UA79065C2 - Composition of valdecoxib, method of its preparation and use - Google Patents

Abstract

Pharmaceutical compositions are provided comprising particulate valdecoxib in an amount of about 1 mg to about 100 mg and one or more pharmaceutically acceptable excipients. The compositions are useful in treatment or prophylaxis of cyclooxygenase-2 mediated conditions and disorders.

Description

Description of the invention

The present invention relates to orally deliverable pharmaceutical compositions containing 2 valdecoxib as an active ingredient, methods of preparing such compositions, methods of treating cyclooxygenase-2-mediated diseases comprising orally administering such compositions to a subject, and the use of such compositions for the manufacture of medicaments .

Prerequisites for creating an invention

The compound 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide, also referred to herein as valdecoxib, was disclosed in (U.S. Patent No. 5,633,272 (Taylor et al.)) along with methods for preparing such a compound and related compounds Valdecoxib has the following structure: ko 4 i 15 , Yi sn, tseni sia

M

20

The compounds described in the above-mentioned US patent Mo. 5,633,272), including valdecoxib, are disclosed as being used as anti-inflammatory, analgesic and antipyretic agents, which are characterized by high selectivity of inhibition of cyclooxygenase-2 (COX-2) in relation to cyclooxygenase-1 (COX-1). The above c 25 (US patent Mo. 5,633,272) also contains general references to compositions for the introduction of such compounds, Ge) including dosage forms delivered orally, such as tablets and capsules.

European patent application Mo. 0 863 134) discloses orally delivered compositions comprising a drug that selectively inhibits cyclooxygenase-2, namely: 2-(3,5-difluorophenyl)-3-(4-methyl-sulfonyl)phenyl)-2- cyclopenten-1-one, combined with about 30 filler ingredients, including microcrystalline cellulose, lactose monohydrate, "hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate.

International Patent Publication (Mo. UMO 00/32189) discloses orally deliverable compositions comprising a drug that selectively inhibits cyclooxygenase-2, particularly F celecoxib, in combination with excipient ingredients selected from a large list of 35 acceptable solvents , agents promoting decomposition, binders, moisturizing agents, lubricants, etc. -

Valdecoxib is characterized by extremely low solubility in water, and for this reason, much more soluble prodrugs of parecoxib, which, when split, will form valdecoxib, have been proposed for parenteral administration. See, for example, the work of |Dion (Oioppe (1999), "SOH-2 ippiriugv-IVS Sopiegepse, 12-13 Argi « 1999, Sogopado, SA, 0.5.A.", IOgodv, 2(7), 664-666) ). C 70 However, it would be convenient to have an orally delivered form of valdecoxib that has good bioavailability and immediate release capability.

As will be shown below, the administration of valdecoxib is indicated or potentially indicated for a variety of conditions and diseases mediated by cyclooxygenase-2. For this reason, it would be very useful to have orally deliverable compositions with bioavailability suitable for such indications.

It would be particularly useful to develop orally-delivered immediate-release formulations that exhibit pharmacokinetics consistent with a rapid onset of action. (se) Such compositions would provide significant "advantages in the treatment of conditions and diseases mediated by cyclooxygenase-2. o Provided are pharmaceutical compositions comprising valdecoxib particles in an amount of about 1

Gee! 20 mg to about 10 mg per dose and one or more pharmaceutically acceptable excipients.

In one embodiment of the invention, a single dose when administered orally to a subject on an empty stomach provides a temporary concentration of valdecoxib in the blood serum and is characterized by at least one of the following parameters: (a) the time to reach the threshold concentration for providing a therapeutic effect does not exceed 0.5 hours after

Introduction;

HF) (b) the time to reach the maximum concentration (T pah) is not greater than approximately 3 hours after administration; and (c) the maximum concentration (C/tukh) is not less than approximately 10 ng/ml.

The term "threshold concentration for providing a therapeutic effect" means the minimum concentration of valdecoxib in blood serum capable of providing a therapeutic effect for the specific indication according to which valdecoxib is administered. Typically, the threshold concentration is at least about 2 ng/ml, for example, from about 25 to about 74ng/ml.

The composition can be in the form of separate solid forms, such as tablets, pills, hard or soft capsules, lozenges, sachets or lozenges - from one specific form to some plurality that makes up a single dose; alternatively, the composition may be in the form of a substantially homogeneous flowable mass, such as a solid substance consisting of particles or granules, or a liquid suspension from which individual single doses may be measured.

In the preferred embodiment of the present invention, the composition is in the form of tablets, in which the fillers include a water-soluble solvent, a disintegrant, a binder and a lubricant. Most preferably, the binder includes pregelatinized starch.

In addition, the present invention contemplates a method of treating a pathological condition or disease in a subject to whom treatment with a cyclooxygenase-2 inhibitor is indicated, comprising oral administration of a composition according to the present invention from one to about four times per day.

Other features of the invention will be apparent in part and will be described in more detail below.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a diagram illustrating a representative method of preparing valdecoxib tablets according to the present invention.

Fig. 2 is a diagram illustrating an alternative method of obtaining valdecoxib tablets according to the present invention.

Fig. 3 is a graph showing the concentration of valdecoxib in the plasma of humans after oral administration of valdecoxib tablets according to the present invention.

The composition according to the present invention consists of particles of valdecoxib in a dosage that includes them in an amount from about mg to about 10Omg. Such a composition has better characteristics in terms of immediate release of the active ingredient from the dosage form, so that said form is capable of providing rapid relief of cyclooxygenase-2-mediated disease when administered orally to a subject, more specifically, a person suffering from such a disease.

It should be pointed out, without delving into the discussion of the theoretical bases, that the high clinical effect achieved when using the composition according to the present invention is associated with the improved bioavailability of valdecoxib, and in particular, with the surprisingly effective absorption of valdecoxib in the gastrointestinal tract when administered orally such a composition. Said effective absorption can be confirmed by any expert of ordinary skill in the art by monitoring valdecoxib serum concentrations in subjects undergoing treatment for a certain time after administration. At the same time, it is desirable, as possible i) to reach the threshold concentration of valdecoxib in the blood plasma as early as possible, which would be sufficient for effective inhibition of cyclooxygenase-2.

