WO2009100245A1

WO2009100245A1 - Low dose hmg-coa reductase inhibitor with reduced side effects

Info

Publication number: WO2009100245A1
Application number: PCT/US2009/033255
Authority: WO
Inventors: Lance Liu; Kenan Gu; Michael Novinski; Cristina Castelli
Original assignee: Emisphere Technologies Inc.
Priority date: 2008-02-05
Filing date: 2009-02-05
Publication date: 2009-08-13

Abstract

The present invention relates to pharmaceutical formulations for lowering cholesterol in a human subject comprising (a) a HMG-CoA reductase inhibitor, (b) at least one of SNAC, SNAD, 5CNAC, 4CNAB, 4M0AC, 4HPO, 5-PPA, 3-TBA, 2-HPOD, 7-OPHA, 3-HPSB, 4- IBOA and 3-FPSB (c) optionally CoEnzyme Q and (d) optionally, a pharmaceutically acceptable excipient.

Description

Low Dose HMG-CoA Reductase Inhibitor With Reduced Side Effects

FIELD QF THE INVENTION

[0001] The present invention relates to pharmaceutical formulations containing a HMG-CoA reductase inhibitor, (b) at least one of SNAC, SNAD, 5CNAC, 4CNAB, 4MOAC, 4HPO, 5-PPA, 3-TBA, 2-HPOD, 7-OPHA, 3-HPSB, 4-IBOA and 3-FPSB.

BACKGROUND OF THE INVENTION

[0002] HMG-CoA reductase inhibitors, such as atorvastatin, have been used as pharmaceutical agents to lower cholesterol levels in people with or at risk for cardiovascular disease. These inhibitors lower cholesterol by inhibiting the enzyme HMG-CoA reductase which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels. [0003] One of the most popular HMG-CoA reductase inhibitors is atorvastatin which is currently marketed by Pfizer under the trade name Lipitor^®, in tablets (10, 20, 40 or 80 mg) for oral administration. Tablets are white, elliptical, and film coated. In some countries it may also be known as: Sortis, Torvast, Totalip, Tulip, Xarator, Atorpic, or Liprimar. It is also packaged in combination with other drugs, such as is the case with Pfizer's Caduet. With 2005 sales of USS 12.2 billion under the brand name Lipitor^®, it is the largest selling drug in the world (see Jerry Avorn, M.D., "Torcetrapib and Atorvastatin — Should Marketing Drive the Research Agenda?" New England Journal of Medicine Volume 352:2573-2576 June 23, 2005). [0004] However, atorvastatin, like other HMG-CoA reductase inhibitors, causes many adverse drug reactions, including muscle pain, myalgia, muscle cramps, mild transient gastrointestinal symptoms, elevated hepatic transaminase concentrations, headache, insomnia, and/or dizziness. Myopathy and rhabdomyolysis can also occur in some patients. Such risk increases in patients with renal impairment, serious concurrent illness; and/or concomitant use of drugs which inhibit CYP3A4 (see Nissen S. et al., "Effect of very high- intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial," JAMA 295 (13): 1556-65, 2006). So far, various efforts to improve the safety profile of HMG-CoA reductase inhibitors, such as atorvastatin, have failed. With millions of patients taking HMG-CoA reductase inhibitors every day, there is a need to reduce the side effects of these HMG-CoA reductase inhibitors.

SUMMARY QF THE INVENTION [0005] The present invention provides a pharmaceutical composition for lowering cholesterol in a human subject comprising (a) a HMG-CoA reductase inhibitor, (b) at least one of SNAC, SNAD, 5-CNAC, 4-CNAB, 4-MOAC, 4-HPO, 5-PPA, 3-TBA, 2-HPOD, 7- OPHA, 3-HPSB, 4-IBOA and 3-FPSB (c) optionally CoEnzyme Q and (d) optionally, a pharmaceutically acceptable excipient. [0006] The present invention also provides a solid pharmaceutical dosage form for lowering cholesterol level in a human subject comprising (a) from about 0.1 mg to about 200 mg of HMG-CoA reductase inhibitor, and (b) from about 25 mg to about 600 mg of at least one of SNAC, SNAD₅ 5CNAC, 4CNAB, 4MOAC, 4HPO₅ 5-PPA, 3-TBA, 2-HPOD, 7- OPHA, 3-HPSB, 4-IBOA and 3-FPSB. [0007] The present invention further provides a method of lowering cholesterol in a human subject, comprising the step of orally administering an effective amount of the pharmaceutical formulation which comprises (a) a HMG-CoA reductase inhibitor, (b) at least one of SNAC, SNAD, 5-CNAC, 4-CNAB, 4-MOAC, 4-HPO, 5-PPA, 3-TBA, 2-HPOD, 7- OPHA, 3-HPSB, 4-IBOA and 3-FPSB (c) optionally CoEnzyme Q and (d) optionally, a pharmaceutically acceptable excipient.

