# US 7,744,909 B2 · Dispersions for the formulation of slightly or poorly soluble agents > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,744,909 B2 - Document ID: US7744909B2 - Status: Granted - Kind: B2 - Application number: 11/408,967 - Filed: 2006-04-24 - Published: 2006-08-24 - Granted: 2010-06-29 - Earliest claimed: 2000-07-28 - Assignees: Abbott GmbH & Co. KG - Inventors: Rainer H. Muller - Web page: https://patentgrep.com/patent/US7744909B2 ## CPC - A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)} - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 31/10: Antimycotics - A61P 31/12: Antivirals - A61P 35/00: Antineoplastic agents - A61P 37/00: Drugs for immunological or allergic disorders - A61K 9/0048: {Eye, e.g. artificial tears} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The invention provides a dispersion having an oily phase, an aqueous phase, in the form of an oil-in-water emulsion or a water-in-oil emulsion, and at least one active ingredient that is only slightly or with difficulty soluble in the oily phase and the aqueous phase. The dispersion is free from toxicologically dangerous organic solvents. The dispersion contains the active ingredient dissolved in a quantity that is greater than the quantity which results additively from its maximum solubility in the oily and the aqueous phase of the emulsion prior to forming the emulsion. ## Claims ### Claim 1 A supersaturated dispersion which comprises: an oily phase; an aqueous phase, in the form of an oil-in-water emulsion or a water-in-oil emulsion; and at least one active ingredient that is only slightly or with difficulty soluble in the oily phase and the aqueous phase, wherein the dispersion is free from toxicologically dangerous organic solvents and the dispersion is supersaturated containing the active ingredient dissolved in a quantity that is at least 5 times greater than the quantity which results additively from its maximum solubility in the oily and the aqueous phase of the emulsion, said dispersion obtained by combining; the aqueous phase, the oily phase, which oily phase is not or only partially miscible with the aqueous phase, the surfactant or stabilizer, and a solid phase, which comprises the one active ingredient, to form a pre-dispersion, wherein the active ingredient is suspended in at least a portion of the aqueous phase before contacting the active ingredient with the oily phase, which pre-dispersion of liquid and solid phases is subjected to a high-energy homogenization process wherein no toxicologically dangerous solvents are used, and wherein at least one of the at least one active ingredient is incorporated as solid particles into the liquid phases of the dispersion without previously being dissolved, the at least one active ingredient is pulverized to form particles, the particles of active ingredient are triturated or mixed with an oil-in-water emulsion or a water-in-oil emulsion to form the pre-dispersion, or the at least one active ingredient is pulverized to form particles, the particles of active ingredient are added to a surfactant solution, said surfactant solution is homogenized and mixed with an oil-in-water emulsion or a water-in-oil emulsion to form the pre-dispersion. ### Claim 2 (depends on 1) Dispersion according to claim 1, wherein the active ingredient, in addition to the dissolved state, is partially present in highly dispersed solid crystalline form, resulting in a dispersion with a heterogeneously dispersed phase of oil drops and active ingredient crystals. ### Claim 3 (depends on 2) Dispersion according to claim 2, wherein at least 90% of the active ingredient crystals present are smaller than 5 μm, volume distribution determined by laser diffractometry. ### Claim 4 (depends on 2) Dispersion according to claim 2, wherein at least 95% of the active ingredient crystals present are smaller than 5 μm, volume distribution determined by laser diffractometry. ### Claim 5 (depends on 2) Dispersion according to claim 2, wherein about 100% of the active ingredient crystals present are smaller than 5 μm, volume distribution determined by laser diffractometry. ### Claim 6 (depends on 2) Dispersion according to claim 2, wherein at least 90% of the active ingredient crystals present are smaller than 3 μm, volume distribution determined by laser diffractometry. ### Claim 7 (depends on 2) Dispersion according to claim 2, wherein at least 95% of the active ingredient crystals present are smaller than 3 μm, volume distribution determined by laser diffractometry. ### Claim 8 (depends on 2) Dispersion according to claim 2, wherein about 100% of the active ingredient crystals present are smaller than 3 μm, volume distribution determined by laser diffractometry. ### Claim 9 (depends on 2) Dispersion according to claim 2, wherein at least 90% of the active ingredient crystals present are smaller than 1 μm, volume distribution determined by laser diffractometry. ### Claim 10 (depends on 2) Dispersion according to claim 2, wherein at least 95% of the active ingredient crystals present are smaller than 1 μm, volume