# US 8,541,400 B2 · Compositions forming non-lamellar dispersions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,541,400 B2 - Document ID: US8541400B2 - Status: Granted - Kind: B2 - Application number: 11/658,857 - Filed: 2005-08-04 - Published: 2008-07-03 - Granted: 2013-09-24 - Earliest claimed: 2004-08-04 - Assignees: Camurus AB - Applicants: Markus Johnsson; Fredrik Joabsson; Fredrik Tiberg - Inventors: Markus Johnsson; Fredrik Joabsson; Fredrik Tiberg - Web page: https://patentgrep.com/patent/US8541400B2 ## CPC - A61K 9/1274: Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases or cochleates; Sponge phases - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 25/24: Antidepressants - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 31/04: Antibacterial agents - A61P 31/10: Antimycotics - A61P 31/12: Antivirals - A61P 35/00: Antineoplastic agents - A61P 37/02: Immunomodulators - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)} - 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 present invention relates to compositions containing a) at least one monoacyl lipid; b) at least one diacyl glycerol and/or tochopherol; and c) at least one fragmentation agent; and optionally an active agent. The compositions are capable of self-dispersing to provide colloidal non-lamellar particles upon contact with an aqueous fluid. The invention additionally provides a method for forming non-lamellar particles from such compositions, and pharmaceutical formulations containing the compositions, plus non-lamellar particles formable from the compositions. ## Claims ### Claim 1 A composition which self-disperses upon contact with an aqueous fluid to provide colloidal non-lameller particles having at least an internal region adopting a non-lamellar phase structure and having a monomodal size distribution with an average particle size of no more than 5 μm, said composition comprising a) at least one monoacyl lipid, wherein said component a) consists of a monoacyl lipid or mixture of monoacyl lipids which forms a micellar or lamellar phase upon contact with water; b) at least one diacyl glycerol, at least one tocopherol, or mixtures thereof, wherein said component b) comprises at least one diacyl glycerol with acyl groups each having 12 to 22 carbon atoms and between 0 and 3 unsaturations, or at least one tocopherol, or mixtures thereof and c) at least one fragmentation agent, wherein said component c) is selected from polymeric fragmentation agents, polyol surfactants, proteins, anionic surfactants, cationic surfactants, monoacyl lipids and mixtures thereof; and optionally an active agent; wherein a/(a+b), being the ratio by weight of component a) to the sum of components a) and b) is between 0.2 and 0.9; c/(a+b+c), being the ratio by weight of component c) to the sum of components a), b) and c), is between 0.01 and 0.3. ### Claim 2 (depends on 1) A composition as claimed in claim 1 wherein said non-lamellar particles are reversed hexagonal liquid crystalline particles. ### Claim 3 (depends on 1) A composition as claimed in claim 1 wherein, upon self dispersion, at least 50% by weight of components a), b) & c) are present as non-lamellar particles. ### Claim 4 (depends on 1) A composition as claimed in claim 1 wherein said colloidal particles have a monomodal size distribution with an average particle size of no more than 5 μm. ### Claim 5 (depends on 1) A composition as claimed in claim 1 wherein said component a) comprises at least one monoacyl oligoglycerol. ### Claim 6 (depends on 1) A composition as claimed in claim 1 wherein said component b) forms an oil or L2 phase upon contact with water and consists of at least one component selected from diacyl glycerols, mixtures of diacyl glycerols, tocopherols and mixtures of tocopherols. ### Claim 7 (depends on 1) A composition as claimed in claim 1 wherein component a) comprises diglycerolmonooleate and component b) comprises glyceroldioleate. ### Claim 8 (depends on 1) A composition as claimed in claim 1 additionally comprising at least one component selected from charged lipids, surfactants, polymeric solidifying agents and polymeric surface modifiers. ### Claim 9 (depends on 1) A composition as claimed in claim 1 containing no organic solvent or hydrotrope. ### Claim 10 (depends on 1) A composition as claimed in claim 1 containing up to 15% by weight of an organic solvent. ### Claim 11 (depends on 1) A composition as claimed in claim 1 comprising a shear-sensitive and/or heat-sensitive active agent. ### Claim 12 (depends on 1) A composition as claimed in claim 1 comprising at least one active agent selected from progesterone, fenofibrate, fulvestrant, ketoconazole benzydamine, propofol, octreotide, and testosterone undecanoate. ### Claim 13 (depends on 1) A composition as claimed in claim 1 wherein component b) consists of a diacyl glycerol or mixtures thereof. ### Claim 14 (depends on 1) A pharmaceutical formulation comprising