Therapeutic Compositions and Methods

BACKGROUND OF INVENTION

Statins are a class of compounds that have been prescribed, for example, to treat lipid related disorders such as elevated cholesterol. In some instances administration of a statin to a patient causes some level of muscle toxicity In some cases, the muscle toxicity is so severe as to cause the patient to discontinue the statin therapy

Statins are HMG co-A reductase inhibitors whose primary medical application is the reduction of cholesterol by interfering with its production. In addition, statins have the capacity to interfere with another cellular signaling cascade that results in inflammation and shock. It does this by reducing the generation of farnesylpyrophosphates and geranygeranylpyrophosphates, which affect the GTP- binding protem-based intracellular inflammatory signaling cascade that can lead to inflammation GTP-bmding proteins ultimately control the cellulai production of nuclear factor NF-kappa-beta, which in turn stimulates the generation of many of the inflammatory and shock-inducing cytokines such as tumor necrosis alpha, mterleukm 1 alpha and beta, interleukin-6, and others NF-kappa-beta activators include gram- positive and gram-negative bacteria and bacterial products as well as viral infection, most particularly influenza.

By reducing availability of these two phosphate compounds to GTP-binding proteins, the statins significantly downregulate the production of NF-kappa-B, thus reducing inflammation induced by specific infectious agents. Influenza infection is associated with a diamatic increase in cardiovascular and stioke mortality In experimental and naturally occurring human influenza infections, levels of pro inflammatory cytokines such as TNF alpha and IL-6 have been positively coirelated with clinical illness The H5N1 influenza viruses currently causing fatal disease in humans are exceptionally potent inducers of these inflammatory cytokines, and cytokine dysregulation, so-called "cytokine storm" is now thought to be a major contπbutoi to mortality from influenza

The same "cytokine storm" is thought to be involved in the pathogenesis of septic shock, and therefore likely part of the pathogenesis of shock from plague, tularemia, postradiation sepsis, and the cytokinemia triggered by lethal factor of anthrax In a study involving the administration of LPS to normal healthy male volunteers randomized to receive either simvastatin 80 mg per day or placebo for four days prior to LPS administration, high dose simvastatin treatment reduced the expression of toll receptois 2 and 4 on circulating monocytes, as well as reducing TNF alpha expression, suggesting a short-term effect of simvastatin on key receptors of the innate immune response contributing to shock from overwhelming bacterial or viral infection Ob\iously, only four days of therapy was necessary to see this effect (Niessner e t ill 2006)

Statins also modulate coagulation by a number of mechanisms, including decreased tissue factor expression, increasing activity of thrombomodulin, and increasing tissue plasminogen actn ator All of these facfors are involved in mediating septic shock, are presumed to be involved m mediation of shock from influenza, and are likely involved in shock scene with the hemorrhagic viruses In a murine model of sepsis, statin treatment six and 18 hours after sepsis induction by cecal ligation dramatically increased survival This effect was diminished 24 hours after discontinuing the drug (Merx et al 2005)

A number of clinical reports have suggested that statins benefit patients with acute bacterial sepsis In one study of 388 patients hospitalized with gram-negative or staphylococcus aureus bacteremia, theie was a significant reduction in all cause hospital moitality and death attributable to bacteremia in patients receiving statin therapy at the time of bacteremia The reduction in all cause hospital mortality and death attributable to bacteremia was more pronounced in patients who continued to have statin therapy after the diagnosis of bacteremia (Kruger et al 2006)

In a very laige population-based cohort analysis performed in Canada, the incidence of sepsis was lower in patients receiving statins than in controls (Hackam et al 2006) In anothei prospective obsen ational population based study involving almost 12 dozen patients, the pπmaiy outcome measured was infection-related moitality The nsk of infection i elated moitality was significantly lowei in the statin

treated as compared to non-statin treated group. Hazard analysis revealed a strong protective effect of statins adjusted for all known confounders. The affect was highly significant (Almog et al. 2007).

Finally, there is information to suggest that statins increased the survival of mice from plague challenge by aerosol from 10 to 70% when the statins were added to doxycycline treatment. Similar data was seen in mice challenged by aerosolized anthrax and treated with doxycycline; day nine survival was 0% with doxycycline alone, while the addition of statins increased survival to 30%. Given the potent downregulation of shock-producing cytokines, these data are exciting but not altogether surprising.

SUMMARY OF INVENTION

The inventors have discovered that muscle toxicity in a subject being treated with a statin can be reduced by also administering curcumin or a derivative thereof to the subject. In some embodiments, the curcumin is administered in a form having improved oral availability.

In one aspect, the invention features a method of reducing muscle toxicity in a subject who is being treated with a statin, the method comprising administering to the subject a statin and curcumin or a derivative thereof (e.g., curcumin). In some embodiments, the curcumin or derivative thereof is co-administered with the statin. In some embodiments, the method includes administering curcumin to the subject.

