CN106572984A

CN106572984A - Fixed dose combination for pain relief without edema

Info

Publication number: CN106572984A
Application number: CN201580040734.5A
Authority: CN
Inventors: 翁·德留
Original assignee: Otto Tai Rick LLC
Current assignee: Otto Tai Rick LLC; Autotelic LLC
Priority date: 2014-06-08
Filing date: 2015-06-08
Publication date: 2017-04-19
Also published as: EP3151823A1; CA2956899A1; TW201642854A; JP2017517529A; CA2956897A1; CN106572985A; AU2015274895A1; KR20160091349A; AU2015274908A1; EP3151822A1; EP3151823A4; WO2015191473A1; WO2015191460A1; KR20160091348A; TW201642906A; WO2015191473A9; EP3151822A4; JP2017517575A

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

The dosage combination of the fixation of oedema is not caused for pain relief

Cross-Reference to Related Applications

The U.S. Provisional Patent Application the 62/009,300th and 2014 that patent application claims on June 8th, 2014 submits to The rights and interests of the U.S. Provisional Patent Application the 62/023rd, 962 that on July 14, in submits to, the two applications are incorporated by reference into. The application also requires the rights and interests of PCT application PCT/US2015/011148 of the submission of on January 13rd, 2015, and it is incorporated by reference into.

Background of invention

Extensively accepted, nonsteroidal anti-inflammatory drug (" NSAID ") is height as anodyne (pain reliever) Effectively.However, NSAID also has main and secondary side effect.One of these side effects are drug-induced oedema.

" oedema " is abnormal accumulation of the fluid in the tissue space of body, chamber or capsular ligament, causes region swelling.Oedema Can occur in tissue or body spaces such as pleural cavity or peritoneal spaces.Clinically, depending on oedema position and serious journey Degree, oedema has different consequences.For example, when subcutaneous dropsy is slight, it may be showed only as its own as tight in worn Shoes.By contrast, chronic, serious subcutaneous dropsy can cause skin breakdown, ulcer and severe infections.Similarly, although Leural effusion can spontaneous regression, but ascites (oedema in peritoneal spaces) becomes because of bacterial peritonitis difficult to treat It is complicated.See, e.g., Harrison ' s Internal Medicine, the 16th edition, the 213-214 page.Exist and various cause water Swollen the reason for.

In Pathological Physiology, when the increase of the rising and/or capillary permeability that there is capillary hydraulic pressure or between When matter colloid osmotic pressure (oncotic pressure) exceedes plasma colloid osmotic pressure, there is oedema.Such change can be due to Various situations and disease.For example, in congestive heart failure, the activation of RAS causes capacity super negative Lotus, this causes increased capillary hydraulic pressure.Kidney controls extra-cellular fluid volume by adjusting the excretion of sodium and water.Work as renal function When impaired, oedema can be caused.In cirrhosis, the such as albuminous generation of haemocyanin of reduction causes plasma colloid osmotic pressure Relative to the reduction of interstitial colloid osmotic pressure, fluid is caused to be transferred in interstitial (intersitum).Venous insufficiency is served as reasons The common cause of the edema of lower extremity increased in capillary hydraulic pressure.Harrison ' s Internal Medicine, the 16th edition, the 213-214 page；O ' Brian etc., Treatment of Edema, American Family Physician, 71 (11) .2111- 17。

Many medicines can cause oedema, including steroid hormone class, vasodilator such as hydrolazine, estrogens, NSAID, immunomodulator such as interleukin 2 and calcium channel blocker.Such as the oedema of other forms, drug-induced water Swollen Pathological Physiology is in extensive range.Drug-induced oedema can be arranged the sodium of kidney by vasodilation (such as hydrolazine), medicine The effect for letting out (for example, steroidal) and capillary damage (for example, interleukin 2) causes.Drug-induced oedema is usually agent Amount is dependent, and its order of severity increases over time.Harrison ' s Internal Medicine, the 16th edition, The 213-214 page；O ' Brrin etc., Treatment of Edema, American Family Physician, 71 (11) .2111-17.Many NSAID can cause oedema.The mechanism of the oedema of NSAID inductions be assumed to be shunk from Renal vascular. Harrison ' s Internal Medicine, the 16th edition, the 213-214 page.NSAID suppresses cyclooxygenase (COX), the enzyme to urge Change the formation of various prostaglandins.Two kinds of main COX hypotypes are COX-1 and COX-2.Research display, the therapeutic effect of NSAID Cyclooxygenase is all relied on both side effects to suppress.Generally, the selective depressant of COX-2 has as conventional NSAID Strong therapeutic effect, but with less side effect.However, Selective COX-2 inhibitor can still cause oedema.Süleyman Deng, Anti-inflammatory and side effects of cyclooxygenase inhibitors, Pharma.Reports,2007 59:247-258。

Any suitable method can be used to detect and quantitative widely varied oedema.For example, hydrops (chest, peritonaeum or the heart Oedema in bag) can be based on the fluid levels when patient stand is imaged come quantitative.Most commonly, oedema is swollen based on being pressed into In swollen skin or make swelling skin " depression " ability subjective measurement.

Celebrex (celecoxib (celecoxib)) is standard selective cox 2 inhibitor, and Celebrex (celecoxib) The first page of package insert lists oedema as " bad reaction ".The table 1 of the package insert is disclosed, and for comfort Agent, naproxen, Diclofenac and brufen are respectively 1.1%, 2.1%, 1.0% and compare with 3.5%, with celecoxib treatment 2.1% development oedema in patient.The tolerance and bad thing to the adverse events in the clinical testing of celecoxib such as Moore The summary of part rate finds that the oedema incidence at any position is typically about 3%, but in two tests, oedema incidence is then It is much higher, it is 23% and 38%.Arthritis Res.&Therapy,2005,7(6),R644-R664,R658-59.

