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(2) Patent Application Publication (10) Pub. No.: US 2016/0015649 A1 Chen Et Al

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(2) Patent Application Publication (10) Pub. No.: US 2016/0015649 A1 Chen Et Al US 2016.0015649A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2016/0015649 A1 Chen et al. (43) Pub. Date: Jan. 21, 2016 (54) PHARMACEUTICAL COMPOSITIONS AND in-part of application No. 09/375,636, filed on Aug. DOSAGE FORMS FOR ADMINISTRATION OF 17, 1999, now Pat. No. 6,309.663. HYDROPHOBIC DRUGS Publication Classification Applicant: Lipocine Inc., Salt Lake City, UT (US) (71) (51) Int. Cl. (72) Inventors: Feng-Jing Chen, Danbury, CT (US); A61 K 9/48 (2006.01) Mahesh V. Patel, Salt Lake City, UT A61 K. 3 1/568 (2006.01) (US); David T. Fikstad, Stanford, CA A61 K. 3 1/5685 (2006.01) (US); Huiping Zhang, Malvern, PA A61 K. 3 1/585 (2006.01) (US); Chandrashekar Gillyar, Salt A61R 3 1/57 (2006.01) Lake City, UT (US) A61 K. 3 1/473 (2006.01) (52) U.S. CI. CPC ............... A61K 9/4866 (2013.01); A61K3I/57 (21) Appl. No.: 14/732,342 (2013.01); A61K 9/4858 (2013.01); A61 K 31/473 (2013.01); A61 K3I/5685 (2013.01); (22) Filed: Jun. 5, 2015 A61K3I/585 (2013.01); A61K3I/568 (2013.01) Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 12/625,284, filed on Pharmaceutical compositions and dosage forms for adminis Nov. 24, 2009, now abandoned, which is a continu tration of hydrophobic drugs are provided. The pharmaceu ation of application No. 10/444,935, filed on May 22, tical compositions include a therapeutically effective amount 2003, which is a continuation-in-part of application of a hydrophobic drug, preferably a steroid; a solubilizer, and No. 09/716,029, filed on Nov. 17, 2000, now Pat. No. a surfactant. The synergistic effect between the hydrophobic 6,982,281, which is a continuation-in-part of applica drug and the solubilizer results in a pharmaceutical formula tion No. 09/877,541, filed on Jun. 8, 2001, now Pat. tion with improved dispersion of both the active agent and the No. 6,761,903, which is a continuation-in-part of solubilizer. As a result of the improved dispersion, the phar application No. 09/345,615, filed on Jun. 30, 1999, maceutical composition has improved bioavailability upon now Pat. No. 6,267,985, which is a continuation-in administration. Methods of improving the bioavailability of part of application No. 09/751,968, filed on Dec. 29, hydrophobic drugs administered to a patient are also pro 2000, now Pat. No. 6,458,383, which is a continuation vided. US 2016/0015649 A1 Jan. 21, 2016 PHARMACEUTICAL COMPOSITIONS AND follows, and in part will become apparent to those skilled in DOSAGE FORMS FOR ADMINISTRATION OF the art upon examination of the following, or may be learned HYDROPHOBIC DRUGS by practice of the invention. CROSS-REFERENCE INCORPORATION BY REFERENCE [0001] This application is a continuation of Ser. No. [0009] All publications, patents, and patent applications 12/625,284, filed Nov. 24, 2009, which is a continuation of mentioned in this specification are herein incorporated by Ser. No. 10/444,935, filed May 22, 2003, which is a continu reference to the same extent as if each individual publication, ation-in-part of U.S. Pat. No. 6,982,281 filed Nov. 17, 2000, patent, or patent application was specifically and individually and a continuation-in-part of U.S. Pat. No. 6,761,903 filed indicated to be incorporated by reference. Jun. 8, 2001, which is a continuation-in-part of U.S. Pat. No. 6,267,985 filed Jun. 30, 1999, and a continuation-in-part of DETAILED DESCRIPTION OF THE INVENTION U.S. Pat. No. 6,458,383, filed Dec. 29, 2000, which is a continuation-in-part of U.S. Pat. No. 6,309,663 filed Aug. 17, I. Definitions and Nomenclature 1999, the disclosures of which are incorporated herein by [0010] Before the present formulations and dosage forms reference in their entireties. are disclosed and described, it is to be understood that unless otherwise indicated this invention is not limited to specific BACKGROUND OF THE INVENTION dosage forms, solubilizers, or the like, as such may vary. It is [0002) Numerous therapeutic agents are poorly soluble in also to be understood that the terminology used herein is for aqueous medium and present difficult problems in formulat the purpose of describing particular embodiments only and is ing for effective administration to patients. Steroids in par not intended to be limiting. ticular have very low water solubility and are useful thera [0011] It must be noted that, as used in the specification and peutic agents for a wide variety of medical conditions. the appended claims, the singular forms “a,” “an” and “theº Conventional formulations that incorporate these therapeutic include plural referents unless the context clearly dictates agents suffer from several disadvantages such as incomplete otherwise. Thus, for