AU2015274895A1 - Fixed dose combination for pain relief without edema - Google Patents

Abstract

Methods for individualized therapy of arthritic pain using a non-steroidal anti-inflammatory drug (iCOX-2 inhibitor). Said methods comprise basing COX-2 inhibitor dose on each patient's pharmacokinetic response to said COX-2 inhibitor. Provided is a composition for treating pain without inducing edema comprising a COX-2 inhibitor and a diuretic, wherein the composition is administered in a fixed-dose combination.

Description

PCT/U S2015/034706 WO 2015/191460

FIXED DOSE COMBINATION FOR PAIN RELIEF WITHOUT EDEMA

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Applications Nos. 62/009,300, filed June 8, 2014, and 62/023,962, filed July 14, 2014, which are both incorporated by reference. This application also claims the benefit of PCT Application PCT/US2015/011148, filed January 13, 2015, which is incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] It is well appreciated that non-steroidal anti-inflammatory drugs (“NSAID”) are highly active as pain relievers. However, NSAIDs also have major and minor side effects. One of these side effects is drug induced edema.

[0003] “Edema” is an abnormal accumulation of fluid in the tissue spaces, cavities, or joint capsules of the body, causing swelling of the area. Edema can occur in the tissues or body spaces such as the plural cavities or the peritoneal space. Clinically, edema has variable consequences dependening on the site and severity of the edema. For example, when subdermal edema is mild it may only manifest itself as with tight shoes. In contrast, chronic, severe subdermal edema can cause skin break down, ulceration and serious infection. Similarly, While a pleural effusion may spontaneously resolve, ascites (edema in the paritoneal space) can be complicated by difficult to treat bacterial peritonitis. See, e.g., Harrison’s Internal Medicine, 16th edition, p.213-214. There are multiple causes for edema.

[0004] Pathophysiologically, edema occurs when there is an elevation in capillary hydraulic pressure, and/or an increase in capillary permeability or when the interstitial oncotic pressure exceeds the plasma oncotic pressure. Such changes can result from a variety of conditions and diseases. For example, in congestive heart failure the activation of the renin-angiotensin system causes volume overload which results in increased capillary hydraulic pressure. The kidneys control extracellular fluid volume by adjusting sodium and water excretion. When renal function is impaired, edema can result. In cirrhosis the reduced production of serum proteins such as albumin result in a decrease in the plasma oncotic pressure relative to interstitial oncotic pressure resulting fluid shifts into the intersitum. Venous insufficiency is a common cause of edema of the lower extremities from an increase WO 2015/191460 2 PCT/US2015/034706 in capillary hydraulic pressure. Harrison’s Internal Medicine, 16th edition, p.213-214 ; O’Brian et al.. Treatment of Edema, American Family Physician, 71(11). 2111-17.

[0005] Many drugs can cause edema including steroid hormones, vasodilators such as hydralazine, estrogens, NSAIDs, immunomodulators such as interleukin 2, and calcium channel blockers. Like other forms of edema, the pathophysiolog of drug induced edema is wide ranging. Drug induced edema may be caused by vasodilation (e.g. hydralazine), drug effects on the kidneys’ sodium excretion (e.g., steroids), and capillary damage (e.g., interleukin 2). Drug induced edema is usually dose-dependent and its severity increases over time. Harrison’s Internal Medicine, 16th edition, p.213-214; O’Brrin et al., Treatment of Edema, American Family Physician, 71(11). 2111-17. Many NSAIDs can cause edema. The mechanism for NSAID induced edema has been postulated to be from renal vasoconstriction. Harrison’s Internal Medicine, 16th edition, p.213-214. NSAIDs inhibit cyclogenases (COX), the enzymes that catalyzes formation of various prostaglandins. The two principle COX isoforms are COX-1 and COX-2. Studies have shown that both therapeutic and side effects of NSAIDs are dependent on cyclooxygenase inhibition. In general, selective inhibitors of COX-2 have therapeutic effects that are as strong as conventional NSAIDs but with fewer side effects. Nevertheless, selective COX-2 inhibitors still can cause edema. SUleyman et al., Anti-inflammatory and side effects of cyclooxygenase inhibitors, Pharma. Reports, 2007 59:247-258.

[0006] Any suitable means may be used in the detection and quantification edema varies widely. For example, effusions (edema in the thoracic, peritoneal, or pericardium) can be quantified based on the level of fluid when imaged with the patients standing. Most commonly, edema is measured subjectively based on the ability to push into or “pit” the swollen skin.

[0007] Celebrex (celecoxib) is a prototypic selective COX-2 inhibitor and the first page of the Celebrex (celecoxib) Package Insert lists edema as an “adverse reaction.” Table 1 of this Package Insert discloses that 2.1% of patients treated with celecoxib develop edema, as compared to 1.1%, 2.1%, 1.0%„ and 3.5 % for placebo, naproxen, diclofenac, and ibuprofen, respectively. Moore et al.’s review of the tolerability and rate of adverse events in clinical trials of celecoxib found that the incidence of edema at any site was usually about 3%, but in two trials the incidence of edema much higher at 23% and 38%. Arthritis Res. & Therapy, 2005, 7(6), R644-R664, R658-59. WO 2015/191460 3 PCT/U S2015/034706 [0008] Treatment of edema consists of reversing the underlying disorder (if possible), restricting dietary sodium to minimize fluid retention, and, usually, employing a diuretic drug. O’Brian et al., Treatment of Edema, American Family Physician, 71(11). 2111-17.

