MXPA00002682A - Synergistic analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor - Google Patents

Abstract

The invention relates to the use of a combination of an opioid analgesic together with a COX-2 inhibitor.

Description

ANALGESIC COMBINATION SYNERGY OF OPIOID ANALGESIC AND CYCLIOXYGENASE INHIBITOR-2 FIELD OF THE INVENTION The present invention relates to analgesic pharmaceutical compositions containing an opioid analgesic and an inhibitor of cyclooxygenase-2 (COX-2). The present invention also relates to methods for pain treatment comprising administering these pharmaceutical compounds to human patients. BACKGROUND OF THE INVENTION There is a continuing need for analgesic drugs capable of providing highly effective relief for pain and at the same time reducing the possibility of undesirable effects. Nonsteroidal anti-inflammatory drugs (MAINE), including compounds such as ibuprofen, ketoprofen and diclofenac, have anti-inflammatory action and are also effective for the pain associated with the secretion of prostaglandins and other mediators of inflammation. For example, diclofenac is considered to be extremely potent and effective as an analgesic and as an anti-inflammatory agent. Diclofenac is approved in the United States for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is also considered useful in the short-term treatment of acute musculoskeletal trauma, pain acute of shoulders, post-operative pain and dismensrrea. However, MAINs such as diclofenac cause side effects in 20% of patients that require cessation of medication. Side effects include, for example, gastrointestinal bleeding and abnormal elevation of liver enzymes. Opioids are a group of drugs, both natural and synthetic, which are primarily used as centrally acting analgesics and whose properties are similar to opium and morphine (Gilman et al., 1980, GOODMAN AND GILMAN 'S. THE PHARMACOLOGICAL BASIS OF THERAPEUTICS , chapter 24: 494-534, Pergamon Press, incorporated herein by reference). Opioids include morphine and orphinoid homologs, including, for example, semi-synthetic derivatives such as codeine (methyl orphine) and hydrocodone (dihydrocodeinone) among many other such derivatives. Morphine and related opioids exhibit agonist activity in the μ (mu) opioid receptors of the central nervous system or CNS (meaning the brain and spinal cord), and have affinity with the opioid receptors d and K, producing a range of effects that They include analgesia, drowsiness, changes in mood and mental fog. In addition to its potent analgesic effects, opioids related to morphine can also cause various undesirable effects, including, for example, respiratory depression, nausea, vomiting, dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary tract pressure, urinary retention, and hypotension. Another undesirable effect is the development of tolerance to opioid drugs, the risk of chemical dependence and the abuse of these drugs. Morphine, considered the prototype of the opioid analgesic, has been available in many dosage forms, including oral immediate-release dose presentations and, more recently, 12-hour controlled-release formulations (eg, MS Contin® tablets). , commercially available from Purdue Frederick Company). Other opioid analgesics are also available as immediate release oral dose presentations, such as hydromorphone (e.g., Dilaudid®, commercially available from Knoll Pharmaceuticals). More recently, another controlled-release opioid analgesic, oxycodone (OxyContin®, commercially available from Purdue Pharma) was available. There are, of course, many other oral opioid presentations of immediate release and sustained release commercially available throughout the world. Previous publications report that analgesic potency can be improved and at the same time reduce undesirable effects by combining an opioid with an MAINE or an analgesic such as acetylsalicylic acid or acetaminophen, in such a way that a synergistic analgesic effect is obtained, allowing a reduction in the total dose of both the MAINE and the analgesic. For example, U.S. Pat. No. 4,569,937, issued February 11, 1986 to Baker et al., discloses a combination of oxycodone with ibuprofen in an oxycodone / ibuprofen ratio of between 1: 6 to 1: 400. U.S. Pat. No. 4,690,927, issued on September 1, 1987 to Voss et al., discloses a combination of the MAIN diclofenac and codeine in a weight ratio of diclofenac to codeine of between about 1: 1 versus about 3: 1. U.S. Pat. No. 5,190,947, issued March 2, 1993 to Riess et al., discloses a salt of diclofenac-codeine ([2- [2,6-dichlorophenyl) -amino] -phenyl] -acetic acid). U.S. Pat. No. 4,844,907, issued July 4, 1989 to Elger et al., describes a multiphasic tablet that combines a narcotic analgesic phase and a MAINE phase in separate layers. U.S. Pat. No. 4,587,252, issued May 6, 1986 to Amold et al., describes a process for treating pain using a combination of hydrocodone and ibuprofen. Nonsteroidal anti-inflammatory drugs (MAINEs) exert most of their anti-inflammatory activities inflammatory, analgesic and antipyretic, and inhibit hormonally induced uterine contractions and certain types of cancer growth by inhibiting the prostaglandin G / H synthase, also known as cyclooxygenase. Fatty acid cyclooxygenase (COX) was described as the source of prostaglandins, thromboxanes and a variety of other biologically active hydroxylated metabolites derived from arachidonic acid and higher desaturated fatty acids. Beginning in the late 1960s, B. Sammuelsson, S. Bergstrom and their colleagues discovered the biological activity and elucidated the structures of the cyclooxygenase products. At the end of the 60s and the beginning of the 70s, J. Vane discovered that aspirin and other MAINE exert their main biological activities by inhibiting cyclooxygenase. COX is directly responsible for the formation of PGG and PGH, and these function as intermediates in the synthesis of PGD, PGE, PGF, PGI and TXA. In the late 1970s and early 1980s, it was noted that many hormones and other biologically active agents could regulate the cellular activity of COX. Initially, it was assumed that the COX induction was simply the result of the oxidative inactivation of COX, which happens after only a few substratum productions. This is common among enzymes that incorporate molecular oxygen in their substrates, and Oxygen degrades the enzyme very quickly. These enzymes are sometimes referred to as suicide enzymes. In response to the rapid inactivation (in a matter of seconds) of cyclooxygenase, its message is transcribed, and the enzyme is rapidly induced to replace what was lost by catalysis. Several groups noted that cyclooxygenase was induced to replace the lost enzyme to a much greater extent than necessary. Using an oligonucleotide targeting the cloned COX-1 enzyme, a second band was identified in Northern blots at low stringency. This gene was cloned and identified as a second COX enzyme, which was called COX-2, and was found to be almost absent in many cells under basal conditions, but which was rapidly induced by various cytokines and neurotransmitters. It was found that the expression of this enzyme was mainly responsible for the COX excess activity previously observed in activated cells. The genes of COX-1 and COX-2 are different, where the gene for COX-1 is 22 kb and the message size is 2.8 kb, while the gene for COX-2 is 8.3 kb and the size of the message is 4.1 kb. While the COX-1 promoter does not contain recognized transcription factor binding sites, the COX-2 promoter contains sites for NF-? B, AP-2, NF-IL-6 and glucocorticoids (HR Herschman, Canc. Goals, Rev. 13: 256, 1994). There are some differences in the active sites of the enzymes. The aspirin inhibits the activity of the cyclooxygenase of COX-1, but leaving its peroxidase activity intact, while aspirin converts COX-2 from a cyclooxygenase to a 15-lipoxygenase (EA Meade et al., J. Biol. Chem. 268 : 6610, 1993). It has been proposed that COX-1 is responsible, in many cells, for the endogenous basal release of prostaglandins, and is important in the physiological functions of prostaglandins that include maintaining gastrointestinal integrity and renal blood flow. The inhibition of COX-1 causes several side effects, including the inhibition of platelet aggregation associated with coagulation disorders, and gastrointestinal toxicity with the possibility of ulcerations and hemorrhage. It is thought that gastrointestinal toxicity is due to a decrease in the biosynthesis of prostaglandins that are cytoprotective of the gastric mucosa. Historically, a high incidence of side effects is associated with the chronic use of classical inhibitors of cyclooxygenase, all of them approximately equipotent for COX-1 or COX-2, or which are COX-1-selective.

