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WO2018031577A1 - Association médicamenteuse à dose fixe destinée au soulagement de la douleur sans induire d'œdème - Google Patents

Association médicamenteuse à dose fixe destinée au soulagement de la douleur sans induire d'œdème Download PDF

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Publication number
WO2018031577A1
WO2018031577A1 PCT/US2017/045953 US2017045953W WO2018031577A1 WO 2018031577 A1 WO2018031577 A1 WO 2018031577A1 US 2017045953 W US2017045953 W US 2017045953W WO 2018031577 A1 WO2018031577 A1 WO 2018031577A1
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celecoxib
dose
composition
edema
hydrochlorothiazide
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Vuong Trieu
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Autotelic LLC
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Autotelic LLC
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Priority claimed from US15/490,883 external-priority patent/US20170326109A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • NSAID non-steroidal anti-inflammatory drugs
  • drugs are highly active analgesics.
  • NSAIDs also can have clinically significant side effects.
  • One such side effects is drug induced edema.
  • 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 depending on the site and severity of the edema. 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 peritoneal space) can be complicated by difficult to treat bacterial peritonitis. See, e.g., Harrison's Internal Medicine, 16th edition, p.213-214.
  • edema occurs when one or more of the following is present: elevated capillary hydraulic pressure, increased capillary permeability an when the interstitial oncotic pressure exceeds the plasma oncotic pressure.
  • elevated capillary hydraulic pressure increases capillary permeability an when the interstitial oncotic pressure exceeds the plasma oncotic pressure.
  • 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.
  • Drug induced edema can cause edema including, without limitation, steroid hormones, vasodilators such as hydralazine, estrogens, NSAIDs, immunomodulators such as interleukin 2, and calcium channel blockers. Like other forms of edema, the pathophysiology 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.
  • NSAIDs inhibit cyclogenases (COX), the enzymes that catalyzes formation of various prostaglandins.
  • COX cyclogenases
  • 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.
  • 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.
  • Heyman et al. Anti -inflammatory and side effects of cyclooxygenase inhibitors, Pharma. Reports, 2007 59:247-258.
  • edema in the thoracic, peritoneal, or pericardium
  • effusions edema in the thoracic, peritoneal, or pericardium
  • edema is measured subjectively based on the ability to push into or "pit" the swollen skin.
  • Celecoxib (under the brand name "CELEBREX®") is a prototypic selective COX-2 inhibitor and the first page of the CELEBREX® 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 was 23% and 38%.
  • 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.
  • the invention provides compositions for treating pain without inducing edema comprising a NSAID, preferably a COX-2 inhibitor, most preferably celecoxib, and a diuretic drug, preferably a diuretic, most preferably HCTZ, wherein the composition is administered in a fixed-dose combination (FDC) of the NSAID and the diuretic.
  • a NSAID preferably a COX-2 inhibitor, most preferably celecoxib
  • a diuretic drug preferably a diuretic, most preferably HCTZ
  • the preferred embodiment is celecoxib/HCTZ FDC. This was from our discovery that patient treated simultaneously with celecoxib and HCTZ have significantly lower incidence of edema than patient treated with celecoxib and any other drugs. HCTZ was selected since we found that non-Thiazide diuretic actually caused an increase in edema when combined with Celebrex.
  • celecoxib/HCTZ FDC During our development of celecoxib/HCTZ FDC, we found that celecoxib suppressed the dissolution of HCTZ during dissolution studies and simple mixture of the two drug substance to make an FDC is not acceptable.
  • the two components have to be formulated in separate compartments and excipients of the HCTZ component have to be adjusted to compensate for the suppression of dissolution by celecoxib.
  • 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 preferred embodiment the NSAID is celecoxib.
  • This application seeks the treatment of patients at target celecoxib AUC of 3400 ng*hr/mL (Mean AUC of 100 mg dose) or celecoxib AUC of 6800 ng*hr/mL (Mean AUC of 200 mg dose).
