EP1877053A2 - Combination formulation - Google Patents
Combination formulationInfo
- Publication number
- EP1877053A2 EP1877053A2 EP06750311A EP06750311A EP1877053A2 EP 1877053 A2 EP1877053 A2 EP 1877053A2 EP 06750311 A EP06750311 A EP 06750311A EP 06750311 A EP06750311 A EP 06750311A EP 1877053 A2 EP1877053 A2 EP 1877053A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- agents
- administration
- cox
- active
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 238000009472 formulation Methods 0.000 title description 16
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- 150000001875 compounds Chemical class 0.000 claims description 32
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- 229940079593 drug Drugs 0.000 abstract description 12
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
Definitions
- the invention relates to a composition comprising a Cox II inhibitor and a compound directed to treating cardiovascular disease.
- Non-steroidal anti-inflammatory drugs are known to be associated with a slight risk of hypertension. Such analgesics generally inhibit Cox I.
- Recent new drugs are inhibitors of Cox II, which is specific for the prostacyclin synthetic pathway, whereas Cox I is involved in both the prostacyclin pathway as well as the thromboxane metabolic pathway.
- Cox II inhibitors are taught in U.S. Pat. Nos. 5,474,995; 5,466,823; 5,563,165; 5,633,272; and 5,691,374.
- An object of the instant invention is to provide a product and a process for ameliorating any attending cardiovascular side effects from the use of Cox II inhibitors by combining same with a suitable cardiovascular disease drug.
- It is an object of the instant invention to provide a composition comprising a combination of a Cox II inhibitor and a cardiovascular disease drug.
- the two active ingredients can be combined into a single form or may be divided into separate entities for simultaneous or sequential administration.
- Vioxx promotes oxidative damage to low density lipoproteins (LDL) and phospholipids. That may lead to endothelial damage, for example, and hypertension.
- LDL low density lipoproteins
- the first pharmacologically active compound is a Cox II inhibitor.
- Suitable such inhibitors include 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide, which is a diaryl substituted isoxazole (Bextra, Pfizer); 4-(l , 1 , 1 -trifluoromethyl-5-(4-methylphenyl pyrazol- 1 -y l)-(benzenesulfonamidebeta) Celebrex, Pfizer); 4-[4-(methylsulfonyl) phenyl]-3-phenyl-2(5H)-furanone (Vioxx, Merck); 5-chloro-6'-methyl-3-[4-(methylsulfonyl) phenyl]-2,3'-bipyridine (Arcoxia, Merck); and other products such as parecoxib and reciracoxib (Prexige, Novartis).
- NSAIDs are associated with unanticipated or unintended cardiac and vasculature involvement, such as myocardial infarction, heart attack, sudden cardiac death, stroke, hypertension, congestive heart failure, pulmonary edema and so on. Therefore, the instant invention relates to products and processes for minimizing the untoward cardiovascular side effects associated with Cox II inhibitors.
- the invention teaches combining administering a Cox II inhibitor with a cardiovascular disease agent.
- a number of antihypertensive agents can be used in the practice of the instant invention, including diuretics, beta blockers, alpha blockers, alpha/beta blockers, glycation end product cross link blocker, rennin inhibitors, aldosterone inhibitors, sympathetic nerve inhibitors, angiotensin converting enzyme inhibitors, calcium channel blockers, angiotensin receptor blockers and son on.
- Commonly known examples include amiloride (Midamor), chlorothiazide (Diuri), furosemide (Lasix), methylclothiazide (Enduron), propranolol (Inderal), metoprolol (Lopressor), prazosin (Minipress), SPPlOO, a renin inhibitor (Aliskiren, Novartis), valsartan, an angiotensin receptor blocker (Diovan, Novartis), labetalol (Mormodyne), clonidine (Catapres), captopril (Capoten), ramipril, an angiotensin converting enzyme or ACE inhibitor (Altace), diltiazem (Cardizem), nifedipine (Procardia) and irbesartan (Avapro).