As indicated above, in one variant of the present invention, a single dose when administered orally to a subject in a fasting state provides a temporary maintenance of the concentration of valdecoxib in the blood serum and is characterized by at least one of the following parameters: the effect (in a typical case of at least approximately 2Ong/ml) does not exceed 0.5 hours after administration; (b) the time to reach the maximum concentration (T pah) is not greater than approximately 3 hours after administration; and me) (c) the maximum concentration (Sdach) is not less than approximately 10Ong/ml. uh-

It should be understood that the amount of valdecoxib in a standard dose effective to provide serum concentrations satisfying any of criteria (a) through (c) above depends on the patient's body weight. In the case when the specified subject is a child or a small animal (for example, a dog), it is likely that to satisfy at least one of the criteria from (a) to (c), for example, a relatively small "

Amounts of valdecoxib falling within the indicated range are from about 1 mg to about 100 mg. In the case of c, when the specified subject is an adult person or a large animal (for example, a horse), a relatively higher dosage of valdecoxib is required to achieve the specified concentration of valdecoxib in the blood serum. In the case of an adult, an acceptable amount of valdecoxib in a dose of a composition according to the present invention, required to provide the specified concentrations of valdecoxib in blood serum, is typically from about 5mg to about 4Omg. -I In the preferred embodiment of the invention, the bioavailability of the composition is such that when a dose of 20 mg is administered orally to an adult on an empty stomach, i.e. (a) the concentration of valdecoxib in the blood serum equal to 2Ong/ml, more preferably, 5Ong/ml, is reached no later than than 0.5 hour after administration, (6) (Tdah) is no greater than about 3 hours after administration; and

Me, (c) (Sdach) is not less than about 100 ng/ml. The compositions according to the present invention contain valdecoxib in the form of particles. Primary particles of valdecoxib obtained, for example, during grinding or trituration, or during precipitation from a solution, may stick together to form repeated aggregated particles. The term "particle size" in the context of this description 5B refers to the size of the primary particles in the maximum measurement, unless the context suggests otherwise.

Particle size is believed to be an important parameter influencing the clinical efficacy of valdecoxib.

F) Thus, one embodiment of the invention contemplates a composition characterized by such a size distribution of valdecoxib particles that the size of the Yudo particles is smaller than approximately 75 μm. The term "Yow particle size" in the context of this specification means a particle size such that the 909w/w particles are smaller, in their maximum measurement, than the stated particle size.

Also, alternatively, the particles of valdecoxib in the composition according to the present invention preferably have a weight average particle size of from about 1µm to about 1µm and most preferably from about 5µm to about 1µm.

In yet another embodiment, the valdecoxib particles of the present invention have a weighted average size of from about 1O0nm to about 1000m (μm), for example from about 100nm to about 40Onm or from about 50O0nm to about 80Onm.

The compositions of the present invention include valdecoxib in combination with one or more excipients selected from solvents, disintegrants, binders, wetting agents, and lubricants. In one preferred embodiment of the present invention, at least one filler

IS a water-soluble solvent or wetting agent. It is believed that such a water-soluble solvent or wetting agent contributes to the dispersion and dissolution of valdecoxib in the gastrointestinal tract. Preferably, at least a water-soluble solvent is present. In another preferred embodiment of the present invention, at least one of the fillers is a decomposition-promoting agent. In another preferred embodiment of the present invention, at least one of the fillers is the binder specified above, and it is particularly preferred that pregelatinized starch is present as a binder. In another preferred embodiment of the invention, at least one of the fillers is a fattening agent. It is particularly preferable that the composition additionally includes each of the following components to valdecoxib: a water-soluble solvent, a disintegrant, a binder and a lubricant.

The composition according to the present invention may be a substantially homogeneous fluid mass, such as a solid consisting of particles or granules, or a liquid, or it may take the form of discrete forms such as capsules or tablets.

In the composition, which is essentially a homogeneous fluid mass, single doses are measured using a suitable device that measures a defined volume, such as a spoon or a cup. Corresponding flow rate 2o Includes, but is not limited to, powders and granules. Alternatively, the fluid mass can be a suspension in which valdecoxib, being in the phase of solid particles, is dispersed in a liquid phase, preferably in an aqueous phase. When making such a suspension, it is useful to use a wetting agent, such as polysorbate 80 or others. similar The suspension can be obtained by dispersing crushed valdecoxib in the liquid phase; alternatively, valdecoxib may be precipitated from solution in a solvent such as an alcohol, preferably ethanol. with

The water vase preferably includes a food carrier such as water, syrup or fruit juice such as apple juice.

Compositions according to the present invention are used in the treatment and prevention of a very broad list of i) diseases mediated by COX-2, and include, but are not limited to, diseases accompanied by inflammation, pain and/or fever. Such compositions are particularly useful as anti-inflammatory agents, e.g. for the treatment of arthritis, with the added advantage of having significantly fewer adverse side effects than conventional non-steroidal anti-inflammatory drug (NSAID) formulations, which do not have selectivity for COX-2 in comparison with COX-1. In particular, the compositions according to the present invention have a reduced potential from the point of view of gastrointestinal toxicity and irritation of the gastrointestinal tract, the formation of ulcers and bleeding of the upper part of the gastrointestinal tract, are characterized by a reduced potential from the point of view of negative effects on the kidneys, such as a decrease in renal function, which leads to fluid retention and increased hypertension with a reduced effect on bleeding time, including inhibition of platelet function, and possibly a reduced ability to cause asthma attacks in aspirin-sensitive asthmatics, compared to the compositions of traditional NSAIDs3. Thus, the compositions according to the present invention are particularly useful as an alternative to traditional NSAIDs, in those cases where such NSAIDs are contraindicated, for example, in patients with peptic ulcer, gastritis, regional enteritis, ulcerative colitis, diverticulitis, or "recurrence of diseases of the gastrointestinal tract, patients with gastrointestinal bleeding, disorders /--) with in the blood coagulation system, including anemia, such as hypoprothrombinemia, hemophilia, or in connection with others. problems related to bleeding; in the case of kidney disease or in the case of patients before surgical procedures or patients taking anticoagulants.

The described compositions are used for the treatment of many diseases of an arthritic nature, including, but not limited to, rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.

These compositions are used in the treatment of asthma, bronchitis, menstrual colic, premature labor, tendinitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis, including HIV-induced apoptosis, lumbago, liver disease, including hepatitis, conditions associated with the lesion skin, such as psoriasis, eczema, acne, burns, dermatitis, skin lesions caused by ultraviolet radiation,

Me, including sunburn, as well as post-operative inflammation, including the condition after ophthalmic surgery, sp such as cataract surgery or refractive surgery.