[0009] In view of the persistent problem of drug induced edema and, in particular, edema induced by drugs with known efficacy for the treatment of pain, there remains a need for better approaches to preventing and treating drug induced edema. In addition, despite progress in the art, because each of the multiple mechanisms that produce drug induced edema require a specalized treatment, there remains a need for better approaches to preventing and treating drug induced edema.

BRIEF SUMMARY OF THE INVENTION

[0010] Provided is a composition for treating pain without inducing edema comprising a COX-2 inhibitor and a diuretic, wherein the composition is administered in a fixed-dose combination.

[0011] Additionally, provided is a method for individualized therapy of pain without inducing edema using a NSAID including wherein the NSAID may be a COX-2 inhibitor and in a perfered embodiment the NSAID is celecoxib, comprising: a. administering a first NSAID formulation comprising a first dose of a combination with a diuretic in specific amounts, to a first patient suffering from pain; b. determining the NSAID and diuretic concentration in the first patient’s blood at a plurality of time points after the first NSAID formulation was administered to the first patient; c. transforming the first patient’s and diuretic concentration/time data points in to one or more pharmacokinetic (PK) parameters; d. comparing the first patient’s values for said PK parameters to a predetermined ranges of values for each PK parameter and if one or more of the first patient’s PK parameters fall outside of a predetermined range, designing a new NSAID formulation, wherein the dose of said NSAID inhibitor, the diuretic, or both is different from that of the first NSAID formulation; e. administering the new NSAID formulation to the first patient; f. repeating steps b-e until all the PK parameters used in step d are within said predetermined ranges, and WO 2015/191460 4 PCT/US2015/034706 g. if pain control is adequate, toxicity is tolerable, and the patient is not experiencing edema, maintaining the first patient on the NSAID formulation at frequency of administration that satisfied the comparison in step d.

[0012] Related compositions and methods for individualizing therapy of arthritic pain are disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 is a scatterplot graph displaying the relationship between LPS-stimulated plasma PGE2 ex vivo, an index of NSAID activity, and log plasma concentrations of celecoxib 2, 4, 6, and 24 hours after dosing. PGE2 is expressed as a percentage of predosing values. A steep but variable dose-response is evident. (P , 0.01 vs. placebo) (from McAdam et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. PNAS. 1999; 96:272-7.) [0014] FIG. 2 depicts the pharmacokinetic parameters produced by different doses of celecoxib.

[0015] FIG. 3 displays the result of a meta-analysis of the one dose AUC from patients in different age groups.

[0016] FIGS. 4-6 display the results of a meta-analysis of the edema rates in populations treated with celecoxib doses ranging from 100 mg/day to 800 mg/day.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The invention provides compositions and methods for individualized therapy of pain, including but not limited to arthritic pain, using a NSAID, preferably a COX-2 inhibitor, and a diuretic (e.g., hydrochlorothiazide). The high patient to patient variability in response to a dose of any NSAID and/or diuretic makes the mere clinical monitoring of patients an inadequate way to treat patients with this class of drugs. Even the measurement of “blood levels” (i.e., the ocasional measurement of the drug’s concentration in the plasma) is unlikely to lead to effective nontoxic regimens. Given the complexity of NSAIDs’ dose response relationships both alone and in combination with one or more diuretics, a more comprehensive set of metrics must employed in each patient. The methods claimed herein take advantage of a pharmacokinetic (“PK”) analysis for each patient. As such, the claimed methods go beyond the measurement of a single blood level at a single time point. Instead, the claimed methods make use of data on the plasma drug concentraion from several time WO 2015/191460 5 PCT/US2015/034706 points (at least 2, peferably at least 5, 6, 7, 8, 9, 10, 11, 12 over period of at least 12, 18, 24, 36, 48, 60, 72 hours) and take advantage of the full scope of PK parameters to generate a PK Profile of a patient for a particular drug. There is no known method of predicting individual PK profile for celecoxib due to the complexity of human pharmacokinetics. As such, there is no natural law known that can predict human pharmacokinetics without administering at least one dose of given drug to an individual. In addition, the multitude of potential determining factors make defining such law impractical. Therefore, the claimed method seeks to determined the individual’s PK profile directly.

[0018] As used herein the phrase “individualized therapy” refers to a specific treatment regimen for a patient comprising the administration of one or more drugs, which is the result of analyzing pharmacokinetic and/or pharmacodynamic parameters of the subject to maximize drug efficacy at the lowest dosage of the drug(s) possible.

[0019] As used herein “pain” refers to physical suffering or discomfort caused by an illness or injury, e.g., arthritis.