- Another suitable anti-hypertensive agent is 4-hydroxy-2,2,2,6,6-tetramethylpiperidine-l-oxyl (Tempol), a stable nitroxide which is a free radical scavenger, U.S. Patent Nos. 6,096,759 and 6,617,337.
- cardiovascular drugs A variety of other cardiovascular drugs are known. Some are those noted above for treating hypertension, and are included herein by reference.
- suitable such drugs include adrenergic stimulants, antiarrhythmics, phosphodiesterase inhibitors, antilipemic agents, bile acid sequestrants, fibric acid derivatives, HMG- CoA reductase inhibitors, nicotinic acid, inotropic agents, vasodilators, vasopressors and so on.
- Examples include Aldoril, Catapres, Combipres, Procanbid, Betapace, Inderal, Corvert, Cardizem, Adenocard, Lanoxin, Colestid, Altromid, Baycol, Lescol, Lipitor, Zocor, Digitek, Lanoxin, Primacor, Activase, Demser, Retavase, Lndur, Isordil, Natecor, Flolan and Aramine.
- the cardiovascular disease compound is Tempol
- the choice of delivery form generally will depend on the characteristics, properties and delivery form which is most conducive to the Cox ⁇ inhibitor.
- a common free radical is an oxygen molecule with an odd number of electrons. Free radicals such as the superoxide anion, are involved in progressing many disease states associated with pain and inflammation.
- SOD superoxide dismutase
- Suitable antioxidants include vitamin C, vitamin, E, vitamin K, certain phytochemicals, such as ⁇ carotene, glutathione, flavinoids, such as silymarin, as well as particular compounds with antioxidant activity, such as acetyCys, selegeline, certain lipoic acids and 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl (Tempol), a stable nitroxide, U.S. Pat. Nos. 6,096,759 and 6,617,337.
- Tempol is a nitroxide SOD mimetic that, for example, following infusion or oral administration, lowers mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR). Kidney Intl., 68:179-187 (2005). Tempol is a stable molecule that is metal independent and is membrane permeable.
- Tempol has been administered in a variety of ways including intravenously, intracranially, orally, for example, as a drop or added to water, intraperitoneally, used as a food supplement, subcutaneously, and so on. Doses range from, for example, about 1-1500 mg/kg/d, about 1-500 mg/kg as a food supplement and about 1-500 mmol/kg/h.
- the instant invention is not limited thereto.
- the choice of the second active ingredient is dependent on the cardiovascular manifestation observed or expected, based, in part, on the Cox II inhibitor used, and patient history.
- the active ingredients also can be formulated as "prodrugs,” which term is used in a broad sense and is meant to encompasses analogs, derivatives and the like of the two active ingredients of interest that are converted in vivo to the compounds of the invention.
- Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative. See, for example, U.S. Pat. Nos. 6,797,725 and 7,018,987.
- a pharmaceutical composition of the invention for use as disclosed herein is formulated to be compatible with the intended route of administration. Many of the compounds noted above are marketed, and thus, the delivery form can follow that currently available. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal and rectal administration.
- Solutions or suspensions used for parenteral, intradermal or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as HCl or NaOH.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- Suitable oral forms which can be presented as discrete units such as capsules, sachets or tablets, each contain a predetermined amount of one or both of the active ingredients; or can be provided as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, in a depot or as a paste.
- Tablets may be made by compression or molding as known in the art, generally with one or more accessory ingredients as taught herein and as known in the art.
- Compressed tablets may be prepared using as a starting reagent a free-flowing form such as a powder or granules which then are mixed with, for example, a binder, a diluent, a preservative, a disintegrant (such as, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose or other cellulosic compounds, a polyvinyl alcohol), surface-active or dispersing agent, and so on.
- the tablet may then be layered with an enteric coating.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- Oral compositions generally include an inert diluent or an edible carrier.
- the composition can be enclosed in gelatin capsules or compressed into tablets.
- the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules.
