MXPA01008055A - Valdecoxib compositions - Google Patents
Valdecoxib compositionsInfo
- Publication number
- MXPA01008055A MXPA01008055A MXPA/A/2001/008055A MXPA01008055A MXPA01008055A MX PA01008055 A MXPA01008055 A MX PA01008055A MX PA01008055 A MXPA01008055 A MX PA01008055A MX PA01008055 A MXPA01008055 A MX PA01008055A
- Authority
- MX
- Mexico
- Prior art keywords
- composition
- valdecoxib
- compositions
- amount
- concentration
- Prior art date
Links
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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
COMPOSITIONS OF VALDECOXIB
FIELD OF THE INVENTION The present invention relates to orally deliverable pharmaceutical compositions containing valdecoxib as an active ingredient, to processes for preparing such compositions, to methods of treating disorders mediated by cyclooxygenase-2 comprising orally administering such compositions: a subject, and use of such compositions in the manufacture of medicines.
BACKGROUND OF THE INVENTION The compound 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide, also referred to herein as valdecoxib, was described in U.S. Pat. 5,633,272 for Talley et al. , With
processes to prepare this and related compounds. Valdecoxib has the structure:
The compounds reported in U.S. Pat. 5,633, 272 cited above, including valdecoxib, are described herein
as anti-inflammatory, analgesic and antipyretic drugs useful having a high degree of selectivity for the inhibition of cyclooxygenase-2 (COX-2) on cyclooxygenase-1 (COX-1). U.S. Patent No. 5,633,272 cited above also contains general references to 5 formulations for the administration of such compounds, including orally deliverable dosage forms, such as tablets and capsules. The European patent application no. 0 863 1 34 describes orally deliverable compositions comprising a medicament
selective cyclooxygenase-2 inhitory, specifically 2- (3,5-difluorophenyl) -3- (4-methyl-sulfonyl) phenyl) -2-cyclopenten-1 -one, in combination
• with excipient ingredients including microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate. 15 International patent publication no. WO 00/321 89 discloses orally deliverable compositions comprising a selective inhibitory drug of cyclooxygenase-2, specifically celecoxib, in combination with excipient ingredients selected from extensive lists of diluents, disintegrators, binding agents, agents
• 20 suitable humectants, lubricants, etc. Valdecoxib has extremely low solubility in water, and for this reason, it has been proposed to administer parenterally a much more soluble prodrug, parecoxib, which is cut to form valdecoxib. See, for example, Dionne (1 99), "COX-2 inhibitors - IBC
?? *? A * t? IáA? I. ... * ... *.
Conference (COX-2 inhibitors - Conference I BC), 12-1 April 3, 1999, Coronado, CA, USA ", Idruqs, 2 (79), 664-666. However, it will be beneficial to have a form of orally deliverable dosing of valdecoxib that exhibits good bioavailability and immediate release properties As indicated hereinafter, the administration of valdecoxib is indicated or potentially indicated in a very wide array of conditions and disorders mediated by cyclooxygenase-2. Therefore, it would be of great benefit to provide orally deliverable formulations having bioavailability characteristics designed for such indications.It would be of particular benefit to provide immediate release oral formulations, which exhibit consistent pharmacokinetics with a rapid onset effect Such formulations would represent a significant advance in the treatment of conditions and disorders mediated by cyclo-oxygenase-2.
BRIEF DESCRIPTION OF THE INVENTION A pharmaceutical composition comprising particulate valdecoxib in an amount of about 1 mg to about 1000 mg per dose one or more pharmaceutically acceptable excipients is now provided. In one embodiment, a single dose, upon oral administration to a fasting subject, provides a time course of valdecoxib concentration in blood serum having at least one of the following:
(a) a time to reach a threshold concentration for therapeutic effect no greater than about 0.5 h after administration; (b) a time to reach the maximum concentration (Tmax) not greater than about 3 h after administration; and (c) a maximum concentration (Cmax) not less than about 100 ng / ml. By "a threshold concentration for therapeutic effect" means a minimum concentration of valdecoxib in blood serum consistent with therapeutic benefit for the particular indication for which valdecoxib is administered. Typically, this threshold concentration is at least about 20 ng / ml, for example, about 25 to about 75 ng / ml. The composition may be in the form of discrete solid articles, such as tablets, pills, soft or hard capsules, diamond-shaped pills, sachets or pills, one to a small plurality of which constitute a single dose; alternatively, the composition may be in the form of a substantially homogenous, flowable mass, such as a particulate or granular solid, or a liquid suspension, from which single doses are removably measurable. In a currently preferred embodiment, the composition is in the form of tablets, wherein the excipients include a water-soluble diluent, a disintegrant, a binding agent and a lubricant. Most preferably, the binding agent comprises pregelatinized starch.
A method is also provided for treating a medical condition or disorder in a subject, wherein treatment with a cyclooxygenase-2 inhibitor is indicated, comprising orally administering a composition of the invention one up to about four times a day. Other characteristics of the invention they will be partly evident and partly signaled from now on.
BRIEF DESCRIPTION OF THE DIAMETERS Figure 1 is a flow chart illustrating a representative method for the preparation of valdecoxib tablets of the invention. Figure 2 is a flow chart illustrating an alternative method for the preparation of valdecoxib tablets of the invention. Figure 3 is a graph showing plasma concentration of valdecoxib in dogs following oral administration of valdecoxib tablets of the invention. Figure 4 is a graph showing plasma concentration of valdecoxib in humans, following the oral administration of valdecoxib tablets of the invention.