The treatment of oedema is consisted of：Potential disorder (if possible), RD sodium are reversed so that fluid retention Minimize and normally adopt diuretic.O ' Brian etc., Treatment of Edema, American Family Physician,71(11).2111-17。

In view of drug-induced oedema and especially by the drug-induced oedema with known treatment pain curative effect Persistent problem, the better method to preventing and treating drug-induced oedema still suffers from demand.Although in addition, this area takes Obtained progress, because each in the number of mechanisms for producing drug-induced oedema requires special treatment, to prevention and The better method of the oedema of medicine induction still suffers from demand.

Summary of the invention

The composition of oedema is not induced there is provided for treating pain, the composition includes cox 2 inhibitor and profit Urine agent, wherein the composition is applied with fixed dosage combination.

Additionally, it is provided a kind of be used to using NSAID (can be cox 2 inhibitor including wherein NSAID, and at one In preferred embodiment, NSAID is celecoxib) individualized treatment pain and the method that do not induce oedema, methods described bag Include：

A., first NSAID preparations are applied to the first patient for suffering from pain, a NSAID preparations include first dose The NSAID with specified quantitative and diuretic combinations of amount；

B. determine in the blood of the first patient in the multiple time points being applied in a NSAID preparations after the first patient NSAID and diuresis agent concentration；

C. the NSAID of the first patient and diuresis agent concentration/time data point are converted to into one or more medicines for power Learn (PK) parameter；

D. the value of the PK parameters of the first patient is compared with the preset range of the value of each PK parameter, and such as Really one or more in the PK parameters of the first patient fall outside a predetermined range, then design new NSAID preparations, wherein institute The dosage for stating NSAID, the diuretics or both is different from the dosage of a NSAID preparations；

E. new NSAID preparations are applied to into the first patient；

F. repeat step b-e, until all PK parameters used in step d are all within the preset range, and

If g. Pain management is enough, toxicity is endurable and patient does not experience oedema, the first patient is made The frequency of administration of the comparison in meet step d maintains NSAID preparations.

Disclosed herein is for the compositions related and method of individualized treatment arthritis ache.

Brief description

Fig. 1 is to be displayed in the blood plasma PGE2 that the LPS- in vitro afterwards of administration 2,4,6 and 24 hours stimulates (a kind of NSAID is active Index) and celecoxib PC logarithm between relation scatter diagram.PGE2 is represented as the percentage of pre-administration value Than.Drastically but variable dosage-response is obvious.(P, relative to placebo 0.01) is (from Systemic such as McAdam 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 parameter produced by the celecoxib of various dose.

Fig. 3 shows the knot of the meta-analysis (meta-analysis) of the single dose AUC of the patient from age groups Really.

Fig. 4-6 shows that with dosage range be oedema in the colony that the celecoxib from 100mg/ days to 800mg/ days is treated The result of the meta-analysis of rate.

Detailed description of the invention

The invention provides for individual using NSAID (preferably cox 2 inhibitor) and diuretics (for example, Hydrochioro) Bodyization treats pain, the including but not limited to composition and method of arthritis ache.In response to any NSAID of doses And/or it is to be suffered from such drug therapy that the variability between the high patient and patient of diuretics causes only clinical monitoring patient The imperfect mode of person.Even if measurement " blood level " (that is, the concentration of medicine in blood plasma is measured once in a while) is also impossible to cause Effective nontoxic scheme.In view of the dose response pass individually and with the NSAID of both one or more of diuretic combinations The complexity of system, must be using more fully set of metrics in each patient.Method claimed herein is utilized to each trouble Pharmacokinetics (" the PK ") analysis of person.Thus, method required for protection surpasses blood water single in single point in time measurement It is flat.Conversely, method required for protection utilize with regard to from several time points (through at least 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 60 hours, at least 2, preferably at least 5 of 72 hours sections, 6,7,8,9,10 It is individual, 11,12) plasma drug level data, and produce patient to certain drug using the four corner of PK parameters PK spectrum.Due to the complexity of Human pharmacokinetic, the known method of the individual PK spectrums of celecoxib is not previously predicted.Thus, Do not have not by the given medicament administration of at least one dosage to individuality in the case of can predict Human pharmacokinetic Know the natural law.In addition, many potential determination factors cause to define such rule it is unrealistic.Therefore, it is required for protection Method seeks directly to determine individual PK spectrums.

As used herein, wording " individualized treatment " refers to the special therapeutic scheme for patient, and it includes administration one Plant or more kinds of medicines, it is to analyze the pharmacokinetics of experimenter and/or the result of pharmacodynamic parameter so that lowest dose level The curative effect of medication of one or more of medicines is maximized and is possibly realized.

As used herein, " pain " refers to by illness or damage, for example, physical pain or discomfort that arthritis causes.

As used herein, " osteo-arthritic pain " refers to the pain caused by osteoarthritis (also known as " degenerative joint disease ") Bitterly.

As used herein, " preparation (formulation) " or " preparation (a formulation) " refers to active component and medicine The combination of acceptable carrier on, wherein it is every kind of be in each other fixed ratio (that is, the hundred of the fixation of every kind of composition in formulation Point ratio) it is present in formulation.

