US 2003O236236A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0236236A1 Chen et al. (43) Pub. Date: Dec. 25, 2003 (54) PHARMACEUTICAL COMPOSITIONS AND now Pat. No. 6,267,985, and which is a continuation DOSAGE FORMS FOR ADMINISTRATION in-part of application No. 09/751,968, filed on Dec. OF HYDROPHOBC DRUGS 29, 2000, now Pat. No. 6,458,383, which is a con tinuation-in-part of application No. 09/375,636, filed (76) Inventors: Feng-Jing Chen, Salt Lake City, UT on Aug. 17, 1999, now Pat. No. 6,309,663. (US); Mahesh V. Patel, Salt Lake City, UT (US); David T. Fikstad, Salt Lake Publication Classification City, UT (US); Huiping Zhang, Salt Lake City, UT (US); Chandrashekar (51) Int. Cl." ....................... A61K 31156; A61K 31/355; Gilyar, Salt Lake City, UT (US) A61K 31/122 (52) U.S. Cl. ........................... 514/171; 514/458; 514/682 Correspondence Address: REED & EBERLE LLP (57) ABSTRACT 800 MENLO AVENUE, SUITE 210 Pharmaceutical compositions and dosage forms for admin MENLO PARK, CA 94025 (US) istration of hydrophobic drugs, particularly Steroids, are provided. The pharmaceutical compositions include a thera (21) Appl. No.: 10/444,935 peutically effective amount of a hydrophobic drug, prefer (22) Filed: May 22, 2003 ably a steroid; a solubilizer, preferably a vitamin E sub stance, and a Surfactant. The Synergistic effect between the Related U.S. Application Data hydrophobic drug and the Vitamin E Substance results in a pharmaceutical formulation with improved dispersion of (63) Continuation-in-part of application No. 09/716,029, both the active agent and the solubilizer. As a result of the filed on Nov. 17, 2000. improved dispersion, the pharamaceutical composition has Continuation-in-part of application No. 09/877,541, improved bioavailability upon administration. Methods of filed on Jun. 8, 2001, which is a continuation-in-part improving the bioavailability of hydrophobic drugs admin of application No. 09/345,615, filed on Jun. 30, 1999, istered to a patient are also provided. US 2003/0236236A1 Dec. 25, 2003 PHARMACEUTICAL COMPOSITIONS AND Micelles, and pharmaceutical compositions containing DOSAGE FORMS FOR ADMINISTRATION OF micelles, have been extensively Studies and are described in HYDROPHOBC DRUGS detail in the literature, See, e.g., Remington's Pharmaceuti cal Sciences, 17" ed. (1985). Although micellar formula REFERENCE TO RELATED APPLICATIONS tions can Solubilize a variety of hydrophobic therapeutic 0001. This application is a continuation-in-part of U.S. agents, the loading capacity of conventional micelle formu patent application Ser. No. 09/716,029, filed Nov. 17, 2000, lations is limited by the Solubility of the therapeutic agent in and a continuation-in-part of U.S. patent application Ser. No. the micelle Surfactant. For many therapeutic agents, Such 09/877,541, filed Jun. 8, 2001, which is a continuation-in solubility is too low to offer formulations that can deliver part of U.S. patent application Ser. No. 09/345,615, filed therapeutically effective doses. Jun. 30, 1999, and a continuation-in-part of U.S. application 0007 Another approach is to solubilize the active sub Ser. No. 09/751,968, filed Dec. 29, 2000, which is a con stance in a triglyceride Solvent, Such as a digestible Veg tinuation-in-part of U.S. application Ser. No. 09/375,636, etable oil. For example, U.S. Pat. No. 4,900,734 to Maxson filed Aug. 17, 1999, the disclosures of which are incorpo et al. discloses a composition in which progesterone is rated herein by reference in their entireties. dissolved in a highly unsaturated edible oil. These triglyc erides are water insoluble themselves and do not normally TECHNICAL FIELD disperse in aqueous environments Such as the gastrointesti 0002 The present invention relates generally to the deliv nal tract. Typically, they must by emulsified by high Shear or ery of hydrophobic drugs, Such as Steroids and benzoquino high temperature homogenization and Stabilized with emul nes. More specifically, the invention relates to novel phar sifiers. In Simplest form, a triglyceride-containing formula maceutical compositions in which a therapeutically effective tion Suitable for delivering hydrophobic agents through an amount of a hydrophobic active agent is combined with a aqueous environment is an oil-in-water emulsion. The col Vitamin E Substance and a Surfactant to form a uniform loidal oil particles are relatively large and will often spon dispersion wherein the active agent is Solubilized in the taneously agglomerate, eventually leading to complete aqueous environment in a readily absorbable form. phase Separation. The large size slows the rate of transport of the colloidal particle and hence the rate of absorption of BACKGROUND the therapeutic agent. Thus these triglyceride compositions are Subject to a number of Significant limitations and dis 0003) Numerous therapeutic agents are poorly soluble in advantages, Such as physical instability and lack of homo aqueous medium and present difficult problems in formu geneity, and are likely to Suffer from poor and variable lating for effective administration to