In some embodiments, the statin is selected from the group consisting of atorvastatin. fluvastaun, lovastaun, pravastatin, simvastatin, rosuvastatin, and cerivastatin. In some embodiments, the statin is atorvαstatin.

In some embodiments, the subject i-- being -reused for for example, hypercholesteremia. hi some embodiment, the "subject is being treated for a disorder wherein inhibition of NFKB ϊS benefitia], for example, an inflammatory disorder, cancer, an infectious disease, or .Alzheimer ^' s disease. in some emhe«iiments. the creatine phosphokina^c level m the subject being treated fhe hiatin j.s mure (ban the creatine phosphokinase level in the subject

- A -

priuj ti. treatment w ith the εlann lυ sonic embodiments, JK Atrogin-1 expression level m the ^■ -u jject brim* treated v, Jtn the Jdtin is mure than J301 S the Atrogin-1 expression level in the subj ^e ct pαoj en ticatment with the &tatm

In some embodiments, the muscle toxicity is muscle weakness, muscle tenderness, or muscle pain In some embodiments, the muscle toxicity is loss of muscle mass

In some embodiments, the subject is administered a daily dose of curcumin of from about 15 mg/kg to about 40 mg/kg per day In some embodiments, the curcumin is admmisteied 1 2 or 3 times a day In some embodiments, the statin is admmisteied 1 time a day In some embodiments, the curcumin and the statin are both administered 1 time a day In some embodiments, the curcumin and the statin are co admmisteied In some embodiments, the curcumin and the statin are administered in a single dosage form In some embodiments, the subject is administered a daily dose of the statin of from about 0 1 mg/kg to about 1 0 mg/kg per day. In some embodiments the curcumin is formulated in an oral dosage form

In some embodiments, at least 2 5% of the curcumin is orally available In some embodiments the curcumin is formulated as a microcapsule, or the curcumin is formulated into a composition comprising a lipid, or the curcumin is formulated into a composition comprising a phospholipid, for example, hydrogenated soy phosphatidyl choline, or the curcumin is formulated into a composition comprising a micelle- forming polymer, for example, MePEGm-b-PCLig, or the curcumin is administered together with an inhibitoi of glucuronidation, for example, pipeπne

In one aspect, the invention features a method of treating a subject having ^j '> shpi(jemκ. the method compiising administering to the subject a statin and curcumin or a derivative thereof In some embodiments, the LDL cholesterol of the subject is greatei than about 70 mg/dl In some embodiments, the LDL of the subject is greatei than about 90 mg/dl

In some embodiments, the cui cumin oi derivative thereof is co-admmistered with the statin In some embodiments, the method includes administeiing cui cumin to the subject

In some embodiments, the statin is selected from the group consisting of atofvastaϋπ, fluvastatin, lovastatm, pravastatin, simvastatin, rosuvastafin. and ccrivastaiin. In some embodiments, the starin is atorvastarin.

Tn some embodiments, the creatine phosphokmase level in the subject being treated with the statin !-; more rhαn the creatine phosphokinase level in the subject prior to treatment with the statin, in some embodiments, the Atrogin-1 expression level in the subject being treated wish fhe statin is more than about the Atrogin-1 expression level in the subject prior to treatment with the ptaon,

In some embodiments, the muscle toxicity is muscle weakness, muscle tenderness, or muscle pain. In some embodiments, the muscle toxicity is loss of muscle mass.

In some embodiments, the subject is administered a daily dose of curcumin of from about 1.5 mg/kg to about 40 mg/kg per day (15 mg/kg to about 40 mg/kg per day). In some embodiments, the curcumin is administered 1 , 2 or 3 times a day. In some embodiments, the statin is administered 1 time a day. In some embodiments, the curcumin and the statin are both administered 1 time a day. In some embodiments, the curcumin and the statin are co-administered. In some embodiments, the curcumin and the statin are administered in a single dosage form.

In some embodiments, the subject is administered a daily dose of the statin of from about 0.1 mg/kg to about 1.0 mg/kg per day. In some embodiments, the curcumin is formulated in an oral dosage form.

In some embodiments, at least 2.5%, of the curcumin is orally available, e.g., at least about 3%, 4%, 5%, 7.5%, 10%, 15%, 20%, or 25%. In some embodiments, the curcumin is formulated as a microcapsule, or the curcumin is formulated into a composition comprising a lipid, or the curcumin is formulated into a composition comprising a phospholipid, for example, hydrogenated soy phosphatidyl choline, or the curcumin is formulated into a composition comprising a micelle-forming polymer, for example, MePEGi ₁₄ -b-PCLig, or the method includes administering to the subject an inhibitor of glucuronidation, for example, piperine, with the curcumin.