As used herein, " the first preparation " be cox 2 inhibitor preparation, its include the first dosage with specified quantitative and one Determine the diuretics and the optionally cox 2 inhibitor of pharmaceutically acceptable carrier combination of dosage, first preparation is administered to Patient is beginning through the process that it determines PK parameters." new cox 2 inhibitor preparation " is based on by the first cox 2 inhibitor The preparation of the PK parameter designings that preparation is produced.Thus, " new cox 2 inhibitor preparation " can have cox 2 inhibitor dosage, The change of the dosage of diuretics or the composition of carrier.Alternatively, the composition of carrier can be changed, and keeps cox 2 inhibitor and profit The dosage of urine agent is constant.In order to evaluate the PK parameters produced by new cox 2 inhibitor preparation, new cox 2 inhibitor preparation Replace " the first cox 2 inhibitor preparation ", and repeat the process.Comprising the first dosage with specified quantitative and diuretic combinations The new cox 2 inhibitor preparation of cox 2 inhibitor can be the second preparation.

As used herein, wording " according to the first preparation of first scheme " and " the first preparation " refer to that individuality is carrying out wanting The cox 2 inhibitor preparation of the dosage initially received before the one or more steps for asking the invention of protection.For example, according to First preparation of one scheme can be for patient more than 60kg open place twice daily for osteoarthritis and standard Standard 100mg or the celecoxib of 200mg dosage of the diuretic hydrochlorothiazide combination of 25mg dosage.

As used herein, wording " cox 2 inhibitor and diuresis agent concentration/time data point " refers to next comfortable administration COX- Before or after 2 inhibitor and diuretics in time given point in time experimenter blood plasma unit volume (for example, 1ml) In cox 2 inhibitor and diuresis agent concentration.

As used herein, wording " cox 2 inhibitor and diuresis agent concentration/time data point of conversion patient " refers to number Student movement calculation, formula, theory and/or principle are applied to the cox 2 inhibitor or diuresis agent concentration/time data point of individuality to derive PK parameters (for example, for calculate the formula of AUC).

As used herein, wording " preset range of value " refers to the scope of the PK parameter related to desired curative effect of medication, Wherein minimum toxicity is determined by statistical analysis patient for the PK spectrums of the known results of the preparation applied.The value it is predetermined The identification of scope can be by means of data compaction (for example, factor analysis or principal component analysis) and clustering computer agreement (for example, K- Average or SOM) completing (referring to U.S. Patent No. 7,412,333；No. 8,660,370；No. 8,990,135；9th, No. 002,658；No. 9,026,536；With No. 9,043,321).

As used herein, " design " refer to using the logical sum experience of those of ordinary skill in the art, based on patient data Activating agent dosage, preparation and/or scheme change.The design can according to the present invention by means of association area common skill Statistics known to art personnel and data mining technology (it can identify most important pharmacokinetic parameter and formulation components) are entered OK.It will be appreciated by the skilled addressee that iterative process claimed herein will be produced in 4-6 of doses change circulation Stable state PK of raw NSAID and diuretics is composed, and single dose and stable state preset range will take the circumstances into consideration be used.

Completely pharmacokinetics spectrum can cause such substantial amounts of variable element to cause to be incited somebody to action between the variable of reasonable consideration There is too many paired correlation.Especially, in the case of such multi-parameter, the powerful side of data analysis is typically started The figure shows of formula may be unavailable.Unexpectedly, in the case of 12 variables, there will be more than 200 three-dimensional scatterplots Figure.In order that such complex data is in more useful form, the number of variable is simplified to the most of change explained in data What the several explainable linear combination of property was a need for.

" factor analysis " is provided the method for data compaction to several key parameters.In each factor analysis, exist The equal number of factor existed with variable.Each factor captures a certain amount of population variance, and factor is always solved according to them The order of how many population variances released is arranged in the result (referring to U.S. Patent No. 8,660,370).

" principal component analysis " is another kind of data simplifying method.Assume there are 12 variables, principal component analysis can be by this Simplify to several (2-3) principal components.Such as factor analysis, master can be performed to initial data or to correlation or covariance matrix Constituent analysis (referring to U.S. Patent No. 7,412,333).

As used herein, " significantly bad drug response " refer to Finding case cannot stand, damage physiological function and/or Patient is made in immovable and/or dead risk or the ADR of its combination.

As used herein, " notable side effect " refer to that Finding case cannot be stood, damage physiological function and/or make at patient In immovable and/or dead risk or the side effect of its combination.

As used herein, " determine therapeutic level " to refer to using objective (for example, pharmacokinetics) and subjective testing (example Such as, pharmacodynamics), sign and symptom to characterize, it is quantitative or evaluate symptom (for example, pain) and (for example, filled in by applying active component To examine former times and diuretics) controlled degree.

As used herein, " determine toxic level " and refer to using objective and subjective testing, sign and symptom to characterize, quantitatively Or evaluation is by the conspicuousness of any side effect of administration active component generation.

As used herein, " micro oedema (trace edema) " is just above the detection threshold value for physical examination (inconsistent depression) and significantly do not damage function or patient of the patient in society physiological function oedema.

As used herein, " Pain management is enough " refer to patient willingness stand it and live and significantly infringement suffer from The pain level of the physiological function of function or patient of the person in society.

As used herein, " toxicity is acceptable " refers to and do not exist that notable side effect and patient willingness stand it and give birth to The toxic level of physiological function living and significantly not damaging function or patient of the patient in society.