  • Celecoxib AUC can be determined for example by LC/MS method with blood samples at various time points over a 48 hr period. There is no known method of predicting celecoxib AUC- therefore actual celecoxib AUC determination for each patient is required.
  • This invention is the AUC dosing of celecoxib/HCTZ for the optimum treatment of osteoarthritis pain without increase risk of edema from celecoxib.
  • the preferred embodiment is celecoxib/HCTZ formulated as either pill in pill, capsule in capsule, bilayer tablet or other formulation method with physical separation between celecoxib and HCTZ. Additionally, the HCTZ excipients were designed to counter the suppression of HCTZ dissolution by celecoxib.
  • 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 pre-dosing 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.)
  • FIG. 2 depicts the pharmacokinetic parameters produced by different doses of celecoxib.
  • FIG. 3 displays the result of a meta-analysis of the one dose AUC from patients in different age groups.
  • FIG. 4 displays the result of a meta-analysis of the celecoxib dose dependence of edema.
  • FIG. 5 displays the result of a regression analysis of the celecoxib dose dependence of edema.
  • FIGS. 6-11 display the incidence of edema for celecoxib given alone or with other drugs.
  • HCTZ hydrochlorothiazide
  • CCB calcium channel blocker
  • ARB angiotensin receptor blocker
  • ACE angiotensin converting enzyme inhibitor
  • non-thiazide diuretic beta blocker
  • FIGS. 12 and 13 depict the dissolution profiles from a FDC
  • FIG. 14 depicts dissolution profiles for HCTZ + celecoxib filled as a mixture or filled separately.
  • FIG.15 A-H shows dissolution profiles for HTCZ + celecoxib in a bilayer tablet.
  • FIG. 16 A-H shows dissolution profiles for HTCZ + celecoxib in a tablet plus powder in a capsule.
  • FIG. 17 A-H shows dissolution profiles for HTCZ + celecoxib in a powder plus powder in a capsule.
  • FIG. 18 A-H shows dissolution profiles for HTCZ + celecoxib in a capsule in a capsule.
  • the invention provides methods for treating osteoarthritis pain with a COX- 2 inhibitor, in general, and celecoxib or celecoxib/HCTZ FDC, in specific.
  • a dosing regimen targeting specific AUC is provided in which AUC determined from first dosing with celecoxib is used to adjust subsequent dosing to achieve the targeted AUC.
  • the targeted AUC dosing regimen for celecoxib was made possible by our discovery of: 1) the targeted AUC value derived from our analysis of celecoxib pharmacokinetics; and 2) the method of adjustment taking advantage of our demonstration of celecoxib dose proportionality.
  • the pharmacokinetic parameter used in the method is area-under- the-curve (AUC).
  • the therapeutic agent is celecoxib/HCTZ FDC.
  • the methods of the invention are effective in treating osteoarthritis pain.
  • 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, more preferably the COX-2 inhibitor celecoxib and an antihypertensive drug, such as a diuretic (e.g., hydrochlorothiazide).
  • a NSAID preferably a COX-2 inhibitor, more preferably the COX-2 inhibitor celecoxib and an antihypertensive drug, such as a diuretic (e.g., hydrochlorothiazide).
  • a NSAID preferably a COX-2 inhibitor, more preferably the COX-2 inhibitor celecoxib and an antihypertensive drug, such as a diuretic (e.g., hydrochlorothiazide).
  • a diuretic e.g., hydrochlorothiazide
  • 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 concentration from several time points (at least 2, preferably 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" unique to a given patient for a particular drug.
  • the multitude of potential contributing factors make defining such a law impractical. Therefore, the methods disclosed herein seek to determine the individual's PK profile directly.
  • pain refers to physical suffering or discomfort caused by an illness or injury, e.g., arthritis.
  • osteoarthritic pain refers to pain resulting from, e.g. osteoarthritis (aka, “degenerative joint disease”).