In one aspect, the invention features a pharmaceutical composition including a statin and curcumin or a derivative thereof. In some embodiments, the composition is an oral dosage form. In some embodiments, the composition includes curcumin. In some embodiments, the statin is selected from the group consisting of aiorva^taϋn. fluvastatin, lovastatin, pravastatin, simvastatin, ro^uvastafin, and cerivaslatin. In some embodiments, the statin is aforvastatin.

In some embodiments, at least 2.5%, of the curcumin is orally available, e.g., at least about 3%, 4%, 5%, 7.5%, 10%, 15%, 20%, or 25%. In some embodiments, the curcumin is formulated as a microcapsule, or the curcumin is formulated into a lipid, or the curcumin is formulated into a phospholipid, for example, hydrogenated soy phosphatidyl choline, or the curcumin is formulated into a micelle-forming polymer, for example. MePEGn ₄ -b-PCLj ₉ .

In one aspect, the invention features an oral dosage form comprising a statin and curcumin or a derivative thereof. In some embodiments, the oral dosage form includes curcumin. In some embodiments, the statin is selected from the group consisting of atorvastatin, fiuvastatin, iovastaiin, pravastatin, simvastatin, rosuvastatin. and ceiivastatin. In some embodiments, the statin is atorvastaftn.

In some embodiments, at least 2.5%, of the curcumin is orally available, e.g., at least about 3%, 4%, 5%, 7.5%, 10%, 15%, 20%, or 25%. In some embodiments, the curcumin is formulated as a microcapsule, or the curcumin is formulated into a lipid, or the curcumin is formulated into a phospholipid, for example, hydrogenated soy phosphatidyl choline, or the curcumin is formulated into a micelle-forming polymer, for example, MePEGm-b-PCLis).

In some embodiments, the oral dosage form includes from about 100 mg to about 1,000 mg of curcumin. In some embodiments, the oral dosage form includes from about 10 mg to about 100 mg of a statin.

The term "muscle toxicity," as used herein, refers to weakness, pain, soreness, or tenderness in the muscle, for example, the skeletal muscle of a subject. In some instances, muscle toxicity can result in a loss of muscle mass in a subject. Muscle toxicity can be measured, for example, by evaluating a subject for the level of one or more biological markers such as atrogin-1 or creatine phcwphoksiia.se (CPK S.

The term "statin' ^" as used herein, refers to a compound that lowers cholesterol in a subject by inhibiting the enzyme HMG-CoA reductase. Exemplary statins include the following: atorvasratm (,LIFIT UR ^1M ), fluvastatin (Lfc ^' SCQL ^'lv j, lovastatin (MIiVACOR^ ), pravastatin (PRλVACHOL™ }, simvastatin (ZOCOR ^{1 M} ), rosuvastatin (CRF.STOR™). and cerivastatin i BA VCOL™)- T« i>ome embodiments, the statin, as used herein, can be administered to a subject for a purpose other than for lowering cholesterol.

The term "curcumin or a derivative thereof as used herein refers to curcumin and other curcuminoids, for example, demethoxycurcumin and bis- demethoxycurcumin. In some embodiments, a derivative of curcumin has increase solubility or oral availability than curcumin. The structure of curcumin is shown below:

In some embodiments, a derivative of curcumin includes one or more modifications on a phenol ring of the curcumin.

In some embodiments, the curcumin is substantially pure. Curcumin can be isolated from turmeric. In some embodiments, the cucumin is substantially free of other compounds found in turmeric, for example, being substantially free of other curcuminoids.

The term "oral availability" as used herein, refers to a compound or composition wherein at least about 2.5%, of an active ingredient (i.e., the compound or an active ingredient such as "the compound" of the composition) reaches the systemic circulation and the site of action when administered to a subject. In some embodiments, oral availability is measured by determining the AUC (i.e., area under the curve) of the active ingredient in a subject e.g.. at least about 3%, 4%. 5%, 7.5%, 10%, 15%, 20%, or 25%. In some embodiments, a compound or composition has an improved oral availability relative to another, comparison, compound or composition, e.g., at least about 1.5 times more orally available than the comparison compound, at

least 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times ore more orally more available than the comparison compound

The term "co-admmistered" as used herein, refers to the administration of two (or more) agents wherein the agents are administeied to a subject at the same time or within an interval such that there is overlap of an effect of each agent on the patient Preferably they are administered within 60, 30 15, 10, 5, or 1 mmute of one another Preferably the admmistiations of the agents are spaced sufficiently close together such that a combinatorial effect is achieved The agents can be administered simultaneously, for example in a combined unit dose (providing simultaneous deliver}' of both agents) Alternat ely, the agents can be administered at a specified time interval for example, an interval of minutes, hours, days oi weeks Generally, the agents are concurrently bioavailable, e g detectable, in the subject