These compositions are used in the treatment of gastrointestinal conditions, such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.

These compositions are used in the treatment of inflammation in the case of such diseases as headaches caused by migraine, periarteritis nodosa, thyroiditis, hypoplastic anemia, Hodgkin's disease, scleroderma,

F) rheumatic attack, type I diabetes, neuromuscular ligament disease, including severe pseudoparalytic myasthenia gravis, white matter disease, including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behçet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling that occurs after damage, including brain edema, myocardial ischemia, etc.

These compositions are used in the treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia, and acute damage to eye tissue.

These compositions are used in the treatment of pulmonary inflammation, such as inflammation caused by viral infections and cystic fibrosis, as well as in the case of bone resorption, such as in the case of osteoporosis. 65 These compositions are used in the treatment of certain disorders of the central nervous system, such as cortical dementias, including Alzheimer's disease, neurodegeneration and damage to the central nervous system resulting from stroke, ischemia and trauma. The term "treatment" in the context of this description includes the partial or complete inhibition of dementia, including Alzheimer's disease, vascular dementia, dementia arising from multiple infarcts, presenile dementia, alcoholic dementia and sepsis dementia.

These compositions are used in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome and liver disease.

These compositions are used for pain relief, including but not limited to postoperative pain, dental pain, muscle pain, and cancer pain. So, for example, the specified compositions are used to relieve pain, heat and inflammation in the case of conditions including rheumatic attack, influenza and other viral 7/0 infections including the common cold, lower back and neck pain, dysmenorrhea, headache, toothache, sprains and tension, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns and injuries after surgical and dental procedures.

These compositions are used in the treatment and prevention of diseases of the cardiovascular system / 5 of an inflammatory nature, including vascular disease, coronary artery disease, aneurysm, vascular rejection reaction, arteriosclerosis, atherosclerosis, including atherosclerosis caused by heart transplantation, myocardial infarction, embolism, stroke, thrombosis , including venous thrombosis, angina pectoris, including unstable angina pectoris, inflammation associated with the presence of plaques in the coronary artery, bacterial inflammation, including inflammation caused by chlamydia, viral inflammation, and inflammation associated with surgical procedures such as vascular grafts , including coronary artery bypass grafting, revascularization procedures including angioplasty, stenting, endarterectomy, or other invasive procedures performed on arteries, veins, and capillaries.

These compositions are used in the treatment of disorders associated with angiogenesis in subjects, for example, to inhibit angiogenesis in a tumor process. Such compositions are used in the treatment of neoplasms, including metastases, as well as ophthalmic conditions such as corneal transplant rejection, ocular revascularization, retinal revascularization, including revascularization after damage or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia, and revascularized glaucoma. , in the treatment of peptic ulcers such as peptic ulcers, pathological but non-malignant conditions such as hemangioma, including congenital hemangioma, nasopharyngeal angiofibroma and avascular necrosis of bone, and disorders of the female reproductive system such as endometriosis.

These compositions are used in the treatment and prevention of benign and malignant tumors and neoplasms, including cancers such as colorectal cancer, brain cancer, bone cancer, epithelial cell neoplasms (epithelial carcinoma), such as basal cell carcinoma, adenocarcinoma, gastric cancer - intestinal tract, such as cancer of the lip, cancer of the oral cavity, cancer of the esophagus, cancer of the small intestine, cancer of Me

Stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell and basal cell cancer, prostate cancer, cancer kidney cells and other known cancers that affect epithelial cells throughout the body. Neoplasms in which the compositions of the present invention may be particularly useful include gastrointestinal cancer, Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, cancer lung, breast cancer and skin cancer. The compositions specified in c can also be used in the treatment of fibrosis arising during radiation therapy. Said compositions can be used to treat subjects having adenomatous polyps, including those; who has congenital familial polyposis (FPC). In addition, such compositions can be used to prevent polyps in patients at risk of developing PSP.

These compositions inhibit prostanoid-induced contraction of smooth muscles due to inhibition of -I synthesis of contractile prostanoids, and in this connection can be used in the treatment of dysmenorrhea, in case of premature birth, in asthma and eosinophil-related diseases. They can also be used to reduce bone loss, especially in menopausal women (for example, in the treatment of osteoporosis) or in the treatment of glaucoma.

Preferred uses of the compositions of the present invention include the treatment of rheumatoid arthritis

Me, arthritis, osteoarthritis, its use to relieve general pain (especially in the case of pain after sp intraoral surgery, after general surgery after orthopedic surgery and in the case of acute hyperemia in osteoarthritis), in the treatment of Alzheimer's disease and for chemoprevention of colon cancer.

In addition to being used for human treatment, the compositions according to the present invention can be used in veterinary medicine to treat pets, exotic animals, farm animals and others, especially mammals. More specifically, the compositions of the present invention can be used to (F) treat diseases mediated by COX-2 in horses, dogs and cats. The present invention also relates to a therapeutic method of treating a condition or disease in which administration of an agent that inhibits COX-2 is indicated, wherein said method includes oral administration of a Composition according to the present invention to a subject in need thereof. The dosage regimen used to prevent, achieve relief and reduce the severity of a disease state or disorder, preferably corresponds to one or two doses per day, but can be modified depending on many factors. Such factors include the type, age, weight, sex, diet and health of the subject, as well as the nature and state of the disease. Thus, the dosage regime actually used can vary widely and therefore depart from the preferred dosage regimes indicated above.

The start of treatment can be carried out in the dosage regimen indicated above. Usually, treatment is continued as needed for a period of time ranging from several weeks to several months or years, until the condition or disorder is controlled or eliminated. Subjects undergoing treatment with the compositions of the present invention are continuously monitored by conventional methods known in the art to determine the effectiveness of the therapy. Constant analysis of the data of such monitoring allows modification of the treatment regimen, so as to introduce optimally effective doses at each moment of time and so as to determine the optimal duration of treatment. In this case, the treatment regimen and dosage regimen may be rationally changed during therapy so that the smallest amount of the composition that provides satisfactory efficacy is administered, and so that the administration is continued only for the period of time necessary to successfully treat the specified 7/0 condition or disease.