  • 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 ingredient in the dosage form.)
  • COX-2 inhibitor 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.
  • the phrase "transforming" the patient's COX-2 inhibitor and the antihypertensive drug "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).
  • 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.
  • 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.
  • toxicity 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.
  • 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. NSAIDs include both COX-1 and COX-2 inhibitors.
  • 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.
  • 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-I activity, e.g., celecoxib.
  • 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-I and COX-2 enzymes in a subject and inhibits at least some COX-I and COX- 2 activity, e.g., ibuprofen.
  • 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.
  • MIDAMOR® MIDAMOR®
  • BUMEX® bumetanide
  • chlorothalidone HOGROTON®
  • EECRIN® ethacrynic acid
  • the combination can also include a "fixed dose combination" (FDC).
  • FDC fixed dose combination
  • These fixed dose combinations can be in the form of pill in pill, capsule in capsule, bilayer tablet or other formulation method with physical separation between celecoxib and HCTZ.
  • 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, preferably hydrochlorothiazide.
  • NSAID non-steroidal anti-inflammatory drug
  • the invention provides methods for predicting the outcome of the therapy of pain with a composition comprising NSAID, preferably a COX-2 inhibitor, most preferably celecoxib, and a diuretic, preferably hydrochlorothiazide.
  • 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
  • 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 composition, including arthritic and osteoarthritic pain.
  • 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.
  • the COX-2 inhibitor is celecoxib.
  • 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.
  • the diuretic is hydrochlorothiazide.
  • the combination can include a "fixed dose combination" (FDC).
  • FDC fixed dose combination
  • These fixed dose combinations can be in the form of pill in pill, capsule in capsule, bilayer tablet or other formulation method with physical separation between celecoxib and HCTZ.
  • the composition may be administered, for example, daily, twice a day, three times a day, four times a day, or every other day.
  • One or more pharmaceutically acceptable carriers or excipients may be included in the composition.
  • Any suitable pharmaceutical carrier can be used in accordance with the 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, crospovidone, 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,poly ethylene glycols; clays, gum tragacanth or sodium alg
  • 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 oleat, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, polysorbates and combinations thereof.
  • humectants such as lactose, dextrose, saccharose, cellulose, ethyl oleat, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, polysorbates and combinations thereof.
  • the formulations of this invention can include other suitable agents such as flavoring agents, preservatives and antioxidants.
  • antioxidants would be food acceptable and could include vitamin E, carotene, BHT or other antioxidants known to those of skill in the art.
  • 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/hydrochlorothiazide) 100mg/12.5mg : 200mg/12.5mg, 100mg/25mg, 200mg/25mg.
  • the composition may include any suitable NSAID and diuretic dosage.
  • the composition 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 composition may comprise 25 to 200 mg, 50 to 150 mg, 75 to 100 mg, 50 mg, 100 mg, 150 mg, or 200 mg of diuretic.
  • the composition may be administered to any suitable subject, including mammals. Suitable mammals include but are not limited to humans.
  • any suitable NSAID can be used in accordance with the invention, including without limitation, a COX-I-specific inhibitor, a COX-2-specific inhibitor, a mixed COX-1 and 2 inhibitor or a combination thereof
  • the NSAID can be a salicylate, propionic acid derivative, acetic acid derivative, enolic acid derivative, anthranilic acid derivative or combinations thereof
  • the NSAID can be, aspirin (acetylsalicylic acid), ibuprofen, naproxen, indomethacin, sulindac, piroxicam, clonixin, preferably celecoxib or a combination thereof
  • 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
  • the approved prescribing information for CELEBREX® (celecoxib) 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.
  • the package insert includes a 100 mg BID regimen:
  • OA Osteoarthritis
  • Rheumatoid Arthritis 100 mg BID or 200 mg BID.
  • JRA Juvenile Rheumatoid Arthritis
  • Ankylosing Spondylitis 200 mg once daily single dose or 100 mg BID.