DETAILED DESCRIPTION OF THE INVENTION A composition of the invention comprises particulate valdecoxib in a dosage amount of about 1 mg to about 1000 mg. Such a composition is a dosage form
tá-ia-ataa A -, a. Aaafe * tA- i of superior immediate release, capable of providing rapid relief of a disorder mediated by cyclooxygenase-2, when administered orally to a subject, more particularly to a human subject, suffering from such a disorder. It is believed, without being bound by theory, that the strong clinical benefit provided by a composition of the invention results from improved bioavailability of valdecoxib, in particular, of surprisingly effective absorption of valdecoxib in the gastrointestinal tract, when administered orally. in such composition. Such effective absorption can be verified by a person skilled in the art by monitoring the concentration of valdecoxib in blood serum in a treated subject for a period following administration. It is desired to achieve, in as short a time as possible, a concentration threshold of valdecoxib in the blood serum, consistent with the inhibition of effective cyclooxygenase-2. As indicated above, in a single dose modality, over oral administration to a fasting subject, provides a time course of valdecoxib concentration in blood serum having at least one of the following: (a) a time to achieve a threshold concentration for therapeutic effect (usually at least about 20 ng / ml) no greater than about 0.5 h after administration; (b) a time to reach the maximum concentration (Tmax) not greater than about 3 h after administration; and (c) a maximum concentration (Cmax) not less than about 1 00 ng / ml. It will be understood that the amount of valdecoxib in an effective dose unit to provide blood serum concentrations in compliance with any of criteria (a) to (c) above, is dependent on the body weight of the subject being treated. Where the subject is a child or a small animal (e.g., a dog), for example, a relatively low amount of valdecoxib in the indicated range of about 1 mg to about 1000 mg is unlikely to provide consistent serum concentrations. with at least one of criteria (a) to (c). Where the subject is an adult human or a large animal (eg, a horse), the indicated blood serum valdecoxib concentrations are likely to require a relatively higher dosage amount of valdecoxib. For an adult human, an adequate amount of valdecoxib per dose in a composition of the present invention to provide the blood serum concentrations indicated is usually about 5 mg to about 40 mg. In a preferred embodiment, the bioavailability of the composition is such that, when a dose of 20 mg is administered orally to a fasting adult human subject: (a) a blood serum valdecoxib concentration of 20 ng / ml, more preferably of 50 ng / ml, is reached no more than about 0.5 h after administration;
- * »J s (b) Tmax is not greater than about 3 h after administration; and (c) Cmax is not less than about 100 ng / ml The compositions of the invention contain valdecoxib in the form
particulate. The primary valdecoxib particles, generated, for example, by grinding or milling, or by precipitation of solution, can agglomerate to form secondary aggregate particles. The term "particle size", as used herein, refers to size, in the longest dimension, of particles? or primary, unless the context demands otherwise. It is believed that particle size will be an important parameter that affects the clinical effectiveness of valdecoxib. Thus, in one embodiment, a composition has a particle size distribution of valdecoxib, so that the particle size D90 is less than about
75 μm The "D90 particle size" is defined herein, as a particle size so that 90% by weight of the particles are smaller, in their longer dimension, than the particle size. In addition or alternatively, the valdecoxib particles in a composition of the invention preferably have a particle size
weight average of about 1 μm to about 10 μm, most preferably about 5 μm to about 7 μm. In a further embodiment, the valdecoxib particles in a composition of the invention have an average particle size of
weight from about 10 nm to about 1000 nm (1 μm),
for example about 1 00 nm to about 400 nm, or about 500 nm to about 800 nm. The compositions of the invention comprise valdecoxib together with one or more excipients selected from diluents, disintegrants, binding agents, wetting agents and lubricants. In a preferred embodiment, at least one of the excipients in a water soluble diluent or wetting agent. It is believed that such a water-soluble diluent or wetting agent aids in the dispersion and dissolution of valdecoxib in the gastrointestinal tract. Preferably, at least one water-soluble diluent is present. In another preferred embodiment, at least one of the excipients is a disintegrant. In another preferred embodiment, at least one of the excipients is a binding agent; as indicated above, it is particularly preferred that the pregelatinized starch be present as a binding agent. In another preferred embodiment at least one of the excipients is a lubricant. It is especially preferred that the composition comprises, in addition to valdecoxib, each of a water-soluble diluent, a disintegrant, a binding agent and a lubricant. A composition of the invention may be a substantially homogenous flowable mass, such as a solid or a particulate or granular liquid, or it may be in the form of discrete articles, such as capsules or tablets. In a composition that is a mass capable of flowing, substantially homogeneous, simple doses are removably measurable using a suitable volumetric measuring device, such as a spoon or cup. Suitable flowable masses include, but
They are not limited to powders and granules. Alternatively, the flowable mass can be a suspension having the valdecoxib in a solid particulate phase, dispersed in a liquid phase, preferably an aqueous phase. To prepare such a suspension, the use of a wetting agent, such as polysorbate 80 or the like, is likely to be beneficial. A suspension can be prepared by dispersing ground valdecoxib in the liquid phase; alternatively, valdecoxib can be precipitated from the solution in a solvent, such as an alcohol, preferably ethanol. The aqueous phase preferably comprises a tasty vehicle, such as water, syrup or fruit juice, for example, apple juice. The compositions of the invention are useful in the treatment and prevention of a very wide range of disorders mediated by COX-2, including but not limited to disorders characterized by inflammation, pain and / or fever. Such compositions are especially useful as anti-inflammatory agents, such as, in arthritis treatment, with the additional benefit of having significantly less damaging side effects than conventional nonsteroidal anti-inflammatory drug compositions (NSAIs Ds), which lack selectivity for COX-2 over COX-1. In particular, the compositions of the invention have reduced potential for gastrointestinal toxicity and gastrointestinal irritation, including upper gastrointestinal ulceration and bleeding, reduced potential for renal side effects, such as reduction in renal function, leading to fluid retention and exacerbation of hypertension, reduced effect in bleeding times
including inhibition of platelet function, and possibly a decreased ability to induce asthma attacks in asthmatic subjects sensitive to aspirin, by comparison with conventional NSAI Ds compositions. Thus, the compositions of the invention are particularly useful as an alternative to conventional NSAIs Ds, where such NSAIs Ds are contraindicated, for example, in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal injuries; gastrointestinal bleeding, coagulation disorders including anemia, such as hypoprothrombinemia, hemophilia, or other bleeding problems; kidney disease; or in patients before surgery or patients taking anticoagulants. The contemplated compositions are useful for treating a variety of arthritic disorders, including but not limited to rheumatoid arthritis, spondyloarthropathies, gout arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compositions are useful in the treatment of asthma, bronchitis, menstrual cramps, preterm labor, tendonitis, bursitis, allergic neuritis, cytomegalovirus infectivity, apoptosis including H IV-induced apoptosis, lumbago, liver diseases including hepatitis, related conditions. with the skin, such as psoriasis, eczema, acne, burns, dermatitis and ultraviolet radiation damage, including sunburn, and post-operative inflammation including those following ophthalmic surgery, such as cataract surgery or surgery refractory
Such compositions are useful for treating gastrointestinal conditions, such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. Such compositions are useful for treating inflammation in such diseases as migraine headaches, periatheritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular joint disease, miastenia gravis, syndromes of Behcet, polymyositis, gingivitis, nephritis, hypersensitivity, swelling that occurs after injury including cerebral edema, myocardial ischemia and the like. Such compositions are useful in the treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia and acute injury to eye tissue. Such compositions are useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis and in bone resorption, such as that associated with osteoporosis. Such compositions are useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer's disease, neurodegeneration and central nervous system damage resulting from stroke, ischemia and trauma. The term "treatment" in the present context includes partial or total inhibition of dementias, including Alzheimer's disease, vascular dementia, dementia of multiple infarcts, pre-senile dementia, alcoholic dementia and senile dementia.