Although renal toxicity occurs, it usually becomes evident in patients who already had renal failure (D. Kleinknecht, Sem.Nephrol., 15: 228, 1995). By far the most prevalent and morbid toxicity is gastrointestinal. Yet with relatively non-toxic drugs such as piroxicam, up to 4% of patients experience severe ulcerations and bleeding (M.J.S. Langman et al, Lancet 343: 1075, 1994). It is estimated that in the United States about 2,000 patients with rheumatoid arthritis and 20,000 patients with osteoarthritis die each year due to gastrointestinal side effects related to the use of COX inhibitors. In the United Kingdom, approximately 30% of the 4,000 annual deaths related to peptic ulcer are attributable to COX inhibitors (Scrip 2162, p.17). COX inhibitors cause gastrointestinal and renal toxicity due to the inhibition of the synthesis of homeostatic prostaglandins responsible for, respectively, the production of epithelial mucosa and renal blood flow. The second form of cyclooxygenase, COX-2, is rapidly and easily inducible by various agents, including mitogens, endotoxins, hormones, cytokines, and growth factors. It has been proposed that COX-2 is the main responsible for the pathological effects of prostaglandins, which arise when a rapid induction of COX-2 occurs in response to agents such as hormones, growth factors, cytokines and inflammatory agents. Therefore, a selective inhibitor of COX-2 could have anti-inflammatory, antipyretic and Analgesics similar to a non-steroidal anti-inflammatory drug (MAINE). Additionally, a COX-2 inhibitor would inhibit uterine contractions induced by hormones and possess anti-carcinogenic effects. A COX-2 inhibitor would have advantages over MAINE as a decreased ability to induce some of the side effects based on the mechanism. In addition, it is thought that COX-2 inhibitors have a reduced potential for gastrointestinal toxicity, reduced potential for renal side effects, a reduced effect on bleeding times and a lower ability to induce asthma attacks in asthmatic subjects sensitive to aspirin. Therefore, compounds with high specificity for COX-2 and COX-1 could be useful as alternatives for conventional MAINE. This is particularly the case when the use of MAINE is contraindicated, as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; Bleeding Gl, coagulation disorders including anemia, hypoprothrombinemia, hemophilia and other bleeding problems; kidney disease and in patients about to undergo surgery or who take anticoagulants. Once it was clear that COX-1 and not COX-2 is responsible for the gastrointestinal production of Epithelial prostaglandin and an important contribution to the renal synthesis of prostaglandins, the search for selective inhibitors of COX-2 became extremely active. This quickly resulted in the recognition that several COX inhibitors, including nimesulide and Dup-697, which were known to cause little or no gastrointestinal irritation, are COX-2-selective. - The U.S. patent No. 5,409,944 (Black et al.) discloses certain novel alkane sulfonamido-indanone derivatives useful for the treatment of pain, fever, inflammation, arthritis, cancer and other diseases. Also discussed in this patent are compositions for the treatment of cyclooxygenase-2 mediated diseases comprising the novel alkane sulphone derivatives idoindanone together with a pain remedy including acetaminophen or phenacetin; an enhancer, including caffeine; an H2 antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylonetazoline, propylhexedrine or levo-deoxyeedrine; an anti-tussous including codeine, hydrocodone, caramiphen, carbetapentane or dextromethorphan; a diuretic and / or a sedative or non-sedating antihistamine. Although Black et al mention the use of an antitussive dose of two opioid analgesics (codeine and hydrocodone), they do not describe or suggest the use of their COX-2 inhibitors with analgesically effective amounts with opioid analgesics. SUMMARY OF THE INVENTION It is an object of the present invention to provide a method and pharmaceutical formulation (medicament) that allows reduced plasma concentrations of an opioid analgesic, while providing effective pain management at the same time. It is yet another object of the present invention to provide a pharmaceutical method and formulation (medication) to effectively treat patients suffering from pain with an opioid analgesic that achieves prolonged and effective pain management, while at the same time providing the opportunity to reduce side effects, dependence and tolerance that the patient might experience when undergoing treatment prolonged with an opioid It is yet another object of the present invention to provide a pharmaceutical method and formulation (medication) for the effective treatment of pain in patients by increasing the analgesic effect of an inhibitor COX-2. The present invention is directed to the surprising synergy that is obtained by the administration of an opioid analgesic together with a COX-2 inhibitor.