- Oral compositions also can be prepared using a fluid carrier to yield a syrup or liquid formulation, or for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
- compositions can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch
- a lubricant such as magnesium stearate or Sterotes
- a glidant such as colloidal
- a pharmaceutical composition of interest may comprise at least one additive selected from a disintegrating agent, binder, flavoring agent, preservative, colorant and a mixture thereof, see for example, "Handbook of Pharmaceutical Excipients”; Ed. A. H. Kibbe, 3rd Ed., American Pharmaceutical Association, USA. See also U.S. Pat. Nos. 6,911,455.
- the active agents of interest can be coated by layers of different excipients, the active agents can be mixed with various excipients, can be mixed together with the excipients, can be mixed separately to provide individual units carrying one of the two active agents of interest, which then are combined in a capsule form, and so on.
- the compounds of interest can be presented in the form of an ointment, cream or lotion, for example, or as a transdermal patch.
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Lotions may be formulated with an aqueous or oily base and will, in general, also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, coloring agents and so on.
- compositions include lozenges comprising active agents in a flavored base, containing, for example, sucrose and acacia or tragacanth; pastilles or troches, comprising the active ingredients in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- Solutions or suspensions can be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
- the formulations may be in single or multidose forms. In the latter case, using a dropper or pipette, the administering may be achieved by the patient with a predetermined volume of the solution or suspension.
- a metering atomizing spray pump also may be used.
- Administration to the respiratory tract may be achieved by means of an inhaler device or an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- CFC chlorofluorocarbon
- the aerosol may contain a surfactant, such as lecithin or other lipid.
- the dose of drug may be controlled by provision of a metered valve.
- the active ingredients may be provided in the form of a dry powder, for example, a fine powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- a powder carrier will form a gel in the nasal cavity.
- a powder of nanoparticles can be inhaled as a dry mist, or can be dissolved in a liquid diluent.
- the powder composition may be presented in unit dose form, for example, in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
- the compound will generally have a small particle size, for example, on the order of 5 ⁇ m or less. Such a particle size may be obtained by means known in the art, for example by micronization.
- compositions for rectal administration such as a suppository, may be made with a suitable base comprising, for example, cocoa butter.
- a suitable base comprising, for example, cocoa butter.
- the composition of interest can be delivered as an enema.
- compositions suitable for vaginal administration can be pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient, carriers as are known in the art to be appropriate.
- Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which preferably are isotonic and which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF; Parsippany, NJ) or phosphate-buffered saline (PBS).
- the composition must be sterile and should be fluid to the extent that easy syringability exists.
- the composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like) and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like.
- isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol or sodium chloride in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions can be prepared by incorporating the active compound(s) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze drying that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials; and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injection, immediately prior to use.
- sterile liquid carrier for example, water for injection
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- the two active ingredients also can be presented in other pharmaceutically acceptable forms, such as liquids, elixirs, syrups and so on. Again, the two active agents can be combined into a single liquid, can be prepared as separate liquids which are mixed prior to administration or kept separate and administered either simultaneously or sequentially.
- Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as hereinabove described, or an appropriate fraction thereof, of an active ingredient.
- Systemic administration also can be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants generally are known in the art and include, for example, for transmucosal administration, detergents, bile salts and fusidic acid derivatives.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the active compound(s) are formulated into ointments, salves, gels or creams as generally known in the art.
- Percent by weight relates to the weight relative to the weight of the final pharmaceutical composition.
- excipient diluent and carrier are used interchangeably, and may refer to one and the same compound or element, or to a mixture of same.
- the use and knowledge of said terms is self-explanatory and is well known in the art of pharmaceutical formulation. See, for example, U.S. Pat. No. 7,008,920.
- the various forms of delivery can be based on the forms in which the known cardiovascular disease drugs and Cox II inhibitor drugs currently are marketed or the two active ingredients can be reformulated into a desired delivery vehicle of choice.
- a formulation of interest can contain plural species of the two classes of active ingredients of interest.
- a formulation can contain plural Cox II inhibitors, plural anti-cardiovascular disease drugs or both.
- the plural hypertensives can be of different classes as noted hereinabove.
- the relative amounts of the two active ingredient classes can vary as needed.