Such compositions are useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome and liver disease. Such compositions are useful in the treatment of pain, including but not limited to post-operative pain, dental pain, muscle pain and pain resulting from cancer. For example, such compositions are useful for the relief of pain, fever and inflammation in a variety of conditions including rheumatic fever, influenza and other viral infections including the common cold, neck and lower back pain, dysmenorrhea, headache, pain. teeth, dislocations and sprains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, diseases of degenerative joints (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns and trauma following surgical and dental procedures. Such compositions are useful for treating and preventing cardiovascular disorders related to inflammation, including vascular diseases, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including transplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina including unstable angina, coronary plaque inflammation, bacterial-induced inflammation including Chlamydia-induced inflammation, virus-induced inflammation, and inflammation associated with surgical procedures, such as vascular graft including coronary artery bypass surgery, revascularization procedures including angiopiastia , placement
of stent, endarterectomy or other invasive procedures involving arteries, veins and capillaries. Such compositions are useful in the treatment of disorders related to angiogenesis in a subject, for example, to inhibit tumor angiogenesis. Such compositions are useful in the treatment of neoplasia, including metastasis; ophthalmological conditions, such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases, such as gastric ulcer, pathological conditions, but not malignant, such as hemangiomas, including infantile hemangiomas, angiofibroma of the nasopharynx and avascular bone necrosis; and disorders of the female reproductive system, such as endometriosis. Such compositions are useful in the prevention and treatment of benign and malignant tumors and neoplasia including cancer, such as colorectal cancer, brain cancer, bone cancer, neoplasia derived from epithelial cells (epithelial carcinoma), such as basal cell carcinoma, adenocarcinoma, cancer gastrointestinal, such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, cancer lung, breast cancer, skin cancer, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma and other known cancers that affect epithelial cells throughout the body.
Neoplasms for which the compositions of the invention are contemplated as particularly useful are gastrointestinal cancer, Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, cancer of breast and skin cancer. Such compositions can also be used to treat fibrosis that occurs with radiation therapy. Such compositions can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, such compositions can be used to prevent polyps from forming in patients at risk of FAP. Such compositions inhibit the contraction of smooth muscle induced by prostanoids by inhibiting the synthesis of contractile prostanoids and hence, may be of use in the treatment of dysmenorrhea, premature labor, asthma and disorders related to eosinophils. They may also be of use to decrease bone loss, particularly in post-menopausal women (ie, osteoporosis treatment) and for glaucoma treatment. Preferred uses for compositions of the invention are for the treatment of rheumatoid arthritis and osteoarthritis, for pain management in general (particularly post-operative pain, general post-surgery pain, orthopedic post-surgery pain and acute osteoarthritis reflexes), for the treatment of Alzheimer's disease, and for chemoprevention of colon cancer. In addition to being useful for human treatment, the compositions of the invention are useful for veterinary treatment of animals of
company, exotic animals, farm animals and the like, in particular mammals. More particularly, the compositions of the invention are useful for the treatment of disorders mediated by COX-2 in horses, dogs and cats. The present invention is further directed to a therapeutic method for treating a condition or disorder, wherein treatment with an inhibitory drug of COX-2 is indicated, the method comprising orally administering a composition of the invention to a subject in need of treatment. same. The dosing regimen to prevent giving relief to, or improving the condition or disorder, preferably corresponds to a treatment once a day or two times a day., but can be modified according to a variety of factors. These include the type, age, weight, sex, diet and medical condition of the subject and the nature and severity of the disorder. In this way, the dosage regimen currently employed can vary widely and can therefore deviate from the preferred dosage regimens set forth above. The initial treatment may start with a dosing regimen as indicated above. The treatment is continued in a general manner as is necessary over a period of several weeks to several months or years, until the condition or disorder has been controlled or eliminated. Subjects undergoing treatment with a composition of the invention can be monitored routinely by any of the methods well known in the art to determine the effectiveness of the therapy. The continuous data analysis of such monitoring allows modification of the treatment regimen during therapy,