The present invention is related in part to analgesic pharmaceutical compositions comprising a COX-2 inhibitor together with an opioid analgesic. The opioid analgesic and the COX-2 inhibitor can be administered orally, by implantation, parenterally, sublingually, rectally, topically, by inhalation, etc. In other embodiments of the present invention, the COX-2 inhibitor can be administered separately from the opioid analgesic, as will be specified in greater detail below. The present invention allows the use of lower doses of the opioid analgesic or the COX-2 inhibitor (hereinafter referred to as "seemingly unidirectional synergy" '), or lower doses of both drugs (referred to herein as "bidirectional synergy") than would normally be required when one of these drugs is used alone. By using lower amounts of one or both drugs, the side effects associated with effective pain management in humans are significantly reduced. In certain preferred embodiments, the invention is directed in part to synergistic combinations of a COX-2 inhibitor in sufficient quantity to produce therapeutic effect in conjunction with an opioid analgesic, such that an analgesic effect is obtained which is at least 5 (and preferably and at least 10) times higher than that obtained with the dose of opioid analgesic alone, except for combinations of the COX-2 inhibitor with antitussive doses of hydrocodone or codeine. In certain embodiments, the synergistic combination provides an analgesic effect that is up to 30 to 40 times greater than that obtained with the opioid analgesic dose alone. In such modalities, synergistic combinations present what is referred to herein as "seemingly unidirectional synergy", which means that the dose of COX-2 inhibitor synergistically potentiates the opioid analgesic effect, while the opioid analgesic dose does not seems to significantly enhance the effect of the COX-2 inhibitor. In certain embodiments, the combination is administered in a single dose form. In other embodiments, the combination is administered separately, preferably concomitantly. In certain preferred embodiments, the synergy presented between the COX-2 inhibitor and the opioid analgesic is such that the dose of opioid analgesic would be subtherapeutic if administered without the COX-2 inhibitor dose. In other preferred embodiments, the present invention relates to a pharmaceutical composition comprising an analgesically effective dose of an opioid analgesic together with a dose of a COX-2 inhibitor effective to increase the analgesic effect of the opioid analgesic.

Although certain embodiments of the present invention are directed to synergistic combinations of a COX-2 inhibitor together with an opioid analgesic, when there is an apparent "unidirectional synergy", it is thought that in reality these combinations exhibit bidirectional synergy, which means that the inhibitor COX-2 potentiates the effect of the opioid analgesic, and the opioid analgesic potentiates the effect of the COX-2 inhibitor. Accordingly, other embodiments of the present invention relate to combinations of a COX-2 inhibitor and an opioid analgesic where the dose of each drug is reduced due to the synergy demonstrated between both drugs, and the analgesia derived from the drug combination in Reduced dose is increased surprisingly. Bidirectional synergy is not always immediately apparent in real doses due to the potency ratio of the opioid analgesic to the COX-2 inhibitor (which means that the opioid generally has a much higher relative analgesic potency). In certain preferred embodiments, the present invention is directed to pharmaceutical formulations comprising a COX-2 inhibitor in an amount sufficient to produce a therapeutic effect together with a therapeutically effective or subtherapeutic amount of an opioid analgesic selected from the group consisting of alfentanil, allylprodine, alphaprodin , anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxafetilbutirato, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, phenadoxone, phenazocine, phenomorphan, phenoperidine, fentanyl of etonitazene, heroin, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levalphorphan, levorphanol, levofenacillmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mirofin, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, piminodine, piritramide, profeptazine, promedol, properidin, propiram, propoxyphene, sufentanil, tilidine, tramadol, salts of these, complexes of these, mixtures of any of the foregoing, mixtures of -agonists / antagonists, combinations of mu-antagonists, sale s or complexes of these, and the like. In certain preferred embodiments, the opioid analgesic is a mu or kappa opioid agonist. In certain preferred embodiments, the present invention is directed to pharmaceutical formulations comprising a COX-2 inhibitor in an amount sufficient to produce a therapeutic effect together with a therapeutically effective or subtherapeutic amount of an analgesic. opioid selected from the group consisting of morphine, dihydrocodeine, hydromorphone, oxycodone, oxymorphone, salts thereof and mixtures of any of the foregoing. In certain preferred embodiments, the present invention is directed to pharmaceutical formulations comprising a COX-2 inhibitor in an amount sufficient to produce a therapeutic effect in conjunction with a dose of codeine that is analgesic if administered without the COX-2 inhibitor.

Such a dose of codeine is preferably between 30 to about 400 mg. In certain preferred embodiments, the present invention is directed to pharmaceutical formulations comprising a COX-2 inhibitor in an amount sufficient to produce a therapeutic effect in conjunction with a dose of hydrocodone that is analgesic if administered without the COX-2 inhibitor. Such a hydrocodone dose is preferably between 5 to about 2,000 mg, and preferably at least 15 mg of hydrocodone. The present invention further relates to a method for effectively treating pain in humans, which comprises administering to a human patient a therapeutically effective amount of a COX-2 inhibitor together with a dose of an opioid analgesic, such that the combination provides an effect analgesic that is at least about 5 (and preferably at least 10) times larger than that obtained with the dose of the opioid ansic alone. In certain embodiments, the synergistic combination provides an ansic effect that is up to 30 to 40 times greater than that obtained with the opioid ansic dose alone. In certain preferred embodiments, the doses of the COX-2 inhibitor and the opioid ansic are administered orally. In other preferred embodiments, the doses of the COX-2 inhibitor and the opioid ansic are administered in a single oral dosage form. In certain preferred embodiments, the dose of opioid ansic would be subtherapeutic if administered without the dose of COX-2 inhibitor. In other preferred embodiments, the dose of opioid ansic is effective on its own to provide ansia, but the dose of opioid ansic provides at least five times more ansic effect than typically obtained with that dose of opioid ansic alone. The present invention also relates to the use of a pharmaceutical combination of a COX-2 inhibitor together with an opioid ansic to provide effective pain management in humans. The present invention also relates to the use of a COX-2 inhibitor in the manufacture of a pharmaceutical preparation containing a COX-2 inhibitor and an opioid ansic for the treatment of pain.