distribution determined by laser diffractometry. ### Claim 11 (depends on 2) Dispersion according to claim 2, wherein about 99% of the active ingredient crystals present are smaller than 1 μm, volume distribution determined by laser diffractometry. ### Claim 12 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises an oil-in-water emulsion and contains about 5 to about 99.5 wt. % of aqueous phase, based on the total weight of the dispersion. ### Claim 13 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises an oil-in-water emulsion and contains about 10 to about 95 wt. % of aqueous phase, based on the total weight of the dispersion. ### Claim 14 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises an oil-in-water emulsion and contains about 60 to about 95 wt. % of aqueous phase, based on the total weight of the dispersion. ### Claim 15 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises an oil-in-water emulsion and contains about 70 to about 95 wt. % of aqueous phase, based on the total weight of the dispersion. ### Claim 16 (depends on 1) Dispersion according to claim 1, wherein the dispersion contains at least one selected from the group consisting of emulsifiers and stabilizers. ### Claim 17 (depends on 16) Dispersion according to claim 16, wherein the dispersion contains less than 15 wt. % of emulsifiers and/or stabilizers, based on the total weight of the dispersion. ### Claim 18 (depends on 16) Dispersion according to claim 16, wherein the dispersion contains less than 10 wt. % of emulsifiers and/or stabilizers, based on the total weight of the dispersion. ### Claim 19 (depends on 16) Dispersion according to claim 16, wherein the dispersion contains less than 2 wt. % of emulsifiers and/or stabilizers, based on the total weight of the dispersion. ### Claim 20 (depends on 16) Dispersion according to claim 16, wherein the dispersion contains from about 0.6 to about 1.2 wt. % of emulsifiers and/or stabilizers, based on the total weight of the dispersion. ### Claim 21 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises at least one emulsifier selected from the group consisting of egg lecithin, soya lecithin, phospholipids of egg or soya, sorbitan esters, sorbitane trioleate, polyethylene glycol sorbitan esters, polyoxyethylene sorbitane monooleate, sodium glycocholate, sodium lauryl sulphate, and mixtures thereof. ### Claim 22 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises at least one stabilizer selected from the group consisting of block co-polymers, poloxamers, Poloxamer 188 and 407, poloxamines, Poloxamine 908, polyvinyl pyrrolidone, polyvinyl alcohol, gelatine, polysaccharide, hyaluronic acid, chitosan, derivatives of chitosan, polyacryl acid, derivatives of polyacryl acid, polycarbophil, cellulose derivatives, methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sugar esters, saccharose monostearate, sodium citrate individually, and mixtures thereof. ### Claim 23 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises an oil-in-water emulsion and the oil phase used for the preparation of the dispersion comprises lipids which are solid at room temperature. ### Claim 24 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises an oil-in-water emulsion and the oil phase used for the preparation of the dispersion comprises lipids which are liquid at room temperature. ### Claim 25 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises an oil-in-water emulsion and the oil phase used for the preparation of the dispersion comprises a mixture of one or more lipids which are liquid at room temperature with one or more lipids which are solid at room temperature. ### Claim 26 (depends on 25) Dispersion according to claim 25, wherein the mixture of liquid lipid:solid lipid varies from about 99:1 to about 1:99 parts by weight. ### Claim 27 (depends on 26) Dispersion according to claim 26, wherein proportion of liquid lipid in mixture of lipids is at least 10 parts by weight. ### Claim 28 (depends on 26) Dispersion according to claim 26, wherein proportion of liquid lipid in mixture of lipids is at least 30 parts by weight. ### Claim 29 (depends on 26) Dispersion according to claim 26, wherein proportion of liquid lipid in mixture of lipids is at least 50 parts by weight. ### Claim 30 (depends on 1) Dispersion according to claim 1, wherein the oil phase comprises at least one individual lipid or mixtures thereof selected from the group consisting of natural and synthetic triglycerides, natural and synthetic monoglycerides, natural and synthetic diglycerides, self-emulsifying modified lipids, natural and synthetic waxes, fatty alcohols, esters of fatty alcohols, ethers of fatty alcohols, hard wax, Imwitor 900, glycerol trilaurate, glycerol myristate, glycerol palmitate glycerol stearate, glycerol behenat, waxes, cetyl palmitate, carnauba wax, white wax, hydrocarbons, and hard paraffin. ### Claim 31 (depends on 1) Dispersion according to claim 1, wherein the an oil phase comprises at least one selected from the group consisting of soya oil, safflower oil, long-chain