the following treatments: One 18-mg Diclofenac Nanoformulation Capsule and one placebo capsule; One 35-mg Diclofenac Nanoformulation Capsule and one placebo capsule; Two 200-mg Celecoxib Capsules and two placebo capsules. STUDY DURATION: Up to approximately 5 weeks for each individual, including a 4-week scan period and a post-treatment follow-up visit approximately 1 week after dosing with the study drug. INVESTIGATION LOCATIONS OR COUNTRIES: Two study sites in the United States (USA). STUDY ENDPOINTS: Efficacy Endpoints:

The primary efficacy endpoint is the sum of total pain relief (TOTPAR) during hours 0 to 12 (TOTPAR-12) after time 0. Secondary endpoints are as follows: • Sum of total pain relief (TOTPAR) during hours 0 to 12 (TOTPAR-12) after Time 0. • TOTPAR at 0 to 4 hours (TOTPAR-4) and at 0 to 8 hours (TOTPAR-8) after Time 0. • VAS pain intensity difference (VASPID) at each time point after Time 0. • Time to onset of analgesia (measured as time to perceived pain relief confirmed by significant pain relief). • VAS pain intensity rating at each time point. • Difference in summed pain intensity of VAS (VASSPID) during 0 to 4 hours (VASSPID-4), during 0 to 8 hours (VASSPID-8), and during 0 to 12 hours (VASSPID-12) after Time 0. • Summed pain relief and intensity difference (sum of TOTPAR and VASSPID [SPRID]) during 0 to 4 hours (SPRID-4), during 0 to 8 hours (SPRID-8), and during 0 to 12 hours (SPRID-12) after Time 0. • Rating of pain relief at each scheduled time point after Time 0. • Peak pain relief • Time to onset of peak pain relief • Time to first perceptible pain relief • Time to significant pain relief • Proportion of individuals using rescue medication. • Time to first use of rescue medication (duration of analgesia). • Global assessment of study drug patient. Final safety checkpoints:

The safety endpoints are the incidence of treatment-emergent adverse events (TEAEs) and changes in vital sign measurements. SUMMARY OF STATISTICAL METHODS: Analysis Populations: The analysis populations include the following: • The intended treatment population (ITT) will consist of all individuals who are treated with the study drug and who have at least one assessment of pain relief after Time 0. The ITT population is the primary population for the efficacy analysis. • The per-protocol (PP) population will consist of all ITT individuals who remain in the study for at least 12 hours of treatment and who do not incur a major protocol violation that would challenge the validity of their data. This population will be used to assess the sensitivity of the primary efficacy analysis. • The safety population will include all individuals who are treated with the study drug. The safety population is the population for all safety assessments. Individual characteristics: Demographic and baseline characteristics (including age, sex, race, weight, BMI, medical history, duration of surgery, and baseline values of variables and efficacy) will be summarized for each treatment group and for the general population using descriptive statistics. No formal statistical analysis will be performed. Efficacy analyses:

The null hypothesis in this study is that the TOTPAR-12 for placebo is equal to the TOTPAR-12 for Diclofenac Nanoformulation Capsules. This will be analyzed using analysis of covariance (ANCOVA) models, which include treatment effect and significant covariates. The effects of potential covariates, such as sex, baseline pain intensity, and surgical trauma classification, will be assessed using appropriate ANCOVA models. The analysis will be based on a two-sided test with a significance level of 0.05.

Other comparisons between treatment regimens, including 18-mg Diclofenac Nanoformulation Capsules versus placebo and 400-mg celecoxib capsules versus placebo, will be considered secondary. No P-value adjustment will be made for multiple endpoints or multiple comparisons. Each efficacy endpoint will be summarized descriptively by treatment group.

For continuous secondary endpoints such as pain intensity score, VASPID at each point in the programmed time, peak pain intensity, TOTPAR-4, TOTPAR-8, VASSPID-4, VASSPID-8, VASSPID-12, SPRID-4, SPRID-8, and SPRID-12, descriptive statistics (such as mean, standard error, average, minimum, and maximum) will be provided for each treatment regimen. Nominal P-values from 2-sample tests comparing the placebo group with other treatment groups will be provided, but no formal statistical inference will be determined based on these tests.

For secondary ordinal endpoints, such as pain relief at each point in the scheduled time, peak pain relief, and overall study drug assessment, descriptive summaries will be provided to include the number and percentage of individuals in each treatment group category. Nominal P-values from Fisher's exact tests (or chi-square tests, as appropriate) comparing the placebo group with other treatment groups will be provided, but no formal statistical inferences will be made based on these tests.

For each time-to-event endpoint, the Kaplan-Meier method will be used to assess the treatment effect. Time to onset of analgesia (measured as time to perceived pain relief confirmed by significant pain relief) will be based on data collected using the 2-stopwatch method. Time to onset of analgesia will be censored to the right at 12 hours for individuals who did not experience perceived pain relief and significant pain relief during the 12-hour time interval after Time 0. The summary table will provide the number of individuals analyzed, the number of censored individuals, estimates for the quartiles, and 95% confidence intervals (CIs) for the estimated median and restricted mean estimate. P-values from Wilcoxon or log-rank tests (as appropriate) will be used to examine the treatment effect. Cox proportional harm models will be used to explore potential covariates such as sex, baseline pain intensity, and surgical trauma classification, if appropriate.