[0020] As used herein “osteoarthritic pain” refers to pain resulting from osteoarthritis (aka. “degenerative joint disease.”) [0021] As used herein, “formulation” or “a formulation” refers to a combination of active ingredients and pharmaceutically acceptable carriers wherein each is present in a dosage form at fixed ratios to one another (i.e., fixed percentages of each ingrediant in the dosage form.) [0022] As used herein, “first formulation” is the COX-2 inhibitor formulation comprising a first dose of a COX-2 inhibitor combined with a dose of diuretic and, optionally, pharmaceutically acceptable carriers in specific amounts that is administered to the patient to begin the process by which PK parameters are determined . The “new COX-2 iinhibitor formulation” is the formulation designed based on the PK parameters produced by the first COX-2 iinhibitor formulation. As such, the “new COX-2 inhibitor formulation” may have a change in the dose of the COX-2 inhibitor, the dose of the diuretic or the compostion of the carrier. Alternatively, the compostion of the carrier may be changed while the doses of the COX-2 inhibitor and the diuretic remain the same. To evaluate the PK parameters produced by the new COX-2 inhibitor formulation it replaces the “first COX-2 inhibitor formulation” and the process is repeated. The new COX-2 inhibitor formulation comprising a first dose of a COX-2 inhibitor combined with a diuretic in specific amounts formulation may be a second formulation. WO 2015/191460 6 PCT/US2015/034706 [0023] As used herein the phrases “first formulation under a first regimen” and “first formulation” refer to the dosage of a COX-2 inhibitor formulation that an individual initially receives prior to performing one or more steps of the claimed invention. For example, the first formulation under a first regimen, can be the standard 100 mg or 200 mg dosages of celecoxib prescribed to patients over 60 kg, twice daily for osteoarthritis combined with a standard 25 mg of dose of the diuretic hydrochlorothiazide.

[0024] As used herein, the phrase “COX-2 inhibitor and diuretic concentration/time data points” refers to the COX-2 inhibitor and diuretic concentration in a unit of volume (e.g., 1 ml) of plasma from a subject at a given point in time before or after administration of the COX-2 inhibitor and diuretic.

[0025] As used herein, the phrase “transforming” the patient’s COX-2 inhibitor and diuretic concentration/time data points” refers to the application of mathematical operations, formulas, theories, and/or principles to the COX-2 inhibitor or diuretic concentrations/time data points of an individual to derive PK parameters (e.g., a formula for calculating AUC).

[0026] As used herein, the phrase “predetermined range of values” refers to a range of PK parameters associated with desirable drug efficacy with minimal toxicity determined by a statistical analysis the PK profiles of patients of known outcomes for the formulation administered. The identification of said predetermined ranges of values can be accomplished with the aid of data reduction (e.g., factor analysis or principal components analysis) andclustering computer protocols (e.g., K-means or SOMs) (See U.S. Patent Nos. 7,412,333; 8,660,370; 8,990,135; 9,002,658; 9,026,536; and 9,043,321.) [0028] As used herein, “designing” refers to changes in the active agent’s dose, formulation and/or regiment based on the patient data, using logic and the experience of one of ordinary skill in the art. Said designing may be done in accordance with the invention aided by statistical and data-mining techniques known to those of ordinary skill in the relevant art that can identify the pharmacokinetic parameters and formulation components of greatest importance. It will be appreciated by those of ordinary skill that iterative process claimed herein will lead to steady state PK profiles for the NSAID and the diuretic within 4 -6 cycles of dose changes and single dose and steady state predetermined ranges will be used as appropriate.

[0029] Complete pharmacokinetic profiles may result in such a large number of variable parameters that there would be too many pairwise correlations between the variables to reasonably consider. In particular, with so many parameters graphical display, usually a WO 2015/191460 7 PCT/US2015/034706 powerful way to begin data analysis, may not be useful. Surprisingly, with 12 variables, there will be more than 200 three-dimensional scatterplots. To put the such complex data in a more useful form, it is necessary to reduce the number of variables to a few, interpretable linear combinations which account for most of the variability in the data.

[0030] “Factor Analysis” offers a way to reduce the data to a few critical parameters.

In every factor analysis, there are the same number of factors as there are variables. Each factor captures a certain amount of the overall variance and the factors are always listed in the results in the order of how much of the overall variance they explain, (see US Patent No. 8,660,370.) [0031] “Principal components analysis is another data reduction method. Suppose that there are a dozen variables, principal components analysis can reduce these to a few (2-3) principal components. Principal components analysis, like factor analysis, can be performed on raw data or on a correlation or a covariance matrix, (see US Patent No. 7,412,333.) [0027] As used herein, “Significant adverse drug reactions” refer to ADRs that the patient finds intolerable, impair physiologic functions, and/or put the patient at risk for immobility and/or death or combinations thereof.

[0028] As used herein “Significant side effects” refer to side effects that the patient finds intolerable, impair physiologic functions, and/or put the patient at risk for immobility and/or death or combinations thereof.

[0029] As used herein, “determining the level of efficacy” refers to the use of objective (e.g., pharmacokinetic) and subjective tests (e.g., pharmacodynamic), signs and symptoms to characterize, quantify or evaluate how well symptoms (e.g., pain) are controlled by the administration of the active ingredient (e.g., celecoxib and a diuretic).

[0030] As used herein, “determining the level of toxicity” refers to the use of objective and subjective tests, signs and symptoms to characterize, quantify or evaluate the significance of any side effects produced by the administration of the active ingredient.

[0031] As used herein, “trace edema” is edema that is just above the threshold for detection on physical exam (inconsistently pitting) and does not significantly impair the patient’s functioning in society or the patient’s physiologic functions.