These compositions can be used in combination therapy with opioids and other analgesics, including, but not limited to, narcotic analgesics, My receptor antagonists, Carr receptor antagonists, non-narcotic (i.e., non-addictive) analgesics, monoamine uptake inhibitors, agents regulating adenosine metabolism, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists, and sodium channel blockers. A preferred combination therapy includes the use of the compositions of the present invention in combination with one or more compounds selected from aceclofenac, acemetacin, ε-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), 5-adenosylmethionine, alclofenac, alfentanil, allylprodine , alminoprofen, alloxiprin, alphaprodin, aluminum bis(acetylsalicylate), amfenac, aminochlortenoxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylone, aminopyrine, amixetrin, ammonium salicylate, ampiroxicam, amtolmetin-guacil, anileridine, antipyrine, antipyrine salicylate, anthrafenin, apazone, bendazac, benorylate, benoxaprofen, benzpiperylone, benzidamsh, benzylmorphine, bermoprofen, bezitramide, a-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromsaligenin, bucetin, bucloxinic acid, bukoloma, bufexamak, bumadizone, buprenorphine, butacetin, butibufen, c butophanol, acet calcium ilsalicylate, carbamazepine, carbifen, carprofen, karsalam, chlorobutanol, chlortenoxazine, choline salicylate, zincophen, cinmetacin, cyramadol, clidanac, clomethacin, clonitazen, i) clonixin, clopirac, clov, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cropropamide , кротетаміду, дезоморфіну, дексоксадролу, декстромораміду, дезоцину, діампроміду, натрій-диклофенаку, дифенамізолу, дифенпіраміду, дифлунізалу, дигідрокодеїну, енолацетату дигідрокодеїнону, дигідроморфіну, ю зо ацетилсаліцилату дигідроксіалюмінію, дименоксадолу, димефептанолу, диметилтіамбутену, бутирату діоксафетилу, дипіпанону, дипроцетилу, дипірону, ditazol, droxicam, emorphazone, enphenamic acid, ise) epirizol, eptazocin, ethersalate, ethenamide, etoheptazine, etoxazen, ethylmethylthiambutene, ethylmorphine, «3 etodolac, etofenamate, etonitazen, eugenol, felbinac, fenbufen, phenclosic acid, fendozale, fenoprofen, fentanyl, fentiazak, fepradinol, feprazone, flok tafenin, fluphenamic acid, me) flunoxaprofen, fluresone, flupirtine, fluproquazone, flurbiprofen, phosphozal, gentisic acid, i-glafenin, glucomethacin, glycol salicylate, guaiazulene, hydrocodone, hydromorphone, hydroxypethidine, ibuprofen, ibuprofen, ibuproxam, imidazin salicylate, indoprofen, isofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p-lactophenetide, lefetamine, levorphanol, lofentanil, lonazolac, lornoxicam, loxoprofen, acetylsalicylate of lysine, magnesium acetylsalicylate, meclofenamic acid, mefenamine , meptazinol, She) with mesalamine, metazocin, methadone hydrochloride, methotrimeprazine, methiazine acid, metofolin, . metopone, mofebutazone, mofezolac, morazone, morphine, morphine hydrochloride, morphine sulfate, salicylate and? morpholine, mirofin, nabumetone, nalbuphine, 1-naphthylsalicylate, naproxen, narcein, nefopam, nicomorphine, niphenazone, niflaminic acid, nimesalide, 5-nitro-2i--propoxyacetanilide, norlevorphanol,

Normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxamethacin, oxaprozin, -I oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paraniline, parsalmid, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocol, phenoperidine, phenopyrazone, phenylacetylsalicylate, phenylbutazone, phenylsalicylate, phenyramidol, picetoprofen, piminodine, pipebuzone, piperylon, piperofen, pyrazolac, pyritramide, piroxicam, pranoprofen, proglumetacin, proheptazine, 5o promedol, propacetamol, propiram, propoxyphene, propifenazone, proquazone, protisic acid,

Me, ramifenazone, remifentanil, rimazolium methylsulfate, salacetamide, salicin, salicylamide, sp o-acetic acid salicylamide, salicylsulphuric acid, salsalt, salverine, symetride, sodium salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismatase, suprofen, succibuzone, talniflamate, tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic acid, thiaramide, tilidine, dv Linoridine, tolfenamic acid, tolmetin, tramadol, tropezin, viminol, xenbucin, ximoprofen, zaltoprofen, and zomepirac (see Te Megsk Ipdeh, 12 her Eayop, Tnpegaretsshiis Sabedogu apa Vioiodisa! Asiimiu

F) Ipdeh, hey. 5. Vidamagi (1996), yr. Tyeg-2 (about Tpeg-3 apa Tpeg-12 (ApaYdesis (Oepia!), ApaYdevis (Magsoiis), ka Apaidevis (Mop-pagsoiis), Apii-ishShattaiyogu (Mopviegoiidai)).

A particularly preferred combination therapy includes the use of a composition according to the present invention together with an opioid compound, more specifically, when the opioid compound is codeine, meperidine, morphine or a derivative thereof.

The composition of valdecoxib according to the present invention can be administered in combination with a second selective COX-2 inhibitor, for example, with celecoxib, rofecoxib, etc.

The compound, which can be administered in combination with valdecoxib, can be obtained separately from valdecoxib 65 or administered in a general composition with valdecoxib in the composition of the drug according to the present invention. In the event that valdecoxib is formulated with a second drug, such as an opioid, the second drug may be formulated in an immediate-release, rapid-onset, sustained-release, or bi-bump release formulation.

The compositions of the present invention are generally suitable for administering valdecoxib in a daily dosage of from about 1mg to about 1000mg. Each dosage standard unit of the composition according to the present invention typically includes an amount of valdecoxib from about one-tenth of a daily dose to a full daily dose. A preferred daily dosage is from about 2 mg to about b00 mg, more preferably from about 5 mg to about 400 mg, for example, about 5 mg, about 10 mg, about 20 mg, or about 400 mg. Where the standard dosage is in the form of individual preparations suitable for oral administration, such as capsules or tablets, each such preparation comprises from about 1mg to 10mg, preferably from about 5mg to about 1mg, and more preferably from about 1O0mg to about 5OmgH, for example, about 1Omg, about 20mg, or about 40mg of valdecoxib.

