Patent Application
20080027032
This invention relates to pharmaceutical compositions and uses, in particular to pharmaceutical compositions for use in the selective inhibition of COX-2 activity and for treating conditions in mammals which are responsive to COX-2 inhibition.
It has been proposed to treat a condition selected from the group consisting of acute coronary ischemic syndrome, thrombosis, thromboembolism, thrombotic occlusion and reocclusion, transient ischemic attack, and first or subsequent thrombotic stroke, in a patient having the condition, comprising administering to the patient a therapeutically effective amount of an antiplatelet agent in combination with a therapeutically effective amount of a COX-2 inhibitor (U.S. Pat. No. 6,136,804; Merck). This combination therapy is stated to provide enhanced treatment options as compared to administration of either the antiplatelet agent or the COX-2 inhibitor alone. Aspirin is identified as an antiplatelet agent that may be used in this combination therapy and recommended for use at dosages generally in the range from 75 mg up to about 325 mg per day. It has now been found, in accordance with the present invention, that diseases involving platelet aggregation, such as those identified above, may be treated or avoided during treatment with a COX-2 inhibitor if the COX-2 inhibitor is administered in combination with aspirin at dosages lower than hitherto used; and furthermore that particular advantageous results are obtained if a 5-alkyl-2-arylaminophenylacetic acid derivative COX-2 inhibitor is used in combination with aspirin as antiplatelet inhibitor.
Accordingly the present invention provides a pharmaceutical composition for treatment of conditions in mammals which are responsive to COX-2 inhibition which comprises in combination an effective amount of a COX-2 inhibitor and low-dose aspirin, for simultaneous, sequential or separate use.
Further the invention provides the use of a COX-2 inhibitor for the preparation of a medicament, for use in combination with low-dose aspirin for treatment of conditions in mammals which are responsive to COX-2 inhibition.
In a further embodiment the invention provides a method of treating a patient suffering from a condition which is responsive to COX-2 inhibition comprising administering to the patient an effective amount of a COX-2 inhibitor in combination with low-dose aspirin.
Yet further the invention provides use of low-dose aspirin to treat acute coronary ischemic syndrome, thrombosis, thromboembolism, thrombotic occlusion and reocclusion, transient ischemic attack, myocardial infarction, and first or subsequent thrombotic stroke, in a patient having the condition, when the low-dose aspirin is administered in combination with an effective amount of a COX-2 inhibitor. Advantageously low dose aspirin is administered together with the COX-2 inhibitor for cardio-protection, e.g. in view of the anti-platelet aggregation activity of aspirin.
In the present description the term “treatment” includes both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as ill patients. In preferred embodiments of the invention “treatment” comprises primary or secondary prevention of cardiovascular disease.
The invention is generally applicable to the treatment of conditions in mammals which are responsive to COX-2 inhibition. For instance, for the treatment of cyclooxygenase dependent disorders in mammals, including inflammation, pyresis, pain, osteoarthritis, rheumatoid arthritis, migraine headache, neurodegenerative diseases (such as multiple sclerosis), Alzheimer's disease, osteoporosis, asthma, lupus and psoriasis. Moreover, COX-2 inhibitors are further useful for the treatment of neoplasia particularly neoplasia that produce prostaglandins or express cyclooxygenase, including both benign and cancerous tumors, growths and polyps. COX-2 inhibitors may be employed for the treatment of any neoplasia as for example as recited in International Patent Application Publication No. WO 98/16227, published 23 Apr. 1998, in particular epithelium cell-derived neoplasia. COX-2 inhibitors are in particular useful for the treatment of liver, bladder, pancreas, ovarian, prostate, cervical, lung and breast cancer and, especially gastrointestinal cancer, for example cancer of the colon, and skin cancer, for example squamus cell or basal cell cancers and melanoma.
The compositions, uses and methods of the present invention represent an improvement to existing therapy of conditions in mammals which are responsive to COX-2 inhibition.
In the present description the term “low-dose aspirin” means an aspirin dose of less than 75 mg per day, typically a dose in the range from about 70 mg down to about 10 mg or less (e.g. at least about 5 mg) per day. Preferred low-dose aspirin dosages are in the range from about 20 mg up to about 60 mg per day, more preferably from about 30 mg up to about 50 mg per day.