[0032] As used herein, “pain control is adequate” refers to a level of pain the patient is willing to live with and which does not significantly impair the patient’s functioning in society or the patient’s physiologic functions. WO 2015/191460 8 PCT/U S2015/034706 [0033] As used herein, “toxicity is acceptable” refers to the absence of significant side effects and a level of toxicity that the patient is willing to live with and does not significantly impair the patient’s functioning in society or the patient’s physiologic functions.

[0034] As used herein, “NSAID” or “non-steroidal anti-inflammatory drug” refers to a class of drugs which provide pain-reducing and fever reducing effects as well as antiinflammatory effects in a subject, e.g., a human patient. NSAlDs include both COX-1 and COX-2 inhibitors.

[0035] As used herein, a “COX-1 inhibitor” refers to a non-steroidal anti-inflammatory drug that is capable of directly targeting the COX-1 enzyme in a subject and inhibits at least some COX-1 activity, e.g., aspirin.

[0036] As used herein, a “COX-2 inhibitor” refers to a non-steroidal anti-inflammatory drug that is capable of directly targeting the COX-2 enzyme in a subject and inhibits at least some COX-1 activity, e.g., celecoxib. As used herein, a “mixed COX-1 and COX-2 inhibitor” refers to a non-steroidal anti-inflammatory drug that is capable of directly targeting both the COX-1 and COX-2 enzymes in a subject and inhibits at least some COX-1 and COX-2 activity, e.g., ibuprofen.

[0037] As used herein the term “diuretic” refers to any substance that promotes the production of urine. A diuretic may also exhibit an antihypertensive action. Suitable diuretics for use in the compositions and methods disclosed herein include but are not limited to amiloride (Midamor®), bumetanide (Bumex®), chlorothalidone (Hygroton®), ethacrynic acid (Edecrin®), furosemide (Lasix®), hydrochlorothiazide (Diuril®), indapamide (Lozolv®), metolazone (Zaroxolyn®), torsemide (Demadex®), triamterene, acetazolamide, theophylline, chlorthalidone, spironolactone, and combinations thereof.

[0038] As used herein “controlled release” refers to the delivery of the NSAID, the diuretic, or both in response to in vivo stimuli. For example, pH changes in the digestive tract. As used herein “delayed release” refers to prolonged dissoldution time, e.g., increase dissolution time by 2, 4 or 6 hours, (see e..g., US Patent No. 8,992,979) [0039] As used herein “enteric coated” refers to a dosage form with polymer barrier which is resistant to dissolution at gastric pH levels but dissolves at the higher pH levels typical of in the intestine, applied to the composition comprising a NSAID and a diuretic.

[0040] As used here the combination can also include a “fixed dose combination” (FDC) or simply dosing with multiple pills each of a single agent to achieve a desired effect. WO 2015/191460 9 PCT/US2015/034706 [0041] The invention provides compositions and methods for individualized therapy of pain, including but not limited to arthritic pain, using a non-steroidal anti-inflammatory drug (NSAID), preferably celecoxib in combination with a diuretic, prefereably hydrochlorothiazide. In addition, the invention provides methods for predicting the outcome of the therapy of pain with a composition comprising NSAID, preferably celecoxib, and a diuretic, preferably hydrochlorothiazide. Further, the invention provides methods of using a NSAID, preferably celecoxib, and a diuretic, preferably hydrochlorothiazide, in the manufacture of medicament for the treatment of pain.

[0042] The invention provides endpoints (i.e., an individualized drug therapy) based on the achievement of predetermined PK results, as well as the clinical condition of the patient.

[0043] In one embodiment, provided is a composition for treating pain without inducing edema comprising a NSAID and a diuretic, wherein the composition is administered in a fixed-dose combination. Any type of pain may be treated by the compostion, including arthritic and osteoarthritic pain.

[0044] The NSAID may be one or more of the following NSAIDs, but is not limited thereto: diclofenac, diflusnisal, etodolac, fenoprofen, flubiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, salicylate, sulindac, tolmetin, celecoxib, rofecoxib, etoricoxib, lumiracoxib, parecoxib , valdecoxib, chlorthalidone and combinations thereof. In a preferred embodiment, the COX-2 inhibitor is celecoxib.

[0045] The diuretic may be one or more of the following diuretics: amiloride, bumetanide, chlorothalidone, ethacrynic acid, furosemide, hydrochlorothiazide, indapamide, metolazone, torsemide, triamterene, acetazolamide, theophylline, chlorthalidone, spironolactone, and combinations thereof. In a preferred embodiment, the direutic is hydrochlorothiazide.

[0046] The composition may be in the form of a capsule, a pill, a syrup, a controlled release device, or an injectable solution, and the release of one or both of the NSAID and the diuretic may be controlled. The NSAID and the diuretic may be released substantially simultaneously, or one may be released before the other, in any order. The composition may be administered, for example, daily, twice a day, three times a day, four times a day, or every other day.