DETAILED DESCRIPTION

Methods of reducing muscle toxicity m a subject being administered a statm are described Also described are compositions and dosages foi treating a subject for disorders for which statin therapy is administered

Unit Dosage Formulations and Administration

Methods, compounds and compositions disclosed herein can be used to reduce muscle toxicity in a subject being administered a statm

As discussed elsewhere herein, subjects are treated with a combination of a statin, for example, rt on Jf4aun _V J ϊPH OR ^h ' t ϊhu λ \ SC OI ^!N i lo^ astαfm iMfcλ ACOR ^M ) fuavasfitiπ <TRλ\ ACHOL ¹¹¹ J sirm a:>tatiUz.UtOR ^nr i lo&uvasialin _v < RESTOR ^M ! ancKem asiatm (B W < < >L ^{I M} t pieferably Jtorv«statin, and cui cumin or a derivative thereof, e g , curcumin These agents are generally administered orally They can be administered separately, e g , in separate unit dosage formulations, e g one pill oi capsule containing a statm and a separate pill or capsule containing curcumin In some embodiments, the two agents are provided as a combined formulation A combined formulation is one in which the two agents provided together in a unit dosage formulations, e g one pill oi capsule containing a statin such as atorvastatin and cuicumm

In another embodiment, the first and second agent (e g.. a statin and curcumin) are further combined with a third agent, and can be, for example, co formulated as a single pill (e g , tablet, gel. or other dosage unit) for administration together For example, the administration of the dose formula can be one, two or three times daily, e g , as required

In some embodiments, one or more of the agents (e g the statin or curcumin or a derivative thereof) is formulated as a pharmaceutically acceptable salt Examples of pharmaceutically acceptable include those derived from pharmaceutically acceptable inorganic and oiganic acids and bases Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, mcotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate and undecanoate Salts derived from appropriate bases include alkali metal (e g , sodium), alkaline earth metal (e g . magnesium, calcium), ammonium and N-(alkyl) ₄ ⁺ salts This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein Water or oil-soluble or dispersible products may be obtained by such quaternization

Unit dosage formulations for a statin, for example, atriva^ raf Ώ can tc fjom about 30 to about 160 tuς Unit dosage formulations for curcumin, include, for example from about 200 mg to about 2,000 mg of curcumin In some instances, foi example, where the curcumin is formulated into a unit dosage having improved oral availability such as a microcapsule, a composition including a lipid such as a phospholipid, a composition including a micelle-forming polymer, or a composition including piperme, then the amount of curcumin m the unit dosage formulation can be reduced

In some embodiments, one or more of the agents herein are formulated with a phaimaceutically acceptable carriei oi adjuvant The teim "pharmaceutically acceptable carrier or adjuvant ^" refers to a carriei or adjuvant that may be administered to a patient, togethei with a compound of this invention, and which does not destioy

the pharmacological activity thereof and is nontoxic when administered m doses sufficient to deliver a therapeutic amount of the compound

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeiic delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate. partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium tnsilicate, polyvinyl pyrrolidone. cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyεthylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat Cyclodextrins such as α-, β-, and γ- cyclodextπn, or chemically modified derivatives such as hy droxy alky Icy clodextπns, including 2- and 3-hydroxypiopyl-β-cyclodextπns, or othei solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein

The agents descπbed herein are preferably administered orally, for example as a component in a pharmaceutical composition The pharmaceutical compositions may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles In some cases, the pH of the formulation may be adjusted with phaimaceutically acceptable acids, bases or buffeis to enhance the stability of the formulated compound or its delivery form

The phaimaceutical compositions of this invention may be orally administeied in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions In the case of tablets foi oral use earners which are commonly used include lactose and corn starch Lubiicatmg agents, such as magnesium stearate, aie also typically added Foi oial admmistiation in a capsule form, useful diluents include lactose and dried corn starch

When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents If desired, certain sweetening and/or flavoring and/or coloring agents may be added

In some preferred embodiments, one or more of the statin or the curcumin or derivative thereof is formulated into a composition that results in improved oial availability In some preferred embodiments, curcumin is formulated into a composition resulting in improved oral availability Exemplary compositions that provide impioved oral availability include miciocapsule, lipid containing compositions such as a phospholipid, micelle-forming polymers, and compositions including pipeπne

Exemplary methods of formulating curcumin are described, for example, in WO 2006/129323 which incorporated by reference herein, wherein the volatile oil of turmeric is isolated by conventional methods of s^eam distillation to isolate essential oils as well known in the art Curcumin is isolated from the de oiled turmeric by solvent extraction Suitable solvents for this purpose include acetone, hexane, ethyl acetate, dichloroethane, chloroform, etc The extraction is conveniently carried out at moderate temperatures (40-55° C) and the solvent is partially remoλ ed to yield a concentrate containing 30 60% solids The solution is cooled to obtain crystals of curcumin which are isolated by any suitable method such as filtration or centrifugation This product typically contains about 95% of curcumin Curcumin and the volatile oils of curcumin are mixed and blended to get a uniform product The ration of curcumin to oil can be varied between 3 1 to 99 1 , preferably in the ratio 85 15 A more preferred ratio is 95 5 Gelatin capsules containing 500 mg of the blend are prepared