The COX-2 inhibitors used in the pharmaceutical compositions and treatment methods of the present invention are typically those which have an IC50 for COX-2 inhibition less than about 2 μM and an IC50 for COX-1 inhibition greater than about 5 μM, e.g. when measured in the assays described by Brideau et al in Inflamm. Res. 45:68-74 (1996). Preferably the COX-2 inhibitor has a selectivity ratio of at least 10, more preferably at least 40, for COX-2 inhibition over COX-1 inhibition.
Thus, for example, suitable COX-2 inhibitors for use in the invention may include any of the COX-2 inhibitors identified in U.S. Pat. No. 6,136,804; in particular the following compounds or a pharmaceutically acceptable salt thereof, or any hydrate thereof rofecoxib, etoricoxib, celecoxib, valdecoxib, parecoxib, or a 5-alkyl-2-arylaminophenylacetic acid derivative COX-2 inhibitor, e.g. of formula I as defined below.
In a particular embodiment a COX-2 inhibitor for use in the present invention comprises a compound of formula I
wherein R is methyl or ethyl;
(a) wherein R is methyl; R1 is fluoro; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; and R5 is chloro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof;
(b) wherein R is methyl; R1 is fluoro; R2 is hydrogen; R3 is fluoro; R4 is hydrogen; and R5 is chloro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof;
(c) wherein R is ethyl; R1 is fluoro; R2 is fluoro; R13 is hydrogen; R4 is fluoro; and R5 is fluoro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof; and
(d) wherein R is ethyl; R1 is chloro; R2 is hydrogen; R3 is chloro; R4 is hydrogen; and R5 is methyl; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof.
The general definitions used herein have the following meaning within the scope of the present invention
The compounds of formula I are UV absorbers and are useful for blocking or absorbing UV radiation; for instance, for the treatment and prevention of sunburn, e.g. in suntan products
The compounds of formula I may also be used in ocular applications which include the treatment of ocular disorders, in particular of ocular inflammatory disorders, of ocular pain including pain associated with ocular surgery such as PRK or cataract surgery, of ocular allergy, of photophobia of various etiology, of elevated intraocular pressure (in glaucoma) by inhibiting the production of trabecular meshwork inducible glucocorticoid response (TIGR) protein, and of dry eye disease.
In a second aspect the invention also provides a pharmaceutical composition for treatment of conditions in mammals which are responsive to COX-2 inhibition which comprises in combination an effective amount of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof and an effective amount of aspirin, for simultaneous, sequential or separate use.
Further the invention provides the use of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof for the preparation of a medicament, for use in combination with an effective amount of aspirin for treatment of conditions in mammals which are responsive to COX-2 inhibition.
In a yet further embodiment of this second aspect the invention provides a method of treating a patient suffering from a condition which is responsive to COX-2 inhibition comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof in combination with an effective amount of aspirin.
The “effective amount of aspirin” for use in this second aspect of the invention includes those amounts commonly known and used by physicians when using aspirin as an anti-platelet agent. Conveniently the “effective amount of aspirin” is generally in the range from about 10 mg to about 400 mg, more usually from about 75 mg to about 325 mg per day. For example, the composition of this second aspect may contain 75 mg, 80 mg, 160 mg, 250 mg or 325 mg of aspirin.
Pharmaceutically acceptable salts of the compound of formula I are preferably salts with bases, conveniently metal salts derived from groups Ia, Ib, IIa and IIb of the Periodic Table of the Elements, including alkali metal salts, e.g. potassium and especially sodium salts, or alkaline earth metal salts, preferably calcium or magnesium salts, and also ammonium salts with ammonia or organic amines.
The Agents of the Invention (a the COX-2 inhibitor and the low-dose aspirin or b the compound of formula I or pharmaceutically acceptable salt or prodrug thereof and effective amount of aspirin) are preferably used in the form of pharmaceutical preparations that contain the relevant therapeutically effective amount of each active ingredient (either separately or in combination) optionally together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for administration. The COX-2 inhibitor and aspirin active ingredients may be present in the same pharmaceutical compositions, though are preferably in separate pharmaceutical compositions. Thus the active ingredients may be administered at the same time (e.g. simultaneously) or at different times (e.g. sequentially) and over different periods of time, which may be separate from one another or overlapping.