[0047] One or more pharmaceuteically acceptable carriers or excipients may be included in the composition. Any suitable pharmaceutical carrier can be used in accordance with the WO 2015/191460 10 PCT/US2015/034706 invention. Suitable pharmaceutical carriers include, without limitation, sterile water, saline, dextrose, dextrose in water or saline, sium or calcium stearate and/or polyethylene glycols, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, cellulose, cros povidone, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, solvents, ethanol, isopropyl alcohol, methylene chloride or sugar, lactose, gelatin, starch, silicon dioxide, diethyl phthalate, diethyl sebacate, triethyl citrate, cronotic acid, propylene glycol, butyl phthalate, dibutyl sebacate, castor oil, diethyl phthalate, diethyl sebacate, lactose, dextrose, saccharose, cellulose, starch or calcium phosphate, olive oil or ethyl oleate silica, talc, stearic acid, magnesium or calcium stearate,polyethylene glycols; clays, gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, polyvinylpyrrolidone, alginic acid, sodium starch glycolate, polysorbates , laurylsulphates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations, lactose, dextrose, saccharose, cellulose, ethyl oleate, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, polysorbates and combinations thereof.

[0048] it should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention can include other suitable agents such as flavoring agents, preservatives and antioxidants. Such antioxidants would be food acceptable and could include vitamin E, carotene, BHT or other antioxidants known to those of skill in the art. In embodiments where the composition is in the form of a pill, the pill may be bilayered, enteric coated, or a combination thereof. The pill may be administered orally.

[0049] The composition may be administered in a fixed dose combination, for example, without limitation, wherein the NSAID and the diuretic are at the following strengths (celecoxib/hydrochlorothizide) 100mg/12.5mg, 200mg/12.5mg, 100mg/25mg, 200mg/25mg [0050] The composition may include any suitable NSAID and direutic dosage. For example, the compostion may comprise 50 to 400 mg, 75 to 350 mg, 100 to 300 mg, 150 to 250 mg, 50 mg, 100 mg, 200 mg, or 400 mg of NSAID. The compostion may comprise 10 to 200 mg, 20 to 150 mg, 25 to 75 mg, 50 mg, 100 mg, 150 mg, or 200 mg of diuretic.

[0051] The composition may be administered to any suitable subject, including mammals. Suitable mammals include but are not limited to humans.

[0052] The PK parameters used is one or more of concentration, concentration time course, peak concentration, time after administration to peak concentration, terminal half-life, WO 2015/191460 11 PCT/U S2015/034706 AUC, bioavailability, absorption, volume of distribution, metabolism, excretion, biotransformation, clearance or a combination thereof.

[0053] Any suitable NSAID can be used in accordance with the invention, including without limitation, a COX-1-specific inhibitor, a COX-2-specific inhibitor, a mixed COX-1 and 2 inhibitor or a combination thereof. As such, the NSAID can be a salicylate, propionic acid derivative, acetic acid derivative, enolic acid derivative, anthranilic acid derivative or combinations thereof. Accordingly, the NSAID can be, aspirin (acetylsalicylic acid), ibuprofen, naproxen, indomethacin, sulindac, piroxicam, clonixin, preferably celecoxib or a combination thereof. In addition, the invention can be used with combinations of NSAIDs and other analgesic drugs such as lidocaine, opiates, acetaminophen, tricylic antidepressants, anticonvulsants, carbamazepine, gabapentin, and pregabalin; other anti-inflammatory drugs such as steroids and immunosuppressants. Further, the invention can be used with combinations of NSAIDs and other therapies for arthritis, including but not limited to, methotrexate and gold-salts.

[0054] The composition comprising a NSAID and a diuretic can be administered in accordance with the invention via any suitable route including, without limiting, orally, rectally, by inhalation, trans-cutaneously, by injection, intra-venously or intra-arterially. The non-NSAID component of any combination therapy can be administered in accordance with the invention by any suitable route including, without limiting, orally, rectally, by inhalation, trans-cutaneously, by injection, intra-venously or intra-arterially. Any suitable regimen can be used in accordance with the invention to administer two or more drug components, including without limitation, simultaneously (within minutes of one another), substantially simultaneously (within an hour of one another) or at different times.

[0055] Other treatments for chronic diseases can be included such as treatments for diabetes, cardiovascular diseases, dementia, cholesterol, and hypertension. For example, fixed dose combination for pain relief without edema or hypertension , may be practiced in conjunction with the administration of a prescribed cholesterol regulator, such as atorvastatin.

[0056] Any suitable PK parameter or parameters can be used in accordance with the invention, including without limiting concentration, concentration time course, peak concentration, and time after administration to peak concentration, terminal half-life, AUC, bioavailability, absorption, volume of distribution, clearance metabolism, excretion, biotransformation, or a combination thereof. Of note, single dose pharmacokinetics can be used to determine parameters such as loading and maintence doses for long term therapy in WO 2015/191460 12 PCT/US2015/034706 the steady state (see Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications, 4th Edition, by Johan Gabrielsson and Daniel Weiner) [0057] Any suitable pharmacodynamic parameter or parameters can be used in accordance with the invention, including without limiting the physiological changes of cells, tissues and ligaments of a patient, patient or physician reported pain level, the frequency of side effects, or a combination thereof.

[0058] Any suitable method for the assessment of pain known to those of ordinary skill in the art can be used in accordnce with the invention, including, but not limited to, onedimensional pain intensity scales, Wisconsin Brief Pain Questionnaire, Brief Pain Inventory, The McGill Pain Questionnaire and the short-form, McGill Pain Questionnaire (See Breivik et al.: Assessment of pain, British Journal of Anaesthesia 2008, 101 (1): 17-24).