[0008] The contents of the patents and publications cited herein and the contents of documents cited in these patents and publications are hereby incorporated herein by reference to the extent permitted.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Fig. 1 is a graph showing the Mean serum ATV (atorvastatin) concentration

Value in ng/ml over Time in minutes at a dose of 10 mg/kg.

[0010] Fig. 2 is a graph showing the Mean serum ATV (atorvastatin) concentration

Value in ng/ml over Time in minutes at a dose of 40 mg/kg.

DETAILED DESCRIPTION OF THE INVENTION

[001 1] The phrase "pharmaceutically acceptable" refers to compounds or compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal.

[0012] The term "bioavailability" refers to the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes systematically available.

[0013] As used herein, the term "HMG-CoA Reductase Inhibitor" means statin, a class of hypolipidemic drugs used to lower cholesterol levels in people with or at risk of cardiovascular disease. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevolonate pathway of cholesterol synthesis. Commonly used HMG-CoA Reductase inhibitors include, but are not limited to [0014] The term "CoEnzyme Q" means a class of vitamin-like substance that are present in most human cells and are responsible for the production of the body's energy. One of the most common CoEnzyme Q is CoEnzyme QlO, wherein Q refers to the quinone chemical group and 10 refers to the number of isoprenyl chemical subunits. [0014] The term "SNAC" as used herein refers to N-(8-[2-hydroxybenzoyl]-amino) caprylic acid and pharmaceutically acceptable salts thereof, including its monosodium and disodium salt as well as SNAC free acid. The term "SNAC free acid" refers to N-(8-[2- hydroxybenzoyl]- amino) caprylic acid which has the following structure:

Unless otherwise noted, the term "SNAC" refers to all forms of SNAC, including all amorphous and polymorphic forms of SNAC, such as SNAC trihydrate and those described in U.S. Serial Nos. 60/619,418 and 60/569,476, both of which are hereby incorporated by reference. The term "SNAC trihydrate" as used herein refers to a crystalline form of SNAC in which three molecules of water are associated with each molecule of SNAC. SNAC can be prepared by the procedures described in U.S. Patent No. 5,650,386 and International Publication Nos. WO00/46182 and WOOO/59863.

[0014] The term "SNAD" as used herein refers to N-(10-[2-hydroxybenzoyl]-amino) dccanoic acid and pharmaceutically acceptable salts thereof, including its monosodium salt and disodium salts as well as SNAD free acid. Unless otherwise noted, the term "SNAD" refers to all forms of SNAD, including all amorphous and polymorphic forms of SNAD. The term "SNAD free acid" refers to N-(10-[2-hydroxybenzoyl]-amino) decanoic acid which corresponds to the following structure:

[0015] The term "4-CNAB" as used herein refers to 4-[(4-chloro-2-hydroxy- benzoyl)amino]butanoic acid (also known as 4-[(2-hydroxy-4- chlorobenzoyl)amino]butanoate) and pharmaceutically acceptable salts thereof, including its sodium salt (e.g., monosodium salt and disodium salt) as well as 4-CNAB free acid. Unless otherwise noted, the term "4-CNAB" refers to all forms of 4-CNAB, including all amorphous and polymorphic forms of 4-CNAB. The term "sodium 4-CNAB" and "mono-sodium 4- CNAB" refer to monosodium 4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate, including anhydrous, monohydrate, and isopropanol solvates thereof and amorphous and polymorphic forms thereof (including those described in International Publication No. WO 03/057650 which is hereby incorporated by reference), unless otherwise indicated. The term "4-CNAB free acid" refers to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid which has the following structure:

[0016] The term "5-CNAC" as used herein refers to N-(8-[5-chloro-2- hydroxybenzoyl]-amino)octanoic acid and pharmaceutically acceptable salts thereof, including its monosodium and disodium salts. Unless otherwise noted, the term "5-CNAC" refers to all forms of 5-CNAC, including all amorphous and polymorphic forms of 5-CNAC. The term "5-CNAC free acid" refers to N-(8-[5-chloro-2-hydroxybenzoyl]-amino) octanoic acid which corresponds to the following structure:

[0017] The term "4-MOAC" as used herein refers to N-(8-[4-methoxy-chIoro-2- hydroxybenzoylj-amino) octanoic acid and pharmaceutically acceptable salts thereof, including its sodium salt and disodium salt as well as 4-MOAC free acid. The term "4- MOAC free acid" refers to N-(8-[4-methoxy-chIoro-2-hydroxybenzoyl]-amino) octanoic acid which has the following structure:

[0018] The term "4-HPO" as used herein refers to 8-(4-hydroxyρhenoxy) octanoic acid and pharmaceutically acceptable salts thereof, including its sodium salt and disodium salt as well as 4-HPO free acid. The term "4-HPO free acid" refers to 8-(4-hydroxyphenoxy) octanoic acid which has the following structure:

[0018] The term "4-HPO" as used herein refers to 8-(4-hydroxyρhenoxy) octanoic acid and pharmaceutically acceptable salts thereof, including its monosodium and disodium salts. Unless otherwise noted, the term "4-HPO" refers to all forms of 4-HPO, including all amorphous and polymorphic forms of 4- HPO. The term "4- HPO free acid" refers to 8-(4- hydroxyphenoxy)octanoic acid which corresponds to the following structure

[0019] The term "5-PPA" as used herein refers to 5-phenylpentanoic acid and pharmaceutically acceptable salts thereof, including its monosodium salt. Unless otherwise noted, the term "5-PPA" refers to all forms of 5-PPA, including all amorphous and polymorphic forms. The term "5-PPA free acid" refers to 5-phenylpentanoic acid which corresponds to the following structure:

[0020] The term "2-PHOD" as used herein refers to 2-(5-pentanoic acid)-5-(2- hydroxyphenyl)-l ,3,4-oxadiazole and pharmaceutically acceptable salts thereof, including its monosodium and disodium salts. Unless otherwise noted, the term "2-PHOD" refers to all forms of 2-PHOD, including all amoiphous and polymorphic forms of 2-PHOD. The term "2-PHOD free acid" refers to 2-(5-pentanoic acid)-5-(2-hydroχyphenyl)-l,3,4-oxadiazole which corresponds to the following structure:

[0021] The term "3-TBA" as used herein refers to 4-m-toIyloxybutyric acid and pharmaceutically acceptable salts thereof, including its monosodium salt. Unless otherwise noted, the term "3-TBA" refers to all forms of 3-TBA, including all amorphous and polymorphic forms of 3-TBA. The term "3-TBA free acid" refers to 4-m-tolyloxybutyric acid which corresponds to the following structure:

[0022] The term "2-HPOD" as used herein refers to 8-(2- hydroxyphenoxy)octyldiethanolamine and pharmaceutically acceptable salts thereof, including its hydrochloride, hydrobromidc, mesylate, acetate, trifluoroacetate, propionate, fumarate, tartrate, citrate, phosphate, succinate, bisulfate, or besylate salts. Unless otherwise noted, the term "2-HPOD" refers to all forms of 2-HPOD, including all amorphous and polymorphic forms of 2-HPOD. The term "2-HPOD free base" refers to 8-(2- hydroxyphenoxy)octyϊdiethanolamine which corresponds to the following structure:

[0023] The term "7-OPHA" as used herein refers to 7-oxo-7-phenylheptanoic acid and pharmaceutically acceptable salts thereof, including its monosodium salt. Unless otherwise noted, the term "7-OPHA" refers to all forms of 7-OPHA, including all amorphous and polymorphic forms of 7-OPHA. The term "7-OPHA free acid" refers to 7-oxo-7- phenylheptanoic which corresponds to the following structure:

[0024] The term "3-HPSB" as used herein refers to 4-(3- hydroxyphenylsulfanyl)butyric acid and pharmaceutically acceptable salts thereof, including its monosodium and disodium salts. Unless otherwise noted, the term "3 -HPSB" refers to all forms of 3 -HPSB, including all amorphous and polymorphic forms of 3-HPSB. The term "3- HPSB free acid" refers to 4-(3-hydroxyphenylsulfanyl)butyric acid which corresponds to the following structure:

[0025] The term "4-IBOA" as used herein refers to (4-isopropylbenzyloxy)acetic acid and pharmaceutically acceptable salts thereof, including its monosodium salt. Unless otherwise noted, the term "4-IBOA" refers to all forms of 4-IBOA, including all amorphous and polymorphic forms of 4-IBOA. The term "4-IBOA free acid" refers to (4- isopropylbenzyloxy)acetic acid which corresponds to the following structure:

[0026] The term "3-FPSB" as used herein refers to 4-(3-fluorophenylsulfanyI)butyric acid and pharmaceutically acceptable salts thereof, including its monosodium salt. Unless otherwise noted, the term "3-FPSB" refers to all forms of 3-FPSB, including all amorphous and polymorphic forms of 3-FPSB. The term "3-FPSB free acid" refers to 4-(3- fluorophenylsulfanyl)butyric acid which corresponds to the following structure:

[0027] Pharmaceutical composition may be in the form of tablets, capsules (including hard and soft gelatin capsules), and particles, such as powders and sachets. An oral tablet is a preferred dosage form of the present invention. Solid pharmaceutical dosage forms may be prepared by mixing the solid form of the earner with the solid form of the HMG-CoA reductase inhibitor.