- the two active ingredients can be applied in a 1:1 molar or weight ratio or in ratios that vary from unity such that the ratio of one active agent can range from 2 to 4 to 6 to 8 to 10 to 20 to 40 or more times that of the other.
- the ratio of the two active agents can be, for example, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12 and so on, by weight, molarity or other standard measure of amount.
- the ratio can be greater than 12:1 and 1:12, as needed.
- the dosage of the combined formulation of interest can combine the currently used dosages of each of the active agents when used alone.
- the dosage can be provided, for example, once, twice, thrice or four times a day.
- each of the active agents per unit can be based on the currently offered doses, or can be varied, at times practically limited by the total amount of active agent that can be incorporated in a unit delivery form, such as a pill.
- the does of each of the actives can be between about 1 mg and about 1 gm, preferably between about 10 mg and 500 mg.
- the actual dose will depend on the general condition of the patients (age, weight, etc.), the degree of severity of the disorder and the potency of the individual active ingredients being used.
- a suitable dosage of each component can be the current approved dosage of available drugs of each category. That known dosage can be altered for use in the combination therapy taught herein as needed practicing methods known in the art and practiced in the drug approval process.
- the active compound is prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
- a controlled release formulation including implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.
- Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies) also can be used as pharmaceutically acceptable carriers. Those can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent Nos. 4,522,811 and 6,984,395.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the dosages for example, preferred route of administration and amounts, are obtainable based on empirical data obtained from preclinical and clinical studies, practicing methods known in the art. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of the therapy is monitored easily by conventional techniques and assays.
- WO 94/04188 An exemplary dosing regimen is disclosed in WO 94/04188.
- the specification for the dosage unit forms of the invention is dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
- the pharmaceutical compositions can be included in a container, pack or dispenser together with instructions for administration.
- Another method of administration comprises the addition of a compound of interest into or with a food or drink, as a food supplement or additive, or as a dosage form taken on a prophylactic basis, similar to a vitamin.
- the actives of interest can be encapsulated into forms that will survive passage through the gastric environment. Such forms are commonly known as enteric-coated formulations.
- the actives of interest can be modified to enhance half-life, such as by chemical modification of the reactive sites, to ensure stability for oral administration, as known in the art.
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Abstract
A combination treatment and product of a Cox II inhibitor and a drug for treating cardiovascular disease, such as hypertension, is provided.
Description
S P E C I F I C A T I O N
TITLE OF THE INVENTION COMBINATION FORMULATION
FIELD OF THE INVENTION
[0001] The invention relates to a composition comprising a Cox II inhibitor and a compound directed to treating cardiovascular disease.
BACKGROUND OF THE INVENTION
[0002] Non-steroidal anti-inflammatory drugs (NSAIDs) are known to be associated with a slight risk of hypertension. Such analgesics generally inhibit Cox I.
[0003] Recent new drugs are inhibitors of Cox II, which is specific for the prostacyclin synthetic pathway, whereas Cox I is involved in both the prostacyclin pathway as well as the thromboxane metabolic pathway. Various Cox II inhibitors are taught in U.S. Pat. Nos. 5,474,995; 5,466,823; 5,563,165; 5,633,272; and 5,691,374.
SUMMARY OF THE INVENTION
[0004] An object of the instant invention is to provide a product and a process for ameliorating any attending cardiovascular side effects from the use of Cox II inhibitors by combining same with a suitable cardiovascular disease drug.
[0005] It is an object of the instant invention to provide a composition comprising a combination of a Cox II inhibitor and a cardiovascular disease drug. The two active ingredients can be combined into a single form or may be divided into separate entities for simultaneous or sequential administration.
[0006] It is another object of the instant invention to provide a method for treating or ameliorating cardiovascular disease from the use of a Cox II inhibitor by administering simultaneously or consecutively a cardiovascular disease drug.
DETAILED DESCRIPTION OF THE INVENTION
[0007] Some of the side effects observed with the use of Cox II inhibitors include heart attack, stroke, congestive heart failure and pulmonary edema. Vioxx
promotes oxidative damage to low density lipoproteins (LDL) and phospholipids. That may lead to endothelial damage, for example, and hypertension.