example, reference to “a solubilizer” or slow dissolution and/or highly variable dissolution pro includes a single solubilizer or mixtures of two or more solu files. Furthermore, following oral administration, these con bilizers, reference to “an additive” refers to a single additive ventional formulations exhibit low and/or variable absorp or mixtures of different additives, reference to “an additional tion. A well-designed formulation must, at minimum, be active agent” includes a single additional active agent or capable of presenting a therapeutically effective amount of combinations of two or more additional active agents, and the the active substance to the desired absorption site, in an like. absorbable form. [0012] In this specification and in the claims that follow, reference will be made to a number of terms which shall be SUMMARY OF THE INVENTION defined to have the following meanings: [0013]. “Optional” or “optionally” means that the subse [0003] Accordingly, it is a primary object of the invention quently described circumstance may or may not occur, so that to address the above-mentioned need in the art by providing a the description includes instances where the circumstance pharmaceutical composition and dosage form for orally occurs and instances where it does not. administering hydrophobic therapeutic agents. [0014] The terms “active agent,” “drug” and “pharmaco [0004] It is another object of the invention to provide such logically active agent” are used interchangeably herein to a composition and dosage form comprising a therapeutically refer to a chemical material or compound which, when effective amount of a hydrophobic therapeutic agent and a administered to an organism (human or animal, generally solubilizer. human) induces a desired pharmacologic effect. In the con [0005] It is another object of the invention to provide such text of the present invention, the terms generally refer to a a composition and dosage form wherein the solubilizer com hydrophobic therapeutic active agent, unless the context prises a vitamin E substance, a trialkyl citrate, a lactone, a clearly indicates otherwise. nitrogen-containing solvent or a combination thereof. [0015] By “pharmaceutically acceptable” is meant a carrier [0006] It is still another object of the invention to provide comprised of a material that is not biologically or otherwise such a composition and dosage form wherein the solubilizer undesirable. comprises a phospholipid. It is yet another object of the [0016] “Carrier” or “vehicle” as used herein refer to carrier invention to provide such a composition and dosage form materials suitable for drug administration. Carriers and wherein the solubilizer comprises a glyceryl acetate, a fatty vehicles useful herein include any such materials known in acid esterofan acetylated glyceride or a combination thereof. the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, It is a further object of the invention to provide such a com surfactant, or the like, which is nontoxic and which does not position and dosage form wherein the solubilizer comprises a interact with other components of the composition in a del lower alcohol fatty acid ester. eterious manner. [0007] The present invention also encompasses methods of [0017] The terms “treating” and “treatment” as used herein improving the bioavailabilty of active agents, and steroids in refer to reduction in severity and/or frequency of symptoms, particular, in patients through the administration of the elimination of symptoms and/or underlying cause, prevention claimed pharmaceutical compositions in suitable dosage of the occurrence of symptoms and/or their underlying cause, forms. and improvement or remediation of damage. Thus, for [0008] Additional objects, advantages and novel features of example, “treating” a lipid disorder, as the term “treating” is the invention will be set forth in part in the description which used herein, encompasses both prevention of lipid disorders US 2016/0015649 A1 Jan. 21, 2016 in a predisposed individual and treatment of lipid disorders in tion offenofibrate is already solubilized in the compositions. a clinically symptomatic individual. In addition, the present compositions are not dependent on [0018] “Patient” as used herein refers to a mammalian, lipolysis for the absorption offenofibrate since the composi preferably human, individual who can benefit from the phar tions do not require triglycerides or vegetable oils. maceutical compositions and dosage forms of the present invention. A. Active Agent [0019. The term “vitamin E substance” refers to both vita [0025] The active agentin the present invention is generally min E and derivatives thereof. hydrophobic in nature (log P greater than 2, P is the intrinsic [0020) By the terms “effective amount” or “therapeutically octanol partition coefficient).
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