triglycerides, medium-chain triglycerides, miglyols, fish oils, oils with an increased constituent of unsaturated fatty acids, and acetylated partial glycerides. ### Claim 32 (depends on 1) Dispersion according to claim 1, wherein the aqueous phase comprises water or mixtures of water with water-miscible organic liquids. ### Claim 33 (depends on 1) Dispersion according to claim 1, wherein the aqueous phase comprises water and at least one liquid polyethylene glycol. ### Claim 34 (depends on 1) Dispersion according to claim 1, wherein the aqueous phase contains at least one additive selected from the group consisting of electrolytes, non-electrolytes, glycerol, glucose, mannitol, xylite, gel forming agents, cellulose, and cellulose derivatives. ### Claim 35 (depends on 1) Dispersion according to claim 1, wherein the active ingredient is selected from the group consisting of medical drugs for treatment of human or animal bodies. ### Claim 36 (depends on 1) Dispersion according to claim 1, wherein the dispersion contains one or more active ingredients selected from the group consisting of anaesthetics, antibiotics, antimycotics, antiinfectives, corticoids, hormones, antiestrogens antiseptics, vasoactivating agents, glauco agents, beta blocker, cholinergics, sympathomimetics, carboanhydrase inhibitors, mydriatics, virustatics, agents for tumor therapy, antiallergics, vitamins, antiinflammytory drugs, immuno-supressives, ciclosporine, and any combination thereof. ### Claim 37 (depends on 1) Dispersion according to claim 1, wherein the dispersion is positively charged. ### Claim 38 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises at least one positively charged stabilizer. ### Claim 39 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises at least on positively charged stabilizer selected from the group consisting of stearylamine, positively charged phospholipids, and positively charged lipids. ### Claim 40 (depends on 1) Dispersion according to claim 1, wherein the dispersion comprises an oil-in-water emulsion adapted for intravenous injection, and wherein the dispersion comprises at least on positively charged stabilizer. ### Claim 41 (depends on 40) Dispersion according to claim 40, wherein the dispersion further includes at least one lecithines or nonionic stabilizers. ### Claim 42 (depends on 40) Dispersion according to claim 40, wherein the dispersion further comprises at least one poloxamer polymer. ### Claim 43 (depends on 1) Dispersion according to claim 1, wherein the active ingredient comprises ciclosporine. ### Claim 44 (depends on 1) Dispersion according to claim 1, wherein the active ingredient comprises at least one selected from the group consisting of anti-mycotics, Amphotericin B, anti-infectives, Buparvaquone, Atovaquone, immuno-suppressives, Cyclosporin A, natural and synthetic derivatives of Cyclosporin A, tumor therapy drugs, Paclitaxel, and Taxotere. ### Claim 45 (depends on 1) Dispersion according to claim 1, wherein the active ingredient has a solubility of less than 1 part per 100 parts in the aqueous phase. ### Claim 46 (depends on 1) Dispersion according to claim 1, wherein the active ingredient has a solubility of less than 1 part per 1000 parts in the aqueous phase. ### Claim 47 (depends on 1) Dispersion according to claim 1, wherein the active ingredient has a solubility of less than 1 part per 10,000 parts in the aqueous phase. ### Claim 48 (depends on 1) Dispersion according to claim 1, wherein the active ingredient has a solubility of less than 1 part per 100 parts in the oily phase. ### Claim 49 (depends on 1) Dispersion according to claim 1, wherein the active ingredient has a solubility of less than 1 part per 1000 parts in the oily phase. ### Claim 50 (depends on 1) Dispersion according to claim 1, wherein the active ingredient has a solubility of less than 1 part per 10,000 parts in the oily phase. ### Claim 51 (depends on 1) Dispersion according to claim 1, wherein the size of water phase and oily phase droplets is less than about 10 μm. ### Claim 52 (depends on 1) Dispersion according to claim 1, wherein the size of water phase and oily phase droplets is less than about 5 μm. ### Claim 53 (depends on 1) Dispersion according to claim 1, wherein the size of water phase and oily phase droplets is less than about 1 μm. ### Claim 54 (depends on 1) Dispersion according to claim 1, wherein a pH of the dispersion is between 4 and 8. ### Claim 55 (depends on 1) Dispersion according to claim 1, wherein a pH of the dispersion is between 5 and 7.5. ### Claim 56 (depends on 1) Dispersion according to claim 1, wherein a pH of the dispersion is between 6 and 7.5. ### Claim 57 (depends on 1) Dispersion according to claim 1, wherein the active ingredient is present in an amount of from about 0.01 to about 30 wt. %, based on the total weight of the dispersion. ### Claim 58 (depends on 1) Dispersion according to claim 1, wherein the active ingredient is present in an amount of from about 0.1 to about 10 wt. %, based on the total weight of the dispersion. ### Claim 59 (depends on 1) Dispersion according