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(12) Patent Application Publication (10) Pub. No.: US 2009/0196889 A1 Penhasi (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2009/0196889 A1 Penhasi (43) Pub US 20090196.889A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0196889 A1 Penhasi (43) Pub. Date: Aug. 6, 2009 (54) CONTROLLED ABSORPTION OF STATINS IN Related U.S. Application Data THE INTESTINE (60) Provisional application No. 60/629,336, filed on Nov. 22, 2004. (75) Inventor: Adel Penhasi, Holon (IL) Publication Classification Correspondence Address: (51) Int. Cl. WINSTON & STRAWN LLP A6IR 9/00 (2006.01) PATENT DEPARTMENT A6IR 9/28 (2006.01) 1700 KSTREET, N.W. A63L/35 (2006.01) WASHINGTON, DC 20006 (US) (52) U.S. Cl. .......................... 424/400; 424/472: 514/460 (57) ABSTRACT (73) Assignee: DEXCEL PHARMA TECHNOLOGIES LTD. The present invention provides a controlled absorption for mulation in which modified release of active ingredient pref erentially occurs in the lower gastrointestinal tract, including (21) Appl. No.: 11/719,786 the colon. The formulation Supports a significantly higher bioavailability of the active ingredient into the body of the (22) PCT Filed: Nov. 22, 2005 subject than can be achieved from the currently used conven tional formulation, Such that therapeutically significant (86). PCT No.: PCT/LOS/O1234 plasma levels of statin are maintained for an extended period after administration. The formulation preferably features a S371 (c)(1), core over which an outer coating is layered. The core is (2), (4) Date: Mar. 12, 2009 optionally and preferentially in the form of a tablet. Patent Application Publication Aug. 6, 2009 Sheet 1 of 4 US 2009/O196889 A1 Patent Application Publication Aug. 6, 2009 Sheet 2 of 4 US 2009/O196889 A1 100.0 80.0 60.0 40.0 20.0 Patent Application Publication Aug. 6, 2009 Sheet 3 of 4 US 2009/O196889 A1 i Patent Application Publication Aug. 6, 2009 Sheet 4 of 4 US 2009/O196889 A1 OOO 80.0 600 -Sample 4 i 4.O.O 200 O O. O. O.5. 1 O 15 2.O 2.5 3.0 Time, h Figure 4 US 2009/0196.889 A1 Aug. 6, 2009 CONTROLLED ABSORPTION OF STATINS IN tors, are described in M. Yalpani, “Cholesterol Lowering THE INTESTINE Drugs, Chemistry & Industry, pp. 85-89 (1996). 0007. The statins are orally effective in the reduction of FIELD OF THE INVENTION serum cholesterol levels, by competitively inhibiting 3-hy 0001. The present invention relates to a formulation for the droxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, controlled absorption of a medication, and in particular, to a and play an important role in primary and secondary preven formulation for the delayed onset, modified release of HMG tion of ischemic heart disease and myocardial infarct. CoA reductase inhibitors (statins) predominantly in the lower 0008. The statins include natural fermentation products gastrointestinal (GI) tract. lovastatin (described in U.S. Pat. No. 4,231.938) and mevas tatin (described in U.S. Pat. No. 3,671,523); as well as a BACKGROUND OF THE INVENTION variety of semi-synthetic and totally synthetic products, 0002 Modified release formulations for oral administra which include simvastatin (U.S. Pat. No. 4,444,784); pravas tion of drugs are beneficial for a number of reasons. For tatin sodium salt (U.S. Pat. No. 4.346,227); fluvastatin example, they enable the patient to ingest the formulation less sodium salt (U.S. Pat. No. 5,354,772); atorvastatin calcium frequently, which may lead to increased patient compliance salt (U.S. Pat. No. 5,273.995); and cerivastatin sodium salt with the dosing regimen. They may also result in fewer side (also known as rivastatin: U.S. Pat. No. 5,177,080). effects, as peaks and troughs of the level of the drug in the 0009. An osmosis-controlled release formulation for a sta bloodstream of the patient may be decreased, leading to a tin is taught in U.S. Pat. No. 5,916,595, to Andrx which more even drug level in the blood over a period of time. Such comprises a core containing a water Swellable polymerandan formulations may also provide a longer plateau concentration osmotic agent, a channeling agent and a water insoluble cel of the drug in the blood. The size and frequency of dosing is lulose polymer. Water is drawn into the tablet, which expands determined by the pharmacodynamic and pharmacokinetic to the point where the outer coating fails in one particular area properties of the drug. The slower the rate of absorption, the to form a constricted opening which releases the internal less the blood concentrations fluctuate within a dosing inter contents of the tablet which contain the drug. Thereafter, the val. This enables higher doses to be given less frequently. For aqueous medium of the tablet shell continues to release the drugs with relatively short half-lives, the use of modified drug as it dissolves until the osmotic pressure inside the tablet release products may maintain therapeutic concentrations shell equals that of the Surrounding environment. At the late over prolonged periods. stages of the in vivo release, the tablet shell collapses and/or 0003 Currently, delayed onset, modified release drug disintegrates completely in order to Substantially release the delivery systems administered by the oral route are usually remaining drug. Complete release occurs over a period of based on either a gel forming matrix or coated formulations, 4-30 h. or the combination thereof. 