  • AP Acute Pain
  • PD Primary Dysmenorrhea
  • Applicant's meta-analysis of the reported PK parameters in different populations demonstrates that the elderly show a higher variability than younger patients.
  • the elderly and younger patients demonstrate highly significant differences in drug exposure as defined by AUC (FIG. 3).
  • AUC AUC
  • 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).
  • Example 4 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.
  • both the upper limit of the edema event rate and the average edema event rate in osteoarthritic populations receiving 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).
  • 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 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 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.
  • a database was created which contains: 1) Claims data from SYMPHONY DATABASE® pertaining to anti-hypertensives, Statins, COX-2's, and NSAIDS.
  • SYMPHONY DATABASE® contains true patient level data - All Data S ources be it RX or JVIX 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.
  • 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 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.
  • Example 6 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 surprising in that edema can only be controlled selectively by HCTZ (a thiazide diuretic) and not by other non-thiazide diuretics.
  • HCTZ thiazide diuretic hydrochlorothiazide
  • 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.
  • Table 4 presents cases of edema (%) among patients taking CELEBREX ® and any other Rx, CELEBREX ® only, CELEBREX ® + HCTZ, and CELEBREX ® + non-thiazide diuretics.
  • Table 6 presents the incidence of edema when patients taking CELEBREX® alone, CELEBREX® + any other drug, CELEBREX® + various classes of anti-hypertensive. For this group, the patients are on CELEBREX® for more than 180 days. Table 6. Incidence of edema, patients on celecoxib more than 180 days.
  • This application seeks the treatment of patients at target celecoxib AUC of 3400 ng*hr/mL (Mean AUC of 100 mg dose) or celecoxib AUC of 6800 ng*hr/mL (Mean AUC of 200 mg dose).
  • Celecoxib AUC can be determined for example by LC/MS method with blood samples at various time points over at 48 hr period. There is no known method of predicting celecoxib AUC- therefore actual celecoxib AUC determination for each patient is required.
  • the target AUCs were determined as the means of all available PK data for celecoxib at 100 mg and 200 mg dose levels as shown in Example 2. Table 7
  • Dissolution testing very widely used in formulation development, in monitoring the manufacturing process and as a quality control test. It can also be used to predict the in vivo performance of certain products. Dissolution testing has been successfully used for development and approval of generic solid oral dosage forms. Most recently, the use of dissolution testing has been extended to other solid generic dosage forms. Further, dissolution testing plays significant role in identifying the need for additional bioequivalence studies. Dissolution testing should be carried out under physiological conditions, if possible. This allows interpretation of dissolution data with regard to in vivo performance of the product. However, strict adherence to the gastrointestinal environment need not be used in routine dissolution testing. The testing conditions should be based on physicochemical characteristics of the drug substance and the environmental conditions the dosage form might be exposed to after oral administration.
  • the volume of the dissolution medium is generally 500, 900, or 1000 mL. Sink conditions are desirable but not mandatory.
  • An aqueous medium with pH range 1.2 to 6.8 ionic strength of buffers the same as in USP
  • a dissolution medium of pH 6.8 should be employed. A higher pH should be justified on a case-by -case basis and, in general, should not exceed pH 8.0.
  • SGF gastric fluid
  • a dissolution medium of pH 1.2 should be employed without enzymes. The need for enzymes in SGF and SIF should be evaluated on a case-by-case basis and should be justified.
  • All dissolution tests for IR dosage forms should be conducted at 37 ⁇ 0.5°C.
  • the basket and paddle method can be used for performing dissolution tests under multimedia conditions (e.g., the initial dissolution test can be carried out at pH 1.2, and, after a suitable time interval, a small amount of buffer can be added to raise pH to 6.8).
  • the initial dissolution test can be carried out at pH 1.2, and, after a suitable time interval, a small amount of buffer can be added to raise pH to 6.8.
  • an enzyme it can be added after initial studies (without enzymes).