Valdecoxib used in the compositions of the present invention may be prepared by any known method, including the method cited above (U.S. Patent No. 5,633,75, 2121.

In addition to valdecoxib, compositions according to the present invention include one or more excipients suitable for oral administration. The indicated fillers must be pharmaceutically acceptable in the sense of their compatibility with other ingredients of the composition and harmlessness for the patient. The fillers used can be solid or liquid, or they can be a combination of both.

The compositions of the present invention contain a desired amount of valdecoxib per dose and may be in the form of, for example, a tablet, pill, hard or soft capsule, lozenge, dispensable sachet, powder, granule, suspension, or any other form suitable for oral administration. Tablets, pills and other forms containing or without a coating can be obtained.

Compositions according to the present invention, suitable for transbuccal or sublingual administration,

Includes, for example, lozenges containing valdecoxib in a flavored base such as sucrose and gum arabic or tragacanth, as well as lozenges containing valdecoxib in an inert base such as gelatin, glycerin and) or sucrose and gum arabic.

Liquid dosage forms include suspensions of valdecoxib in a liquid solvent, which is typically aqueous. These suspensions may contain additional fillers, for example, wetting agents, emulsifiers and suspending agents, stabilizers, thickeners, sweeteners, flavors and fragrances.

The compositions of the present invention can be prepared using any acceptable pharmaceutical method, which includes the step of bringing valdecoxib and excipient(s) into contact. In general, the composition is obtained by uniformly and thoroughly mixing valdecoxib with a liquid or finely divided solid solvent and then, if necessary, encapsulating or molding the resulting mixture. So, for example, a tablet can be obtained by pressing or forming such a mixture in the form of a powder or granules, optionally in combination with one or more additional fillers. Pressed tablets can be obtained by pressing in a suitable tablet machine a free-flowing composition, such as powder or granules, including valdecoxib, optionally mixed with one or more solvents, disintegrants, binders and lubricants. Molded tablets can be "obtained by molding valdecoxib powder in a suitable machine, optionally with the addition of one or more excipients moistened with a liquid solvent.

By appropriate selection and combination of excipients, it is possible to obtain compositions with improved properties in terms of effectiveness, bioavailability, elimination time, stability, compatibility of valdecoxib and excipients, safety, dissolution parameters, decomposition parameters and/or other pharmacokinetic, chemical and/or physical properties. The excipients preferably include one or more materials belonging to -I water-soluble and water-dispersible, and have a wetting ability in order to combine with the low water solubility and hydrophobicity of valdecoxib. In the case when the composition is prepared in the form of a tablet, and the selected combination of fillers makes it possible to obtain tablets with improved, among other properties, parameters of dissolution and decomposition, hardness, resistance to crushing and/or fragility.

Compositions according to the present invention optionally include one or more pharmaceutically acceptable solvents as excipients. Acceptable diluents include, by way of example, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate, starches, including directly pressed starches and hydrolyzed starches (eg, Seishar™ and Etadecht™), mannitol, sorbitol, xylitol, dextrose (e.g., Segeiovzetm 2000) and dextrose monohydrate, dibasic calcium phosphate dihydrate, sucrose-based solvents, confectioners' sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, granulated calcium lactate trihydrate, dextrates, inositol, hydrolyzed grain powder, amylose, o cellulose , including microcrystalline cellulose, sources of α- and amorphous cellulose of food quality (for example, ko Kehseitm) and powdered cellulose, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, etc. Said solvents, if present, comprise a total of from about 595 to about 9995, preferably from about 60 to about 1095 to about 8595, and most preferably from about 2095 to about 8095 of the total weight of the composition. Thinners or solvents are chosen preferably so that they have acceptable fluidity properties and, in the case when tablets are desired, compressibility.

Lactose and microcrystalline cellulose, either alone or in combination, are preferred solvents. Both solvents are chemically compatible with valdecoxib. Extragranular microcrystalline cellulose 65 (which is microcrystalline cellulose added to the wet granulated composition after the drying step) can be used to improve hardness (in the case of tablets) and/or disintegration time. Especially preferred is lactose, in particular lactose monohydrate. Lactose in a typical case allows to obtain compositions with acceptable indicators of release of valdecoxib, stability, fluidity before pressing and/or ability to dry - at a relatively low cost of the solvent. It allows you to get a substrate of high density,

Which allows you to compact the product during granulation (when wet granulation is used) and in this case improves the fluidity of the mixture.

Compositions according to the present invention include as excipients one or more pharmaceutically acceptable disintegrants, and especially in the case of tablet compositions. Acceptable disintegrants include, either alone or in combination, starches including sodium starch glycolate 7/0 (e.g., Echrioartm from Rep. UmUezO) and pregelatinized corn starch (e.g.,

Myopaitm 1551, Myopaitm 1550, CoIosogptm1500), clays, (for example, MeedittmNU), cellulose, such as purified cellulose, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose, croscarmellose sodium, (for example, As-Oi-Zoitm from the company EMS ), alginates, crospovidone, and gums such as agar, guar, carob, caraway, pectin, and tragacanth.

Agents that promote decomposition can be added at any appropriate stage during the preparation of the composition, especially before granulation or during the oiling stage before pressing. Such disintegrants, if present, comprise a total of from about 0.295 to about 3095, preferably from about 0.295 to about 1095, and more preferably from about 0.295 to about 595, by weight of the total composition.

Croscarmellose sodium is a preferred tablet or capsule disintegrant and, if present, is preferably from about 0.295 to about 1095, more preferably from about 0.295 to about 795, and even more preferably from about 0.295 to about 595 from the weight of the entire composition.