[0059] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLE 1 [0060] The approved prescribing information for Celebrex® as listed on its package insert for US/EU/ROW instructs that a physician should use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient. For four of the six approved indications the package insert includes a 100 mg BID regimen:

[0061] 1) Osteoarthritis (OA): 200 mg QD or 100 mg BID

[0062] 2) Rheumatoid Arthritis (RA): 100 mg BID or 200 mg BID

[0063] 3) Juvenile Rheumatoid Arthritis (JRA): 50 mg BID in patients 10-25 kg. 100 mg BID in patients more than 25 kg [0064] 4) Ankylosing Spondylitis (AS): 200 mg once daily single dose or 100 mg BID.

[0065] 5) Acute Pain (AP) and 5) Primary Dysmenorrhea (PD). 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg BID as needed [0066] Unexpectedly, however, the inventor’s analysis of the actual prescribing behavior using Evaluate Pharma/IMS database deteremined that the 200 mg is the predominant dose being prescribed by physicians by more than 10 to 1. These data are consistent with data from a MEPS survey (Table 2) and Medicaid survey (Table 3). In view of predominance of the 200 mg dosage form sales and the evidence that the 100 mg and 200 mg doses produce overlapping PK and pharmacodynamic results, it is questionable that the package insert’s admonition that “the lowest dose of Celebrex® should be sought for each patient” is WO 2015/191460 13 PCT/US2015/034706 followed. Instead, the data indicates that it is likely that there are numerous patients at risk for ADRs because their celecoxib dose is higher than it needs to be (i.e., e.g., 200 mg BID rather than 100 mg BID).

Table 2. MEPS Survey Data

Package description Strength (mg) USA sales 2008 ($m) USA sales 2011 ($m) 100 capsule in bottle (0025-1525-31) 200 1,553 1,650 500 capsule in 1 bottle (0025-1525-51) 200 323 132 100 capsule in 1 bottle (0025-1520-31) 100 65 142 500 capsule in 1 bottle (0025-1520-51) 100 - 17 100 blister pack in 1 carton (0025-1520-34) > 1 capsule in 1 blister pack 100 - 7 120 capsule in 1 bottle (63629-3021-5) 200 - 2 30 capsule in 1 bottle, plastic (67544-204-30) 200 - 32 Total 1,989 1,982

Table 3. Prescribing information derived from Medicaid

Dose (mg) Number of RXs 2008 Number of RXs 2009 Number of RXs 2010 Number of RXs 2011 Number of RXs 2012 Number of RXs 2013 Number of RXs 2014 50 293 485 856 1169 1167 1396 726 100 33,436 36,023 43,755 47,524 35,399 34,178 16,628 200 320,628 330,521 380,546 384,404 285,764 250,985 114,532 400 1,383 1,636 3,116 3,476 2,565 2,240 1,093 355,740 368,665 428,273 436,573 324,895 288,799 132,979 EXAMPLE 2 [0067] The combined plots of published pharmacokinetic data including those from the Summary basis for approval are shown in FIG. 2. The variability of Celebrex® pharmacokinetics were unexpectedly high. The PK results for the 200 mg dose shows a substantial overlap with that of the 100 mg dose. Accordingly, the dose proportionality may not be as is described by the package insert for Celebrex®. As a result of the failure to determine and pursue target PK ranges, in some instances patients receiving 100 mg patients may not get enough of the drug and the 200 mg patients may receive too much of the drug. WO 2015/191460 14 PCT/US2015/034706 EXAMPLE 3 [0068] Applicant’s meta analysis of the reported PK parameters in different populations demonstrates that the elderly show a higher variability than younger patients. For Example, when the applicant’s meta analysis is presented in age-based subgroups, the elderly and younger patients demonstrate highly significant differences in drug exposure as defined by AUC (FIG. 3). In other words, the most efficacious celecoxib dosage is not well defined among the elderly. The problem may be more widespread than expected as elderly here is defined as patients greater than >40 or >50, not the usually definition of elderly (age greater >65). Previously, there has been reported impaired PK with elderly and the package insert issued warning on impaired PK in elderly but did not suggest dose reduction. Our finding suggests that the issue is more substantial and more widespread and includes middle aged groups also.