  • Certain drug products and formulations are sensitive to dissolved air in the dissolution medium and will need de-aeration.
  • capsule dosage forms tend to float during dissolution testing with the paddle method. In such cases, it is recommended that a few turns of a wire helix (USP) around the capsule be used.
  • USP wire helix
  • the apparatus suitability tests should be carried out with a performance standard (i.e., calibrators) at least twice a year and after any significant equipment change or movement. However, a change from basket to paddle or vice versa may need recalibration.
  • the equipment and dissolution methodology should include the product related operating instructions such as de-aeration of the dissolution medium and use of a wire helix for capsules. Validation of automated procedures compared to the manual procedures should be well documented. Validation of determinative steps in the dissolution testing process should comply with the set standards for analytical methodology.
  • the common agitation (or stirring speed) is 50- 100 rpm; with the paddle method, it is 50-75 rpm.
  • Validation of the dissolution apparatus/methodology should include (1) the system suitability test using calibrators; (2) d-aeration, if necessary; (3) validation between manual and automated procedures; and (4) validation of a determinative step (i.e., analytical methods employed in quantitative analysis of dissolution samples).
  • a dissolution profile can characterize the product more precisely than a single point dissolution test.
  • a dissolution profile comparison between pre-change and post-change products for SUP AC related changes, or with different strengths, helps assure similarity in product performance and signals bio-inequivalence.
  • f2 is the simplest.
  • Moore and Flanner proposed a model independent mathematical approach to compare the dissolution profile using two factors, fl and f2 where Rt and Tt are the cumulative percentage dissolved at each of the selected n time points of the reference and test product respectively.
  • the factor fl is proportional to the average difference between the two profiles
  • factor f2 is inversely proportional to the average squared difference between the two profiles, with emphasis on the larger difference among all the time-points.
  • the factor f2 measures the closeness between the two profiles.
  • At least 12 units should be used for each profile determination.
  • Mean dissolution values can be used to estimate the similarity factor, 12.
  • the % coefficient of variation at the earlier point should not be more than 20% and at other time points should not be more than 10%.
  • the dissolution measurements of the two products should be made under the same test conditions.
  • the dissolution time points for both the profiles should be the same, e.g., for immediate release products 15, 30, 45 and 60 minutes, for extended release products 1, 2, 3, 5 and 8 hours.
  • Example 10 Surprisingly, celecoxib interferes with the dissolution of hydrochlorothiazide in art recognized dissolution assays, as described in Example 9, using USP dissolution methods for pH 1.2 (FIG. 14). Also surprisingly, celecoxib interference with HCTZ dissolution can be virtually eliminated by filling HCTZ and celecoxib sequentially and separately into a single capsule (FIG. 14). Additional studies were undertaken to confirm celecoxib's interference with the dissolution of HCTZ, determine the scope of this effect, and find solutions to it. Additional formulations were prepared which are set forth in Table 8.
  • HCTZ/celecoxib capsule formulations of Table 8 were tested against the appropriate RLDs (Table 9). At pH 1.2 the dissolution of HCTZ was suppressed in all formulations.
  • the solution to the dissolution interference problem is, most often, the separation of HCTZ and celecoxib (including, but are not limited to, i.e., a bilayer tablet, a capsule with separate and sequential filling, a capsule in a capsule or a tablet or minitablets in a capsule.)
  • disintegrants were required in the celecoxib portion of the formulation but not in the HTCZ portion. Suitable disintegrants include, but are not limited to, povidone (for example, KOLIDONETM), crospovidone (for example, POLYPLASDONETM), croscarmellose sodium, carboxymethylcellulose calcium and L-HPC.
  • the resulting dissolution of celecoxib matched that of the RLD when the disintegrant was added to celecoxib (but not to HTCZ) (See Table 12).
