US 2004.0053894A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0053894 A1 MaZeSS et al. (43) Pub. Date: Mar. 18, 2004 (54) FORMULATION FOR LIPOPHILICAGENTS (21) Appl. No.: 10/247,765 (75) Inventors: Richard B. Mazess, Madison, WI (22) Filed: Sep. 18, 2002 (US); Jeffrey W. Driscoll, Middleton, WI (US); Creighton Reed Publication Classification Goldensoph, DeForest, WI (US); Leon W. LeVan, Oregon, WI (US) (51) Int. Cl." ..................................................... A61K 31/59 (52) U.S. Cl. .............................................................. 514/167 Correspondence Address: MICHAEL BEST & FRIEDRICH, LLP ONE SOUTH PINCKNEY STREET (57) ABSTRACT PO BOX 1806 MADISON, WI 53701 The invention relates to pharmaceutical formulations of lipophilic therapeutic agents in which Such agents are Solu (73) Assignee: Bone Care International, Inc., Middle bilized in largely aqueous vehicles, and processes for pre ton, WI paring and using the same. US 2004/0053894 A1 Mar. 18, 2004 FORMULATION FOR LIPOPHILICAGENTS core of the micelle, or can entangle the agents at various positions within the micelle walls. Although micellar for CROSS-REFERENCE TO RELATED mulations can Solubilize a variety of lipophilic therapeutic APPLICATIONS agents, the loading capacity of conventional micelle formu lations is limited by the Solubility of the therapeutic agent in 0001. Not applicable. the micelle Surfactant. For many lipophilic therapeutic STATEMENT REGARDING FEDERALLY agents, Such Solubility is too low to offer formulations that SPONSORED RESEARCH OR DEVELOPMENT can deliver therapeutically effective doses. 0008. The formation of complexes, solid solutions and 0002) Not Applicable Solid dispersions by means of the use of Suitable polymers is another approach for increasing the water-Solubility of BACKGROUND OF THE INVENTION pharmaceutically active Substances. In Such a case, the 0003. This invention relates to pharmaceutical formula active ingredient is incorporated in a Suitable hydrophilic tions of lipophilic therapeutic agents in which Such agents carrier, which increases the solubility and the bioavailability are Solubilized in largely aqueous vehicles, and uses for Such thereof without any formal covalent bonds originating formulations. The formulations are stable in aqueous-based between the drug and the polymer matrix. The difference vehicles, and have therapeutically and commercially useful between a Solid Solution and a Solid dispersion is typically concentrations of active ingredient. in the form of the active ingredient. In a Solid Solution, the active is present in the amorphous molecular form, while in 0004. Many pharmacologically active substances are a dispersion the active is present in a crystalline form, as fine lipophilic, i.e., only sparingly or negligibly water-Soluble. as possible. Lipophilic therapeutic agents span the entire range of bio logically and/or pharmacologically active Substances. For 0009 Even more widespread and studied is the use of the example, they include certain analgesics and anti-inflamma interaction between a polymer and a drug to give rise to a tory agents, anti-asthma agents, anti-bacterial agents, anti true complex, wherein chemical bonds of a noncovalent Viral agents, anti-coagulants, anti-depressants, anti-neoplas nature are involved. Complexing polymers employed in the tic agents and immunosuppressants, 3-blockers, pharmaceutical field include, e.g., polyethylene glycols, corticosteroids, opioid analgesics, lipid regulating agents, polypropylene glycols, cyclodextrins, carboxymethylcellu anxiolytics, Sedatives, hypnotics and neuroleptics. lose, polyvinylpyrrolidone (PVP) 0005 The poor water-solubility of these lipophilic agents 0010 Co-precipitation is yet another widespread method often results in major difficulties in formulation, particularly for the preparation of complexes with increased Solubility. In when easily Sterilizable and administrable homogeneous this method, the Substance and the polymer are dissolved in aqueous Solutions are needed. Efficacious aqueous-based an organic Solvent in which they are both Soluble, and the formulations are particularly problematic for Systemic Solution is then evaporated at atmospheric preSSure, under administration, in particular parenteral administration (i.e., Vacuum, by Spray-drying or by lyophilization, to yield a dry injectable Solutions) and for certain liquid preparations for, product actually made of the complex of the treated drug. e.g., topical gynecologic, dermatologic ophthalmic, etc. use, Such complexes can also be obtained by applying other and for use on the oral mucous membranes. methods, Such as grinding and mixing the ingredients in a mill, or by extrusion of a paste containing the two products 0006. A