As used herein, " NSAID " or " nonsteroidal anti-inflammatory drug " refers to and provides pain in experimenter such as human patientses Pain mitigates and generates heat a class medicine of mitigation effect and antiinflammatory action.NSAID includes both COX-1 and cox 2 inhibitor.

As used herein, " COX-1 inhibitor " refers to the COX-1 enzymes being directly targeted in experimenter and suppression at least The nonsteroidal anti-inflammatory drug of a little COX-1 activity, for example, aspirin.

As used herein, " cox 2 inhibitor " refers to the COX-2 enzymes being directly targeted in experimenter and suppression at least The nonsteroidal anti-inflammatory drug of a little COX-2 activity, for example, celecoxib.As used herein, " the COX-1 and COX-2 suppression of mixing Preparation " refers to both COX-1 and COX-2 enzymes being directly targeted in experimenter and suppresses at least some COX-1 and COX-2 active Nonsteroidal anti-inflammatory drug, for example, brufen.

As used herein, term " diuretics " refers to any material for promoting urine to produce.Diuretics also can show to resist Hypertension is acted on.A meter Luo is included but is not limited to for the suitable diuretics used in compositions disclosed herein and method ProfitBumetanideChlorthalidoneEthacrynic acidFuran plug Rice (furosemide)HydrochioroIndapamideMetolazoneTorasemide (torsemide)Dyrenium (triamterene), acetyl azoles Amine, theophylline, chlorthalidone, spirolactone and combinations thereof.

As used herein, " control release " refers to the delivering in response to internal NSAID, the diuretics for stimulating or both.Example Such as, the pH changes in alimentary canal.As used herein, " sustained release " refers to the dissolution time of prolongation, for example, dissolution time is increased Add 2 hours, 4 hours or 6 hours (see, e.g., U.S. Patent No. 8,992,979).

As used herein, " enteric coating " refers to the formulation with polymer barrier, and the polymer barrier tolerance exists Dissolving under stomach pH levels, but dissolve under typical higher pH levels in intestines, the polymer barrier is applied to include The composition of NSAID and diuretics.

As used herein, combination may also include " fixed dosage combination " and (FDC) or simply give multiple pills (often One is single dose) to realize intended effect.

The invention provides using the nonsteroidal anti-inflammatory drug (NSAID) combined with diuretics (preferably Hydrochioro) (preferably celecoxib) individualized treatment pain, the including but not limited to composition and method of arthritis ache.In addition, this It is bright to ache there is provided being used to be predicted with the composition comprising NSAID (preferably celecoxib) and diuretics (preferably Hydrochioro) The method of pain treatment results.Additionally, the invention provides using NSAID (preferably celecoxib) and diuretics (preferably hydrogen Chlorothiazide) prepare for treat pain medicine in method.

The invention provides based on the predetermined PK results of acquisition and terminal (that is, the individual chemical drug of the clinical condition of patient Thing is treated).

In one embodiment, there is provided a kind of composition that oedema is not induced for treating pain, the combination Thing includes NSAID and diuretics, wherein the composition is applied with fixed dosage combination.Any kind of pain, including Arthritis and osteo-arthritic pain can be treated by composition.

NSAID can be the one or more of of following NSAID, but be not limited to it：Diclofenac, Diflunisal, support Degree acid, fenoprofen, Flurbiprofen, brufen, Indomethacin, Ketoprofen, ketorolac, Meclofenamic Acid salt (meclofenamate), Nabumetone, naproxen, olsapozine, bute, piroxicam, salicylate, sulindac, Tolmetin, celecoxib, rofecoxib (rofecoxib), Etoricoxib (etoricoxib), Prexige (lumiracoxib), parecoxib (parecoxib), valdecoxib (valdecoxib), chlorthalidone and combinations thereof.Preferred Embodiment in, cox 2 inhibitor is celecoxib.

Diuretics can be the one or more of of following diuretics：Amiloride, bumetanide, chlorthalidone, Yi Tani Acid, frusemide, Hydrochioro, indapamide, metolazone, Torasemide, dyrenium, acetazolamide, theophylline, chlorthalidone, Spirolactone and combinations thereof.In preferred embodiments, diuretics is Hydrochioro.

Composition can be in the form of capsule, pill, syrup, control release device or Injectable solution, and NSAID and profit One or two release in urine agent can be controlled.NSAID and diuretics can substantially simultaneously discharge, or with any suitable Sequence, one kind can discharge in another previously.Composition can for example, daily, twice daily, three times a day, four times per day or often It is applied every two days.

One or more of pharmaceutically acceptable carriers or excipient can be comprised in composition.Can be according to the present invention Using any suitable pharmaceutical carrier.Suitable pharmaceutical carrier includes, but not limited to sterilized water, salt solution, dextrose (dextrose) it is dextrose, in water or salt solution, odium stearate or calcium stearate and/or polyethylene glycol, gum arabic, bright Glue, methylcellulose, carboxymethylcellulose calcium, hydroxypropyl methyl cellulose, ethyl cellulose, cellulose, Crospovidone, poly- dimension Ketone, acrylic acid and methacrylic acid copolymer, medicinal glaze (pharmaceutical glaze), natural gum, solvent, ethanol, isopropyl Alcohol, dichloromethane or sugar, lactose, gelatin, starch, silica, diethyl phthalate, diethyl sebacate, citric acid Triethyl, crotonic acid, propane diols, butyl phthalate, dibutyl sebacate, castor oil, diethyl phthalate, the last of the ten Heavenly stems two Diethyl phthalate, lactose, dextrose, sucrose, cellulose, starch or calcium phosphate, olive oil or ethyl oleate, silica, talcum, Stearic acid, magnesium stearate or calcium stearate, polyethylene glycol；Clay, bassora gum or mosanom, bonding agent such as starch, Arab Natural gum, polyvinylpyrrolidone, alginic acid, sodium starch glycollate, polysorbate, lauryl sulfate (laurylsulphate)；And acceptable auxiliary element on other treatment, such as the additives known of such preparation Wetting agent, preservative, buffer and antioxidant, lactose, dextrose, sucrose, cellulose, ethyl oleate, talcum, stearic acid, Magnesium stearate or calcium stearate and/or polyethylene glycol, gum arabic, gelatin, methylcellulose, carboxymethylcellulose calcium, poly- mountain Pears alcohol ester and combinations thereof.