The present invention also relates to the use of an opioid ansic in the manufacture of a pharmaceutical preparation containing a COX-2 inhibitor and an opioid ansic for the treatment of pain. The present invention is also directed to a method for providing effective pain management in humans, comprising administering an ansically effective or subtherapeutic amount of an opioid ansic, and administering an effective amount of a COX-2 inhibitor in an effective amount to increase the ansic effect provided by the opioid ansic. The COX-2 inhibitor can be administered before, simultaneously with, or after administration of the opioid ansic, as long as the dosage range of the COX-2 inhibitor overlaps with the dosage range of the opioid ansic (or its ansic effects). In other words, in accordance with the method of the present invention, in certain preferred embodiments it is not necessary to administer the COX-2 inhibitor in the same presentation or even by the same route of administration of the opioid ansic. Rather, the method is directed to the surprising synergistic or additive benefits obtained in humans when administering ansically effective levels of an opioid ansic in a human and, before or during the dosing interval of the opioid ansic or while the human is experiencing ansia, an effective amount of inhibitor is administered COX-2 to increase the ansic effect of the opioid ansic. If COX-2 is administered prior to administration of the opioid ansic, it is preferred that the dosing ranges of both drugs overlap, ie, that the ansic effect on at least a portion of the opioid ansic dosage range be at least partially attributable to the COX-2 inhibitor. In a further method of the present invention, the surprising synergistic and / or additive benefits obtained in humans are achieved when administered in a human ansically effective levels of a COX-2 inhibitor and, during the dosing interval for the COX-2 inhibitor. or while the human undergoes ansia by virtue of the administration of a COX-2 inhibitor, an effective amount of an opioid ansic is administered to increase the ansic effect of the COX-2 inhibitor. In yet another embodiment of the present invention, the present invention comprises a solid oral dose presentation comprising an ansically effective amount of an opioid ansic together with an amount of COX-2 inhibitor or pharmaceutically acceptable salt thereof, which increases the effect of the opioid ansic Optionally, the solid oral dose presentation includes a sustained release vehicle that causes the sustained release of the opioid analgesic, or both the opioid analgesic and the COX-2 inhibitor when the dose presentation comes into contact with gastrointestinal fluids. The sustained release dose presentation may comprise a plurality of substrates including the drugs. The substrates may comprise spheroidal matrices or may comprise pharmaceutically acceptable inert beads that are coated with the drugs. The coated beads are then preferably overcoated with a sustained release coating comprising the sustained release carrier. The spheroidal matrix can include the sustained release carrier in the matrix itself, or the matrix can comprise a normal release matrix containing the drugs, wherein the matrix has applied thereto a coating comprising the sustained release carrier. In yet other embodiments, the solid oral dose presentation comprises a tablet core containing the drugs within a normal release matrix, wherein the tablet core is coated with a sustained release coating comprising the sustained release carrier. In still other embodiments, the tablet contains the drugs within a sustained release matrix comprising the sustained release vehicle. In other embodiments, the tablet contains the opioid analgesic within a release matrix sustained and the COX-2 inhibitor coated on the tablet as an immediate release layer. In many preferred embodiments of the present invention, the pharmaceutical compositions containing the COX-2 inhibitor and the opioid analgesic specified in the present invention are administered orally. These oral dosage forms may contain one or both drugs in the form of immediate or sustained release. To facilitate its administration, the oral dosage form containing both drugs is preferred. The oral dosage forms may be in the form of tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, multi-particulate formulations, syrups, elixirs and the like. The pharmaceutical compositions containing the COX-2 inhibitor and / or opioid analgesic described above may alternatively be in the form of microparticles (ie, microcapsules, microspheres and the like), which may be injected or implanted into a human patient, or other dosage forms Implantable family members for those familiar with the technique of pharmaceutical formulations. To facilitate administration, it is preferred that such dosage forms contain both drugs. Additional pharmaceutical compositions contemplated by the present invention include transdermal dosage forms, suppositories, powders or sprays for inhalation and oral tablets. The combination of COX-2 inhibitor and opioid analgesic can also be administered by different routes of administration. It should be understood that, for purposes of the present invention, the following terms will have the following meanings: The term "effective analgesia" is defined, for purposes of the present invention as the satisfactory reduction or elimination of pain, along with the process of tolerable level of side effects, as determined by the human patient. The term "effective pain management" means, for purposes of the present invention, as the objective evaluation of the reaction of a human patient (pain experienced against side effects) to the analgesic treatment administered by the physician, as well as subjective evaluations of the therapeutic treatment. by the patient who undergoes such treatment. The connoisseur of the art will understand that effective analgesia will vary according to many factors, including individual variations from one patient to another. The term "opioid analgesic" is defined, for purposes of the present invention, such as the drug in its basic presentation, or a pharmaceutically acceptable salt or complex thereof. The term "COX-2 inhibitor" is defined, for purposes of the present invention, as the drug in its basic form, or a pharmaceutically acceptable salt or complex thereof. The term "sustained release" is defined, for purposes of the present invention, as the release of the drug (opioid analgesic) from the transdermal formulation at such a rate that the concentrations (levels) in the blood (plasma) are maintained within the therapeutic range (above the "minimum effective analgesic concentration" or "CAME") but below the toxic levels for a period of approximately 12 hours or more. The term "steady state" means that the blood plasma concentration curve for a given drug is essentially repeated from one dose to another. The term "effective minimum analgesic concentration" is defined, for purposes of the present invention, as the minimum therapeutically effective level in blood plasma of the drug at which at least some relief for pain in a given patient is achieved. Those familiar with medical technology will be well aware that the measurement of pain is highly subjective and that they can There are large individual variations between one patient and another. DETAILED DESCRIPTION OF THE INVENTION The COX-2 inhibitors useful in the present invention will have similar anti-inflammatory, antipyretic and analgesic properties as compared to non-spheroidal anti-inflammatory drugs and, in addition, will inhibit uterine contractions induced by hormones and will have anti-inflammatory effects. potential carcinogens, but they will have a diminished capacity to induce some of the side effects based on the mechanism. In particular, these COX-2 inhibitors should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a reduced ability to induce asthmatic attacks in asthmatic subjects sensitive to aspirin. It has been reported in the art and many chemical structures that COX-2 inhibitors are known as inhibitors of cyclooxygenase-2. For purposes of the present invention, the term "COX-2 inhibitor" is defined as all • compounds that would possess COX-2 inhibitory activity and that preferably possess a specificity at least 9 times higher for COX-2 than on COX-1, either in vitro (determined, for example, by IC50 measurements) or in vivo (determined, for example, by ED50 measurements). Such COX-2 inhibitors will be useful in conjunction with the present invention and are considered to be encompassed within the scope of the appended claims. Preferably, the COX-2 inhibitors used in the present invention demonstrate an in vitro IC-50 and / or in vivo ratio ED50 for COX-1 against COX-2 of about 20 times or more, preferably 100 or more or more. , in certain embodiments, more preferably from 1,000 times or more. Preferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxica, β-methoxy-2-naphatylacetic acid (β-MNA), Vioxx (MK-966), nabumetone ( prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614, or combinations thereof. There are several COX-2 inhibitors developed until mid-1998. These include meloxicam (commercially available in the UK since 1996 from Boerhinger-Ingleheim), nimesulide (launched in 1985 in Hesinn's Europe); nabumetone (6-MNA is an active metabolite) (commercially available as Relafin ™ in the US, celecoxib (SC-58635) (NDA record for Searle estimated in September 1998); Vioxx (MK-966, L745337) ( NDA record for Merck estimated in November 1998); D-1367 (Chiroscience, in Phase I in the United Kingdom); T-614 (Toyama, in Phase II in Japan and Phase I in the United Kingdom); and SC-57666 (Monsanto; in Phase I in the USA).