[0069] There is variability in PK results within groups and the Cmax and AUC overlap between the 100 mg and 200 mg groups indicates that correctly dosing elderly patients to maximize celecoxib efficacy at the lowest doses possible depends on many individualized, unpredictable variables. Based on the wide range of AUC values, some patients receiving 100 mg may not get enough of the drug and the 200 mg patients may receive too much of the drug (FIG. 2). EXAMPLE 4 [0070] Applicant’s meta analysis of the reported edema rates in different osteoarthritic populations receiving doses of celecoxib ranging from 100 mg/day to 800 mg/day reveals that edema event rates are significantly higher in osteoarthritic populations receiving doses of celecoxib that are greater than 200 mg/day. For Example, both the upper limit of the edema event rate and the average edema event rate in osteoarthritic populations reiceiving a 400 mg/day dose of celecoxib can be more than twice as high as the upper limit edema event rate and the average edema event rate seen in osteoarthritic populations receiving a 100 or 200 mg/day dose of celecoxib (FIGS. 4-5). Additionally, Applicant’s meta analysis of the reported edema rates in different osteoarthritic populations receiving doses of celecoxib ranging from 100 mg/day to 800 mg/day reveals that patients receiving a 100 or 200 mg/day dose of celecoxib experience remarkably similar edema event rates. This analysis indicates that a patient who is selected to receive a 200 mg/day dose of celecoxib based on, for example, their individual pharmacokinetic data using one or more of the methods described WO 2015/191460 15 PCT/US2015/034706 herein, will not be at a higher risk for an edema event than a patient receiving a 100 mg/day dose of celecoxib, and vice versa. EXAMPLE 5 [0071] Applicant has also compared the edema in patient populations receiving celecoxib alone, celecoxib in combination with a variety of antihypertensives, including thiazides, celecoxib in combination with hydrochlorothiazide, celecoxib with a non-thiazide diuretic and no anti-hypertensives, and celecoxib with a non-thiazide anti-hypertensive. To support this study a database was created which contains: 1) Claims data from Symphony pertaining to anti-hypertensives, Statins, COX-2's, and NSAIDS. The data span the most recent 36 months and 2) registry data from the ACC reporting Blood Pressure (systolic/diastolic), peripheral edema flags (yes, no, missing), Heart rate, LDL, Glucose Level, Ejection fraction, GFR, Height, Weight, BMI, and the like.

[0072] Symphony Database® contains true patient level data - All Data Sources be it RX or MX claims is tied back to individual patients which is tracked and then encrypted based on first name, last name, gender, DOB and zip code to give an accurate picture of patient level informatics year over year regardless of insurance changes. The source of Managed Markets Rx claims data comes from various providers, including Intelligent network services (Switch Data) as well as direct data feeds from pharmacies that do not use Switches so it does not create payer biases.

[0073] The properties for the Symphony Database® are: 1) Takes Celebrex, AH, Statin or NSAID or have OA, RA or some other form of Arthritis, 36 months, 2) Time Frame = Jan 1, 2012 - Dec 31, 2014 (3 years), 3) Number of files = 201, 4) Size = 561 GB zipped (~ 2.5 TB), 5) Unique Patients = 162 million, 6) Patients on Celebrex = 4.3 million, 7) Patients that have OA = 16.3 million (15.4 million only OA), 8) Patients that have RA = 2.3 million (1.4 million only RA).

[0074] The properties of the ACC registry are: 1) Have 3+ BP readings, 2) Time Frame = Jan 1, 2012 - Dec 31, 2014 (3 years), 3) Number of files = 2, 4) Size = 590 MB, 51 MB, 5) Unique Patients = 1.58 million, 6) Patients with BP readings = 1.58 million, 7) Patients with Edema Flag True = 870K.

[0075] The edema rate was then measured in the aforementioned database . The incidence of edema was higher for OA patients than RA, other Arthritis, or Arthritis free patients. The incidence of edema increased when patients was taken Celebrex for all groups WO 2015/191460 16 PCT/US2015/034706 except for RA and no Arthritis free patients. Overall OA seems to be susceptible to Celebrex induced edema. The results confirmed the meta analysis shown above.

[0076] Table 1 showing cases of Edema (%) among OA, RA,Other Arthritis, and No Arthritis.

Group OA RA Other Arthritis No Arthritis W/o Celebrex 12,150 (4.7%) 3,337 (3.0%) 164,837 (2.3%) 69 (0.4%) W/ Celebrex 254 (6.0%) 82 (3.3%) 1702 (4.1%) 451 (0.4%) EXAMPLE 6 [0077] The same database in Example 5 was used to determine whether the thiazide diuretic hydrochlorothiazide (HCTZ) would reduce the incidence of edema in patients taking Celebrex®. There was a steady increase in incidence of edema among patient taking Celebrex® only. This trend was exacerbated by additional Rx. The incidence was lower for patients taking Celebrex® and HCTZ. In contrast, the incidence of patients taking Celebrex® and non-thiazide diuretics resulted in more than doubling of the incidence of edema. The data is surpring in that edema can only be controlled selectively by HCTZ (a thiazide diuretic) and not by other non-thiazide diuretics. The non-thiazide diuretics include: 1) Loop: torsemide, furosemide, bumetanide, ethancrynic acid, 2) Carbonic Anhydrase Inhibitors: acetazolamide, dichlorphenamide, methazolamide, 3) Potassium sparring: triamterene, spironolactone, amiloride, and 4) Others: pamabrom, mannitol.

[0078] Table 2. presents cases of Edema (%) among patients taking Celebrex and any other Rx, Celebrex only, Celebrex + HCTZ, and Celebrex + non-thiazide diuretics.

Days of Therapy Celebrex + Any Rx Celebrex Only Celebrex + HCTZ Celebrex + non-Thiazide Diuretics <60 139,389 (23.9%) 20,663 (19.4%) 455 (19.1%) 2146 (26.7%) 60-120 14,361 (24.7%) 913 (18.1%) 50 (12.0%) 160 (44.4%) 120-180 12,272 (28.2%) 678 (19.3%) 33 (15.2%) 125 (54.4%) 180-240 12,620 (27.6%) 661 (21.6%) 47 (8.5%) 49 (49.0%) >240 55,396 (35.7%) 1,991 (26.7%) 77 (22.1%) 453 (60.9%) [0079] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were WO 2015/191460 17 PCT/US2015/034706 individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0080] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0081] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims (31)

CLAIMS We claim the following:

1. A composition for treating pain without inducing edema comprising a NSAID and a diuretic, wherein the composition is administered in a fixed-dose combination.