0004. A delayed onset drug delivery system should pref 0010 U.S. Pat. No. 5,882,682 to Merck teaches controlled erentially deliver drugs to any part of the lower GI tract, as a delivery of simvastin from a core by use of a water insoluble site for topical delivery and subsequent absorption of the coating which contains apertures. The release rate of the drug. This concept relies on the fact that the retention time of simvastatin is a function of the number and size of the aper the drug delivery system through the colon may be the longest tures in the coating, and again is a slow, extended form of as compared to other parts of gastrointestinal tract. Likewise, release. Such a delivery system could also advantageously use the 0011 U.S. Pat. No. 4,997,658 to Merck teaches a method unique continuous absorption characterizing the colon, for lowering plasma cholesterol by using a HMG-CoA reduc which results in flatter, more consistent concentration levels tase inhibitor in a Sustained release manner over a period of of the drug in blood. Such an absorption, of course, can 6-24 hours as a slow, extended form of release, thereby reduc contribute significantly to reduction of the fluctuations in ing the amount of HMG-CoA reductase inhibitor circulating blood drug concentration thus preventing the side effects in the bloodstream. which may appear upon using either immediate or conven 0012 WO 01/34123 to Andrx teaches a controlled release tional controlled release formulations, thereby improving dosage form for a drug which may include the statins, in compliance which the release is gradual, and occurs at about 10 to about 0005. Many different types of delayed onset formulations 32 hours after oral administration; again the drug emerges for delivery to the colon are known in the art. These include from the formulation in a slow, extended form of release. This pH-dependent delivery systems; pH -independent delivery dosage form is intended to provide a moderate level of plasma systems, including systems depending on factors such as statin concentration, wherein the mean time to maximum hydrolytic degradation, hydrolysis, enzymatic degradation, plasma concentration of the drug is about 10 to 32 hours after and physical degradation, Such as dissolution; and time-de oral administration. This application does not relate to the pendent delivery systems. Time-dependent systems release way by which a higher blood plasma concentration of the their drug load after a preprogrammed time delay. To attain active material may be obtained after administration. colonic release, the lag time should equal the time taken for 0013 WO 04/021972 to Biovail discloses formulations the system to reach the colon. The small intestinal transit time which putatively decrease the concentration of lovastatin and is generally considered to be in the region of three to four simvastatin and their active metabolites in the systemic cir hours. culation and at the same time provide increased concentra 0006. The statins are a class of compounds which contain tions of these statins in the liver. The disclosure teaches a moiety that can exist as either a 3-hydroxylactone ring or as extended release formulations as preferred over a burst the corresponding open ring dihydroxy acid. The structural release formulation, and the structure of the formulations formulas of these and additional HMG-CoA reductase inhibi taught may for example feature a number of compartments. US 2009/0196.889 A1 Aug. 6, 2009 0014 US Patent Application 2003/0176502 to Athap (0024 Physicians’ Desk Reference 58th edition, 2004, harma describes controlled-release formulations of pravasta pages 2113-211.8 teaches the metabolism, pharmacokinetics, tin in the Small intestine, thereby limiting systemic exposure pharmacodynamics and side effects of simvastatin, and is of the body to pravastatin. hereby incorporated by reference as if fully set forth herein. 0015 WO 01/32162 describes a method comprising administration of an HMG CoA reductase inhibitor in a slow SUMMARY OF THE INVENTION release formulation to the small intestine that provides a clinically effective level in the portal vein and liver, but less 0025. The background art does not teach or suggest a than that required to provide a clinically effective blood level delayed onset, modified release formulation for delivery of in the peripheral circulation. statins to the GI tract including the lower GI tract and the 0016 WO 00/33821 to BMS describes an enteric-coated colon, providing an increased blood concentration of a statin pravastatin bead formulation.
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