US 2007 OO15833A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0015833 A1 Flashner-Barak et al. (43) Pub. Date: Jan. 18, 2007 (54) FORMULATIONS OF FENOFIBRATE Publication Classification CONTAINING MENTHOL (51) Int. Cl. A6II 3L/92 (2007.01) (76) Inventors: Moshe Flashner-Barak, Petach Tikva (52) U.S. Cl. .............................................................. 514/571 (IL); E. Itzhak Lerner, Petach Tikva (IL); Vered Rosenberger, Jerusalem (57) ABSTRACT (IL); Naomi Moldavski. D.N. HaNegev The invention provides at least a composition for the treat (IL) ment of elevated levels of triglycerides, comprising a thera peutically effective amount offenofibrate or another fibrate Correspondence Address: drug intimately associated with menthol, optionally in the KENYON & KENYON LLP presence of at least one surfactant mixture. The invention ONE BROADWAY also provides a method for the treatment of elevated levels NEW YORK, NY 10004 (US) of triglycerides in a Subject, comprising administering to the Subject a composition comprising a therapeutically effective amount of fenofibrate or another fibrate drug and menthol, (21) Appl. No.: 11/182,777 wherein the fenofibrate or the other fibrate drug is in intimate association with the menthol, wherein the menthol can be (22) Filed: Jul. 18, 2005 menthol or menthol Surfactant mixture. US 2007/0015833 A1 Jan. 18, 2007 FORMULATIONS OF FENOFIBRATE be reduced from 100 mg per dose to 67 mg per dose and then CONTAINING MENTHOL Subsequently to 54 mg per dose, all with the same bioavail ability in the fed state. Nanoparticle formulations of the drug BACKGROUND have further allowed the reduction of the dose to 48 mg per dose with the bioavailability of the “fasted state' being 0001 Fenofibrate, (2-4-(4-chlorobenzoyl) phenoxy-2- reported as similar to the fed state. There is still room for methyl-propanoic acid, 1-methylethyl ester) is one of the much improvement since it is posited that the true bioavail fibrate class of drugs. It is available as both capsules and ability of fenofibrate is still relatively low. The current tablets. Fenofibrate is apparently a prodrug. The active inventors have Surprisingly found that a composition of moiety is reportedly the metabolite fenofibric acid which is fenofibrate dissolved in menthol and comprising Surface reported to be produced in the body by esterases. When active agents gives a much enhanced bioavailability well dosing fenofibrate, apparently no intact fenofibrate is found beyond anything previously disclosed. The inventors have in the plasma (Physician's Desk Reference 58" ed., 2004, also surprisingly found formulations with or without men pages 522-525 (PDR)). thol of increased solubility and drug release offenofibrate 0002 Fenofibrate is a very poorly soluble drug. Despite its poor solubility, it is reported to be well absorbed when SUMMARY OF THE INVENTION dosed in the “fed state' and less so in the “fasted state'. It is unclear what the bioavailability of the fenofibric acid 0007. The present invention encompasses a composition really is, since much of it is understood to be metabolized to for the treatment of elevated levels of triglycerides that the glucuronide in both presystemic and first pass sites. The comprises a therapeutically effective amount offenofibrate absolute bioavailability offenofibrate cannot supposedly be or another fibrate drug that is intimately associated with determined since the compound is insoluble in media Suit menthol. The intimate association may be in the form of a able for intravenous injection. Following oral administration solution of the fenofibrate or other fibrate in menthol but in healthy volunteers, approximately 60% of a single dose of would encompass compositions where at least part of the radiolabelled fenofibrate appeared in urine, primarily as drug has come out of Such a solution due to a process that fenofibric acid and its glucuronide conjugate, and 25% was induces the precipitation of the drug, e.g. Saturation Such as excreted in the feces. (PDR) The absorption offenofibrate is reducing the Volume of the solvent or cooling. The compo understood to be increased when administered with food. sition may be optionally absorbed in, or adsorbed on a solid With fenofibrate tablets, the extent of absorption is increased carrier by methods exemplified by the teachings in US by approximately 35% when dosed with food (PDR, Mar 2003-0224059 and US 2004-0198646. tindale 33" ed. page 889). 