In clinical trials discussed at the 1996 annual meeting of the American College of Rheumatology, celecoxib was shown to be effective in patients and devoid of gastrointestinal side effects in normal volunteers (Scrip 2175, October 25, 1996, p.15). In studies in normal volunteers, 128 subjects received celecoxib, 100 mg or 200 mg twice daily, or naproxen, or placebo, for a week. In the celecoxib groups and subjects who received placebo, no gastrointestinal signs or symptoms were present, whereas in the naproxen group, 20% of the subjects experienced gastrointestinal signs and symptoms. In addition, in normal volunteers, celecoxib did not cause alterations in platelet functions. In a study in patients, 293 patients with osteoarthritis received 40 mg, 100 mg or 200 mg of celecoxib or placebo twice daily for two weeks. Celecoxib significantly reduced symptoms, and discontinuations in the higher-dose celecoxib groups were lower than with placebo. Patients with rheumatoid arthritis received 100 mg, 200 mg or 400 mg of celecoxib or placebo twice daily for four weeks. As with patients with osteoarthritis, the rating of symptoms was improved in patients receiving celecoxib compared with placebo, and discontinuations were lower in patients who took celecoxib. They were reported in the technique COX-2 inhibitors and many chemical structures that produce the inhibition of cyclooxygenase-2. COX-2 inhibitors are described in U.S. Pat. No. 5,616,601; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944 and 5,130,311, all incorporated herein by reference. Many COX-2 inhibitors can be described chemically as aryl sulfonamides. Certainly, both celecoxib and Vioxx, considered to be "super-selective", are aryl sulfonamides, and more specifically, benzenesulfonamides. These compounds will be useful in the methods and compositions of the present invention. However, the skilled artisan will appreciate that many additional COX-2 inhibitors were identified in the art and could be useful in conjunction with the methods and compositions of the present invention. The use of structure-activity relationships to evaluate COX inhibitors is problematic because these COX inhibitors are suicidal enzymes. Therefore, when analyzed in in vitro tests, the IC50 value will change with respect to time. For this reason, the IC50 published for common COX inhibitors were reported as values that vary by more than two orders of magnitude from one laboratory to another. This makes it difficult to compare the value of COX-1 inhibition obtained from a laboratory with the COX-2 inhibition value obtained from another laboratory. (See, for example, D.E. Griswold and J.L. Adams, Med. Res. Rev. 16: 181-206). Therefore, it is preferable that, when studying COX inhibitors, their relative potencies are compared, comparisons that should be made only using results from the same test, performed at the same time.

When using previously generated data, it is preferable to take data only from lists of several compounds that were generated by a single group, so that the relative powers can be determined. Table 1 below provides representative data for representative MAINE and certain COX-2 inhibitor compounds. Data were collected from several different sources, and were chosen from available laboratories, using references that report several compounds in the same document, and that contain data that is relatively compatible with data obtained from other laboratories (ie, within a range of reasonable variation, based on the understanding that the results of different laboratories can vary up to three orders of magnitude for agents that act as suicide enzymes). It should be borne in mind that most of the values reported in Table 1 are from in vitro tests (except when potency is reported as mg / kg). The literature confirms that the power proportions COX- l / COX-2 is generally kept alive, although this is not always true. For example, indomethacin is always COX-1-selective in vitro and in vivo, but naproxen, which is COX-1-selective in vitro, frequently (though not always) is COX-2-selective in vivo. In part this is due to the highly artificial conditions that are used in in vitro tests. The first two structural series were recognized as COX inhibitors that showed little ulcerogenic activity. These first compounds included the aryl sulfonamides nimesulide, NS-398 and CGP 23238, and the 1,2-diaryloheterocyclics Dup-697 and SC-58125. Griswold and Adams describes in some detail relationships between structure and activity (Med. Res. Rev. 16: 282-206, 1996).