It should be understood that in addition to specifically mentioned composition more than, the preparation of the present invention may include other suitable agent, all Such as flavor enhancement, preservative and antioxidant.Such antioxidant will be acceptable on food, and may include vitamin E, Hu Radish element, BHT or well known by persons skilled in the art other antioxidants.Wherein composition is in the embodiment of pill In, pill can be double-deck, enteric coating or its combination.The orally available administration of pill.

Composition can be applied with fixed dosage combination, such as, but not limited to, which wherein NSAID and diuretics are in Following intensity (celecoxib/Hydrochioro)：100mg/12.5mg、200mg/12.5mg、100mg/25mg、200mg/25mg.

Composition may include any suitable NSAID and diuresis agent dose.For example, composition can comprising 50mg to 400mg, 75mg to 350mg, 100mg to 300mg, 150mg to 250mg, the NSAID of 50mg, 100mg, 200mg or 400mg.Composition can Comprising 10mg to 200mg, 20mg to 150mg, 25mg to 75mg, 50mg, 100mg, 150mg or 200mg diuretics.

Composition can be administered to any suitable experimenter, including mammal.Suitable mammal include but not It is limited to the mankind.

The PK parameters for being used are following one or more：After concentration, concentration-time process, Cmax, administration It is time, t1/2, AUC, bioavilability, absorption, volume of distribution, metabolism, excretion, bioconversion to Cmax, clear Except or its combination.

Can any suitable NSAID used according to the invention, including but not limited to, COX-1 specific inhibitors, COX-2 Specific inhibitor, the COX-1 and cox 2 inhibitor of mixing or its combination.Thus, NSAID can be salicylate, propionic acid spreading out Biology, acetogenin, enolic acid derivative, anthranilic acid derivative or its combination.Therefore, NSAID can be Ah Si Woods (acetylsalicylic acid), brufen, naproxen, Indomethacin, sulindac, piroxicam, Clonixin (clonixin), preferably Ground celecoxib or its combination.In addition, the present invention can with NSAID and other analgesic drug products such as lidocaine, opium, to acetyl Amino phenols, tricyclic antidepressants, anticonvulsant, carbamazepine, Gabapentin and Pregabalin；Other anti-inflammatory drugs such as steroidal It is used together with the combination of immunodepressant.Additionally, the present invention can with NSAID and for arthritic other therapies, including but The combination for being not limited to methotrexate (MTX) and gold salt is used together.

Composition comprising NSAID and diuretics can include but is not limited to mouth according to the present invention via any suitable approach Clothes, rectum, by suction, it is percutaneous, be applied by injection, intravenous or intra-arterial.The non-NSAID components of any combinations therapy Can according to the present invention by any suitable approach including but not limited to oral, rectum, by suction, it is percutaneous, by injecting, it is quiet Arteries and veins is interior or intra-arterial is applied.Any suitable scheme can be used to apply two or more medicine groups according to the present invention Point, including but not limited to simultaneously (in mutual several minutes), substantially simultaneously (in mutual one hour) or different Time.

May include the other treatment for chronic disease, such as diabetes, angiocardiopathy, dementia, cholesterol and The treatment of hypertension.For example, the dosage combination of the fixation for pain relief without oedema or hypertension can combine open the courage at place The administration of sterol conditioning agent such as Atorvastatin is put into practice together.

Any suitable one or more PK parameters can be used according to the present invention, including but not limited to concentration, concentration To time, t1/2, AUC, bioavilability, absorption, the distribution body of Cmax after time course, Cmax and administration Product, removing metabolism, excretion, bioconversion or its combination.It should be noted that Single-dose pharmacokinetics can be used for determination being used for The parameter of extended regimen in the steady state such as load and maintenance dose are (referring to Johan Gabrielsson and Daniel The Pharmacokinetic and Pharmacodynamic Data Analysis of Weiner:Concepts and Applications, the 4th edition).

Any suitable one or more pharmacodynamic parameters can be used according to the present invention, including but not limited to patient The pain level of the physiological change of cell, tissue and ligament, patient or doctor's report, the frequency of side effect or its combination.

Any suitable method for evaluating pain known to persons of ordinary skill in the art can be made according to the present invention With including, but not limited to one-dimensional pain intensity scale, Wisconsin Brief Pain questionnaire (Wisconsin Brief Pain Questionnaire), Brief Pain scale (Brief Pain Inventory), McGill pain questionnaire (McGill Pain ) and skeleton symbol McGill pain questionnaires (the short form, McGill Pain Questionnaire) Questionnaire (referring to Breivik etc.：Assessment of pain,British Journal of Anaesthesia 2008,101(1): 17-24)。

Following examples further illustrate the present invention, but are not construed as limiting its model by any way certainly Enclose.