[0028] The pharmaceutical composition can include any one or combination of excipients, diluents, disintegrants, lubricants, fillers, plasticizers, colorants, flavorants, taste- masking agents, sugars, sweeteners, salts, and dosing vehicles, including, but not limited to, water, 1,2-propane diol, ethanol, olive oil, or any combination thereof. [0029] The amount of HMG-CoA reductase inhibitors, such as atorvastatin, included in the pharmaceutical composition is an amount effective to accomplish the purpose of the atorvastatin for the target indication of lowering cholesterol level in mammals. The amount of HMG-CoA reductase inhibitors, such as atorvastatin in the pharmaceutical composition typically is a pharmacologically, biologically, therapeutically, or chemically effective amount. [0030] One embodiment of the present invention provides a pharmaceutical composition containing a HMG-CoA reductase inhibitor selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and their pharmaceutically acceptable salt, ester and lactone forms thereof. Preferably atorvastatin, its pharmaceutically acceptable salt, ester and lactone forms thereof. More preferably a potassium salt, sodium salt, or calcium salt of atorvastatin. Such pharmaceutical composition further comprises CoEnzyme Q, preferably CoEnzyme QlO. A preferred carrier is SNAC, SNAD, 5CNAC, 4CNAB, 4M0AC, 4HPO, 5-PPA, 3-TBA₅ 2-HPOD, 7-OPHA, 3-HPSB, 4-IBOA or 3-FPSB. A more preferred carrier is SNAC, 4-CNAB and 5-CNAC. Such pharmaceutical composition reduces the side effects of adminstering HMG-CoA reductase inhibitors to human subjects. [0031] The pharmaceutical composition can be in tablet or other forms. Preferably sodium, potassium or calcium salt of atorvastatin is used in the pharmaceutical composition in an amount from about 0.1 mg to about 200 mg, preferably from about 0.2 mg to about 150 mg, more preferably from about 0.4 mg to about 100 mg and the most preferably from about 1 mg to about 50 mg. The amount of at least one of SNAC, SNAD, 5CNAC, 4CNAB, 4MOAC, 4HPO, 5-PPA, 3-TBA, 2-HPOD, 7-OPHA, 3-HPSB, 4-IBOA and 3-FPSB is from about 20 mg to about 700 mg, preferably from about 40 mg to about 600 mg, more preferably from about 60 mg to about 400 mg and the most preferably from about 100 mg to about 200 mg.

[0023] The pharmaceutical composition of the present invention can be administered to treat and/or prevent any disorder for which HMG-CoA reductase inhibitors, such as atorvastatin are known to be capable of treating and/or preventing. Typically, an effective amount of the pharmaceutical composition is administered to treat and/or prevent the desired disorder. Such disorders include, but are not limited to, high cholesterol. The pharmaceutical compositions are useful for administering HMG-CoA reductase inhibitors, such as atorvastin to mammals including, but not limited to, horses, rodents, cows, pigs, dogs, cats, primates, and particularly humans.

[0024] In a preferred embodiment of the present invention, the pharmaceutical composition reduces cholesterol level in a mammal using substantially reduced dosage of HMG-CoA reductase inhibitors, such atorvastatin while reducing the hazardous effects of administering HMG-CoA reductase inhibitors alone, such as reduced level of myalgia, muscle cramps and liver damage.

[0025] In another embodiment of the present invention, the combination of atorvastatin with SNAC increasing the absolute bioavailability of atorvastatin 9-fold as compared with administration of atorvastatin alone. [0026] In still another embodiment of the present invention, the combination of atorvastatin with 5-PPA increases the absolute bioavailability of atorvastatin 8-fold as compared with administration of atorvastatin alone.

[0027] The term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviations, per practice in the art. Alternatively, "about" with respect to the formulations can mean a range of up to 10%, preferably up to 5%.