Table 1. Selectivity of selected cyclooxygenase inhibitors for COX-1 and COX-2 Drug COX-1 COX-2 COX-l / COX-2 Ref. IC50, μM IC50, μM Aspirin 1.67 278 0.004 1 32.4 mg / kg 198 mg / kg 0.16 m Salicylate 254 725 0.36 1 Ibuprofen 4.85 72.8 0.067 1 9.2 18.3 0.5 n Naproxen 4.8 28.4 0.17 to 0.6 2.0 0.3 b 6. 6 3.9 1.7 15.6 28 0.56 n Diclofenac 0.04 0.1 0.4 2.7 20.5 0.13 1.5 1.05 1.4 0.018 0.012 1.5 e Indomethacin 0.1 0.9 0.11 d 13.5 > 1,000 < 0.013 0.0015 0.089 0.15 2.35 mg / kg 0.67 mg / kg 3.3 m S-ketoprofen 0.11 0.18 0.61 n Tenidap 0.39"47.8 0.008 f Piroxica 17.7 > 500 < 0.035 to 1.07 mg / kg 0.76 mg / kg 1.4 m Meloxicam 3.27 0.25 13 k 2.47 mg / kg 0.12 mg / kg 20 m Nimesulide 70 1.27 55 b 9.2 0.52 17.7 n NS-398 > 100 0.1 > 1,000 g 75 1.77 42 b 16.8 0.1 168 N 6-MNA 64 94 0.7 A 240 35 7 H 278 187 1.5 I CGP 28238 72.3 0.015 5, 000 E (flosulide) SC-58125 > 100 0.09 > 1,100 38. 7 0.27 143 Celecoxib 15 O.04 375 (SC-58635) Vioxx 369 1.5 246 n (L 745,337) Dup-697 0.8 0.01 80 to O. Laneuville et al, J. Pharmacol. Exp. Ther. 271: 927, 1994 b J. Barnett et al, Biochi. Biophys Acta 1209: 130, 1994 c J.R. Vane and R.M. Botting, Inflamm. Res. 44: 1, 1995 d J.K. Gierse et al, Biochem. J. 305: 479, 1995 e T. Klein et al, Biochem. Pharmacol. 48: 1605, 1994 f B. Battistini et al, Drug News Perspect. 7: 501, 1994 g R.A. Copeland et al, Proc. Nati Acad, Sci. USA 91: 11202, 1994 h E.A. Mead et al, J. Biol. Chem. 268: 6610, 1993 i. Patrignani et al, J. Pharmacol. Exp. Ther. 271: 1705, 1994 j P. Isakson et al, Adv. Prost. Throm. Res. 23:49, 1995 k M. Pairet et al, Inflamm. Res. 47: 270-276, 1998 1 J.A. Mitchell et al Proc. Nati Acad. Sci. USA 90: 11693-11697, 1994 mG. Engelhardt et al Inflamm. Res. 44: 423-433, 1995 nP. Patrignani et al J Phys Pharmacol. 48: 623-631, 1997 oTD Penning et al. J Med Chem 40: 1347-1365, 1997 For example, as reported by Famaey JP, Inflama Res 1997 Nov; 46 (11): 437-446, nimesulide, a sulfonanilide compound with anti-inflammatory properties, possessed a pharmacological profile suggesting that the compound could be a selective inhibitor of COX-2. In several in vitro assayers using purified preparations of COX-2 or COX-1, or cell preparations (of both animal and human origin) expressing COX-1 or COX-2, ten of eleven distinct groups demonstrated that nimesulide selectively inhibits COX -2. It was reported that the COX-2 / COX-1 inhibitory ratio was variable, according to the test preparation, from 0.76 to 0.0004, that is, a selectivity between 1.3 to 2.512 times higher for COX-2 than for COX-1. In addition, an in vivo whole blood assay performed with healthy volunteers demonstrated a significant drop in the production of COX-2 PGE2 without having any effect on COX-1 TXB2 production (subjects treated with nimesulide 00 mg bid for 2 weeks) against any effect on COX-2 PGE2 and an almost total suppression of COX1-TXB2 in subjects treated with aspirin (300 mg tid for 2 weeks). Nimesulide can therefore be considered a relatively selective COX-2 inhibitor. At the recommended dose of 100 mg b.i.d., it is an analgesic and anti-inflammatory agent as effective as classical MAINE, and a drug well tolerated and with few side effects according to large scale open studies and a global evaluation of a large number of controlled and uncontrolled comparative studies. A non-limiting list of opioid analgesic drugs that can be used in the present invention includes alfentanil, allylprodin, alphaprodin, anileridin, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, cyclazocine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine. , dimenoxadol, dimepheptanol, dimethylthiambutene, dioxafetilbutirato, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, phenadoxone, phenazocine, phenomorphan, phenoperidine, etonitazene fentanyl, heroin, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine meptazinol, metazocine, methadone, metopon, morphine, mirofina, nalbuphine, narcein, nicomorphine, Ñorlevorphanol, normetadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, piminodine, piritramide, profeptazine, promedol, properidin, propiram , propoxyphene, sufentanil, tilidine, tramadol, salts of these, complexes of these, mixtures of any of the foregoing, mixtures of mu-agonists / antagonists, combinations of mu-antagonists, salts or complexes thereof, and the like. In certain preferred embodiments, the opioid analgesic is a mu or kappa opioid agonist. In certain additional preferred embodiments, the opioid analgesic is a selective kappa agonist. In certain preferred embodiments, the opioid analgesic is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, diamorphone, morphine, tramadol, oxymorphone, salts thereof or mixtures thereof. The present invention specifies analgesic preparations for oral administration which provides a combination of a COX-2 inhibitor or a pharmaceutically acceptable salt thereof and an opioid analgesic or pharmaceutically acceptable salt thereof. The combination of preference provides a synergistic effect or at least additive for analgesic doses. The dose levels of COX-2 inhibitor in the range of about 0.005 mg to about 140 mg per kilogram of body weight per day are therapeutically effective in combination with an opioid analgesic. Alternatively, about 0.25 mg is administered to about 7 g per patient per day of a COX-2 inhibitor in combination with an opioid analgesic. For example, inflammation can be effectively treated by administering about 0.005 to 50 mg of the inhibitor COX-2 per kilogram of body weight per day, or alternatively from 0.25 mg to approximately 3.5 g per patient per day. The amount of COX-2 inhibitor that can be combined with vehicle materials to produce a single dose presentation with combined COX-2 inhibitor and opioid analgesic will vary depending on the patient and the particular mode of administration. For example, a formula for oral administration in humans may contain from 0.25 mg to 5 g of COX-2 inhibitor composed of an appropriate and convenient amount of carrier material which may vary from 5 to about 95 percent of the total composition . Unit doses will generally contain between about 0.5 mg to about 1,500 mg of a COX-2 inhibitor, and typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1,000 mg, etc., and up to 1,500 mg. In one embodiment, the COX-2 inhibitor is delivered in a sustained release oral dose presentation with hydromorphone as the therapeutically active opioid in an amount of between about 2 mg to about 64 mg of hydromorphone hydrochloride. Alternatively, the dosage presentation may contain molarly equivalent amounts of other hydromorphone or hydromorphone base salts. In another modality, the Opioid analgesic comprises morphine, and sustained release oral dose presentations of the present invention include from about 2.5 mg to about 800 mg morphine, by weight. In yet another embodiment, the opioid analgesic comprises oxycodone and the oral sustained release dosage forms include from about 2.5 mg to about 800 mg oxycodone. The opioid analgesic may comprise hydrocodone, and sustained release oral dose presentation may include analgesic doses of between about 8 mg to about 50 mg of hydrocodone per unit dose. The opioid analgesic may comprise tramadol and sustained release oral dose presentations may include from about 25 mg to about 800 mg tramadol per unit dose. The dose presentation may contain more than one opioid analgesic to provide an essentially equivalent therapeutic effect. Preferred combinations of the present invention comprise an effective amount of a COX-2 inhibitor selected from the group consisting of nimesulide, meloricam and flosulide, and an effective amount of an opioid analgesic selected from the group consisting of tramadol, hydromorphone, morphine, oxycodone, hydrocodone and dihydrocodeine in the proportions specified in Table 1. In certain preferred embodiments, the proportion of The aforementioned opioid analgesics and the aforementioned COX-2 inhibitors are specified in Table 1. TABLE 1 In other words, Table 1 describes tests of morphine proportions: celecoxib from about 0.001: 1 to about 1: 1; for methadone and flosulide the ratio is from about 0.0001: 1 to about 1: 1, and so on.