[0008] The first pharmacologically active compound is a Cox II inhibitor. Suitable such inhibitors include 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide, which is a diaryl substituted isoxazole (Bextra, Pfizer); 4-(l , 1 , 1 -trifluoromethyl-5-(4-methylphenyl pyrazol- 1 -y l)-(benzenesulfonamidebeta) Celebrex, Pfizer); 4-[4-(methylsulfonyl) phenyl]-3-phenyl-2(5H)-furanone (Vioxx, Merck); 5-chloro-6'-methyl-3-[4-(methylsulfonyl) phenyl]-2,3'-bipyridine (Arcoxia, Merck); and other products such as parecoxib and luniiracoxib (Prexige, Novartis).
[0009] While those compounds are in or are through clinical trials, the instant invention is not limited thereto. The patents teaching such Cox II inhibitors, some of which are referenced herein, and the literature teach other compounds with Cox II inhibitory activity that can be used in the practice of the instant invention.
[0010] Many NSAIDs are associated with unanticipated or unintended cardiac and vasculature involvement, such as myocardial infarction, heart attack, sudden cardiac death, stroke, hypertension, congestive heart failure, pulmonary edema and so on. Therefore, the instant invention relates to products and processes for minimizing the untoward cardiovascular side effects associated with Cox II inhibitors.
[0011] The invention teaches combining administering a Cox II inhibitor with a cardiovascular disease agent.
[0012] One such cardiovascular disease is hypertension. A number of antihypertensive agents can be used in the practice of the instant invention, including diuretics, beta blockers, alpha blockers, alpha/beta blockers, glycation end product cross link blocker, rennin inhibitors, aldosterone inhibitors, sympathetic nerve inhibitors, angiotensin converting enzyme inhibitors, calcium channel blockers, angiotensin receptor blockers and son on.
[0013] Commonly known examples include amiloride (Midamor), chlorothiazide (Diuri), furosemide (Lasix), methylclothiazide (Enduron), propranolol (Inderal), metoprolol (Lopressor), prazosin (Minipress), SPPlOO, a renin inhibitor (Aliskiren, Novartis), valsartan, an angiotensin receptor blocker (Diovan, Novartis), labetalol (Mormodyne), clonidine (Catapres), captopril (Capoten), ramipril, an angiotensin converting enzyme or ACE inhibitor (Altace), diltiazem (Cardizem),
nifedipine (Procardia) and irbesartan (Avapro). Another suitable anti-hypertensive agent is 4-hydroxy-2,2,2,6,6-tetramethylpiperidine-l-oxyl (Tempol), a stable nitroxide which is a free radical scavenger, U.S. Patent Nos. 6,096,759 and 6,617,337.
[0014] A variety of other cardiovascular drugs are known. Some are those noted above for treating hypertension, and are included herein by reference. Thus, suitable such drugs include adrenergic stimulants, antiarrhythmics, phosphodiesterase inhibitors, antilipemic agents, bile acid sequestrants, fibric acid derivatives, HMG- CoA reductase inhibitors, nicotinic acid, inotropic agents, vasodilators, vasopressors and so on.
[0015] Examples include Aldoril, Catapres, Combipres, Procanbid, Betapace, Inderal, Corvert, Cardizem, Adenocard, Lanoxin, Colestid, Altromid, Baycol, Lescol, Lipitor, Zocor, Digitek, Lanoxin, Primacor, Activase, Demser, Retavase, Lndur, Isordil, Natecor, Flolan and Aramine.
[0016] When the cardiovascular disease compound is Tempol, because of the stability of the nitroxide compound, the choice of delivery form generally will depend on the characteristics, properties and delivery form which is most conducive to the Cox π inhibitor.
[0017] Many compounds which are oxidizing agents, that cause oxidation of a composition, are free radicals. A common free radical is an oxygen molecule with an odd number of electrons. Free radicals such as the superoxide anion, are involved in progressing many disease states associated with pain and inflammation.
