Patent EA-001873-B1 (EA)
Title: Stable particle in liquid formulations
Inventor: KAMPINGA JAAP
IPC: A61K38/18
Filed: 1998-03-18
Abstract: 1. A stable particle in liquid formulation comprising a discontinuous phase of microparticles suspended in a continuous phase which is a non-aqueous liquid in which the microparticles are insoluble, wherein the microparticles comprise finely powdered sugar glass holding at least one biomolecular product, the biomolecular product in the sugar glass either being in stable solid solution or being itself in suspension in the sugar glass, and wherein the continuous phase includes a low or very low HLB lipid-soluble surfactant. 2. A formulation according to Claim 1 wherein the sugar glass is formed from one or more sugars selected from the group consisting of trehalose, palatinit, glucopyranosyl sorbitol, glucopyranosyl mannitol, lactitol, and monosaccharide alcohols such as mannitol and inositol. 3. A formulation according to Claim 1 wherein the non aqueous continuous liquid phase is biocompatible. 4. A formulation according to Claim 1 in which the non aqueous continuous phase is a hydrophobic solvent. 5. A formulation according to Claim 1 in which the non aqueous liquid continuous phase is water-soluble. 6. A formulation according to any of Claims 1 to 5 in which the sugar glass microparticles are of diameter from about 0.1 to about 10 μm diameter, preferably less than 10 μm diameter, for example 1 or 2 or 5 μm diameter, most preferably less than 1 μm diameter. 7. A formulation according to Claim 6 wherein the microparticles do not exhibit a wide variation in particle size. 8. A formulation according to any of Claims 1 to 7 in which the microparticles are essentially dry, having a very low water content of less than about 1%. 9. A formulation according to any of Claims 1 to 8 in which the biomolecular product is a drug or other biologically active ingredient such as a protein, antibody, enzyme (e.g. restrictase) and the like, including biological materials such as foods stuffs, dye stuffs, beverages and the like. 10. A formulation according to any of Claims 1 to 9 in which the microparticles constitute a monodisperse suspension in the continuous phase. 11. A formulation according to any of Claims 1 to 10 which contains from about 1% to more than 50%, e.g. about 10% by weight microparticles in the discontinuous phase. 12. A formulation according to Claim 1 wherein the amount of surfactant in the continuous phase is from about 0.01% to about 10%, for example 1%, by volume. 13. A formulation according to Claim 1 or 12 which contains one or more surfactants selected from the group consisting of sorbitan sesquioleate, mannide monooleate, sorbitan tristearate and glycerol monostearate, lecithin (phosphatidyl choline), dipalmitoylphosphatidyl choline, distearoylphosphatidyl choline, dimyristoylphosphatidyl choline, and sorbitan laurate, palmitate, stearate and oleate. 14. A formulation according to Claim 1 in which the continuous non aqueous liquid phase includes or consists of one or more of the hydrophobic non-toxic solvents selected from the group consisting of sesame oil, arachis oil, soya oil, ethyloleate and mineral oil. 15. A formulation according to Claim 1 wherein the non aqueous continuous liquid phase comprises or consists of a water miscible non aqueous solvent selected from the group consisting of polyethylene glycol, glycerol, ethylene glycol, propylene glycol, propylene oxide, polypropylene glycol. 16. A process for producing a stable particle in liquid formulation which comprises the steps of producing microparticles containing one or more biomolecular products held in a sugar glass and adding the microparticles to a non aqueous continuous liquid phase in which the particles are not soluble to form a suspension, to biomolecular product in the sugar glass either being in stable solid solution or being itself in suspension in the sugar glass, and wherein a monodisperse single-particle suspension of microparticles is produced in the non-aqueous continuous liquid phase by inclusion into the continuous phase of at least one surfactant having a low or very low HLB. 17. A process according to Claim 16 wherein the surfactant is added to the continuous non aqueous liquid phase before addition of the particles. 18. A formulation according to Claim 1 which is a binary drug formulation wherein the biomolecular product is a drug precursor and wherein the final active drug component is synthesised or released by a chemical reaction which only begins when the precursor is wetted by body fluids after administration of the formulation to a patient. 19. A formulation according to Claim 1 containing microparticles holding more than one biomolecular product 20. A formulation according to Claim 1 or 19 containing a mixture of microparticles which release more than one type of biomolecular product when contacted with an aqueous environment. 21. A formulation according to Claim 19 or 20 wherein two or more biomolecular products interact when released in an aqueous environment. 22. A method for cutting DNA which uses a formulation according to Claim 1 wherein the biomolecular product is a restrictase, and wherein the formulation is contacted with an aqueous solution of DNA whereby the suspended enzyme held in the sugar glass dissolves in the aqueous phase containing the DNA and is capable of cutting the DNA.