to claim 1, wherein the active ingredient is present in an amount of from about 1 to about 5 wt. %, based on the total weight of the dispersion. ### Claim 60 (depends on 1) A medicament comprising the dispersion according to claim 1. ### Claim 61 (depends on 1) A medicament for treatment of mycoses, inflammations, allergic diseases, tumor diseases, cardiovascular diseases, viral and other infections, or for conducting anaesthetic treatment comprising a dispersion according to claim 1. ### Claim 62 (depends on 1) A medicament which can be administered intravenously, intra- and subcutaneously, intramuscularly, intra-articularly or intraperitoneally comprising a dispersion according to claim 1. ### Claim 63 (depends on 1) A medicament which has a prolonged residence time in the blood, compared to negatively charged dispersions, comprising a dispersion according to claim 1. ### Claim 64 Supersaturated dispersions in form of an oil-in-water emulsion comprising: an oil phase; a water phase; one or more surfactants or stabilizers; and one or more drugs being only slightly or poorly soluble in the water and in the oil, the dispersions are supersaturated and contain an incorporated amount of the drug in dispersion that is at least 5 times higher than the additive solubility calculated from the drug solubility in the oil and water phases of the dispersion, and the dispersions are organic solvent-free, said dispersion obtained by combining; the aqueous phase, the oily phase, which oily phase is not or only partially miscible with the aqueous phase, the surfactant or stabilizer, and a solid phase, which comprises the one or more drugs, to form a pre-dispersion, wherein the active ingredient is suspended in at least a portion of the aqueous phase before contacting the active ingredient with the oily phase, which pre-dispersion of liquid and solid phases is subjected to a high-energy homogenization process wherein no toxicologically dangerous solvents are used, and wherein at least one of the one or more drugs is incorporated as solid particles into the liquid phases of the dispersion without previously being dissolved, the one or more drugs is pulverized to form particles, the particles of drug are triturated or mixed with an oil-in-water emulsion or a water-in-oil emulsion to form the pre-dispersion, or the one or more drugs is pulverized to form particles, the particles of drug are added to a surfactant solution, said surfactant solution is homogenized and mixed with an oil-in-water emulsion or a water-in-oil emulsion to form the pre-dispersion. ### Claim 65 (depends on 64) Dispersions according to claim 64, wherein the concentration of surfactant, stabilizer or mixtures of surfactants and stabilizers is between 0.1% and 20% by weight. ### Claim 66 (depends on 1) Dispersion according to claim 1, wherein the active ingredient is dissolved in a quantity that is at least 10 times greater than the quantity which results additively from its maximum solubility in the oily and the aqueous phase of the emulsion. ### Claim 67 (depends on 64) Dispersions according to claim 64, wherein the active ingredient is dissolved in a quantity that is at least 10 times greater than the quantity which results additively from its maximum solubility in the oily and the aqueous phase of the emulsion. ### Claim 68 A method for the production of a dispersion comprising: an oily phase; an aqueous phase, in the form of an oil-in-water emulsion or a water-in-oil emulsion; and at least one active ingredient that is only slightly or with difficulty soluble in the oily phase and the aqueous phase, wherein the dispersion is free from toxicologically dangerous organic solvents and the dispersion is supersaturated containing the active ingredient dissolved in a quantity that is at least 5 times greater than the quantity which results additively from its maximum solubility in the oily and the aqueous phase of the emulsion, the method comprising: suspending the active ingredient in at least a portion of the aqueous phase to form a suspension and mixing the suspension with said oily phase to form a mixture; subjecting the mixture of liquid and solid phases to a high-energy homogenization process with a homogenizer without using toxicologically dangerous organic solvents, wherein one of: (a) incorporating the active ingredient as a solid into the liquid phases of the dispersion without previously being dissolved, (b) pulverizing the active ingredient, triturating or mixing the pulverized active ingredient with an oil-in-water emulsion or a water-in-oil emulsion to form a pre-dispersion, and subjecting the pre-dispersion to the homogenization or high pressure homogenization process, or (c) pulverizing the active ingredient, dispersing the pulverized active ingredient in a surfactant solution, homogenizing the dispersion to form a homogenized dispersion, then mixing the homogenized dispersion with an oil-in-water emulsion or a water-in-oil emulsion to form a pre-dispersion, and subjecting the pre-dispersion to the homogenization or high pressure homogenization process.