[0018] Because of their potential for disrupting normal states, it is beneficial to reduce or eliminate oxidizing agents, such as free radicals. A common enzyme for destroying a superoxide molecule is superoxide dismutase (SOD). SOD's are naturally occurring enzymes that have superoxide as a substrate and by enzymatic reaction, destroys the reactive superoxide anion.
[0019] Suitable antioxidants include vitamin C, vitamin, E, vitamin K, certain phytochemicals, such as β carotene, glutathione, flavinoids, such as silymarin, as well as particular compounds with antioxidant activity, such as acetyCys, selegeline, certain lipoic acids and 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl (Tempol), a stable nitroxide, U.S. Pat. Nos. 6,096,759 and 6,617,337.
[0020] Tempol is a nitroxide SOD mimetic that, for example, following infusion or oral administration, lowers mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR). Kidney Intl., 68:179-187 (2005). Tempol is a stable molecule that is metal independent and is membrane permeable.
[0021] Tempol has been administered in a variety of ways including intravenously, intracranially, orally, for example, as a drop or added to water, intraperitoneally, used as a food supplement, subcutaneously, and so on. Doses range from, for example, about 1-1500 mg/kg/d, about 1-500 mg/kg as a food supplement and about 1-500 mmol/kg/h.
[0022] While the above is a list of specific compounds, the instant invention is not limited thereto. The choice of the second active ingredient is dependent on the cardiovascular manifestation observed or expected, based, in part, on the Cox II inhibitor used, and patient history.
[0023] Modification of the above-named drugs, as taught in the literature and relevant patents, and as known in the art, other compounds with cardiovascular disease or anti-hypertension activity can be used in the practice of the instant invention. For example, the 4-OH group of the nitroxide, Tempol, can be replaced by a carbonyl group, a primary, secondary or tertiary amino group and so on.
[0024] The active ingredients also can be formulated as "prodrugs," which term is used in a broad sense and is meant to encompasses analogs, derivatives and the like of the two active ingredients of interest that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative. See, for example, U.S. Pat. Nos. 6,797,725 and 7,018,987.
[0025] A pharmaceutical composition of the invention for use as disclosed herein is formulated to be compatible with the intended route of administration. Many of the compounds noted above are marketed, and thus, the delivery form can follow that currently available. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal and rectal administration. Solutions or suspensions used for parenteral, intradermal or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene
glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as HCl or NaOH. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
[0026] Suitable oral forms, which can be presented as discrete units such as capsules, sachets or tablets, each contain a predetermined amount of one or both of the active ingredients; or can be provided as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, in a depot or as a paste.
[0027] Tablets may be made by compression or molding as known in the art, generally with one or more accessory ingredients as taught herein and as known in the art. Compressed tablets may be prepared using as a starting reagent a free-flowing form such as a powder or granules which then are mixed with, for example, a binder, a diluent, a preservative, a disintegrant (such as, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose or other cellulosic compounds, a polyvinyl alcohol), surface-active or dispersing agent, and so on. The tablet may then be layered with an enteric coating. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
[0028] Oral compositions generally include an inert diluent or an edible carrier. The composition can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Oral compositions also can be prepared using a fluid carrier to yield a syrup or liquid formulation, or for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
[0029] Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the
like can contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
[0030] Thus, a pharmaceutical composition of interest may comprise at least one additive selected from a disintegrating agent, binder, flavoring agent, preservative, colorant and a mixture thereof, see for example, "Handbook of Pharmaceutical Excipients"; Ed. A. H. Kibbe, 3rd Ed., American Pharmaceutical Association, USA. See also U.S. Pat. Nos. 6,911,455.
[0031] Various delayed release and extended release formulations are known in the art. Moreover, matrix tablets and microcapsules, microtablets and the like are known in the art. See for example, U.S. Pat. Nos. 6,890,561; 6,746,692; 6,989,195; 6,969,530 and 6,875,793. Thus, the active agents of interest can be coated by layers of different excipients, the active agents can be mixed with various excipients, can be mixed together with the excipients, can be mixed separately to provide individual units carrying one of the two active agents of interest, which then are combined in a capsule form, and so on.