[0028] The following examples are given as specific illustrations of the invention. It should be understood, however, that the invention is not limited to the specific details set forth in the examples. All parts and percentages in the examples, as well as in the remainder of the specification, are by weight unless otherwise specified. Example 1

[0029] The study was conducted in fasted male Sprague-Dawley rats (n=5 for each group as seen in Fig. 1). Atorvastatin was designated ATV. ATV was administered alone to rates orally or intravenously (IV) as controls. For oral dosing, single dose of two mini-tablets were administrated at time 0, in the following manner: (a) each carrier (200 mg/kg) in combination with ATV (10 mg/kg) was administered orally to rats; (b) ATV (10 mg/kg) alone was administered orally to rats; and (c) Lipitor (lOmg/kg) alone was administered orally to rats. For IV dosing, a bolus shut of ATV alone (2mg/kg) was administered to a group of rats. Blood samples were collected by rail clipping pre-dosing (0 minute), and 5, 15, 30, 40, 50, 60, 120 and 240 minutes after dosing. The testing results are shown in Table 1.

Table 1. Increased Absorption of ATV (at 10 mg/kg) In The Presence Of Carriers

Example 2

[0030] The process of example 1 was repeated except that each carrier (200 mg/kg) in combination with ATV (40 mg/kg) was administered orally to rats. The testing results are shown in Table 2.

Table 2. Increased Absorption of ATV (at 40 mg/kg) In The Presence Of Carriers

[0031 ] The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed as limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition for lowering cholesterol in a human subject comprising (a) a HMG-CoA reductase inhibitor, (b) at least one of SNAC₅ SNAD, 5-CNAC, 4-CNAB, 4-MOAC₅ 4-HPO, 5-PPA, 3-TBA, 2-HPOD, 7-OPHA, 3-HPSB, 4-IBOA and 3- FPSB (c) optionally CoEnzyme Q and (d) optionally, a pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1 , wherein said HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and their pharmaceutically acceptable salt, ester and lactone forms thereof.

3. The pharmaceutical composition of claim 1 , further comprising CoEnzyme Q.

4. The pharmaceutical composition of claim 3, wherein said CoEnzyme Q is CoEnzyme QlO.

5. The pharmaceutical composition of claim 1 , wherein said HMG-CoA reductase inhibitor is atorvastatin, its pharmaceutically acceptable salt, ester and lactone forms thereof.

ό. The pharmaceutical composition of claim 5, wherein said atorvastatin is a potassium salt, sodium salt, or calcium salt.

7. The pharmaceutical composition of claim 5, comprising (a) atorvastatin and (b) SNAC.

8. The pharmaceutical composition of claim 1 , comprising (a) atorvastatin and (b) SNAD, 5CNAC, 4CNAB, 4MOAC, 4HPO, 5-PPA, 3-TBA₅ 2-HPOD, 7-OPHA, 3-HPSB, 4-IBOA or 3-FPSB.

9. The pharmaceutical composition of claim 1, wherein the side effects of said

HMG-CoA reductase inhibitor is reduced.

10. A solid pharmaceutical dosage form for lowering cholesterol level in a human subject comprising (a) from about 0.1 mg to about 200 mg of HMG-CoA reductase inhibitor, and (b) from about 25 mg to about 600 mg of at least one of SNAC, SNAD, 5CNAC, 4CNAB, 4M0AC, 4HPO, 5-PPA, 3-TBA, 2-HPOD, 7-OPHA, 3-HPSB, 4-IBOA and 3- FPSB.

1 1. The solid pharmaceutical dosage form of claim 10, wherein said HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and their pharmaceutically acceptable salt, ester and lactone forms thereof.

12. The solid pharmaceutical dosage form of claim 10, wherein said HMG-CoA reductase inhibitor is atorvastatin, its pharmaceutically acceptable salt, ester and lactone forms thereof.

13. The solid pharmaceutical dosage form of claim 12, wherein said atorvastatin is a potassium salt, sodium salt, or calcium salt.

14. The solid pharmaceutical dosage form of claim 10, further comprising from about 10 mg to about 300 mg of CoEnzyme Q.

15. The solid pharmaceutical dosage form of claim 14, wherein said CoEnzyme Q is CoEnzyme QlO.

16. The solid pharmaceutical dosage form of claim 10, comprising from about 25 mg to about 600 mg of SNAC.

17. The solid pharmaceutical dosage form of claim 10, wherein the side effects of said HMG-CoA reductase inhibitor is reduced.

18. A method of lowering cholesterol in a human subject, comprising the step of orally administering an effective amount of the pharmaceutical formulation of claim 1 to said human subject.