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(12) Patent Application Publication (10) Pub. No.: US 2005/0096296A1 Fikstad Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0096296A1 Fikstad Et Al US 2005.0096.296A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0096296A1 Fikstad et al. (43) Pub. Date: May 5, 2005 (54) PHARMACEUTICAL COMPOSITIONS WITH Related U.S. Application Data SYNCHRONIZED SOLUBLIZER RELEASE (63) Continuation of application No. 10/700,838, filed on (76) Inventors: David Fikstad, Salt Lake City, UT Nov. 3, 2003. (US); Srinivasan Venkateshwaran, Salt Lake City, UT (US); Publication Classification Chandrashekar Giliyar, Salt Lake City, UT (US); Feng-Jing Chen, Salt (51) Int. Cl." ..................... A61K 31/724; A61K 31/426; Lake City, UT (US); Mahesh V. Patel, A61K 31/401; A61K 31/366 Salt Lake City, UT (US) (52) U.S. Cl. ............................ 514/58; 514/369; 514/423; 514/460; 514/548; 514/458; Correspondence Address: 514/571 COOLEY GODWARD, LLP 3000 EL CAMINO REAL (57) ABSTRACT 5 PALO ALTO SQUARE PALO ALTO, CA 94.306 (US) Pharmaceutical compositions with Synchronized Solubilizer release as well as various methods associated there with, are (21) Appl. No.: 10/764,016 disclosed and described. More specifically, the aqueous Solubility of a drug is enhanced by Synchronized release of (22) Filed: Jan. 23, 2004 a solubilizer. Patent Application Publication May 5, 2005 Sheet 1 of 10 US 2005/0096296A1 C O C C N Vo V er (u/3m) AllqnOS SnoenbW OZeSOIO Patent Application Publication May 5, 2005 Sheet 2 of 10 US 2005/0096296A1 (%) eSeele JeZIqnOS %0·?–––i--|-----------|--------1–--------|--%0 84.9S#£Z|0 (?)QuiL (%) 9Seele IOZeSOILO Patent Application Publication May 5, 2005 Sheet 3 of 10 US 2005/0096296A1 (poseoal %) 19ZIqnos vzzzOz8191yiz?0189?ºz0 - (?)9uu?L C gld l er N N ym (u?er) AIIIqnoS OZenSolo Patent Application Publication May 5, 2005 Sheet 4 of 10 US 2005/0096296A1 %SZ %9 %) peseele IOZe) SOC) Patent Application Publication May 5, 2005 Sheet 5 of 10 US 2005/0096296A1 (%) eSeee JeZIQnoS C Vad ÞzzzOz8191yiz?0189#7Z0 O O 00I OO Wid ( %) eSeele OpeAue) US 2005/0096.296A1 (%) passala Iopa Aueo Patent Application Publication May 5, 2005 Sheet 7 of 10 US 2005/0096296A1 3uuç‘ZI‘I-0I9Iduexº?-------- L=u‘INGIS+ubºIN –00000|| 000I (u/id) uole. Iuebuo) buse OpeA-b) Patent Application Publication May 5, 2005 Sheet 8 of 10 US 2005/0096296A1 puesunoHZuog(Z"|Hd)-19S?uuOgzu??sex|n|u|gezgoasealax,papua?xE (uudu001.‘IdSn)O.,19?esunoHZZuog(8'9Hd)HISIuuOgzu?K?uenbesqns (unou)au!L (%) peseee Seyn Jez Jo effeueole peen unooW Patent Application Publication May 5, 2005 Sheet 9 of 10 US 2005/0096296A1 ZIIOI68L9gº£zIO (SunOH)Qu?L ·%0 %00|| %08 (%) poseae sex nuge Z. US 2005/0096.296 A1 May 5, 2005 PHARMACEUTICAL COMPOSITIONS WITH increases the aqueous Solubility of the drug when Synchro SYNCHRONIZED SOLUBLIZER RELEASE nously released. Synchronized drug and Solubilizer release may enable modified release and may provide modified 1. TECHNICAL FIELD release characteristics without compromising bioavailabil ity. Further, Synchronized drug and Solubilizer may allow 0001. The inventions disclosed herein relate generally to reduction in dose required for therapeutic effect or reduction pharmaceutical compositions having enhanced aqueous in dose frequency. Synchronized drug and Solubilizer release solubility with synchronized solubilizer release. More spe may also reduce Side effects. Synchronized drug and Solu cifically, disclosed herein are pharmaceutical compositions bilizer may allow administration with or without food while of drugs. Such as, for example, ciloStaZol and carvedilol Still maintaining an acceptable pharmacokinetic and thera where the aqueous Solubility of the drug is enhanced by peutic profile. Further, reduction in drug dosing frequency Synchronized release of a Solubilizer. and Side-effects often improves patient compliance. 2. BACKGROUND 0007. In another aspect, an oral dosage form is provided. The oral dosage form comprises a therapeutically effective 0002 The solubility of many therapeutic agents is a amount of a drug, a Solubilizer and a release modulator Significant problem in effectively administering these drugs where the release of the drug and Solubilizer are Synchro to patients. For example, ciloStaZol, an agent used to treat nized. Many oral dosage forms, Such as tablets, capsules, and prevent various cardiovascular disease, when formu powders, etc. are specifically contemplated. AS readily rec lated as an immediate release tablet dosage form, is absorbed ognized by those of ordinary skill in the art many other following oral administration, but with minimal absolute dosage forms may also be used in practicing the current bioavailability. Furthermore, the absorption of the immedi invention. ate release tablet dosage form of ciloStaZol is not dose proportional, which implies Solubility limited absorption. 