number of approaches for obtaining aqueous together with a minor amount of water, etc. In comparison compositions of sparingly water-Soluble drugs are known. with the Starting drug, the complex typically shows an Such approaches Seek to increase the Solubility, and accord appreciably enhanced water-Solubility. ingly, increase the ease of formulation and the bioavailabil ity of the sparingly Soluble or lipophilic active agents. One 0011. In devising a working method for solubilizing Such approach involves chemical modification of the lipo drugs by complexation, it is necessary to take into account philic drug by introduction of a ionic or ionizable group or the molecular weight of the polymer, Since the Solubility of a group that lowers the melting point. The former generally the active ingredient directly depends thereon. In general, depends upon the lipophilic drug having a hydroxyl or low molecular weights are more Suitable than medium to carboxy group which can be used to form various kinds of high molecular weights. esters. The latter is based on the concept that, to be Solubi 0012 Still another method involves use of various co lized, the molecules have to leave the crystal lattice. Any Solvent Systems, i.e., compositions using a Solvent mixture modification of the molecule that lowers the melting point, containing water and one or more organic Solvents. One and thus reduces the energy of the crystal lattice, tends to approach to Solubilizing lipophilic drug agents in aqueous increase the Solubility thereof in any Solvent. Systems is to employ Some combination of alcohols and 0007 Another method involves physico-chemical solu glycols (PDA.J. Pharm. Sci. Technol. 50(5) 1996; U.S. Pat. bilization techniques Such as micellar Solubilization by Nos. 6,136,799; 6,361,758 and 5,858,999) Organic contents means of Surface-active agents, i.e., the use of Surfactant as high as 50% or more are often required to ensure micelles to Solubilize and transport the therapeutic agent. Solubility during manufacturing, Storage and administration. Micelles are agglomerates of colloidal dimensions formed Although organic levels while high will still be below the by amphiphilic compounds under certain conditions. LD for a low volume parenteral dosage, the amounts are Micelles, and pharmaceutical compositions containing Still typically undesirable. High levels of organic Solvent can micelles, have been extensively Studied and are described in cause pain on injection and tissue necrosis. detail in the literature. In acqueous Solution, micelles can 0013. Other methods involve the formation of complexes incorporate lipophilic therapeutic agents in the hydrocarbon by the addition of chelating agents Such as citric acid, US 2004/0053894 A1 Mar. 18, 2004 tartaric acid, amino acids, thioglycolic acid and edetate invention are not particularly limited. Agents of particular disodium. Others use buffering agents Such as acetate, interest include Vitamin D compounds and analogs. By citrate, glutamate and phosphate Salts. However, buffers and employing a lipophilic, i.e., fat-Soluble, antioxidant, Smaller chelating agents have been implicated in imparting alumi amounts of antioxidant may be used compared to known num levels in products to in exceSS of 3.5 parts per million formulations utilizing water Soluble antioxidants. leading to adverse side effects. (International Patent Appli 0020. The formulations of the present invention preclude cation Publication WO 96/36340) Moreover, certain chelat the need for high organic Solvent contents, which can cause ing agents Such as EDTA have be implicated in adverse irritations in Some patients. In addition, formulations of the effects Such nephrotoxicity and renal tubular necrosis. (U.S. present invention omit buffers and chelating agents. The use Pat. No. 6,361,758) of buffers and chelating agents in, e.g., Some prior Vitamin 0.014. Each of these foregoing methods has its inherent D formulations, has been linked to the introduction of limitations. For many of the pharmaceutical Substances, the undesirable aluminum levels into the product and eventually solubility levels that can be achieved with one or another of into the patient. the methods discussed above are still insufficient to make 0021. The invention also relates to methods for the treat their use in aqueous-based commercial products viable. ment and/or prophylaxis of certain diseases and disorders 0.015. An exemplary and important class of lipophilic comprising administering, e.g., parenterally, to a patient in drug agents are the Vitamin D compounds. Properly metabo need thereof a formulation in accordance with the present lized Vitamin D compounds are necessary for the mainte invention. For example, for formulations containing