Embodiment 1

Such as existing for US/EU/ROWList on package insert with regard toApproval Prescription information to instruct doctor that the minimum effective dose consistent with the therapeutic purpose of individual patient should be used to continue most short lasting Time.For four in the indication of six approvals, package insert includes 100mg BID schemes：

1) osteoarthritis (OA)：200mg QD or 100mg BID

2) rheumatoid arthritis (RA)：100mg BID or 200mg BID

3) juvenile rheumatoid arthritis (JRA)：50mg BID in 10-25kg patient.In the trouble more than 25kg 100mg BID in person.

4) ankylosing spondylitis (AS)：200mg single doses are once a day or 100mg BID.

5) Acute Pain (AP), and 6) primary dysmenorrhea (PD).Initially 400mg, subsequent if necessary to be at first day 200mg dosage.At subsequently many days, as needed for 200mg BID.

Unexpectedly, however, inventor is divided the actually place's of opening behavior using Evaluate Pharma/IMS databases Analysis determines that 200mg opens the major dose at place for doctor, more than 10 to 1.These data investigate (table 1) and medical treatment benefit with from MEPS Help the data of (Medicaid) investigation (table 2) consistent.In view of the advantage and 100mg and 200mg dosage of the sale of 200mg formulations are produced The evidence of the raw PK for overlapping and pharmacodynamic result, it then follows the warning of package insert " should be that every patient seeks lowest dose level 's" it is suspectable.Conversely, as shown by data, it is understood that there may be patient of many in ADR risks, because he Celecoxib dosage higher than its needs dosage (i.e., for example, 200mg BID rather than 100mg BID).

Table 1.MEPS survey datas

Prescription information of the table 2. from medical subsidy

Embodiment 2

The pharmacokinetic data of announcement includes approval foundation (the Summary basis for from general introduction The constitutional diagram of approval) those is shown in Figure 2.The variability of pharmacokinetics is unexpectedly high. The PK results of 200mg dosage show substantially overlapping with the PK results of 100mg dosage.Therefore, dose ratio may not such as by closing InPackage insert described by.Due to not can determine that and follow the trail of target PK scope, in some cases, connect May be cannot get enough medicines by the patient of 100mg, and the patient of 200mg may receive too many medicine.

Embodiment 3

The meta-analysis of PK parameter of the applicant to reporting in different groups shows that the elderly is shown than young patient more High variability.For example, when the meta-analysis of applicant is presented with the subgroup based on the age, gerontal patient and young patient exist Highly significant difference (Fig. 3) is shown in terms of the medicine exposure for such as being defined by AUC.In other words, maximally effective celecoxib dosage It is not well defined in the elderly.The problem may than it is expected more commonly because the elderly is defined herein as greatly In>40 or>50 patient, rather than the definition of common the elderly (age is more than>65).Previously, have reported the elderly's Impaired PK, and package insert have issued the warning with regard to the impaired PK in the elderly, but non-recommended doses are reduced. Our discovery result shows, the problem is more important and more commonly, and also including middle aged group.

In group there is the C between variability, and 100mg and 200mg groups in PK results_maxShow with the overlap of AUC, to old Year patient be correctly administered with maximize with the curative effect of the celecoxib of possible lowest dose level depend on many individuations, no Predictable variable.Based on the AUC of wide scope, some patients for receiving 100mg may cannot get enough medicines, and The patient of 200mg may receive too many medicine (Fig. 2).

Embodiment 4

Applicant is to receiving the different osteoarthritis groups that dosage range is the celecoxib from 100mg/ days to 800mg/ days The meta-analysis of the oedema rate reported in body is disclosed, in the osteoarthritis group of the celecoxib for receiving the dosage more than 200mg/ days Edematous events rate is significantly higher in body.For example, the water in the osteoarthritis colony of the celecoxib for receiving 400mg/ days dosage Both the upper limit of swollen incident rate and average edematous events rate are than in the celecoxib for receiving 100mg/ days or 200mg/ days dosage Osteoarthritis colony in the upper limit edematous events rate observed and average edematous events rate is high is more than twice (Fig. 4-5).In addition, Applicant to receiving the different osteoarthritis colonies that dosage range is the celecoxib from 100mg/ days to 800mg/ days in report Oedema rate meta-analysis disclose, receive 100mg/ days or 200mg/ days dosage celecoxib patient experience it is closely similar Edematous events rate.The analysis shows, using one or more of methods described herein such as their individual medicine generation is based on Dynamics data is chosen the patient of the celecoxib for receiving 200mg/ days dosage will not be than receiving the plug of 100mg/ days dosage To examine the risk of the patient in higher edematous events of former times, and vice versa.

Embodiment 5

Applicant will also receive the oedema in following PATIENT POPULATION and be compared：Single celecoxib and various anti- Celecoxib, celecoxib and non-thiazine that the celecoxib of hypertension agents (including thiazide) combination is combined with Hydrochioro Class diuretics and without antihypertensive and celecoxib and non-thiazide antihypertensive.In order to support the research, create One database, it is included：1) from the ownership related to antihypertensive, Statins, COX-2 and NSAID of Symphony Data (Claims data from Symphony pertaining to anti-hypertensives, Statins, COX- 2 ' s, and NSAIDS). data cross over nearest 36 months, and 2) from report blood pressure (contraction/relaxation), the periphery of ACC Property oedema label (be, no, disappearance), heart rate, LDL, glucose level, LVEF (Ejection fraction), GFR, body The registry data of height, body weight, BMI etc..