Another example of formulation of cucumm is described in European Patent Application EP 060048204, which is incorporated by ieference herein, which describes 20 g of turmeric rhizomes extract ha\ mg a total curcummoid content of 93 8% w/w dissolved in ethanol (800 mL) and the solution refluxed with 80g of soy phospholipids slowly added in portions, undei lefluλ and with stirring The resulting suspension is ieflu\ed with stirring foi 1 hi then hot concentrated undei reduced

pressure and finally dried in oven. 97.6 g of an orange waxy product is obtained having a curcumin content of 13.2% and a total curcuminoid content of 19.9% w/w.

A. Liu, H. Lou, L. Zhao. P. Fan, in J. Pharm. Biomed. Anal. 2006, 40, 720- 727, which is incorporated by reference herein, describe a formulation of curcumin wherein 3.7 g of curcumin and 7.5 g 95% soya phospholipid were dissolved in 30OmL acetone and left under heating and stirring for 3h. The resulting solution is concentrated. The precipitate obtained is dried in a vacuum dryer at -40 ⁰ C for 6h. The product (10.3 g, yield 92%) is obtained as a yellow opaque jell soluble in acetone.

K. Maiti, K. Mukherjee, A. Gantait, B. Pada Saha, P. K. Mukherjee, in Int. J. Pharmaceutics 2007, 330, 155-163, which is incorporated by reference herein, describe a formulation of curcumin wherein a complex is prepared with curcumin and hydrogenated soy phosphatidyl choline (HSPC) at a molar ratio of 1 : 1. Weighed amount of curcumin and HSPC are taken in a 100 ml round bottom flask and 20 ml of dichloromethane is added. The mixture is refluxed at a temperature not exceeding 60 ° C for 2 h. The resultant clear solution is evaporated and 10 ml of n-hexane is added to it with continuous stirring. The curcumin-phospholipid complex is precipitated and the precipitate is filtered and dried under vacuum to remove traces of solvents. The resultant curcumin-phospholipid complex (yield 88%, w/w) is kept in an amber colored glass bottle, flushed with nitrogen and stored at room temperature.

K. Letchford, R. Liggins, H. Burt , in /. Pharm. Sd.. 2008, 97, 3, 1 179-1 190, which is incorporated by reference herein, describe a formulation of curcumin where a micelle-forming polymer MePEGπ ₄ -b-PCL ₁₉ is prepared as a diblock copolymer of methoxypolyethylene glycol (MePEG) and poly(caprolactone) (PCL) as described in the referenced publication, Curcumin is loaded into the polymeric micelles by a solvent evaporation technique in which curcumin and the polymer are dissolved in a common solvent (acetonitrile) at a total polymer concentration 1 % w/w. The solvent is then removed by vacuum evaporation at 4O ⁰ C overnight under vacuum. Micelles are formed by the addition of 37°C PBS (0.01 M, pH 7.4) followed by vortexing until the polymer/drug matrix had dissolved. Drag solutions are incubated at 37°C in a water bath and then transferred to microcentrifuge tubes and centπfuged at 18000g for 3min topellet any precipitate. The supernatant contains a highly solubilized micellar

form of curcumin at the concentration up to 3.9x10 ³ mol/L, which corresponds to ca 130,000-fold increase in solubility as compared to the PBS buffer without the polymer.

Curcumin can also be formulated or co-adimmstered with a compound that inhibits glucuromdation, for example, piperme, which can increase the oral availability of curcumin due to the inhibition of its major metabolism pathway. An example of such a method is described in G Shoba, D. Joy, M. Majeed, R. Rajendran, P.S. Snnivas Planta Med 1998, 64, 4. 353-356, which is incorporated herein by reference.

When the agents described herein are administered in combination, both of the agents should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The agents may be administered separately, as part of a multiple dose regimen. Alternatively, the agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition

In some embodiments, both the statin (e.g.. atorva-raft! (L1Pϊ1 QR ^{) X|} ι ϊiαwisUtm (LESCOL ^v s, lυvastalm (MEV λCOR ^{1 *1} ). piavasumn ( PRAV λU K >L ^{I M} 1 vmivasf aun (ZOCOR™), losuvastahn <f RFSTOR™), υi ceπvasiatin (BAV(Ol " )) and the curcumin or derivative thereof, e.g . curcumin, are formulated so that the two agents are simultaneously released, e g , formulated for immediate or instantaneous release of both agents.