  • the dissolution interference disclosed herein may also be reflected by poor bioavailability of hydrochlorothiazide when given orally to patients. Accordingly, dosage forms which are simple mixture of celecoxib and HCTZ should be avoided. Dissolution should be monitored and controlled to ensure that HCTZ dissolution is not inhibited by celecoxib. FDC with separation of two components should only be used with a disintegrant in the celecoxib portion as shown herein.
  • Disintegrants an important excipient of the tablet formulation, are added to tablets to induce breakup of tablet when it comes in contact with aqueous fluid. This process of desegregation of constituent particles before the drug dissolution occurs is known as disintegration process and excipients which induce this process are known as disintegrants.
  • the objectives behind addition of disintegrants are to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet.
  • Exemplary disintegrants include, e.g., L-HPC (low substituted hydroxypropyl cellulose), other disintegrants include povidone (for example, KolidoneTM, etc.), crospovidone (for example, PolyplasdoneTM, etc.), croscarmellose sodium, and carboxymethylcellulose calcium, as well as modified starches and modified cellulose.
  • Other disintegrants include those listed in the tables below (see also AAPS PharmSciTech. 2012 Dec; 13(4): 1054- 1062., Published online 2012 Aug 17. doi: 10.1208/sl2249-012-9835-y.).
  • Starch was the first disintegrating agent widely used in tablet manufacturing. Before 1906 potato starch and com starch were used as disintegrants in tablet formulation. However, native starches have certain limitations and have been replaced by certain modified starches with specialized characteristics.
  • starch The mechanism of action of starch is wicking and restoration of deformed starch particles on contact with aqueous fluid and in doing so release of certain amount of stress which is responsible for disruption of hydrogen bonding formed during compression.
  • Pregelatinized starch is produced by the hydrolyzing and rupturing of the starch grain. It is a directly compressible disintegrants and its optimum concentration is 5-10%. The main mechanism of action of Pregelatinized starch is through swelling.
  • starch is modified by carboxy methylation followed by cross linking, which is available in market as cross linked starch.
  • carboxy methylation followed by cross linking, which is available in market as cross linked starch.
  • SODIUM STARCH GLYCOLATE is SODIUM STARCH GLYCOLATE.
  • Even low substituted carboxymethyl starches are also marketed as ExplotabO and Primojel(r).
  • Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic structure and is soluble in water. But when it is modified by internally crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium which is nearly water insoluble due to cross linking. It rapidly swells to 4-8 times its original volume when it comes in contact with water.
  • MCC Microcrystalline cellulose
  • MCC exhibit very good disintegrating properties because MCC is insoluble and act by wicking action. The moisture breaks the hydrogen bonding between adjacent bundles of MCC. It also serves as an excellent binder and has a tendency to develop static charges in the presence of excessive moisture content. Therefore, sometimes it causes separation in granulation. This can be partially overcome by drying the cellulose to remove the moisture.
  • Alginates are hydrophilic colloidal substances which has high sorption capacity. Chemically, they are alginic acid and salts of alginic acid. Alginic acid is insoluble in water, slightly acidic in reaction. Hence, it should be used in only acidic or neutral granulation. Unlike starch and MCC. alginates do not retard flow and can be successfully used with ascorbic acid, multivitamin formulations and acid salts of organic bases.
  • Ion exchange resin (AmbreliteO IPR-88) has highest water uptake capacity than other disintegrating agents like starch and Sodium CMC. It has tendency to adsorb certain drugs.
  • This miscellaneous category includes disintegrants like surfactants, gas producing disintegrants and hydrous aluminium silicate.
  • Gas producing disintegrating agents is used in soluble tablet, dispersible tablet and effervescent tablet.
  • PolyplasdoneOXL and PolyplasdoneOXLlO act by wicking, swelling and possibly some deformation recovery. Polyplasdone(r)XL do not reduce tablet hardness, provide rapid disintegration and improved dissolution. Polyplasdone(r) as disintegrating agent has small particle size distribution that impart a smooth mouth feel to dissolve quickly. Chewable tablet does not require addition of disintegrant.