2. The composition of claim 1, wherein the NSAID is selected from the group consisting of aspirin, diclofenac, diflusnisal, etodolac, fenoprofen, flubiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, salicylate, sulindac, tolmetin, celecoxib, rofecoxib, etoricoxib, lumiracoxib, parecoxib , valdecoxib, chlorthalidone and combinations thereofand combinations thereof.

3. The composition of claim 2, wherein the NSAID is a COX-2 inhibitor.

4. The composition of claim 3, wherein the COX-2 inhibitor is celecoxib, etoricoxib, lumiracoxib, parecoxib, valdecoxib, chlorthalidone or a combination thereof.

5. The composition of claim 3, wherein the COX-2 inhibitor is celecoxib.

6. The composition of claim 1, wherein the diuretic is selected from the group consisting of amiloride, bumetanide, chlorothalidone, ethacrynic acid, furosemide, hydrochlorothiazide, indapamide, metolazone, torsemide, triamterene, acetazolamide, theophylline, chlorthalidone, spironolactone, and combinations thereof.

7 The composition of claim of claim 6, wherein the diuretic is hydrochlorothiazide.

8 The composition of any one of claims 1-7, wherein the pain is arthritic pain.

9. The composition of claim 8, wherein the arthritic pain is osteoarthritic pain.

10. The composition of any one of claims 1-7, wherein the composition is in the form of a capsule, a pill, a syrup, a controlled release device, or an injectable solution.

11. The composition of any one of claims 1-7, wherein the release of one or both of the NSAID and the diuretic is controlled.

12. The composition of claim 11, wherein the NSAID and the diuretic are released substantially simultaneously.

13. The composition of claim 11, wherein the NSAID is released prior to the diuretic.

14. The composition of claim 11, wherein the diuretic is released prior to the NSAID.

15. The composition of any one of claims 1-14, further comprising one or more pharmaceutically acceptable carriers.

16. The composition of claim 15, wherein the composition is in the form of pill.

17. The composition of claim 16, wherein the pill is a bilayered pill.

18. The composition of claim 16, wherein the pill is enteric coated.

19. The composition of any one of claims 1- 18, wherein the fixed dose combination comprises celecoxib and hydrocholorthiazide at one of the following strengths (celecoxib/ hydrocholorthiazide) 100mg/12.5mg, 200mg/12.5mg, 100mg/25mg, and 200mg/25mg.

20. The composition of claim 19, wherein the fixed dose combination comprises 50 to 400 mg of celecoxib.

21. The composition of claim 19, wherein the fixed dose combination comprises 5 to 100 mg of hydrochlorothiazide.

22. A method for treating pain in a mammal comprising administering the composition of any one of claims 1-21 to a mammal.

23. The method of claim 22, wherein the arthritic pain is osteoarthritic pain.

24. The method of claim 22, wherein the composition is administered daily, two times a day, three times a day, or four times a day.

25. A method for individualized therapy of pain using a COX-2 inhibitor without inducing edema, comprising: a. administering a first COX-2 inhibitor formulation comprising a first dose of a COX-2 inhibitor combined with a diuretic in specific amounts, to a first patient suffering from pain; b. determining the COX-2 and diuretic concentration in the first patient’s blood at a plurality of time points after the first COX-2 inhibitor formulation was administered to the first patient; c. transforming the first patient’s COX-2 and diuretic concentration/time data points in to one or more pharmacokinetic (PK) parameters; d. comparing the first patient’s values for said PK parameters to a predetermined ranges of values for each PK parameter and if one or more of the first patient’s PK parameters fall outside of a predetermined range, designing a new COX-2 inhibitor formulation, wherein the dose of said COX-2 inhibitor, the diuretic, or both is different from that of the first COX-2 inhibitor formulation; e. administering the new COX-2 inhibitor formulation to the first patient; f. repeating steps b-e until all the PK parameters used in step d are within said predetermined ranges, and g. if pain control is adequate, toxicity is tolerable, and the patient is not experiencing edema, maintaining the first patient on the COX-2 inhibitor formulation at frequency of administration that satisfies the comparison in step d.

26. The method of claim 25, wherein the COX-2 inhibitor formulation is administered orally.

27. The method of claim 25, wherein said predetermined PK ranges are based the PK parameters of other patients suffering from pain who had been successfully treated with said COX-2 inhibitor formulation such that pain control is adequate, toxicity is acceptable and, at most, only trace edema is present.

28. The method of claim 25, wherein the COX-2 inhibitor is celecoxib.

29. The method of claim 25, wherein the PK parameter used is one or more of concentration, concentration time course, peak concentration, time after administration to peak concentration, terminal half-life, AUC, bioavailability, absorption, volume of distribution, metabolism, excretion, biotransformation, clearnce or a combination thereof.

30. The method of claim 25, wherein the COX-2 inhibitor and the diuretic are administered in a fixed dose combination.

31. The method of claim 25, wherein the diuretic is hydrochlorothiazide.