way that is administered in optimally effective doses at any time and so that the duration of treatment can be determined. In this way, the treatment regimen and dosing schedule can be modified rationally over the course of therapy, so that the lowest amount of the composition exhibiting satisfactory effectiveness is administered and so that the administration is continued only by how much time is needed to successfully treat the condition or disorder. The present compositions can be used in combination therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic analgesics (ie, non-addictive), monoamyl uptake inhibitors, reg Adenosine ulators, cannabinoid derivatives, Substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers, among others. Preferred combination therapies comprise the use of a composition of the invention with one or more compounds selected from aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac, alfentanil. allylprodine, alminoprofen, alloxiprine, alphaprodine, alum bis (acetylsalicylate), amfenac, aminoclorteoxazine, 3-amyl-4-hydroxybutyric acid, 2-amino-4-picoline, amopropyl, aminopyrin, amymethrin, salicylate, Ammonium, Ampiroxicam, Amtolmetin Guacil, Anileridine, Antipyrine, Antipyrine Salicylate, Anthrafenin, Apazone, Bendazac, Benorylate, Benoxaprofen, Bencipiperilon, Benzydamine,
benzylmorphine, bermoprofen, bezitramide, a-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucilloxic acid, bucoloma, bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butofanol, calcium acetylsalicylate, carbamazepine, barbifen, carprofen, carsalam, chlorobutanol, clortenoxazine, choline salicylate, cinchofen, cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin, clopirac, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cropropam , crotetamide, desomorphine, dexoxadrol, dextromoram ida, dezocin, diampromide, diclofenac sodium, diphenamizole, diphenpiramide, diflunisal, dihydrocodeine, enol dihydrocodeinone acetate, dihydromorphine, dihydroxyaluminium acetylsalicylate, dimenoxadol, dimetheptanol, dimethylthiambutene, dioxafethyl butyrate, dipinanone, diprocetyl, dipyrone, ditazole, droxicam, emorfazone, enfenamic acid, epirizol, eptazocine, etersalate, etenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac, febufen, fecotic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenin, flufenamic acid, flunoxaprofen, fluoresone, flupirtin, fluproquazone, flurbiprofen, phosfosal, gentisic acid, gáfenina, glucametacina, glycol salicylate, guaiazulene, hydrocodone, hydromorphone, hydroxypetidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac, isolladol, isomethadone, isonixin, isoxepac , isoxicam, ketobemidone, ketoprofen, ketorolac, p-lactofenetide, lefetamine, levorphanol, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate, acid
LÁÁAlí¿A:,? to. -...... a aa-.i- i ...
meclofenamic, mefenamic acid, meperidine, meptazinol, mesalamine, metazocine, methadone hydrochloride, methotrimeprazine, metyazinic acid, metofoline, metopon, mofebutazone, mofezolac, morazone, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, nirofin, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen, narcein, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normetadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacin, oxaprozin, oxycodone, oxymorphone, oxifenbutazone, papaveretum, paraniline, parsalmide, pentazocine, perisoxal, phenacetin, fenadoxone , fenazocine, phenazopyridine hydrochloride, phenocol, phenoperidine, fenopyrazone, phenylacetylsalicylate, phenylbutazone, phenyl salicylate, feniramidol, picetoprofen, pim inodine, pipebuzone, piperilone, piprofen, pyrazolac, piritramide, piroxicam, pranoprofen, proglumetacin, proheptazine, promedol , propacetamol, propiram, propoxyphene, propifenazone, proquazone, proizinic acid, ram ifenazone, remifentanyl, rimazolium methylsulfate, salacetamide, salicin, salicylamide, salicylamide acetic acid, salicylsuiphuric acid, salsate, salverine, symmetry, sodium salicylate , sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terophenamate, tetrandrine, thiazolinobutazone, thiaprofenic acid, thiaramide, til idine, tinoridine, tolfenamic acid, tolmetin, tramadol, tropesin, viminol, xenbucin, ximoprofen, zaltoprofen and zomepirac (see The Merck I ndex, 1st edition, Therapeutic Category and Biological Activity I ndex (index of therapeutic categories and biological activity), ed. S. budavari
; !
(1 996), pp. Ther-2 to Ther-3 and Ther-1 2 (analgesic (dental), analff (narcotic), analgesic (non-narcotic), anti-inflammatory (non-steroidal)). Particularly preferred combination therapies comprise the use of a composition of the invention with an opioid compound, more particularly where the opioid compound is codeine, meperidine, morphine or a derivative thereof. A valdecoxib composition of the invention can also be administered in combination with a second selective COX-2 inhibitory medicament, for example, celecoxib, rofecoxib, etc. The compound to be administered in combination with valdecoxib can be formulated separately from valdecoxib or co-formulated with valdecoxib in a composition of the invention. Where valdecoxib is co-formulated with a second drug, for example, an opioid drug, the second drug can be formulated in the form of immediate release, rapid onset, sustained release or dual release. The compositions of the invention are generally suitable for the administration of valdecoxib in a daily dosage amount from about 1 mg to about 1000 mg. Each dose unit of a composition of the invention typically comprises an amount of valdecoxib from about one tenth of the daily dosage amount for the whole of a daily dosage amount. Preferred daily dosage amounts are about 2 mg to about 60 mg, more preferably about 5 mg to about 40 mg, per
s, A ^ * éá. ~ m *. ~ ^ ü *. **.; * - &sk. .. «... -ja», £. AJA! ** ** (^ - ^ ^ '.J ^ iJ example about 5 mg, about 10 mg, about 20 mg or about 40 mg Where the dosage units are in the form of discrete articles suitable for oral administration , such as capsules or tablets, each such article comprises about 1 mg to about 1000 mg, preferably about 5 mg to about 60 mg, more preferably about 10 mg to about 50 mg, eg, about 10 mg , up to about 20 mg or about 40 mg of valdecoxib Valdecoxib used in compositions of the invention can be prepared by any process known per se, including the manner set forth in the aforementioned US Patent No. 5,633,272.