Croscarmellose sodium adds a better ability to intragranular decomposition of granular Ge! compositions according to this invention. at

Compositions according to the present invention optionally include one or more pharmaceutically acceptable binders or adhesive agents as excipients, especially in the case of a tablet composition. Such binders and adhesives preferably add sufficient adhesion to the tablet powder, which allows normal operations such as size distribution, oiling, pressing and packaging, and also contributes to the decomposition of the tablet and the absorption of the composition during oral administration. Acceptable binders and adhesives include, either singly or in combination, gum arabic, tragacanth, sucrose, gelatin, glucose, starches such as, but not limited to, pregelatinized (3) starches (eg, Mayiopaitm 1551 and Mayiopaitm 1550); cellulose, such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Thuylosetm); alginic acid and salts of Alginic acid, magnesium aluminosilicate, polyethylene glycol (PEG), guar gum, polysaccharide acids, bentonites, polyvinylpyrrolidone (povidone or PVP), for example, povidone K-15, K-30 and K-29/32, polymethacrylates, hydroxypropyl methylcellulose (HPMC), hydroxypropyldelulose (for example, Kiiseitm) and ethyl cellulose (for example, E(Poseyi"m). The specified binding "substances and/or adhesives, if present, are generally from about 0.595 to about 25905, preferably from about 0.7595 to about 1595 and more preferably from about 195 to about 1095 in id Z c weight of the entire composition. "» Pre-gelatinized starch is the preferred binder used to "give stickiness to the powder mixture of valdecoxib and other fillers for the purpose of granulating the valdecoxib composition. Pre-gelatinized starch, if present, is from about 0.595 to about 2095, more preferably from about 595 to about 1595 of the total weight of the composition and its presence facilitates binding of the particles of the mixture to form granules during wet granulation. o Compositions according to the present invention optionally include as excipients one or more pharmaceutically acceptable humectants. Such humectants are preferably chosen to promote close contact of valdecoxib with water, achieving a condition believed to improve

Fu 0200 bioavailability of the composition.

Non-limiting examples of surfactants that can be used as wetting agents in the compositions of the present invention include quaternary ammonium compounds, for example, benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, sodium dioctylsulfosuccinate, polyoxyethylene alkylphenyl ethers, for example, nonoxynol 9, nonoxynol 10 and octoxynol 9, poloxamers 29 (block copolymers of polyoxyethylene and polyoxypropylene), glycerides of polyoxyethylene fatty acids and oil,

GF! e.g. polyoxyethylene (8) caprylic/capric acid mono- and diglycerides (e.g. I argazoitm from Saitzegtozve company), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene alkyl ethers, e.g. polyoxyethylene (20) cetostearyl ether , polyoxyethylene fatty acid ester, for example, polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters 60, for example, polysorbate 20 and polysorbate 80 (for example, Guayeptm 80 from the company ISI), propylene glycol fatty acid ester, for example, propylene glycol laurate (for example, Ashgodiisotm from the company

Sacegozze), sodium lauryl sulfate, fatty acids and their salts, for example, oleic acid, sodium oleate and trietolamine oleate, glyceryl and fatty acid esters, for example, glyceryl monostearate, sorbitan esters, for example, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmylate "Ii bo sorbitan monostearate, tiloxapol and their mixtures. Said humectants, if present, comprise a total of from about 0.2595 to about 1595, preferably from about 0.495 to about 1095 and more preferably from about 0.595 to about 595 by weight of the entire composition.

Preferable humectants that refer to anionic surfactants. A particularly preferred humectant is sodium lauryl sulfate. Sodium lauryl sulfate, if present, is from about 0.2595 to about 795, more preferably from about 0.495 to about 495 and even more preferably from about 0.595 to about 295 of the total weight of the composition.

Compositions according to the present invention optionally include as excipients one or more pharmaceutically acceptable lubricants (including anti-caking and/or anti-slip agents). Acceptable lubricants include, either alone or in combination, glyceryl begapat (e.g., Sotrihypoitm 888), stearic acid and its salts, including magnesium, calcium, and sodium stearates, hydrogenated vegetable oils (e.g.,

Ziegoyekhtm), colloidal silica gel, talc, wax, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, Oi-leucine, polyethylene glycols (for example, Sagromakhtm 4000 and Sagromzhakhtm 6000), sodium oleate, sodium lauryl sulfate and magnesium lauryl sulfate. Said lubricants, if present in the composition, are 75 in total from about 0.195 to about 1095, preferably from about 0/295 to about 895 and more preferably from about 0.2595 to about 595 of the weight of the entire composition.

Magnesium stearate refers to the preferred lubricant, which is used, for example, to reduce friction between the granulated mixture and the equipment during the pressing of the tablet compositions used.

Acceptable anti-caking agents include talc, corn starch, oleicin, sodium lauryl sulfate, and metal stearates. At the same time, talc is a preferred agent that prevents sticking or sliding, which is used, for example, to reduce the adhesion of the composition to the surfaces of the equipment, as well as to reduce static electricity in the mixture. Talc, if present, is from about 0.195 to about 1095, preferably from about 0.2595 to about 595 and more preferably from about 0.595 to about 295 of the total weight of the composition. Gee!

In the compositions according to the present invention, other fillers, such as dyes, flavoring substances and sweeteners, known in pharmaceutical technology can also be used. Tablets may be coated, for example, with an enteric coating or may not contain a coating. Compositions according to the present invention may also include, for example, buffering agents.

A decrease in the particle size of valdecoxib may be reflected in the improvement of bioavailability, in the case of IC) when the drug is made in the form of an oral composition, which is delivered according to the present invention. In this regard, the particle size of valdecoxib OO is preferably less than about 75 µm, more preferably less than about 4 µm, and most preferably less than about 25 µm. In addition or alternatively, valdecoxib preferably has a weighted average particle size in the range of about 1 µm to about 1 µm and more preferably, from about 5 µm to about µm. Any method of grinding, grinding or micronization can be used to reduce the size of Ф particles. -

Capsule and tablet compositions according to the present invention relate to compositions with immediate release that release within about 45 minutes at least about 5095, more preferably at least about 6095 and most preferably at least 7595 of valdecoxib, when measuring ip migo by the standard method of determining the level of dissolution.

Particularly preferred capsule and tablet compositions according to the present invention release ip mygo - s of at least 5095 valdecoxib over about 15 minutes and/or at least about 6095 valdecoxib a over about 30 minutes. Although the compositions of the present invention may be prepared, for example, by direct encapsulation or direct compression, they are preferably wet granulated prior to encapsulation or compression. Wet granulation, in addition to providing other effects, densifies the ground composition, which improves flowability. , compressibility and facilitates measuring or weighing of the composition for encapsulation or tableting. The repeated size of the particles formed after granulation (i.e., (a) granule size) is not limited to a narrow critical range, it is only important that the average granule size be" 50 preferably to allow convenient use and use of the composition in the case of tablets, so that it is possible to obtain a mixture that is easily compressed, from which it is then possible to make pharmaceutically acceptable tablets.