In certain preferred embodiments according to the present invention, an oral dose presentation including the following opioid analgesic / COX-2 inhibitor combinations is preferred: Morphine 40 mg and 40 mg flosulide; morphine 40 mg and 6 mg nimesulide; oxycodone 20 mg and 20 mg of flosulide; oxycodone 40 mg and 4 mg of nimesulide; hydromorphone 5 mg and 20 mg flosulide; or hydromorphone 5 mg and 4 mg of nimesulide. Of course, the dose administered will vary depending on known factors such as the pharmacodynamic characteristics of each agent of the combination and its mode and route of administration, and the age, health and weight of the patient. The dose will also depend on the nature and degree of the symptoms, concurrent treatment, if any, frequency of treatment and the desired result. A composition comprising any of the aforementioned combinations of opioid analgesics and COX-2 inhibitors will be administered in divided doses ranging from 2 to 6 times daily or in a sustained release presentation that provides an effective release rate to obtain the results Deceased The optimal proportions of COX-2 inhibitor and opioid analgesic are determined by conventional assays well known in the art for determining opioid and analgesic activity. For example, it can be used the phenyl-p-benzoquinone test to establish the analgesic effectiveness. The test of seizures induced by phenyl-p-benzoquinone in mice (H. Blumberg et al, 1965, Proc. Soc. Exp. Med. 118: 763-766) incorporated herein by reference; and known modifications of this test) is a conventional procedure that can be used to detect and compare the analgesic activity of different classes of analgesic drugs with good correlation with human analgesic activity. The data of the mice, when presented in an isobologram, can be translated into other species where the effective oral analgesic dose of the individual compounds is known or can be estimated. The method consists of reading the ED50 percentage dose for each dose proportion in the regression analysis curve best adjusted from the isobologram of the mice, multiplying each component by its effective dose per species, and then forming the proportion of the amount of COX-2 inhibitor and opioid analgesic. This basic correlation of analgesic properties allows us to estimate the range of human effectiveness (E.W. Pelikan, 1959, The Pharmacologist 1:73; incorporated herein by reference). The application of an equivefective model of dose substitution and a curvilinear regression analysis that uses all the data of the individual compounds and different proportions of doses for the combinations, it establishes the existence of an unexpectedly increased analgesic activity of combinations of COX-2 inhibitor and opioid analgesic, that is, the resulting activity is greater than the activity that could be expected from the sum of the activities of the individual components. The present invention encompasses immediate release dose presentations of an effective analgesic amount of a combination of a COX-2 inhibitor and an opioid analgesic. An immediate release dose presentation can be formulated as a tablet or multiparticulates that can be encapsulated. Other immediate release dose presentations known in the art may be used. The compositions of the present invention present the opportunity to obtain relief of moderate to severe pain, with or without inflammation. Due to the synergistic or additive effects provided by the combination of the present invention of opioid analgesic and COX-2 inhibitor, it may be possible to use reduced doses of the COX-2 inhibitor and the opioid analgesic. By using smaller amounts of one or both drugs, the side effects associated with each of them can be reduced in quantity and degree. In addition, the combination of the present invention avoids side effects to which certain patients are particularly sensitive.

The present invention encompasses a method for inhibiting COX-2 and treating COX-2 mediated diseases which comprises administering to a patient in need of such treatment a therapeutically effective and non-toxic amount of the COX-2 inhibitor and opioid analgesic combination of the present invention. These diseases include moderate to severe pain produced by different etiologies, including, but not limited to, pain from cancer and post-operative pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza and other viral infections, cold common, back and neck pain, dysmenorrhea, headache, tooth pain, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns and wounds. In addition, the inhibitor combination COX-2 and opioid analgesic is useful as an alternative for non-spheroidal anti-inflammatory drugs or combinations of MAINE with other drugs, particularly in cases where non-spheroidal anti-inflammatory drugs may be contraindicated, such as in patients with peptic ulcers , gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; Bleeding Gl, disorders in coagulation, including anemia such as hypoprothrombinemia, hemophilia and other bleeding problems; renal disease; preoperative or taking anticoagulants. Sustained-release dose presentations of the present invention generally achieve and sustain therapeutic levels essentially without significant increases in the intensity or degree of concurrent side effects, such as nausea, vomiting or dizziness, which are often associated with elevated blood levels of opioid analgesics. There is also evidence to suggest that the use of this dose presentation produces a lower risk of dependence. The combination of COX-2 inhibitor and oral opioid analgesic can be formulated to provide a longer duration of analgesic action, allowing a dose once a day. These formulations, at comparable daily doses of conventional immediate-release drugs, are associated with a lower incidence in the severity of adverse reactions to the drug, and can also be administered at lower daily doses than conventional oral medication, while maintaining control of the drug. pain. The combination of COX-2 inhibitor and opioid analgesic can be used in mixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carriers suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral or any other administration that is suitable and known in the art. Suitable and pharmaceutically acceptable carriers include, but are not limited to, water, saline solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatos, carbohydrates such as lactose, amylose or starch, talc magnesium stearate, silicic acid, viscous paraffin, essences, monoglycerides and diglycerides of fatty acids, fatty acid esters of pentaerythritol, hydroxymethylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents, for example lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, dyes, flavors, aromatics and the like. If desired, they can also be combined with other active agents, for example, other analgesic agents. For parenteral application, aqueous or oily solutions are particularly suitable, as well as suspensions, emulsions or implants, including suppositories. The ampoules are convenient unit doses. For oral application, tablets, dragees, drops, suppositories, or capsules and gel aggregates are particularly suitable. The compositions intended for oral use can be prepared according to any method known in the art, and such compositions can contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, an inert diluent such as lactose; granulating and disintegrating agents such as corn starch, binding agents such as starch, and lubricating agents such as magnesium stearate. The tablets can be coated or not, by known techniques, for elegance or to delay the release of the active ingredients. Formulas for oral use may also be presented as hard gelatin capsules, where the active ingredient is mixed with an inert diluent. The aqueous suspensions contain the above-specified combination of drugs, and the mixture possesses one or more suitable excipients as suspending agents, for example pharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose or natural gums. Oily suspensions may be formulated by suspending the drug combination previously identified in a vegetable or mineral oil. Oily suspensions may contain a thickening agent such as wax or cetyl alcohol. A syrup, elixir or similar can be used where a vehicle is used sweetened. Injectable solutions can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be used. It is also possible to cold-dry the active compounds and use the lyophilized compounds obtained, for example, for the preparation of products for injection. The method of treatment and pharmaceutical formulations of the present invention may further include one or more drugs in addition to a COX-2 inhibitor and an opioid analgesic, wherein the additional drugs or drugs may or may not act synergistically with them. Examples of these additional drugs include non-spheroidal inflammatory agents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, moroprofen, trioxaprofen, suprofen, aminoprofen, triaprofenic acid, fluprofen bucilloxic acid, indomethacin, sulindaco, tometin, zomepiraco, thiopinaco, zidometacin, acemetacin, fentiazaco, clidanaco, oxpinaco, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and Similar. Other additional drugs that may be included in the dose presentations of the present invention include acetaminophen, aspirin and other non-opioid analgesics.