In addition to valdecoxib, the compositions of the invention comprise one or more excipients suitable for oral administration. The excipients should be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and should not be detrimental to the recipient. The excipients used can be solids or liquids or both. A composition of the invention contains a desired amount of valdecoxib per dose and may be in the form of, for example, a tablet, a pill, a hard or soft capsule, a diamond-shaped tablet, a cachet-type capsule, a powder dispensable, granules, a suspension, or any other form reasonably adapted for oral administration. Tablets, pills and the like can be prepared with or without coatings.
i ü ^^^^ i ^^^^^ l ^^^^^^ j ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ include, for example, diamond-shaped lozenges comprising valdecoxib in a flavored base, such as sucrose, and gum arabic or tragacanth, and lozenges comprising valdecoxib in an inert base, such as gelatin and glycerin or sucrose and gum arabic. Liquid dosage forms include suspensions of valdecoxib in an liquid diluent, which is usually aqueous. Such suspensions may contain additional excipients, for example, wetting agents, emulsifying and suspending agents, stabilizing agents, thickening agents and sweetening, flavoring and flavoring agents. The compositions of the invention can be prepared by any suitable pharmacy method, which includes a step of bringing into association the valdecoxib and the excipient (s). In general, the compositions are prepared by uniformly and intimately mixing the valdecoxy b with a finely divided solid liquid or diluent and then, if necessary, encapsulating or shaping the resulting mixture. For example, a tablet can be prepared by compressing or molding a powder or granules of such a mixture, optionally together with one or more additional excipients. Compressed tablets can be prepared by commingling, in a suitable machine, a free flowing composition, such as a powder or granules, comprising valdecoxib optionally mixed with one or more diluents, disintegrants, binding agents and lubricants. Molded tablets can be prepared by molding, in
a suitable machine, valdecoxib powder, optionally with one or more excipients, moistened with a liquid diluent. Through the selection and combination of excipients, compositions can be provided exhibiting improved performance with respect to efficacy, bioavailability, evacuation time, stability, compatibility of valdecoxib and excipients, safety, dissolution profile, disintegration profile and / or other pharmacokinetic, chemical and / or physical properties. The excipients preferably include one or more materials that are water-soluble or water-dispersible and that have wetting properties to compensate for the low aqueous solubility and hydrophobicity of valdecoxib. Where the composition is formulated as a tablet, the combination of selected excipients provides tablets that can exhibit improvement, among other properties, in dissolution and disintegration profiles, hardness, compressive strength and / or friability. The compositions of the invention optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable diluents include, illustratively, either individually or in combination, lactose, including lactose anhydrous and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (eg, Celutab ™ and Emdex ™); mannitol, sorbitol; xylitol; dextrose (e.g., Cerelose ™ 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; diluents based on sucrose, confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; trihydrate
granular calcium lactate; dext ítos; inositol; hydrolyzed cereal solids; amylose; cellulose including microcrystalline cellulose, food grade sources of cellulose α and amorphous (eg Rexcel ™) and powdered cellulose; calcium carbonate; glycine; bentonite; 5 polyvinyl pyrrolidone; and similar. Such diluents, if present, in total constitute about 5% up to about 99%, preferably about 10% up to about 85%, and more preferably about 20% up to about 80%, of the total weight of the composition. The diluent or diluents selected from
Preference exhibits suitable flow properties and, where tablets are desired, compressibility. "Lactose and microcrystalline cellulose, either individually or in combination, are preferred diluents. Both diluents are chemically compatible with valdecoxib. The use of cellulose
Extra-granular microcrystalline (ie, microcrystalline cell added to a wet granulated composition after a drying step) can be used to improve hardness (for tablets) and / or disintegration time. Lactose, especially lactose monohydrate, is particularly preferred. Lactose usually provides
• 20 compositions having suitable release rates of valdecoxib, stability, ability to flow pre-compression, and / or drying properties at a relatively low diluent cost. It provides a high density substrate that helps densification during granulation (where wet granulation is employed) and in
Consequently, it improves the flow properties of the mixture.
. . AEBAB The compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, in particular for tablet formulations. Suitable disintegrants include, either individually or in combination, starches, including sodium starch glycolate (e.g., Explotab ™ from Pen West) and pregelatinized corn starches (e.g., NationalMR 1551, Nat? Onal M R 550, and Colocorn). R 1 500), clays (/ for example, Veegum ™ HV), cellulose such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose,
croscarose sodium (for example, Ac-Di-SolMR from FMC), alginates, crospovidone and gums, such as agar, guar, carob, karaya, pectin and
• tragacanth The disintegrants can be added at any suitable step during the preparation of the composition, in particular before
the granulation or during a lubrication step prior to compression. Such disintegrants, if present, in total constitute about 0.2% to about 30%, preferably about 0.2% to about 10%, and more preferably about 0.2% to about 5%, of the
• 20 total weight of the composition. Croscarmellose sodium is a preferred disintegrant for disintegrating tablets or capsules and, if present, preferably constitutes about 0.2% to about 10%, more preferably about 0.25 to about 7%, and
Still more preferably about 0.2% up
about 5%, of the total weight of the composition. Croscarmellose sodium confers intragranular disintegration capabilities superior to granular compositions of the present invention. The compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, in particular for tablet formulations. Such bonding agents and adhesives preferably impart sufficient cohesion to the powder being tabletted, to allow for normal processing operations, such as sizing, lubrication, compression and packing, but still allowing the tablet to disintegrate and the composition to be absorbed onto the tablet. ingestion Suitable binding agents and adhesives include, either individually or in combination, gum arabic; tragacanth; sucrose; gelatin, glucose; starches, such as, but not limited to, pregelatinized starches (e.g., NationalM R 1 51 1 and NationalM R 1 500); cellulose, such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose R); algic acid and alginic acid salts; magnesium aluminum silicate; polyethylene glycol (PEG); guar gum; polysaccharide acids; benton itas; polyvinyl pyrrolidone (povidone or PVP), for example, povidone K-1 5, K-30 and K-29/32; polymethacrylates; hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (e.g., KlucelM R); and ethylcellulose (for example, Ethocel ™). Such binding and / or adhesive agents, if present, in total constitute about 0.5% up to about 25%, preferably about 0.75% up to about 1 5%, and