[0032] For topical administration, the compounds of interest can be presented in the form of an ointment, cream or lotion, for example, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will, in general, also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, coloring agents and so on.
[0033] Other oral formulations include lozenges comprising active agents in a flavored base, containing, for example, sucrose and acacia or tragacanth; pastilles or troches, comprising the active ingredients in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
[0034] Solutions or suspensions can be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be in single or multidose forms. In the latter case, using a dropper or pipette, the administering may be achieved by the patient with a predetermined volume of the solution or suspension. A metering atomizing spray pump also may be used.
[0035] Administration to the respiratory tract may be achieved by means of an inhaler device or an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may contain a surfactant, such as lecithin or other lipid. The dose of drug may be controlled by provision of a metered valve.
[0036] Alternatively, the active ingredients may be provided in the form of a dry powder, for example, a fine powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel in the nasal cavity. Alternatively, a powder of nanoparticles can be inhaled as a dry mist, or can be dissolved in a liquid diluent.
[0037] The powder composition may be presented in unit dose form, for example, in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
[0038] hi formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size, for example, on the order of 5 μm or less. Such a particle size may be obtained by means known in the art, for example by micronization.
[0039] Compositions for rectal administration, such as a suppository, may be made with a suitable base comprising, for example, cocoa butter. Alternatively, the composition of interest can be delivered as an enema.
[0040] Compositions suitable for vaginal administration can be pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient, carriers as are known in the art to be appropriate.
[0041] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which preferably are isotonic and which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
[0042] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF; Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like) and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
[0043] Sterile injectable solutions can be prepared by incorporating the active compound(s) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders
for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
[0044] The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials; and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injection, immediately prior to use.
[0045] Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[0046] The two active ingredients also can be presented in other pharmaceutically acceptable forms, such as liquids, elixirs, syrups and so on. Again, the two active agents can be combined into a single liquid, can be prepared as separate liquids which are mixed prior to administration or kept separate and administered either simultaneously or sequentially.
[0047] Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as hereinabove described, or an appropriate fraction thereof, of an active ingredient.
[0048] Systemic administration also can be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants generally are known in the art and include, for example, for transmucosal administration, detergents, bile salts and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compound(s) are formulated into ointments, salves, gels or creams as generally known in the art.
[0049] Percent by weight relates to the weight relative to the weight of the final pharmaceutical composition.
[0050] Generally, the terms excipient, diluent and carrier are used interchangeably, and may refer to one and the same compound or element, or to a mixture of same. The use and knowledge of said terms is self-explanatory and is well known in the art of pharmaceutical formulation. See, for example, U.S. Pat. No. 7,008,920.
[0051] The various forms of delivery can be based on the forms in which the known cardiovascular disease drugs and Cox II inhibitor drugs currently are marketed or the two active ingredients can be reformulated into a desired delivery vehicle of choice.
[0052] A formulation of interest can contain plural species of the two classes of active ingredients of interest. Thus, a formulation can contain plural Cox II inhibitors, plural anti-cardiovascular disease drugs or both. Moreover, for example, in the case of hypertensive drugs, the plural hypertensives can be of different classes as noted hereinabove.
[0053] The relative amounts of the two active ingredient classes can vary as needed. Thus, the two active ingredients can be applied in a 1:1 molar or weight ratio or in ratios that vary from unity such that the ratio of one active agent can range from 2 to 4 to 6 to 8 to 10 to 20 to 40 or more times that of the other. Thus, the ratio of the two active agents can be, for example, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12 and so on, by weight, molarity or other standard measure of amount. The ratio can be greater than 12:1 and 1:12, as needed.
[0054] Because the active agents have unique mechanisms of action, the dosage of the combined formulation of interest can combine the currently used dosages of each of the active agents when used alone. Thus, the dosage can be provided, for example, once, twice, thrice or four times a day.
[0055] The individual dose of each of the active agents per unit can be based on the currently offered doses, or can be varied, at times practically limited by the total amount of active agent that can be incorporated in a unit delivery form, such as a pill. Thus, the does of each of the actives can be between about 1 mg and about 1 gm, preferably between about 10 mg and 500 mg. The actual dose will depend on the general condition of the patients (age, weight, etc.), the degree of severity of the disorder and the potency of the individual active ingredients being used.