The pharmaceutical compositions may be, for example, compositions for enteral, such as oral, rectal, aerosol inhalation or nasal administration, compositions for parenteral, such as intravenous or subcutaneous administration, or compositions for transdermal administration (e.g. passive or iontophoretic).
Preferably, the pharmaceutical compositions are adapted to oral or parenteral (especially oral) administration. Intravenous and oral, first and foremost oral, administration is considered to be of particular importance. Preferably both the COX-2 inhibitor and aspirin active ingredient are in oral form.
The particular mode of administration and the dosage may be selected by the attending physician taking into account the particulars of the patient, especially age, weight, life style, activity level, etc.
The dosage of the Agents of the Invention may depend on various factors, such as effectiveness and duration of action of the active ingredient, mode of administration, warm-blooded species, and/or sex, age, weight and individual condition of the warm-blooded animal.
More particularly, the pharmaceutical compositions comprise an effective cyclooxygenase-2 inhibiting amount of COX-2 inhibitor or compound of formula I which is substantially free of cyclooxygenase-1 inhibiting activity and of side effects attributed thereto.
The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable formulations for topical application, e.g. to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, for example, for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g. for the treatment of skin cancer, for example, for prophylactic use in sun creams, lotions sprays and the like. In this regard it is noted that compounds of formula I are capable of absorbing UV rays in the range of 290-320 nm while allowing passage of tanning rays at higher wavelengths. They are thus particularly suited for use in topical, including cosmetic formulations as aforesaid well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. Formulations suitable for topical application can be prepared e.g. as described in U.S. Pat. No. 4,784,808. Formulations for ocular administration can be prepared e.g. as described in U.S. Pat. Nos. 4,829,088 and 4,960,799.
The dosage of COX-2 inhibitor administered is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, and on the form of administration. A unit dosage for oral administration to a mammal of about 50 to 70 kg may contain between about 5 and 100 mg, e.g. from 50-800 mg, preferably 100-500 mg of the active ingredient.
COX-2 inhibitor formulations in single dose unit form contain preferably from about 1% to about 90%, and formulations not in single dose unit form contain preferably from about 0.1% to about 20%, of the active ingredient. Single dose unit forms such as capsules, tablets or dragées contain e.g. from about 1 mg to about 1000 mg of the active ingredient.
COX-2 inhibitor pharmaceutical preparations for enteral and parenteral administration are, for example, those in dosage unit forms, such as dragées, tablets or capsules and also ampoules. They are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, where appropriate granulating a resulting mixture and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, into tablets or dragée cores.
Other orally administrable pharmaceutical preparations are dry-filled capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, where appropriate, stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilisers to be added.
Parenteral formulations are especially injectable fluids that are effective in various manners, such as intravenously, intramuscularly, intraperitoneally, intranasally, intradermally or subcutaneously. Such fluids are preferably isotonic aqueous solutions or suspensions which can be prepared before use, for example from lyophilised preparations which contain the active ingredient alone or together with a pharmaceutically acceptable carrier. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
Suitable formulations for transdermal application include an effective amount of the active ingredient with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the active ingredient of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon.
Tablet dose strengths of between 5 and 125 mg can be accommodated by varying total weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1:1 ratio for microcrystalline cellulose: lactose monohydrate.
Tablet dose strengths of between 5 and 125 mg can be accommodated by varying total tablet weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1:1 ratio for microcrystalline cellulose:lactose monohydrate.
Capsule dose strengths of between 1 and 50 mg can be accommodated by varying total fill weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1:1 ratio for microcrystalline cellulose:lactose monohydrate.
Suspension dose strengths of between 1 and 50 mg/5 ml can be accommodated by varying the ratio of the first two ingredients.
Tablets containing 25.0, 50.0 and 100.0 mg, respectively, of a GP IIb/IIIa receptor antagonist and 25 mg COX-2 Inhibitor are prepared as illustrated below:
Table for doses containing from 25-200 mg of aspirin and 25 mg COX-2 inhibitor
Both active compounds, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of GP IIb/IIIa receptor antagonist per tablet, and 25 mg COX-2 inhibitor, per tablet.
** The weight of drug substance is taken with reference to the dried substance (100 percent) on the basis of the assay value (factorization). The difference in weight is adjusted by the amount of microcrystalline cellulose used.