tAA - *? f- .rtS. ** f¿tz ». ,, Ai ?? *, .J: i- ~ * t4.M ~ '¿~ ~ J more preferably approximately 1% to approximately 10%, of the total weight of the composition. Pregelatinized starch is a preferred binding agent used to impart cohesive properties to a powder mixture of valdecoxib and other excipients for granulation of a valdecoxib formulation. The pregelatinized starch, if present, preferably constitutes about 0.5% to about 20%, more preferably about 5% to about 15%, of the total weight of the composition and facilitates the binding of particles in the mixture to form granules during the wet granulation. The compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Such wetting agents are preferably selected to maintain valdecoxib in close association with water, a condition that is believed to improve the bioavailability of the composition. Non-limiting examples of surfactants that can be used as wetting agents in compositions of the present invention include quaternary ammonium compounds, for example, benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, sodium dioctyl sulfosuccinate, polyoxyethylene alkylphenyl ethers , for example, nonoxynol 9, nonoxynol 1 0 and octoxinol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), glycends and polyoxyethylene fatty acid oils, for example, mono- and diglypeps of caprylic / capric polyoxyethylene ( 8) (for example, LabrasolM R from Gattegfosé), castor oil
polyoxyethylene (35) and hydrogenated polyoxyethylene castor oil (40); polyoxyethylene alkyl ethers, for example, polyoxyethylene (20) ketoestearyl ether, esters of polyoxyethylene fatty acids, for example, polyoxyethylene stearate (40), polyoxyethylene sorbitan esters, for example, polysorbate 20 and polysorbate 80 (e.g., TweenM R 80 of ICI), esters of propylene glycol fatty acids, for example, propylene glycol laurate (for example, Lauroglycol R from Gattefgosé), sodium lauryl sulfate, fatty acids and salts thereof, for example, oleic acid, oleate triethanolamine sodium and oleate, esters of glyceryl fatty acids, for example, glyceryl monostearate, sorbitan esters, for example, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol and mixtures thereof. Such wetting agents, if present, in total constitute about 0.25% to about 15%, preferably about 0.4% to about 10%, and more preferably about 0.5% to about 5%, of the total weight of the composition. Wetting agents which are anionic surfactants are preferred. Sodium lauryl sulfate is a particularly preferred wetting agent. Sodium lauryl sulfate, if present, constitutes about 0.25% to about 7%, more preferably about 0.4% to about 4%, and still more preferably about 0.5% to about 2%, of the total weight of the composition.
^^. ^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and / or glidants) as excipients. Suitable lubricants include, either individually or in combination, glyceryl behapate 5 (e.g., Compritol M R 888); stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils (for example, Sterotex ™); colloidal silica; talcum powder; waxes, boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (for example, Carbowax R 4000 and
Carbowax ™ 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, constitute a total
• about 0. 1% to about 10%, preferably about 0.2% to about 8%, and more preferably about 0.25% to about 5%, of the total weight of the
com position. Magnesium stearate is a preferred lubricant used, for example, to reduce friction between the equipment and granulated mixture during compression of tablet formulations. Suitable anti-adherents include talc, corn starch, DL- # 20 leucine, sodium lauryl sulfate and metal stearates. Talc is a preferred anti-tack or glidant used, for example, to reduce the formulation sticking to equipment surfaces and also to reduce static in the mixture. Talc, if present, constitutes approximately 0. 1% up about 10%, more preferably
approximately 0.25% up to about 5%, and even more
preferably about 0.5% to about 2%, of the total weight of the composition. Other excipients, such as colorants, flavors and sweeteners are known in the pharmaceutical art and can be used in compositions of the present invention. The tablets may be coated, for example, with an enteric coating or they may be uncoated. The compositions of the invention may further comprise, for example, buffers. The reduction in the particle size of valdecoxib can lead to improved bioavailability when the drug is formulated as an orally deliverable composition., according to the invention. Accordingly, the D90 particle size of valdecoxib is preferably less than about 75 μm, still more preferably less than about 40 μm, and most preferably less than about 25 μm. In addition or alternatively, valdecoxib preferably has an average particle size of weight in the range of about 1 μm to about 10 μm, more preferably about 5 μm to about 7 μm.
Any suitable milling, grinding or micronizing method can be used for the reduction of the particle size. The capsule and tablet compositions of the invention are immediate release compositions that release at least about 50%, more preferably at least about 60% and most preferably at least about 75% of valdecoxib, as measured in vitro in a dissolution test standard, within approximately 45 minutes. Especially preferred capsule and tablet compositions of the invention release in vitro at least about 50% of valdecoxib within about 15 minutes, and / or at least about 60% of valdecoxib within about 30 minutes. Although the compositions of the invention can be prepared, for example, by direct encapsulation or direct compression, they are preferably wet granulated prior to encapsulation or compression. Wet granulation, among other effects, densifies the milled compositions resulting in improved flow properties, improved compression characteristics and easier measurement or dispensing of weight of the compositions for encapsulation or tabletting. The secondary particle size resulting from granulation (ie, granule size) is not narrowly critical, it being important only that the average granule size is preferably such that it permits convenient handling and processing and, in the case of tablets, which allows the formation of an easily compressible mixture that forms pharmaceutically acceptable tablets. The desired bulk density of the granules, when empty, is typically from about 0.3 to about 10 g / ml, for example about 0.6 to about 0.9 g / ml. To prepare tablets by compression, the granulated mixture in an amount sufficient to make a batch of tablets can be
? *. < ! **, ** i ,,, -: - * < "-t * ± £ ¡.-i, .í, - aaa ..j-atai-afc.