patients. Steroids in absorption. A further disadvantage of triglyceride-contain particular have very low water Solubility and are useful ing compositions is the dependence of the therapeutic agent therapeutic agents for a wide variety of medical conditions. Conventional formulations that incorporate these therapeu absorption on the rate and extent of lipolysis (e.g. See WO tic agents Suffer from Several disadvantages Such as incom 9524893 and WO 97.40823). plete or slow dissolution and/or highly variable dissolution 0008. Other solubilizers of particular utility for hydro profiles. Furthermore, following oral administration, these phobic active agents are described in U.S. patent application conventional formulations exhibit low and/or variable Ser. No. 09/716,029 to Chen et al. The vitamin E substances absorption. A well-designed formulation must, at minimum, disclosed therein include fatty acid esters of glycerol, Such be capable of presenting a therapeutically effective amount as mono-, di-, and triglycerides and acetylated mono- and of the active Substance to the desired absorption Site, in an diglycerides, and mixtures thereof, fatty acid esters of pro absorbable form. pylene glycol, Such as mono- and di-fatty acid esters of 0004. A number of approaches are known for formulating glycerol and mixtures thereof, trialkyl citrate, glyceryl therapeutic agents that are poorly Soluble in water, for both acetate and lower alcohol fatty acid esters. oral and parenteral delivery. 0009 WO 01/49262; U.S. Pat. No. 6,458,373; and U.S. Pat. No. 6,193,985 disclose the use of Solubilizers that 0005 One approach to improving the bioavailability of require high levels of hydrophilic Surfactants, high shear, or Such active Substances is to micronize the particles and to high temperature homogenization to disperse the Solubiliz Suspend them in a pharmaceutically acceptable matrix. For erS Sufficiently to form even a coarse dispersion in an example, U.S. Pat. Nos. 4,196, 188; 4.963,540; and 5,140, adequate medium. Formation of a fine dispersion, which 021 disclose compositions for oral delivery of progesterone would make an effective carrier for oral delivery of the comprising micronized particles of crystalline progesterone active agent, is often difficult or impossible to achieve. AS in triglyceride vehicles. Such Suspensions are difficult to with the triglyceride emulsions, these can be difficult to manufacture, may be physically unstable, and may still manufacture and/or unstable on Storage, and may lead to suffer from poor dissolution and low and/or highly variable absorption. Similarly, compositions utilizing Solid disper poor and variable absorption. sions, such as the approach in FR 2, 647,346, which dis 0010 Thus, there is a need for pharmaceutical composi closes a Solid dispersion of the metastable progesterone II tions for the delivery of therapeutic levels of active agents polymorph in a hydrophilic excipient, are difficult to manu that overcome the Solubility, physical Stability, and absorp facture consistently and may Suffer from physical Stability tion limitations of conventional approaches using microni problems. Additionally this approach may still suffer from Zation, emulsification, or Solubilization. poor dissolution and low and/or highly variable absorption. SUMMARY OF THE INVENTION 0006 Another well-known approach uses surfactant 0011. In the present invention, we have found an unex micelles to Solubilize and transport the therapeutic agent. pected Synergism between an active agent and a Solubilizer. US 2003/0236236A1 Dec. 25, 2003 We have found that for certain therapeutic actives, the active readily absorbable form. A Synergistic combination of an agent has a critical role in improving the dispersion of the appropriate active agent and Solubilizer is observed, Such Solubilizer upon dilution in an aqueous media, allowing for that the presence of the active agent improves the dispersion dispersion of much higher levels of both solubilizer and of the solubilizer (i.e. increases the amount of solubilizer active agent in the aqueous environment. In particular, Such which may be dispersed) and thus further increases the Synergism can be exemplified by compositions comprising amount of active agent which can be dispersed in a readily an active agent, a vitamin ESubstance as the Solubilizer, and absorbable form. a Surfactant as a dispersing aid, wherein the presence of the active agent improves the dispersion of the Solubilizer and 0019. Within the context of the present invention, the thus further increases the amount of active agent which can term “dispersion” is used to refer to the extent to which the be dispersed in a readily absorbable form. This unexpected composition, in particular the active agent and the Solubi Synergism between the active agent, a Vitamin E Substance, lizer, are uniformly distributed in the aqueous phase after and a Surfactant allows for very high drug loading as well as dilution in an aqueous medium, Such as water, Simulated excellent dispersion, keeping the drug Substantially Solubi gastric fluid, or Simulated intestinal fluid.