In some embodiments, for example, where one or more of the agents is administered once per day, the agent is formulated to provide extended release. For example, the agent is formulated with an enteiic coating. In an alternative embodiment, the agent, for example, the statin or curcumin, is formulated using a biphasic controlled release delivery system, thereby providing prolonged gastric residence. For example, in some embodiments, the delivery system includes (1 ) an inner solid particulate phase formed of substantially uniform granules containing a phaimaceutical having a high water solubility, and one oi moie hydiophihc polymeis one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/oi fatty acid esters, and (2) an outer solid

continuous phase in which the above granules of inner solid particulate phase are embedded and dispersed throughout, the outer solid continuous phase including one or more hydrophobic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, which may be compressed into tablets or filled into capsules

In some embodiments, the statm and/or cuicumin, in the formulation is not formulated with two different ielease piopeities, e g , two different time release properties For example, the statm and curcumin is formulated in a single release formulation, a formulation with a single kinetic property Preferably, the statm is released with the same kinetics, as the curcumin Methods of treatment

The compounds, compositions and methods heiein can be used to treat a subject that is being administered a statin Exemplary disorders for statin therapy include those disorders « here inhibition of NFKB IS beneficial, for example, dyshpidemia, inflammatory disorders, neoplastic disorders, infectious diseases, and Alzheimer's disease Dyslipidemia

Applicants have discovered that muscle toxicity can be reduced in a subject being admimstred a statm by also administering to that subject curcumin or a derivative thereof The methods and compositions described herein can be useful for any subject being administered a statin The statin can be administered for any purpose, for example for treating Dyshpidemia (e g , hypercholesteπmia) or any other disorder wherein statm therapy is beneficial For example, the methods and compositions described herein can be useful for a subject being Heated for a disorder wherein inhibition of HMG-CoA reductase is beneficial

Examplary disorders that can be tieated with a composition or method described herein include Dyshpidemia (e g hypercholesterolemia), inflammatory disorders such as atherosclerosis, cancer, infectious diseases, and Alzheimer's disesase

Dyshpidemia is a disruption of the amount of lipids in the blood of a subject A common foim of dyshpidemia is hypeihpidemia wheiein a subject has an elevation

of lipids m the blood, for example, caused by diet, lifestyle, genetics, or a combination thereof Lipid and lipoprotein abnormalities common and can be a risk factor for cardiovascular disease due to the influence of cholesterol, one of the most clmicall) relevant lipid substances, on atherosclerosis In addition, some forms of hyperlipidemia can predispose a subject to acute pancreatitis Hyperhpidemias are classified according to the Fredrickson classification which is based on the pattern of lipopi oteins on electrophoresis or ultracentrifugation It was later adopted by the World Health Organization (WHO) Inflammatory disorders:

Atherosclerosis is an example of an inflammatory disorder that can be treated with a compound, composition or method described herein Atherosclerosis is a disease affecting arterial blood vessels It is a chronic inflammatory response in the walls of aiteπes, in large part due to the accumulation of macrophage white blood cells and promoted by low density (especially small particle) lipoproteins (plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the maciophages by functional high density lipoproteins It is commonly referred to as a ' hardening" or "furring' of the artenes It is caused by the foi mation of multiple plaques within the arteries

Multiple sc lei osis is an example of an inflammatory disorder that can be tieated with a compound composition or method described herein Multiple sclerosis is a chronic, inflammatory, demyelinating disease that affects the central nervous system Disease onset usually occurs in young adults, is more common in women, and has a prevalence that ranges between 2 and 150 per 100,000 depending on the country or specific population

MS affects the areas of the bram and spmal cord known as the white matter White matter cells carry signals between the grey matter areas, wheie the processing is done and the rest of the body More specifically, MS destioys oligodendrocytes which are the cells responsible for creating and maintaining a fatty layer, known as the mvelin sheath, which helps the neuions cany electrical signals MS iesults in a thinning oi complete loss of myelin and, less fiequently, the cutting (transection) of the neui on's extensions oi axons

Other examples of inflammatory disorders which can be treated using the compounds, compositions, methods described herein include appendicitis, peptic, gastric or duodenal ulcers, ileus, peritonitis, pancreatitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, , alveahtis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, iespiratory syncytial virus, herpes, disseminated bacteremia, Dengue fever, candidiasis, malaria, filanasis, amebiasis, hydatid cysts, vasulitis, angiitis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocardial ischemia, periarteritis nodosa, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis uveitis, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, synovitis, thryoiditis, Goodpasture's syndiome, Behcet's syndrome, allograft rejection, giaft- versus host disease. Type I diabetes, Beigei's disease, Type II diabetes, Berger's disease, Reiter's syndrome, or inflammatory bowel disease, iheumatoid arthritis, psoriasis Neoplastic Disorders