0008. In still another aspect, a solid oral dosage form is Absorption of the immediate release tablet dosage form of provided. The oral dosage form comprises a therapeutically ciloStaZol, is also significantly affected by food consump effective amount of a drug, a Solubilizer and a release tion, which is another indicator of solubility limited absorp modulator where the release of the drug and Solubilizer are tion. A high fat meal Significantly increases absorption of the Synchronized. immediate release tablet dosage form of ciloStazol with C. increasing by about 90% and AUC by about 25%. The 4 BRIEF DESCRIPTION OF THE DRAWINGS Significant increase in ciloStazol absorption caused by food consumption leads to deleterious Side effects, Such as head 0009 FIG. 1 illustrates aqueous solubility of cilostazol ache and palpitations, when the immediate release tablet as a function of Solubilizer concentration in Simulated intes dosage form of ciloStaZol is administered after food con tinal fluid without enzyme at 37 C. and pH of 6.8; Sumption. Therefore, the immediate release tablet dosage 0010 FIG. 2 illustrates cilostazol and solubilizer release form of cilostazol must be taken twice a day, at least 30 from Example 6.2 USP Apparatus I, 100 rpm, 37° C., 1000 minutes before or at least two hours after breakfast. ml simulated gastric fluid without enzyme--0.275% w/v 0.003 Conventional controlled release dosage forms for Sodium dodecyl Sulfate; drugs with solubility-limited absorption are ineffective. 0011 FIG. 3 illustrates release of solubilizers and Without significant and Sustained improvement in drug enhancement of cilostazol solubility from Example 6.3 Solubility, conventional controlled release of a poorly Extended release tester, 10 rpm, 37 C.; 0–2 hours: 100 ml Soluble drug will not improve absorption thus leading to SGF w/o enzyme, 2+ hours: 100 ml SIF S/o enzyme (pH inadequate Systemic drug concentration over the desired 6.8); period of time. 0012 FIG. 4 illustrates release of cilostazol from 0004. Accordingly, what is needed are pharmaceutical Examples 6-1 and 6-2 USP Apparatus I, 100 rpm, 37 C., compositions and oral dosage forms for increasing the 1000 ml simulated intestinal fluid without enzyme (pH 6.8); Solubility of drugs, particularly of drugs with Solubility limited absorption such as cilostazol. Preferably, the phar 0013 FIG. 5 illustrates release of carvedilol and solubi maceutical compositions and oral dosage forms can be lizer from Example 9-1 and 9-2 USP Apparatus I, 100 rpm, administered in modified release dosage forms. 37° C., 0-2h: 1,000 ml SGF (pH 12); 2+h: 1,000 ml SIF (pH 6.8); 3. SUMMARY 0014 FIG. 6 illustrates release of carvedilol from 0005 The present invention satisfies these and other Example 10-1 and Comparator 10-1. Extended release needs by providing drug compositions having enhanced tester; 10 rpm, 37° C., 100 ml SGF (pH 1.2) or 100 ml SIF aqueous Solubility with Synchronized Solubilizer release. (pH 6.8); More Specifically, pharmaceutical compositions are pro 0015 FIG. 7 illustrates carvedilol plasma concentration Vided where the aqueous Solubility of the drug is enhanced as a function of time for Example 10-1 and Comparator 11-1 by Synchronized release of a Solubilizer. in a Single-dose randomized croSSover in healthy Volunteers, 0006. In one aspect, a pharmaceutical composition is provided. The pharmaceutical composition comprises a 0016 FIG. 8 illustrates release of Zafirlukast from therapeutically effective amount of a drug, a Solubilizer and Examples 12-1, 12-2 and 12-3; a release modulator where the release of the drug and 0017 FIG. 9 illustrates release of Zafirlukast from Solubilizer are Synchronized. The Solubilizer Significantly Examples 12-4 and 12-8; and US 2005/0096.296 A1 May 5, 2005 0018 FIG. 10 illustrates release of pioglitazone from disulfonic acid, 2-hydroxyethaneSulfonic acid, benzene Examples 15-1 to 15-3. Sulfonic acid, 4-chlorobenzeneSulfonic acid, 2-naphthalene Sulfonic acid, 4-toluenesulfonic acid, camphorSulfonic acid, 5. DETAILED DESCRIPTION 4-methylbicyclo2.2.2-Oct-2-ene-1-carboxylic acid, gluco heptonic acid, 3-phenylpropionic acid, trimethylacetic acid, 5.1 Definitions tertiary butylacetic acid, lauryl Sulfuric acid, gluconic acid, ss glutamic acid, hydroxynaphthoic acid, Salicylic acid, Stearic 0019. The singular forms “a,”“an,” and, “the” include acid, muconic acid, and the like; or (2) Salts formed when an plural referents unless the context clearly dictates otherwise. acidic proton present in the parent compound is replaced by Thus, for example, reference to “the solubilizer” and “the a metal ion, e.g., an alkali metal ion, an alkaline earth ion, release modulator” includes reference to one or more Spe or an aluminum ion; or coordinates with an organic base cific Solubilizers and release modulators, reference to “an Such as ethanolamine, diethanolamine, triethanolamine, additive' includes reference to one or more of Such addi N-methylglucamine and the like. tives, and reference to “the plasticizing agent' includes reference to one or more of Such agents. 0028) “Preventing” or “prevention” refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least 0020 “AUC” is the area under the plasma drug concen one of the clinical Symptoms of the disease not to develop tration-Versus-time curve extrapolated from Zero time to in a patient that may be exposed to or predisposed to the infinity.
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