*** Removed during processing.
**** Includes a 50% excess for loss during the coating process.
Table 1, above, sets out the formula for a batch of approximately 250,000 immediate release film-coated tablets of 5-methyl-2-(2′-chloro-6′-fluoroanilino)-phenylacetic acid. To make the tablets, titanium dioxide is dispersed in water, followed by the addition of povidone and mixing for 20 minutes to make a povidone/titanium dioxide suspension. The drug substance, lactose, microcrystalline cellulose, and croscarmellose are mixed in a high shear mixer (e.g., a Collette Gral) for 5 minutes to form a drug mixture. The drug mixture is granulated in the high shear mixer with the povidone/titanium dioxide suspension. The suspension is pumped at a rate of 3 kg/min into the drug mixture. The resulting mixture is mixed an additional 90 seconds after all the suspension is added. The wet granulation is dried in a fluid bed dryer, using an inlet air temperature of 50° C. The residual water target is 3.5% (with a permissible range of 2.5-4.5%). The dried granulation is passed through a screen using a mill (oscillator) and a 30 mesh screen. The previous steps are repeated to make a second granulation.
The extra-granular phase titanium dioxide is passed through a 60 mesh hand screen. The dry granulations are mixed with the extra-granular phase microcrystalline cellulose, croscarmellose sodium and titanium dioxide in a twin shell mixer for 300 revolutions to form a penultimate mixture. Magnesium stearate is passed through a 60 mesh hand screen and is mixed with the penultimate mixture in a twin shell mixer for 50 revolutions to form a tableting mixture. The tableting mixture is pressed into tablets using a tablet press and oval punches.
The coating powders (Opadry) are mixed with purified water to make a 15% w/w coating suspension. The tablets are film coated with the coating suspension in a coating pan using 60° C. to 75° C. inlet air temperature.
Table 2 sets out the contents of a 200 mg 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid film-coated tablet.
* removed during processing
In addition, the tablet formulations may contain 5-methyl-2-(2′-chloro-6′-fluoroanilino)benzyl alcohol and/or 5-methyl-2-(2′-chloro-6′-fluoroanilino)benzoic acid in an amount between about 0.01 and 2% by weight, more specifically between about 0.1 and 1.
The following clinical study is carried out using 5-methyl-2-(2′-chloro-6′-fluoroanilino phenylacetic acid (COX 189) as selective COX-2 inhibitor.
Exclusion Criteria:
The following patients will be excluded:
The following patients will be excluded:
Recruitment 39 weeks period
Prior concomitant medications, adverse events and serious adverse events will be collected by using the standard forms.
Visit Schedule:
Visit 1: Screening
Visit 2: Baseline (randomization)
Visit 3: 4 weeks/(plus or minus 4 days)
Visit 4: 13 weeks (plus or minus 2 weeks)
Visit 5: 20 weeks (plus or minus 2 weeks)
Visit 6: 26 weeks (plus or minus 2 weeks)
Visit 7: 39 weeks (plus or minus 2 weeks)
Visit 8: 52 weeks (plus or minus 2 weeks), or early discontinuation
Follow-up: by a phone call at 4 weeks after discontinuation for follow up on serious gastrointestinal events and for selected cardiovascular events (myocardial infarction, stroke and cardiovascular death).
About the Number of Patients:
Randomization will be stratified by age group (<65, 65 to 74, >74) and by use of low dose aspirin by an IVRS system (4,524 ASA users (ca. 24%) and 14,148 non ASA users (ca. 76%)).
Statistical Methods
The trial is designed to demonstrate that a significant difference in time-to-event curves on complicated ulcers of the upper gastrointestinal tract as compared to NSAIDs (naproxen and ibuprofen). For the primary endpoint an exponential maximum likelihood test of equality of time-to-event curves with one-sided significance level of 0.025 will be performed. A Cox proportional hazard model will be used to compare the relative risk between the two treatment groups. Covariates included in this model will be treatment group indicator and strata of age and prior history of POBs.
The Calculation of Sample Size is Based on the Following Assumptions:
By using a generalized Lachin and Foulkes method, a sample size of 18,672 patients (9,336 in both treatment arms) is required to observe 156 serious GI events (56 in the COX189 treatment arm and 100 in the NSAIDs group) in the overall COX189 TARGET population.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0124459.9 | Oct 2001 | GB | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10487759 | Feb 2004 | US |
| Child | 11834748 | Aug 2007 | US |