  • the open-ended transitional term "comprising" (and equivalent open-ended transitional phrases thereof like including, containing and having) encompasses all the expressly recited elements, limitations, steps and/or features alone or in combination with unrecited subject matter; the named elements, limitations and/or features are essential, but other unnamed elements, limitations and/or features may be added and still form a construct within the scope of the claim.
  • the meaning of the open- ended transitional phrase “comprising” is being defined as encompassing all the specifically recited elements, limitations, steps and/or features as well as any optional, additional unspecified ones.
  • the meaning of the closed-ended transitional phrase “consisting of” is being defined as only including those elements, limitations, steps and/or features specifically recited in the claim whereas the meaning of the closed-ended transitional phrase “consisting essentially of is being defined as only including those elements, limitations, steps and/or features specifically recited in the claim and those elements, limitations, steps and/or features that do not materially affect the basic and novel characteristic(s) of the claimed subject matter.
  • the open-ended transitional phrase “comprising” includes within its meaning, as a limiting case, claimed subject matter specified by the closed-ended transitional phrases “consisting of or “consisting essentially of.”
  • claimed subject matter specified by the closed-ended transitional phrases “consisting of or “consisting essentially of.”
  • embodiments described herein or so claimed with the phrase “comprising” are expressly or inherently unambiguously described, enabled and supported herein for the phrases “consisting essentially of and “consisting of.”

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Abstract

L'invention concerne des compositions et des méthodes pour le traitement individualisé de la douleur arthritique sans provoquer d'oedème, à l'aide de médicaments anti-inflammatoires non stéroïdiens (inhibiteur de COX -2) en combinaison avec un médicament diurétique. L'anti-inflammatoire non stéroïdien est de préférence du célécoxib et le diurétique est de préférence l'hydrochlorothiazide en une dose unique.
PCT/US2017/045953 2016-08-09 2017-08-08 Association médicamenteuse à dose fixe destinée au soulagement de la douleur sans induire d'œdème Ceased WO2018031577A1 (fr)

Applications Claiming Priority (4)

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US201662372790P 2016-08-09 2016-08-09
US62/372,790 2016-08-09
US15/490,883 2017-04-18
US15/490,883 US20170326109A1 (en) 2014-07-14 2017-04-18 Fixed Dose Combination for Pain Relief Without Edema

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042221A1 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Forme solide de celecoxib, presentant une biodisponibilite accrue
US20060111345A1 (en) * 2004-11-23 2006-05-25 Transform Pharmaceuticals, Inc. Pharmaceutical compositions comprising a selective COX-2 inhibitor and a diuretic
EP2392319A1 (fr) * 2010-06-04 2011-12-07 Laboratorios Del. Dr. Esteve, S.A. Composition pharmaceutique contenant des co-cristaux de tramadol et d'un coxib
US20160120885A1 (en) * 2014-07-14 2016-05-05 Autotelic Llc Fixed dose combination for pain relief without edema
US20170071956A1 (en) * 2014-07-14 2017-03-16 Autotelic Llc Fixed Dose Combination for Pain Relief Without Edema

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042221A1 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Forme solide de celecoxib, presentant une biodisponibilite accrue
US20060111345A1 (en) * 2004-11-23 2006-05-25 Transform Pharmaceuticals, Inc. Pharmaceutical compositions comprising a selective COX-2 inhibitor and a diuretic
EP2392319A1 (fr) * 2010-06-04 2011-12-07 Laboratorios Del. Dr. Esteve, S.A. Composition pharmaceutique contenant des co-cristaux de tramadol et d'un coxib
US20160120885A1 (en) * 2014-07-14 2016-05-05 Autotelic Llc Fixed dose combination for pain relief without edema
US20170071956A1 (en) * 2014-07-14 2017-03-16 Autotelic Llc Fixed Dose Combination for Pain Relief Without Edema

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