For the proportion of individuals using rescue medication, a logistic regression model adjusting for baseline pain intensity, if appropriate, will be used to assess the treatment effect. Subgroup analysis by sex may be performed if it is found to be a statistically significant covariate for TOTPAR-12. Baseline values are defined as the last measurements taken before dosing with a study drug.

For pain intensity, missing observations will be imputed using baseline observation performed (BOCF) for individuals who dropped out of the study due to lack of efficacy or an adverse event/intolerance to the study drug. BOCF imputation will be applied in place of all scheduled assessments after the early termination time due to lack of efficacy or an adverse event/intolerance to the study drug using the baseline observation taken before Time 0.

For individuals who dropped out of the study due to reasons other than lack of efficacy or an adverse event/intolerance to the study drug, the missing observations for pain intensity and pain relief will be imputed using last observation performed (LOCF). LOCF imputation will be applied in place of all scheduled assessments after the early termination time due to reasons other than lack of efficacy or an adverse event/intolerance to the study drug.

For individuals taking any dose of rescue medication, subsequent measurements after the first dose of rescue medication will be disregarded. Instead, all scheduled assessments after the first dose of rescue medication will be imputed using BOCF using the baseline observation taken before Time 0. Missing single data points will be imputed using linear interpolation if they do not occur at the end of the study. For other conditions prior to early termination or rescue medication, missing data will be imputed using LOCF. Safety analysis:

Data listings will be provided for safety data specified by protocol. The Medical Dictionary for Regulatory Activities (MedDRA) (Version 9.1 or higher) will be used to classify all AEs with respect to individual organ class and preferred term. Adverse event summaries will include only TEAEs, which will be summarized only for each treatment group. Fisher's two-sided exact test will be used to compare occurrence rates between commercially available metaxalone tablets and metaxalone nanoformulation capsules for all TEAEs.

For vital sign measurements, descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from baseline for vital signs will be calculated for each individual, and descriptive statistics will be provided on changes in vital signs from baseline for each treatment group at each scheduled time point after baseline. No formal statistical tests will be performed. Sample Size.

The standard deviation of TOTPAR-12 is assumed to be < 14.0. A sample size of 50 individuals per treatment group will provide □ 80% of the power to detect a minimum difference of 8.0 in TOTPAR-12 using a 2-sample t-test with a two-sided significance level of 0.5 (nQuery v6.0). Table 16a. Timeline of Events A: Scan (Days -28 to -1); B: Day of Surgery (Day 1); C: Preoperative; D: Postoperative; E: Pre-dose; F: 0 h; G: 15, 30, 45 min; H: 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 h; I: 12 h; J: Day 2; K: Follow-up (Day 8 ± 2 days or ET). The times listed are relative to the dosage with the study drug.

Medical history and concomitant medication use will be updated on Day 1 before surgery. c A complete physical examination (excluding genitourinary examination) will be performed at the scan. A brief confirmatory physical assessment, including an examination of the individual's mouth and neck, will be performed at the Follow-up visit (or Early Termination visit). d Vital signs will be recorded after the individual has been sitting for 5 minutes at the following times: at the scan, before surgery, before Time 0, 12 hours after Time 0, and/or immediately before the first dose of rescue medication, and at the Follow-up visit (or Early Termination visit). e Serum pregnancy test at the scan and urine pregnancy test before surgery on Day 1 (women of childbearing age only). Test results must be negative for the individual to remain in the study. f Oral radiographs taken within 1 year prior to the scan will be acceptable and do not need to be repeated. g Pain assessments will be conducted at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after Time 0 and immediately before the first dose of rescue medication. Pain intensity will also be assessed pre-dose. At each assessment time point, the pain intensity assessment will be completed first, and the pain relief assessment will be completed afterward. Subjects will not be able to compare their responses to previous responses. h Two timers will be started immediately after the subject has swallowed the study drug with 8 ounces of water (Time 0). Subjects will record the time to first perceptible and significant pain relief, respectively, by stopping the timers. i Subjects will complete a global assessment of the study drug 12 hours after Time 0 or immediately before the first dose of rescue medication (whichever occurs first). j Side effects will be monitored and recorded from the time the informed consent form (ICF) is signed until the Follow-up Visit (or Early Termination visit).

Claims (5)

1. Composition characterized in that it comprises diclofenac acid particles dispersed in at least two partially ground grinding materials, wherein a) the at least two grinding materials are: i. sodium lauryl sulfate and lactose monohydrate; or ii. sodium lauryl sulfate and anhydrous lactose; and b) the particles have an average particle size, as measured in terms of particle volume, less than or equal to a size selected from the group consisting of: 1000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, 300nm, 200nm and 100nm. 2. Composition according to claim 1, characterized in that the composition comprises 8-20% by weight of diclofenac, 0.5-2% by weight of sodium lauryl sulfate, and 76-90% by weight of lactose monohydrate, when the milling materials are sodium lauryl sulfate and lactose monohydrate. 3. Composition according to claim 2, characterized in that it comprises 15% by weight of diclofenac, 1% by weight of sodium lauryl sulfate, and 84% of lactose monohydrate. 4. Pharmaceutical composition characterized by comprising the composition as defined in any one of claims 1 to 3. 5. Pharmaceutical composition, according to claim 4, characterized by being used in medicine.