0008. The present invention encompasses a composition for the treatment of elevated levels of triglycerides that 0003. Much effort has been expended to improve the comprises a therapeutically effective amount offenofibrate formulation of fenofibrate. U.S. Pat. Nos. 4,895,726 and or another fibrate drug that is dissolved in menthol and 5,880,148 disclose co-micronizing the fenofibrate with sur further comprises at least one Surface active agent. The face active agents. U.S. Pat. Nos. 6,074,670 and 6,277,405 composition may be optionally absorbed on a solid carrier. disclose micronized fenofibrate coated onto hydrosoluble carriers with optional surface active agents. U.S. Pat. No. 0009. The present invention encompasses a composition 6,814,977 discloses fenofibrate dissolved in a medium chain that comprises a therapeutically effective amount offenofi glycerolester of fatty acid, U.S. Pat. No. 6,719,999 discloses brate or another fibrate drug that is dissolved in menthol and fenofibrate dissolved in glycerin, propylene glycol, or dim further comprises at least one Surface active agent. The ethylisosorbide and U.S. Pat. No. 5,827,536 discloses composition can have a dissolution property in that, when fenofibrate dissolved in diethyleneglycol monoethyl ether. tested in 50 ml 0.1 NHCl at 37° C. and 150 rpm, at least about 10%, 30% or 80% of the fenofibrate or the other 0004 Several patents disclose specific formulations of fibrate drug dissolved in 15 minutes. The composition can micronized fenofibrate with specific polymeric or surface also have a dissolution property in that, when tested in 500 active agent additives while several others describe emul ml 0.5% Sodium lauryl sulfate (SLS) in water at 37° C. and sions and suspensions. US Patent Application Publication 50 rpm, at least about 70% of the fenofibrate or the other No. 20040087656 discloses fenofibrate of particle size less than 2000 nm with an improved bioavailability. US Patent fibrate drug dissolved in 5 minutes. Application Publication No. 20030224059 discloses micro 0010. The present invention encompasses a composition particles of active pharmaceutical ingredients, drug delivery that comprises a therapeutically effective amount offenofi vehicles comprising same, and methods for making them. brate or another fibrate drug that is dissolved in menthol and The disclosure of US20030224059 is incorporated herein by further comprises at least one surface active agent that when reference in its entirety. administered orally to beagle dogs shows a bioavailability of fenofibric acid based on Area Under the Curve (AUC) of the 0005 US Patent Application Publication No. concentration V. time profile in plasma that is at least three 20040198646 discloses compositions comprising solutions times that of the Trichor R. 54 mg product on a per milligram of drugs in menthol, especially drugs that are poorly soluble basis (when normalized to equal weight). in water, and to methods for making Such compositions. The disclosure of US200401986.46 is incorporated in its entirety 0011. The present invention also encompasses the by reference. method of preparing a composition of the invention, which method comprises: 0006 Micronization of the drug and the addition of Surface active agents have moderately raised the bioavail 0012 a) heating menthol to about 60° C. in order to ability of fenofibrate allowing the amount of drug dosed to effect melting thereof, US 2007/0015833 A1 Jan. 18, 2007 0013 b) adding at least one surface active agent to the lyceridemia. The term “fenofibrate' includes the 1-methyl melt, ethyl ester of 2-4-(4-chlorobenzoyl)-phenoxy-2-methyl propanoic acid and any pharmaceutically acceptable salts 0014) c) cooling the product of step b) to about 50° C., thereof. One aspect of this invention is to compositions of 0015 d) dissolving fenofibrate or another fibrate drug fenofibrate that is dissolved in menthol. Fenofibrate dis in the product of step c) with stirring, solves up to about 37% in melted menthol at 60° C. Formulations may be made where all the fenofibrate is 0016 e) cooling9. the pproduct of stepp d) to room tem dissolved in the menthol or where only some of the fenofi perature to obtain the composition of the invention, and brate is so dissolved and the rest present in a solid form in 0017 f) if capsules are desired. (A) dispensing the the fully saturated menthol medium. In a preferred embodi product of step e) into capsules, or (B) alternatively ment of the invention, the fenofibrate is fully dissolved in the menthol. In one embodiment of the invention, the menthol adding a solid carrier Such as microcrystalline cellu melt may be filled into capsules in the liquid state or may be lose, lactose or Sorbitol, to the product of step e), solidified, optionally milled, and filled into capsules. The mixing well, cooling to room temperature and filling capsules used for the liquid fill in one embodiment may be the powder thus obtained into capsules. hard gelatin capsules. In a preferred embodiment, the hard 0018. The present invention encompasses a composition gelatin capsules are banded to prevent leakage. In a more that comprises a therapeutically effective amount offenofi preferred embodiment, the liquid formulation may be filled brate or another fibrate drug that is dissolved in a surfactant into soft-gel capsules. In another embodiment, the Solidified mixture, such as Polyethylene Glycol (PEG) 1000 and menthol solution is optionally milled and filled into hard Poloxamer 407. The composition may be optionally gelatin capsules or equivalent capsules of other materials absorbed or adsorbed on a solid carrier.