The compounds, compositions, and methods descπbed herein can be used in the treatment of cancer As used herein, the teims "cancer", "hyperprohfeiative", "malignant' ^" , and "neoplastic" are used interchangeably, and refer to those cells an abnormal state 01 condition chaiacteπzed by rapid proliferation or neoplasm The terms include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, irrespective of histopathologic type or stage of invasiveness "Pathologic hyperprohferative" cells occur in disease states characterized by malignant tumor growth

The common medical meaning of the term "neoplasia ^" iefeis to "new cell giowth that results as a loss of responsiveness to normal growth controls, e g to neoplastic cell growth A "hypeiplasia" iefeis to cells undergoing an abnormally high

rate of growth. However, as used herein, the terms neoplasm and hyperplasia can be used interchangeably, as their context will reveal, referring generally to cells experiencing abnormal cell growth rates. Neoplasms and hyperplasias include "tumors." which may be benign, premalignant or malignant

Examples of cancerous disorders include, but are not limited to, solid tumors, soft tissue tumors, and metastatic lesions. Examples of solid tumors include malignancies, e.g., sarcomas, adenocarcinomas, and caicmomas, of the various organ systems, such as those affecting lung, breast, lymphoid, gastrointestinal (e g , colon), and genitourinary tract (e g , renal, urothelial cells), pharynx, prostate, ovary as well as adenocarcinomas which include malignancies such as most colon cancers, rectal cancer, renal cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine and so forth Metastatic lesions of the aforementioned cancers can also be treated or prevented using a compound described herein

The subject method can be useful in treating malignancies of the various organ systems, such as those affecting lung, breast, lymphoid, gastrointestinal (e g , colon), and genitourinary tract, prostate, ovary, pharynx, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus Exemplary solid tumors that can be treated include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma Ewmg's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancel, prostate cancel, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcmoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumoi, cervical cancel, testicular tumor, lung carcinoma, small cell lung caicinoma, non- small cell lung carcinoma, bladdei caicinoma epithelial carcinoma, glioma, ashocytoma, medulloblastoma craniopharyngioma, ependymoma, pinealoma,

hemangioblastoma. acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and ietinoblastoma

The term ' carcinoma" is recognized by those skilled in the art and refeis to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary The term also includes carcmosaicomas, e g which include malignant tumois composed of carcinomatous and sarcomatous tissues An "adenocarcinoma" refers to a carcinoma derived from glandular tissue or in which the tumor cells form lecognizable glandular structures

The term "sarcoma" is recognized by those skilled in the art and refers to malignant tumors of mesenchymal derivation.

The subject method can also be used to inhibit the proliferation of hyperplastic/neoplastic cells of hematopoietic origin, e g , arising from myeloid, lymphoid or erythroid lineages, or precursor cells thereof For instance, the invention contemplates the treatment of various myeloid disorders including, but not limited to, acute promyeloid leukemia (APML), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) (reviewed in Vaickus, L (1991 ) Crit Rev m Oncol /Hemotol 11 267-97) Lymphoid malignancies which may be treated by the subject method include, but are not limited to multiple myeloma ( MM), the premalignant related condition , monoclonal gammopathy of unknown significance (MGUS), acute lymphoblastic leukemia (ALL), which includes B lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL). prolymphocyte leukemia (PLL), hairy cell leukemia (HLL) and Waldenstrom's macroglobulmemia (WM) Additional forms of malignant lymphomas include, but are not limited to, non- Hodgkin's lymphoma and variants thereof, peripheral T-cell lymphomas, adult T cell leukeniia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), laige granular lymphocytic leukemia (LGF) and Hodgkin's disease

Alzheimer's Disease

The compounds, compositions, and methods can be used to treat Alzheimer's Disease (AD), which is a complex neurodegenerative disease that results in the irreversible loss of neurons and is an example of a neurodegenerative disease that has symptoms caused at least in part by protein aggregation. A compound described herein can be used to ameliorate at least one symptom of a subject that has AD.

Clinical hallmarks of Alzheimer's Disease include progressive impairment in memory, judgment, orientation to physical surroundings, and language. Neuropathological hallmarks of AD include region-specific neuronal loss, amyloid plaques, and neurofibrillary tangles. Amyloid plaques are extracellular plaques containing the β amyloid peptide (also known as Aβ, or Aβ42), which is a cleavage product of the β-amyloid precursor protein (also known as APP). Neurofibrillary tangles are insoluble intracellular aggregates composed of filaments of the abnormally hyperphosphorylated microtubule-associated protein, tau. Amyloid plaques and neurofibrillary tangles may contribute to secondary events that lead to neuronal loss by apoptosis (Clark and Karlawish, Ann. Intern. Med. 138(5):400-410 (2003). For example, β-amyloid induces caspase-2-dependent apoptosis in cultured neurons (Troy et al. J. Neurosci. 20(4): 1386-l 392). The deposition of plaques in vivo may trigger apoptosis of proximal neurons in a similar manner.