processed in a standard tablet press production scale machine at normal compression pressure (for example, applying a force of about 1 to about 50 kN in a normal tabletting die). The hardness of the resulting tablet should be convenient with respect to handling, manufacture, storage and ingestion so that it can be used; however, a minimum hardness of about 4 kP, preferably about 5 kP and more preferably about 6 kP, is desirable to avoid excessive friability, and a maximum hardness of about 1 8 kP, preferably about 1.5 kP, and more preferably about 1 2 kP, it is desirable to avoid a subsequent difficulty in hydrating the tablet when exposed to gastric fluid. When the hardness is in an acceptable range, the friability of the tablet is usually less than about 1.0%, preferably less than about 0.8% and more preferably less than about 0.5%, in a standard test. The excipients, in particular a disintegrant, for immediate release capsule and tablet compositions of the invention, are preferably selected to provide a disintegration time in a standard in vitro assay of less than about 30 minutes, preferably less than about 25 minutes. minutes, more preferably less than about 20 minutes and still more preferably less than about 15 minutes. The invention is further directed to methods for the preparation of compositions comprising particulate valdecoxib. In a modality
-.- a .. In particular, the invention is directed to methods for the preparation of such compositions in the form of tablets. Although dry granulation or direct compression methods can be used, methods comprising a wet granulation step are currently preferred. In two illustrative modalities, the wet granulation is carried out under low and high cut, respectively. A low-cut process is indicated diagrammatically in Fig. 1. In this illustrative process, the micronized valdecoxib is mixed, for example, in a planetary mixer, with one or more solid particulate diluents, for example, lactose monohydrate (primary diluent) and microcrystalline cellulose (secondary diluent) and a binding agent, preferably, pregelatinized starch, to form a premix. Water is then added, with continued mixing, in an amount to promote the formation of granules. The granules are dried, for example, in a furnace, and then they are sized in a comel with appropriate size to provide fairly uniform granules. These are then mixed with a disintegrant, for example croscarmellose sodium, and finally with a lubricant, for example, magnesium stearate, to produce a tabletting mixture. It will be noted that in this illustrative process, the microcrystalline cellulose is added intragranularly and the croscarmellose extragranularly. Finally, the tabletting mixture is compressed, for example, in a rotary press to form the tablets. The tablets may optionally be coated using any suitable coating process known in the art.
A high-cut process is indicated diagrammatically in FIG. 2. In this illustrative process, the micronized valdecoxib is mixed in a high-cut mixer with a primary diluent, for example, lactose monohydrate, a first portion of a secondary diluent, for example, microcrystalline cellulose, a binder, preferably pregelatinized starch, and a first portion of disintegrant, for example, croscarmellose sodium, to form a premix. Then water is added, with continuous high-shear mixing, in an amount to promote the formation of granules. The granules are optionally
wetted, and then dried, preferably in a fluidized bed dryer. One step of dry sizing, for
• example, in a Fitz mill, you can drive yourself then. The resulting granules are then mixed with a second portion of the secondary diluent and a second portion of the disintegrant and finally with a
lubricant, for example, magnesium stearate, to produce a tableting mixture. It will be noted that in this illustrative process, the microcrystalline cellulose and the croscarmellose sodium are each added either extragranularly or granularly. Finally, the tableting mixture is compressed and optionally coated, as in the process
• 20 low cut. The present invention is also directed to the use of compositions of the present invention in the preparation of medicaments useful in the treatment and / or prophylaxis of conditions and disorders mediated by COX-2.
EXAMPLES The following examples illustrate aspects of the present invention, but should not be construed as limitations. Unless stated otherwise, all percentages reported in these examples are by weight based on the weight of the total composition.
Example 1: 1 0 mq tablets of valdecoxib prepared by low-cut wet granulation The tablets were prepared having the composition shown in Table 1.
Table 1
The appropriate amount of micronized valdecoxib for the batch size was first mixed with an equal amount of lactose monohydrate, sorted by passing through a 20 mesh screen and added to a Hobart planetary mixer. The rest of the lactose monohydrate and the microcrystalline cellulose are then added to the mixer, which was then operated at a slow impeller speed for about 10 minutes. The resulting premix was then granulated in the planetary mixer by adding purified water manually over 12-1 5 minutes, while continuing to mix at a slow to medium impeller speed. The resulting wet granules were dried on trays in a Gruenberg oven with an inlet air temperature of 60 ± 5 ° C up to a moisture content of 2.0 ± 1.0%, measured by loss in drying. The resulting dry granules were sized through a sieve size 14 using a Quadro comil at medium speed and then placed in a V-mixer by Patterson Kelley together with croscarmellose sodium. The mixer V was operated for about 5 minutes to thoroughly mix the sodium croscarmellose with the granules; magnesium stearate was then added with additional mixing for about 3 minutes to prepare a lubricated mixture. This was compressed on a Manesty DB 1 6 rotary press using a standard 7.5 mm concave assembly to provide a tablet weight of 200 ± 10 mg, having a hardness of 10 ± 4 kP.
ltkÁ?, á.A.M :. S¡m ai •; ^ - -. . .... - ..,. a-a-, -a aaaa. aSaa ^ aai-i .--.
Example 2: 10 mg tablets of valdecoxib prepared by high cut wet granulation Tablets were prepared having the composition shown in Table 2.