a composition as claimed in claim 1 and at least one pharmaceutically acceptable carrier or excipient. ### Claim 15 (depends on 14) A pharmaceutical formulation as claimed in claim 14 wherein said formulation consists of at least 50% by weight of the composition, no more than 10% by weight total organic solvent, including any solvent present in said composition, and the remainder aqueous solvents and/or pharmaceutically acceptable formulating agents. ### Claim 16 (depends on 14) A pharmaceutical formulation as claimed in claim 14 wherein said formulation is suitable for oral administration. ### Claim 17 Colloidal non-lamellar particles comprising a) at least one monoacyl lipid, wherein said component a) consists of a monoacyl lipid or mixture of monoacyl lipids which forms a micellar or lamellar phase upon contact with water; b) at least one diacyl glycerol, at least one tocopherol, or mixtures thereof, wherein said component b) comprises at least one diacyl glycerol with acyl groups each having 12 to 22 carbon atoms and between 0 and 3 unsaturations, or at least one tocopherol, or mixtures thereof and c) at least one fragmentation agent, wherein said component c) is selected from polymeric fragmentation agents, polyol surfactants, proteins, anionic surfactants, cationic surfactants, monoacyl lipids and mixtures thereof; optionally an active agent and optionally an aqueous fluid; wherein said colloidal particles have at least an internal region adopting said non-lamellar phase structure and have a monomodal size distribution with an average particle size of no more than 5 μm; wherein a/(a+b), being the ratio by weight of component a) to the sum of components a) and b) is between 0.2 and 0.9; c/(a+b+c), being the ratio by weight of component c) to the sum of components a), b) and c), is between 0.01 and 0.3. ### Claim 18 (depends on 17) Colloidal non-lamellar particles as claimed in claim 17 formed or formable from a composition. ### Claim 19 (depends on 17) Colloidal non-lamellar particles as claimed in claim 17 wherein said particles are stable to storage in dispersion in an aqueous solvent for at least 10 days. ### Claim 20 (depends on 17) Colloidal non-lamellar particles as claimed in claim 17 wherein fragmentation agent c) comprises at least one monoacyl lipid. ### Claim 21 A kit for the preparation of a dispersion of non-lamellar particles, said kit comprising a composition comprising; a) at least one monoacyl lipid, wherein said component a) consists of a monoacyl lipid or mixture of monoacyl lipids which forms a micellar or lamellar phase upon contact with water; b) at least one diacyl glycerol, at least one tocopherol, or mixtures thereof, wherein said component b) comprises at least one diacyl glycerol with acyl groups each having 12 to 22 carbon atoms and between 0 and 3 unsaturations, or at least one tocopherol, or mixtures thereof and c) at least one fragmentation agent, wherein said component c) is selected from polymeric fragmentation agents, polyol surfactants, proteins, anionic surfactants, cationic surfactants, monoacyl lipids and mixtures thereof; and optionally an active agent; wherein said colloidal particles have at least an internal region adopting said non-lamellar phase structure and have a monomodal size distribution with an average particle size of no more than 5 μm; wherein a/(a+b), being the ratio by weight of component a) to the sum of components a) and b) is between 0.2 and 0.9; c/(a+b+c), being the ratio by weight of component c) to the sum of components a), b) and c), is between 0.01 and 0.3. ### Claim 22 A method for the formation of a dispersion of non-lamellar particles, said method comprising contacting a composition comprising a) at least one monoacyl lipid, wherein said component a) consists of a monoacyl lipid or mixture of monoacyl lipids which forms a micellar or lamellar phase upon contact with water; b) at least one diacyl glycerol, at least one tocopherol, or mixtures thereof, wherein said component b) comprises at least one diacyl glycerol with acyl groups each having 12 to 22 carbon atoms and between 0 and 3 unsaturations, or at least one tocopherol, or mixtures thereof and c) at least one fragmentation agent, wherein said component c) is selected from polymeric fragmentation agents, polyol surfactants, proteins, anionic surfactants, cationic surfactants, monoacyl lipids and mixtures thereof; wherein said colloidal particles have at least an internal region adopting said non-lamellar phase structure and have a monomodal size distribution with an average particle size of no more than 5 μm; wherein a/(a+b), being the ratio by weight of component a) to the sum of components a) and b) is between 0.2 and 0.9; c/(a+b+c), being the ratio by weight of component c) to the sum of components a), b) and c), is between 0.01 and 0.3; and with an aqueous fluid and optionally subjecting the thus-formed mixture to a low energy agitation method.