The desired density of the granules in the mixture for infusion or other distribution is normally from about 0.3 to about 1.0 g/ml, for example from about 0.6 to about 0.9 g/ml.

To obtain tablets by pressing, the granulated mixture in an amount sufficient to obtain a homogeneous batch of tablets is pressed on a machine of appropriate capacity under normal pressing pressure (for example, when applying a force of about 1 to about 5 OKN in a typical tablet machine). The hardness of the resulting tablet should be convenient for the purpose of its use, manufacture, storage and oral administration, however, a minimum hardness of about 4 KcP, preferably about 5 KcP, and more preferably about 60 CcP is desired, in order to avoid excessive friability , and a maximum hardness of about 18kP, preferably about 15Kp, and more preferably about 12KP, in order to avoid further difficulties associated with tablet hydration when entering the gastric fluid. When the hardness falls within an acceptable range, the tablet friability as determined by the standard test is typically less than about 1.095, preferably less than about 0.895 and more preferably less than 65 about 0.595.

Excipients, especially disintegrants, used in the immediate release capsule and tablet compositions of the present invention are preferably selected to provide a disintegration time in a standard IP test of less than about 30 minutes, preferably less than about 25 minutes, more preferably less than about 20 minutes and even more preferably less than about 15 minutes.

The present invention also relates to methods of preparing compositions comprising valdecoxib particles. In a specific embodiment of the invention, it relates to methods of obtaining such compositions in the form of tablets.

Although dry granulation or direct pressing methods may be used, methods involving a wet granulation step are preferred. In two illustrative versions of the implementation of this invention, wet granulation is carried out at low and high shear levels, respectively.

The method with a low level of shift is shown in the diagram of Fig.1. In this method, micronized valdecoxib is mixed, for example, in a planetary mixer with one or more solvents consisting of solid particles, for example, with lactose monohydrate (primary diluent) and microcrystalline cellulose (secondary diluent) and with a binding agent, preferably with it is pre-gelatinized with starch, with /5 formation of the previous mixture. Then water is added with constant stirring in an amount that contributes to the formation of granules. Then the granules are dried, for example, in an oven and after that they are sorted using a crusher set to the appropriate mode to obtain sufficiently uniform granules of the required size. They are then mixed with a disintegrant such as croscarmellose sodium and finally with a fattening agent such as magnesium stearate to form a tablet mixture. It should also be noted that in the indicated 2o illustrative method, microcrystalline cellulose is added intragranularly, and croscarmellose sodium is added extragranularly. As a result, the tablet mixture is pressed, for example, on a rotary press to obtain tablets. Tablets may optionally be coated using any coating method known in the art.

The high shear method is shown in the diagram of Fig.2. In this illustrative method, micronized valdecoxib is mixed in a high shear mixer with a primary solvent, e.g., lactose monohydrate, a first portion of a re-solvent, e.g., microcrystalline cellulose, a binder, preferably pregelatinized starch, and with the first portion of a disintegrant such as croscarmellose sodium to form a premix. Then water is added under constant stirring with a high shear level, in an amount conducive to the formation of granules. Then the yuzo granules are optionally subjected to wet sieving and then dried, preferably in a fluidized bed. A dry sorting step can then be carried out, for example using a Fitz mill (Ri: tii). ise)

The resulting granules are then mixed with a second portion of the re-solvent and a second portion of the disintegrant, and then with a lubricant such as magnesium stearate to form a tablet mixture. It should also be noted that in the specified illustrative method microcrystalline cellulose and croscarmellose sodium Me

They are added, each, intragranularly and extragranularly. And finally, the tablet composition is pressed and the resulting tablets are optionally coated, as in the case of the low-shear method.

The present invention also relates to the use of the composition according to the present invention for the preparation of medicinal products used in the treatment and/or prevention of disorders and diseases mediated by COX-2. "

Examples from c The following examples illustrate aspects of the present invention, but should not be construed as limiting it in any way. Unless specifically stated otherwise, all indicated percentages in the examples represent weights;" percentages relative to the weight of the entire composition.

Example 1: Valdecoxib tablets of 1Omg obtained by wet granulation with low

Shifting -I Receive tablets that have the composition given in Table 1.

F o y

F s | Myfoystalic cellulose ME, (dmsvinRNYSYA) Secondary thinner | 60 ov o 11111100 Zatlnavav avlati 00111100 ka The appropriate amount of valdecoxib, micronized to particles of a certain size, is first mixed with an equal amount of lactose monohydrate, passed through a sieve of 20 me, and added to a Hobart planetary mixer (Norag), Then a balanced amount of monohydrate is introduced into the mixer lactose and microcrystalline cellulose and stir at low impeller speed for about 10 minutes. The resulting preliminary mixture is then granulated in a planetary mixer with the addition of purified water by hand for 12-15 minutes, with continued mixing at slow to medium impeller speed. Then the resulting wet granules are dried on trays in a Grünberg furnace (Sgoepregdomep) with an inlet air temperature of 60-59 and with a 65 moisture content of 2.0-1.095, which is measured by loss on drying. The resulting dry granules are sized through a 14-gauge screen using a Quadro crusher (Otsaago sotia) operating at medium speed, and then placed in a Patterson-Kelly M-mixer (Rayegwop KeMPMeu M-Biepdeg) along with croscarmellose sodium. The M-shaped mixer works for 5 minutes to achieve a thorough mixing of croscarmellose sodium with the granules, then magnesium stearate is added and further mixed for about 3 minutes to obtain an oily mixture. Next, the specified mixture is pressed on a press with a revolver feed of Mapezig ОВ1b using a standard 7.5mm collating device to obtain tablets weighing 200-10mg and having a hardness of 10-4 kKP.

Example 2: Valdecoxib 1Omg tablets obtained by high shear granulation.

Tablets with the composition given in Table 2 are obtained.