SymphonyComprising real patient levels' data-all data sources either RX or MX ownerships It is all associated to be back to individual patient, the individual patient based on name, surname, sex, DOB and postcode it is tracked and and then The accurate figure of year-on-year patient levels' information is encrypted to provide, regardless of whether how insurance changes.Regulating the market (Managed Market) source of Rx Property datas is from multiple suppliers, including intelligent network service (Switch Data) and from medicine The immediate data of switch (therefore it does not produce requestee (payer) deviation) that do not use in shop is fed back.

SymphonyAttribute be：1) take Celebrex, AH, Statins or NSAID or with OA, The arthritis of RA or some other forms, 36 months, 2) December 31-2014 years 1, time frame=2012 on January (3 years), 3) number of files=201, the 4) 561GB (～2.5TB) of size=compression, 5) unique patient=1.62 hundred million, 6) take Western music The patient of luxuriant growth=4,300,000,7) patient with OA=16,300,000 (only OA be 15,400,000), 8) patient with RA=2,300,000 are (only 140 ten thousand) RA is.

The attribute of ACC registration tablies is：1) with 3+BP readings, 2) in December, -2,014 1, time frame=2012 on January (3 years) on the 31st, 3) number of files=2,4) size=590MB, 51MB, 5) unique patient=1,580,000,6) with BP readings Patient=1,580,000,7) with the real patient=870K of oedema label.

Then oedema rate is measured in above-mentioned database.The oedema incidence of OA patient is higher than RA, other joints It is scorching or without arthritic.When all groups of patient takes Celebrex in addition to except RA and without arthritic, oedema is sent out Raw rate increases.Generally speaking, OA seems easily to be affected by the oedema that Celebrex induces.What is more than results verification shown assembles point Analysis.

Table 3 is illustrated in OA, RA, other arthritis and case (%) without the oedema in arthritis.

Group	OA	RA	Other arthritis	Without arthritis
					W/o Celebrexs	12,150 (4.7%)	3,337 (3.0%)	164,837 (2.3%)	69 (0.4%)
W/ Celebrexs	254 (6.0%)	82 (3.3%)	1702 (4.1%)	451 (0.4%)

Embodiment 6

Determine whether thiazide diuretic Hydrochioro (HCTZ) will reduce clothes using the same database in embodiment 5 WithPatient in oedema incidence.Only takingPatient in there is oedema incidence It is stable to increase.The trend is aggravated by other Rx.For takingWith the patient of HCTZ, incidence is relatively low.Compare Under, takeEdematigenous incidence is led with non-thiazide diuretic increased more than one times.Oedema only may be used Optionally do not controlled for this point by other non-thiazide diuretics by HCTZ (thiazide diuretic), data are people Expect.Non- thiazide diuretic includes：1) ring：Torasemide, frusemide, bumetanide, ethacrynic acid, 2) carbonic anhydrase suppression Preparation：Acetazolamide, 3) diclofenamide, methazolamide protect potassium class (potassium sparring)：In dyrenium, spiral shell Ester, amiloride and 4) other：Pamabrom (pamabrom), mannitol.

Table 4. is presented on takes Celebrex and any other Rx, only Celebrex, Celebrex+HCTZ and Celebrex+non-thiazine The case (%) of the oedema in the patient of class diuretics.

All references cited herein, including publications, patent applications and patents are both incorporated herein by reference, its Degree individually and is specifically noted and is incorporated herein by and it is listed in full herein such as each bibliography Equally.

Unless indicated herein in addition or otherwise clearly contradicted, in the description of the invention in the context (especially with In the context of lower claims) term " (a) " that uses and " one (an) " and " should/(the) " and " at least One (at least one) " and similar indicant, are interpreted to cover both odd number and plural number.Unless indicate herein in addition or Otherwise clearly contradicted, the term " at least one " used after the list of one or more entries is (for example, " in A and B At least one ") be interpreted to mean in an entry or listed entry (A and B) of listed entry (A or B) two or Any combinations of more.Unless otherwise indicated, term " include (comprising) ", " having (having) ", " including " and " include (containing) " is interpreted open-ended term (i.e., it is intended that " including but not limited to ") (including). Unless indicated in addition herein, the referring to for scope of value otherwise herein is merely intended to be used as individually to refer within the range Each shorthand method being individually worth, and each single value is merged in this specification, as it is individually listed herein Equally.Unless indicated in addition herein or otherwise clearly contradicted in addition, otherwise all methods described herein can be with any Suitable order is carried out.Unless stated otherwise, otherwise provided in this article any and all embodiments or exemplary language (example Such as, " such as " use) is merely intended to the present invention be better described and not to the scope of the present invention applying restriction.In this specification Language be not necessarily to be construed as indicating that the key element of any failed call protection puts into practice essential to the present invention.

This document describes the preferred embodiment of the present invention, including the present inventor becomes known for carrying out the optimal of the present invention Mode.Read it is described above after, the version of those preferred embodiments can be with for those of ordinary skill in the art Become obvious.The inventors expect that technical staff optionally utilize such version, and the inventors expect that the present invention with Otherwise than as specifically described herein mode is carried out.Therefore, the present invention includes the right appended by the here of applicable law license The all modifications form of the theme listed in claim and equivalent.Additionally, unless indicating herein in addition or in addition and context Clearly contradicted, otherwise above-described key element is comprised in the present invention with any combinations of its all possible version.