Table 2
Mitochondrized valdecoxib, lactose monohydrate, microgranular cellulose, intragranular, pregelatinized starch and intragranular sodium croscarmellose were mixed in a Baker Perkins high cut mixer at high impeller / cutter speed for approximately 3 minutes to form a premix. Purified water was added to the premix via a Watson Marlow peristaltic pump over a period of about 3 minutes and mixing was continued for an additional 45 seconds. The resulting wet granules were dried in an Aeromatic fluidized bed dryer with an inlet air temperature of 60 ± 5 ° C to a moisture content of 2.0 ± 1.0%, as measured by loss in drying, to form a dry granulate. The dried granulate was passed through a 20 mesh screen using a forward-mounted chop mill at 1,800 rpm, and then placed in a V-mixer by Patterson Kelley. Here, the granulate was mixed with the extragranular microcrystalline cellulose and extragranular sodium croscarmellose for about 5 minutes, and then with the magnesium stearate for about 3 additional minutes, to form a lubricated mixture. This was compressed on a Korsch PH-230 rotary press, using a standard 7.5 mm concave assembly to provide a tablet weight of 200 ± 10 mg. The tablets were prepared having hardness of 6, 8, 1 0 and 1 2 kP
Example 3 - Tablets of 5, 1 0, 20 and 40 mg of coated valdecoxib Using the process of Example 2, the tablets were prepared having the composition shown in Table 3. The tablets were film coated with yellow Opadry YS-1 - 1 2525A or white Opadry White YS-1 -1 8027A at 3% uncoated tablet weight, using a 1% suspension of the coating material in water
Table 3
•
•
The properties of the tablets of Example 3 are presented in Table 4. The disintegration was evaluated by the following procedure. Six identical tablets were placed separately in one of six tubes having a wire mesh screen in a
• basket of disintegration. A water bath was preheated to 37 ± 2 ° C and 10 was maintained at that temperature for the duration of the disintegration test. A 1000 ml laboratory beaker was placed in the water bath. The laboratory beaker was filled with a sufficient amount of water to ensure that the wire mesh screen of the tubes remained at least 2.5 cm below the surface of the water during the test. The disintegration basket was inserted into the water and rose and
repeatedly lowered until the test was complete, while maintaining the wire mesh screen of the tubes at least 2.5 cm below the surface of the water. The disintegration time for each tablet was time, measured from the time of insertion of the basket, in which the last portion of the tablet passed through the screen at the bottom of the tube.
Table 4
•
Example 4: Pharmacokinetic properties of valdecoxib tablets in
• dogs A study was carried out in order to determine the pharmacokinetic properties of the valdecoxib composition of Example 2, in 23 beagle dogs. Valdecoxib was administered at a dose of 20 mg (2 15 tablets). Venous blood was collected pre-dose and at 0.5, 1, 1 .5, 2,
2. 5, 3, 4, 6, 8, 12 and 24 hours after the oral dose administration. The plasma was separated from the blood by centrifugation at 3000 G and samples were stored at -20 ° C until analysis. The concentrations of valdecoxib in plasma were determined using an HPLC assay. The results are shown in Fig. 3.
Example 5: Pharmacokinetic properties of valdecoxib tablets in
• humans A study was conducted in order to determine the pharmacokinetic properties of the valdecoxib composition of Example 2 in 24 healthy adult humans. Valdecoxib was administered at a dose of 20 mg (2 tablets). Venous blood was collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 1 2, 1 6 and 24 hours after the administration of the
• oral dose. The blood plasma was separated by centrifugation at 3000 G and the samples were stored at -20 ° C until analysis. The concentrations of valdecoxib in plasma were determined using a
H PLC test. The results are shown in Fig. 4. Cmax calculated was 303 ± 93 ng / ml. Tmax calculated was 2.97 ± 0.73 h.
•
Claims (6)
1 . A pharmaceutical composition comprising particulate valdecoxib in an amount of about 1 mg to about 1000 mg per dose and one or more pharmaceutically acceptable excipients, wherein a single dose, over oral administration to a fasted subject, provides a course of concentration time of valdecoxib in blood serum having at least one of (a) a time to reach a threshold concentration for therapeutic effect no greater than about 0.5 h after administration; (b) a time to reach the maximum concentration (Tmax) no greater than about 3 hours after the administration; and (c) a maximum concentration (Cmax) not less than about 1 00 ng / ml.
2. The composition of claim 1, wherein the threshold concentration for therapeutic effect is about 20 ng / ml.
3. The composition of claim 2, wherein a single dose, upon oral administration to a fasted subject, provides a time course of valdecoxib concentration in blood serum, each having (a) a time to reach a concentration of 20 ng / ml no greater than approximately 0.5 h after the administration; (b) a time to reach the maximum concentration (Tmax) not greater than about 3 h after administration; Y t? ¡* & > ~ - ± * A **? T. ~. ~ ^ (C) a maximum concentration (Cmax) not less than about 100 ng / ml. The composition of claim 1, wherein the valdecoxib is in an amount of about 5 mg to about 40 mg per dose. The composition of any one of claims 1 to 4, which is a tablet wherein the excipients comprise one or more diluents in an amount of about 5% to about 99%, one or more disintegrants in an amount of about 0.2% to about 30%, one or more binding agents in an amount of from about 0.5% to about 25%, and one or more lubricants in an amount of about 0. 1% to about 10%, by weight of the composition. 6. The composition of claim 5, wherein the binding agent is pregelatinized starch. The composition of any one of claims 1 to 4, which is a tablet wherein the excipients comprise lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, pregelatinized almighty and magnesium stearate. The composition of claim 1, further comprising one or more opioid or analgesic drugs. The composition of any one of claims 1 to 3, wherein Dg 0 of the valdecoxib particles is less than about 75 μ. The composition of any of claims 1 to 8, wherein the valdecc * xib particles have a weight average particle size of from about 1 μm to about 10 μm. eleven . The composition of any one of claims 1 to 8, wherein the valdecoxib particles have a weight average particle size of from about 10 nm to about 1000 nm. 2. A method for preparing a composition of any of claims 5 to 7, comprising a step of wet granular valdecoxib together with one or more diluents and a binding agent, drying the resulting granules and compressing the resulting dry granulate to form a tablet 1 3. A method for treating a medical condition or disorder in a subject, wherein treatment with a cyclooxygenase-2 inhibitor is indicated, comprising orally administering to the subject a composition of any of claims 1 to 12 once or twice up to date. A method for using a composition of any one of claims 1 to 12 to make a medicament for treatment or prophylaxis of a disorder mediated by cyclooxygenase-2 in a subject in need thereof. SUMMARY Pharmaceutical compositions comprising particulate valdecoxib are provided, in an amount of about 1 mg to about 1000 mg and one more pharmaceutically acceptable excipients. The compositions are useful in the treatment or prophylaxis of conditions and disorders mediated by cyclooxygenase-2. * *
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US60/169,856 | 1999-12-09 | ||
US60/181,635 | 2000-02-10 | ||
US60/202/269 | 2000-05-05 |
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MXPA01008055A true MXPA01008055A (en) | 2003-02-17 |
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