AND

(AmiseitmR H-101) z.o

Intragranular Extragranular Zo

Internally granular Z

Extragranular With 1111000 I am filling tablets 00111111 2000

Micronized valdecoxib, lactose monohydrate, intragranular microcrystalline cellulose, He pregelatinized starch, and intragranular croscarmellose sodium are mixed in a high shear mixer (VacKeg Regkeepz) with a high speed impeller/vibrator for 3 minutes to form a premix. Purified water is added to the pre-mix using a peristaltic pump (UUaivop Magiom) for about 3 minutes, continuing the mixing for 45 seconds. The obtained wet granules are dried in a fluidized bed Aegotaiys (Aegotaiys) with an air temperature at the entrance of 60-59 and with a moisture content of 2.0--1.095, which is determined by the loss during drying, with the formation of a dry granulate. The dry granulate is graded by passing through a 20-mesh sieve using a Fitz mill (Ri: tii) with protruding knives at a speed of 1800 rpm, and then placed in a Patterson-Kelly M-mixer (Rayegzop KeMeu (Z

M-VIepaeg) At the same time, the granulate is mixed with extragranular microcrystalline cellulose and Fu extragranular croscarmellose sodium for another 5 minutes and then with magnesium stearate for another three minutes to form an oily mixture. The specified mixture is pressed on a Korsha press with a revolver feed - (Kogvesp RN-230) using a standard 7.5 mm collating device, which gives tablets weighing 200-10 mg. Tablets with a hardness of 6, 8, 10 and 12 kP are obtained.

Example 3: Valdecoxib tablets of 5, 10, 20 and 40 mg, coated with a shell Using the method of example "2, tablets with the composition shown in Table 3 are obtained. The tablets are coated with a shell of Oraidgu Mayo 409 u8-1-142525A or Oragu Mu/piye U5-1-18027A, which is 395 of the weight of uncoated tablets, using З 1595 suspension of coating material in water. . g"

F

ME o Microeistalchna cellulose ME 00000060 in 120020

Fo che Sodium rosjarmelloyua MES 60502 12 sl shen SG 12525A

Orastu mne uvylvoyutA 1161 (F) The properties of tablets from example C are presented in Table 4. The level of decomposition is evaluated using the following procedure. Six identical tablets are placed for evaluation of disintegration individually in one of six tubes in a basket with a wire mesh at the bottom. The water bath is preheated to a temperature of 37 2С-296 and is maintained at this temperature during the entire decomposition test. A 1000 ml beaker is placed in a water bath.

The glass is filled with a sufficient amount of water so that during the test the wire sieve of the test tubes remains at least 2.5 cm below the water surface. The decomposition basket is introduced into the water and repeatedly raised and lowered until the end of the test, maintaining the level of the wire sieve in the test tubes at least 2.5 cm below the surface of the water. The time of disintegration of each tablet is determined as the time measured from the moment of introduction of BB Basket to the moment when the very last portion of the tablet passes through the sieve at the bottom of the test tube.

r om | ohm

Example 4: Pharmacokinetic properties of valdecoxib tablets when administered to humans

Research is being conducted to determine the pharmacokinetic properties of the valdecoxib composition from example 2 on 24 healthy adults. Valdecoxib is administered in a dose of 20 mg (2 tablets). Venous blood is collected before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours after oral dosing. Plasma is separated from blood by centrifugation at a speed of 3000 (z), and the samples are stored at 775-209 until analysis. The concentration of valdecoxib in plasma is determined using HPLC analysis. The results are shown in Fig.4

The calculated value of Suah is 303-9Zng/ml. The estimated value of T gah is 2.97-0.73 hours.

Claims (14)

The formula of the invention 1. A pharmaceutical composition containing a unit dose of valdecoxib in the form of particles having an Oeo of less than 75 μm, in an amount of from 1 mg to 100 mg and one or more pharmaceutically acceptable excipients, including at least a water-soluble diluent, the amount of which is from 5 to 99 95 wt., thanks to which Ge! oral administration of a single dose of valdecoxib in the amount of 20 mg to a subject on an empty stomach provides a concentration of valdecoxib in blood serum such that: (a) the threshold concentration for providing a therapeutic effect is approximately 20 ng/ml, reached within 0.5 hours after administration; (b) the time of reaching the maximum concentration (T pah) is within 3 hours after administration; and (c) the maximum concentration (Sdah) reaches at least 100 ng/ml. 2. Pharmaceutical composition according to claim 1, which is characterized by the fact that the specified threshold concentration for providing a therapeutic effect is at least 50 ng/ml. ("in C. Pharmaceutical composition according to claim 2, which is characterized in that a single dose when administered orally to a subject on an empty stomach provides a concentration of valdecoxib in the blood serum such that: F (a) a concentration equal to 50 ng/ml is reached within 0.5 hours after administration; h- (b) the time to reach the maximum concentration (T pah) is not more than 3 hours after administration; and (c) the maximum concentration (Sdah) reaches at least 100 ng/ml. 4. Pharmaceutical composition according to claim 1, which is characterized by the fact that a single dose of valdecoxib contains valdecoxib particles in an amount from 5 mg to 40 mg. 5. Pharmaceutical composition according to any of claims 1-4, which is a tablet, pill, capsule, lollipop, sachet or lozenge, in which fillers include from 0.2 95 to 30 95 wt. one or more agents that promote decomposition, from 0.5 95 to 25 95 wt. one or more binders and from 0.195 to 10 95 wt. "» one or more lubricators. 6. Pharmaceutical composition according to claim 5, which is characterized by the fact that the specified binding agent is pre-gelatinized starch. -and 7. The pharmaceutical composition according to any one of claims 1-4, which is a tablet in which the fillers include lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch and magnesium stearate. (av) 8. Pharmaceutical composition according to claim 1, which additionally includes one or more opioids or analgesics. b" 50 9. Pharmaceutical composition according to any one of claims 1-8, which is characterized by the fact that valdecoxib particles have a weighted average particle size of no more than 10 μm. sl 10. Pharmaceutical composition according to any one of claims 1-8, which is characterized in that the particles of valdecoxib have a weighted average particle size from 1 μm to 10 μm. 11. Pharmaceutical composition according to any one of claims 1-8, characterized in that the valdecoxib particles have a weighted average particle size of 10 nm to 1000 nm. 12. The method of preparation of the composition according to any of claims 5-7, which includes the stage of wet granulation of valdecoxib together with one or more diluents and a binder, drying of the obtained co-granules and pressing of the obtained dry granulate to form a tablet. 13. Use of a pharmaceutical composition according to any one of claims 1-12 for oral administration once or twice a day in the treatment of a condition or disease mediated by cyclooxygenase-2. 14. Use of the pharmaceutical composition according to any of claims 1-12 in the manufacture of a medicinal product for the treatment or prevention of a condition or disease mediated by cyclooxygenase-2. b5