[0056] There also need not be a set ratio of the two active agents as each has an activity. A suitable dosage of each component can be the current approved dosage of available drugs of each category. That known dosage can be altered for use in the
combination therapy taught herein as needed practicing methods known in the art and practiced in the drug approval process.
[0057] In one embodiment, the active compound is prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.
[0058] Methods for preparation of such formulations will be apparent to those skilled in the art. The materials also can be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
[0059] Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies) also can be used as pharmaceutically acceptable carriers. Those can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent Nos. 4,522,811 and 6,984,395.
[0060] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The dosages, for example, preferred route of administration and amounts, are obtainable based on empirical data obtained from preclinical and clinical studies, practicing methods known in the art. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of the therapy is monitored easily by conventional techniques and assays. An exemplary dosing regimen is disclosed in WO 94/04188. The specification for the dosage unit forms of the invention is dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
[0061] The pharmaceutical compositions can be included in a container, pack or dispenser together with instructions for administration.
[0062] Another method of administration comprises the addition of a compound of interest into or with a food or drink, as a food supplement or additive, or as a dosage form taken on a prophylactic basis, similar to a vitamin. The actives of interest can be encapsulated into forms that will survive passage through the gastric environment. Such forms are commonly known as enteric-coated formulations. Alternatively, the actives of interest can be modified to enhance half-life, such as by chemical modification of the reactive sites, to ensure stability for oral administration, as known in the art.
[0063] All documents cited herein are herein incorporated by reference in entirety.
[0064] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.
Claims
1. A composition comprising a Cox II inhibitor and a compound for treating a cardiovascular disease.
2. The composition of claim 1, wherein said cardiovascular disease is hypertension.
3. The composition of claim 1, wherein said compound for treating a cardiovascular disease is Tempol.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US67131205P | 2005-04-14 | 2005-04-14 | |
PCT/US2006/014244 WO2006113531A2 (en) | 2005-04-14 | 2006-04-14 | Combination formulation |
Publications (1)
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EP1877053A2 true EP1877053A2 (en) | 2008-01-16 |
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ID=37115776
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EP06750311A Withdrawn EP1877053A2 (en) | 2005-04-14 | 2006-04-14 | Combination formulation |
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EP (1) | EP1877053A2 (en) |
AU (1) | AU2006236590A1 (en) |
CA (1) | CA2605150A1 (en) |
WO (1) | WO2006113531A2 (en) |
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US9314457B2 (en) | 2014-06-19 | 2016-04-19 | The University Of Utah Research Foundation | Methods of treating and preventing vascular instability diseases |
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US6096759A (en) * | 1997-09-19 | 2000-08-01 | Georgetown University | Method for treating essential hypertension |
US6245797B1 (en) * | 1997-10-22 | 2001-06-12 | Merck & Co., Inc. | Combination therapy for reducing the risks associated with cardio-and-cerebrovascular disease |
US6136804A (en) * | 1998-03-13 | 2000-10-24 | Merck & Co., Inc. | Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions |
US6716829B2 (en) * | 2000-07-27 | 2004-04-06 | Pharmacia Corporation | Aldosterone antagonist and cyclooxygenase-2 inhibitor combination therapy to prevent or treat inflammation-related cardiovascular disorders |
US20050227929A1 (en) * | 2003-11-13 | 2005-10-13 | Masferrer Jaime L | Combination therapy comprising a Cox-2 inhibitor and an antineoplastic agent |
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2006
- 2006-04-14 WO PCT/US2006/014244 patent/WO2006113531A2/en active Application Filing
- 2006-04-14 AU AU2006236590A patent/AU2006236590A1/en not_active Abandoned
- 2006-04-14 CA CA002605150A patent/CA2605150A1/en not_active Abandoned
- 2006-04-14 EP EP06750311A patent/EP1877053A2/en not_active Withdrawn
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AU2006236590A1 (en) | 2006-10-26 |
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