Progressive cognitive impairment is a hallmark of AD. This impairment can present as decline in memory, judgment, decision making, orientation to physical surroundings, and language (Nussbaum and Ellis, New Eng. J. Med. 348(14):1356- 1364 (2003)). Exclusion of other forms of dementia can assist in making a diagnosis of AD.

Neuronal death leads to progressive cerebral atrophy in AD patients. Imaging techniques (e.g., magnetic resonance imaging, or computed tomography) can be used to detect AD-associated lesions in the brain and/or brain atrophy.

AD patients may exhibit biochemical abnormalities that result from the pathology of the disease. For example, levels of tau protein in the cerebrospinal fluid is elevated in AD patients (Andreasen, N. et al. Arch Neurol. 58:349-350 (2001)). Levels of amyloid beta 42 (Aβ42) peptide can be reduced in CSF of AD patients

(Galasko, D., et al. Arch. Neurol. 55:937-945 (1998)). Levels of AD42 can be increased in the plasma of AD patients (Ertekein-Taner, N., et al. Science 290:2303- 2304 (2000)). Techniques to detect biochemical abnormalities in a sample from a subject include cellular, immunological, and other biological methods known in the art. For general guidance, see, e.g., techniques described in Sambrook & Russell, Molecular Cloning: A Laboratory Manual, 3 ^rd Edition, Cold Spring Harbor Laboratory, N.Y. (2001 ), Ausubel et al , Current Protocols in Molecular Biology (Greene Publishing Associates and Wiley Interscience, N.Y. (1989), (Harlow, E. and Lane, D. (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY), and updated editions thereof.

Infectious Diseases:

Infectious diseases that can be treated or prevented by the methods of the present invention are caused by infectious agents including, but not limited to, viruses, bacteria, fungi, protozoa and parasites. Bacterial diseases that can be treated or prevented by the compounds, compositions and methods described herein are caused by bacteria include, but are not limited to, mycobacteria rickettsia, mycoplasma, neisseria and legionella. Protozoal diseases that can be treated or prevented by the compounds, compositions and methods described herein are caused by protozoa including, but not limited to, leishmania, kokzidioa, and trypanosoma. Parasitic diseases that can be treated or prevented by the compounds, compositions and methods described herein are caused by parasites including, but not limited to, chlamydia and rickettsia.

Viral diseases that can be treated or prevented by the compounds, compositions and methods described herein include, but are not limited to. those caused by Influenza A and B, hepatitis type A, hepatitis type B, hepatitis type C, influenza, pneumoniae, sepsis, varicella, adenovirus, herpes simplex type I (HSV-I), herpes simplex type II (HSV-II), rinderpest, rhinovirus, echovirus. rotavirus, respiratory syncytial virus, papilloma virus, papova virus, cytomegaloλ'irus, echinovirus, arbovirus, huntavirus, coxsachie virus, mumps virus, measles virus,

rubella virus, polio virus, human immunodeficiency virus type I (HIV-I), and human immunodeficiency virus type II (HIV-II)

Exemplary bacterial infections that can be treated with the compounds, compositions, and methods described herein include, but are not limited to, seosis and the following organisms Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis , Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps , Proteus sps , Pseudomonas aeruginosa, E coli, Serratia marcesens, Staphylococcus aureus, Coag Neg Staph, Haemophilus infuenzae, Bacillus anthracis, Mycoplasma pneumoniae, Moraxella catarralis, H influenzae Chlamydia pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis, Helicobacter pylori, Staphylococcus epidermidis Chlamydia pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis, Staphylococcus saprophytics, or Heliobacter pylon [00188] In another embodiment, the phaimaceutical compositions and methods of this invention will be useful generally for controlling bacterial infections m vivo caused by the following the following organisms Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Coag Neg Staph, Haemophilus infuenzae, Bacillus anthracis. Mycoplasma pneumoniae, Moraxella catarrahs, H influenzae Chlamydia pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis, Helicobacter pylori, Staphylococcus epidermidis Chlamydia pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis. Staphylococcus saprophytics or Heliobacter pylori

Examples of non-nosocomial uses include but are not limited to urinary tract infections pneumonia, prostatitis, skin and soft tissue infections, intra-i abdominal infections, and therapy for febrile neutropenic patients

This invention is not limited m its application to the details of construction and the arrangement of components set forth in the following desciiption oi illustrated in the drawings The invention is capable of other embodiments and of being practiced or of being carried out in various ways Also, the phraseology and teiminology used heiem is for the purpose of description and should not be regarded as limiting The use of "including," ''compiising, ^* ' oi "having " ' containing ', "involving" and

vaπations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

Having thus described several aspects of at least one embodiment of this invention, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing descπption and drawings are by way of example only.

What is claimed is