Claims

1. a kind of composition that oedema is not induced for treating pain, the composition includes NSAID and diuretics, wherein institute State composition and be applied with fixed dosage combination.

2. composition as claimed in claim 1, wherein the NSAID is selected from group consisting of：Aspirin, double chlorine are fragrant Acid, Diflunisal, Etodolac, fenoprofen, Flurbiprofen, brufen, Indomethacin, Ketoprofen, ketorolac, first chlorine it is fragrant that Hydrochlorate, Nabumetone, naproxen, olsapozine, bute, piroxicam, salicylate, sulindac, tolmetin, plug come Examine former times, rofecoxib, Etoricoxib, Prexige, parecoxib, valdecoxib, chlorthalidone and combinations thereof.

3. composition as claimed in claim 2, wherein the NSAID is cox 2 inhibitor.

4. composition as claimed in claim 3, wherein the cox 2 inhibitor is celecoxib, Etoricoxib, Rumi examining Former times, parecoxib, valdecoxib, chlorthalidone or its combination.

5. composition as claimed in claim 3, wherein the cox 2 inhibitor is celecoxib.

6. composition as claimed in claim 1, wherein the diuretics is selected from group consisting of：Amiloride, Bu Mei His Buddhist nun, chlorthalidone, ethacrynic acid, frusemide, Hydrochioro, indapamide, metolazone, Torasemide, dyrenium, acetyl Azoles amine, theophylline, chlorthalidone, spirolactone and combinations thereof.

7. composition as claimed in claim 6, wherein the diuretics is Hydrochioro.

8. the composition as any one of claim 1-7, wherein the pain is arthritis ache.

9. composition as claimed in claim 8, wherein the arthritis ache is osteo-arthritic pain.

10. the composition as any one of claim 1-7, wherein the composition is in capsule, pill, syrup, control The form of release device or Injectable solution.

11. compositions as any one of claim 1-7, wherein one kind in the NSAID and the diuretics or Two kinds of release is controlled.

12. compositions as claimed in claim 11, wherein the NSAID and the diuretics substantially simultaneously discharge.

13. compositions as claimed in claim 11, wherein the NSAID discharged before the diuretics.

14. compositions as claimed in claim 11, wherein the diuretics discharged before the NSAID.

15. compositions as any one of claim 1-14, the composition also comprising it is one or more of pharmaceutically Acceptable carrier.

16. compositions as claimed in claim 15, wherein form of the composition in pill.

17. compositions as claimed in claim 16, wherein the pill is double-deck pill.

18. compositions as claimed in claim 16, wherein the pill is enteric coating.

19. compositions as any one of claim 1-18, wherein the dosage combination of the fixation is included with following strong The celecoxib and Hydrochioro of one of degree (celecoxib/Hydrochioro)：100mg/12.5mg、200mg/12.5mg、 100mg/25mg and 200mg/25mg.

20. compositions as claimed in claim 19, wherein Sai Laikao of the dosage combination of the fixation comprising 50mg to 400mg Former times.

21. compositions as claimed in claim 19, wherein esodrix of the dosage combination of the fixation comprising 5mg to 100mg Piperazine.

22. it is a kind of for treating mammal in pain method, methods described includes will be arbitrary in such as claim 1-21 Composition described in is applied to mammal.

23. methods as claimed in claim 22, wherein the arthritis ache is osteo-arthritic pain.

24. methods as claimed in claim 22, wherein the composition is daily, twice daily, three times a day or four times per day It is applied.

A kind of 25. methods for not inducing oedema using cox 2 inhibitor individualized treatment pain, methods described includes：

A., first cox 2 inhibitor preparation is applied to the first patient for suffering from pain, the first cox 2 inhibitor preparation bag The cox 2 inhibitor with specified quantitative and diuretic combinations containing the first dosage；

B. the multiple time points after the first cox 2 inhibitor preparation to be applied to first patient determine described Cox 2 inhibitor and diuresis agent concentration in the blood of one patient；

C. the cox 2 inhibitor of first patient and diuresis agent concentration/time data point are converted to into one or more medicines For dynamics (PK) parameter；

D. the value of the PK parameters of first patient is compared with the preset range of the value of each PK parameter, and such as One or more in the PK parameters of really described first patient fall outside a predetermined range, then design new cox 2 inhibitor Preparation, wherein the dosage of the cox 2 inhibitor, described diuretics or both is different from the first cox 2 inhibitor preparation Dosage；

E. the new cox 2 inhibitor preparation is applied to into first patient；

If g. Pain management is enough, toxicity is that endurable and described patient does not experience oedema, makes described first Patient to meet step d in the frequency of administration of comparison maintain cox 2 inhibitor preparation.

26. methods as claimed in claim 25, wherein the cox 2 inhibitor preparation is administered orally.

27. methods as claimed in claim 25, wherein the predetermined PK scopes are based on suffers from being pressed down with the COX-2 for pain Preparations successful treatment cause Pain management be enough, toxicity be acceptable and at most only exist micro oedema its The PK parameters of his patient.

28. methods as claimed in claim 25, wherein the cox 2 inhibitor is celecoxib.

29. methods as claimed in claim 25, the PK parameters used in it are following one or more：It is concentration, dense To time, t1/2, AUC, bioavilability, absorption, the distribution of Cmax after degree time course, Cmax, administration Volume, metabolism, excretion, bioconversion, removing or its combination.

30. methods as claimed in claim 25, wherein the cox 2 inhibitor and the diuretics are with fixed dosage combination It is applied.

31. methods as claimed in claim 25, wherein the diuretics is Hydrochioro.