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

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US 2016.0015649A1 (19) United States (12) 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. HYDROPHOBC DRUGS Publication Classification Applicant: Lipocine Inc., Salt Lake City, UT (US) (71) (51) Int. Cl. (72) Inventors: Feng-Jing Chen, Danbury, CT (US); 469/48 (2006.01) Mahesh V. Patel, Salt Lake City, UT A613 L/568 (2006.01) (US); David T. Fikstad, Stanford, CA A613 L/5685 (2006.01) (US); Huiping Zhang, Malvern, PA A613 L/585 (2006.01) (US); Chandrashekar Gillyar, Salt A 6LX3/57 (2006.01) Lake City, UT (US) A613 L/473 (2006.01) (52) U.S. Cl. CPC ............... A61 K9/4866 (2013.01); A61K3I/57 (21) Appl. No.: 14/732,342 (2013.01); A61 K9/4858 (2013.01); A61 K 3 1/473 (2013.01); A61 K3I/5685 (2013.01): (22) Filed: Jun. 5, 2015 A6 IK3I/585 (2013.01); A61 K3I/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 HYDROPHOBC 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 “the 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 meanta 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 ester of an 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 bioavailability 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 agent in 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). Preferred classes of active effective amount of an agent as provided herein are meant a agents from which the hydrophobic drug may be selected nontoxic but sufficient amount of the agent to provide the include the following: analgesics, anti-inflammatory agents, desired therapeutic effect. The exact amount required will anti-helminthics, anti-arrhythmic agents, anti-asthma agents, vary from subject to subject, depending on the age, weight anti-bacterial agents, anti-viral agents, anti-coagulants, anti and general condition of the subject, the severity of the con depressants, anti-diabetics, anti-epileptics, anti-fungal dition being treated, the judgment of the clinician, and the agents, anti-gout agents, anti-hypertensive agents, anti-ma like.
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  • Metabolism of Testoterone and Related Steroids in Metastatic Interstitial Cell Carcinoma of the Testis

    Metabolism of Testoterone and Related Steroids in Metastatic Interstitial Cell Carcinoma of the Testis

    Metabolism of testoterone and related steroids in metastatic interstitial cell carcinoma of the testis. M B Lipsett, … , C W Bardin, L M Fishman J Clin Invest. 1966;45(11):1700-1709. https://doi.org/10.1172/JCI105476. Research Article Find the latest version: https://jci.me/105476/pdf Journal of Clinical Investigation Vol. 45, No. 11, 1966 Metabolism of Testosterone and Related Steroids in Metastatic Interstitial Cell Carcinoma of the Testis * M. B. LIPSETT,t G. A. SARFATY, H. WILSON, C. WAYNE BARDIN, AND L. M. FISHMAN (From the Endocrinology Branch, National Cancer Institute, Bethesda, Md.) Interstitial cell carcinoma of the testis is a singu- production rate has been shown to be a conse- larly rare steroid-producing cancer. Of the seven quence of metabolism of dehydroepiandrosterone reported cases (1-7), urinary 17-ketosteroid (17- sulfate. KS) excretion was high in the four cases in which it was measured. Abelson, Bulaschenko, Trom- Methods mer, and Valdes-Dapena (7) fractionated the uri- Routine methods were used to analyze the following: nary 17-ketosteriods and corticoids in one recently urinary 17-KS (8), urinary 17-hydroxycorticoids (9), reported case. There is, however, no comprehen- plasma Silber-Porter chromogens (10), and plasma tes- tosterone (11). sive study of either the production of androgens Gas-liquid chromatography. We carried out gas-liquid or related steroids by this tumor. We have had chromatography (GLC) in a Glowell Chromolab gas the opportunity to study a patient with metastatic chromatograph utilizing a 'Sr ionization detector oper- interstitial cell carcinoma, and we have examined ating at 1,050 v.