PRESENTATIONS OF PROLONGED LEGACITY DOSE The combination of COX-2 inhibitor and opioid analgesic can be formulated as sustained or controlled oral formulation in any suitable tablet, coated tablet or multi-particle formulation familiar to those skilled in the art. The sustained release dose presentation may optionally include a sustained release vehicle that is incorporated into a matrix together with the opioid, or that is applied as a sustained release coating. The sustained release dose presentation may include the opioid analgesic in sustained release form and the COX-2 inhibitor in sustained release form or in immediate release form. The COX-2 inhibitor can be incorporated into the sustained release matrix together with the opioid; incorporated into the sustained release layer; incorporated as a separate sustained release layer or immediate release layer; or it may be incorporated as a powder, granulation, etc., into a gelatin capsule with the substrates of the present invention. Alternatively, the sustained release dosage presentation may have the COX-2 inhibitor in sustained release presentation and the opioid analgesic in sustained release presentation or immediate release presentation.

An oral dosage form according to the present invention can be supplied as, for example, granules, spheroids or beads (which will henceforth be collectively referred to as "multiparticulates") and / or particles. A number of effective multiparticles can be placed to deliver the desired dose of opioid over time in a capsule, or it can be incorporated in any other suitable oral solid form. In a preferred embodiment of the present invention, the sustained release dose presentation comprises such particles that contain or comprise the active ingredient, wherein the particles have a diameter between 0.1 mm to about 2.5 mm, preferably between 0.5 mm to about 2 mm In certain embodiments, the particles comprise normal release matrices containing the opioid analgesic with or without the COX-2 inhibitor. These particles are then coated with the sustained release vehicle in embodiments where the COX-2 inhibitor is released immediately, the COX-2 inhibitor can be included in separate normal release matrix particles, or they can be coadministered in a different immediate release composition than is wrapped in a gelatin capsule or is administered separately. In still other embodiments, the particles comprise inert beads coated with the opioid analgesic with or without the COX-2 inhibitor. Thereafter, a coating comprising the sustained release vehicle to the beads is applied as overcoating. The particles are preferably coated with a film of a material that allows the release of the opioid (or salt thereof) and, if desired, the COX-2 inhibitor, at a sustained rate in an aqueous medium. The coating film is chosen to achieve, in combination with the other specified properties, a desired rate of in vitro release. The sustained release dose presentations of the present invention should be capable of producing a continuous and resistant film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert and non-viscous. COATINGS The dose presentations of the present invention can optionally be coated with one or more materials suitable for the regulation of the release or for the protection of the formulation. In one embodiment, coatings are applied to allow pH-dependent or pH-independent release, i.e., upon exposure to gastrointestinal fluids. A pH dependent coating functions to release the opioid in desired areas of the gastrointestinal tract (Gl), that is, the stomach or small intestine, such that an absorption profile capable of providing at least twelve hours and preferably up to twenty-four hours of analgesia to a patient is provided. When a pH independent coating is desired, the coating is designed to obtain an optimum release regardless of the pH changes in the surrounding fluid, i.e., the Gl tract. It is also possible to formulate compositions that release a portion of the dose in a desired area of the Gl tract, ie the stomach, and release the remainder of the dose in another area of the Gl tract, ie, the small intestine. The formulas according to the present invention which use pH-dependent coatings to obtain formulas also impart a repeated action effect whereby the deprotected drug is coated on the enteric layer and released into the stomach, while the remainder is left in the stomach. Protected by the enteric layer, it is subsequently released in the gastrointestinal tract. The pH-dependent coatings that can be used in accordance with the present invention include shellac, cellulose acetate phthalate (FAC), polyvinyl acetate phthalate (FAPV), hydroxypropylmethylcellulose phthalate, metracrylic acid ester copolymers, zein and the like. In certain preferred embodiments, the substrate (is say, the core of the tablet and the matrix particle) containing the opioid analgesic (with or without the COX-2 inhibitor) is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures of these. The coating can be applied in the form of an organic or aqueous solution or dispersion. The coating can be applied to obtain a weight gain of between about 2 to about 25% of the substrate, in order to obtain the desired sustained release profile. Such formulations are described in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493, assigned to the assignee of the present invention and incorporated herein by reference. Other examples of sustained release formulations and coatings that may be used in accordance with the present invention include U.S. Pat. Assignee numbers 5,324,351; 5,356,467 and 5,472,712, incorporated herein by reference in their entirety. Alkyl-Acetic Polymers Cellulose materials and polymers, including alkyl celluloses, provide hydrophobic materials that are very suitable for the coating of beads according to the present invention. Simply by way of example, a preferred alkylcellulosic polymer is ethylcellulose, although the skilled artisan will appreciate that other cellulose and / or alkylcellulose polymers can be readily used, alone or in combination, as part or as a whole of a hydrophobic coating according to the present invention. A commercially available aqueous ethylcellulose dispersion is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, USA). Aquacoat® is prepared by dissolving the ethylcellulose in an organic solvent immiscible with water, and then emulsifying it in the presence of a surfactant and a stabilizer. After homogenizing it to generate smaller drops to a miera, the organic solvent is evaporated in vacuo to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing stage. In this way, before using it as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer before using it. Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, USA). This product is prepared by incorporating plasticizer in the dispersion during the manufacturing process. A hot mixture of a polymer, a plasticizer (dibutyl sebacate) and a stabilizer (oleic acid) is prepared as a homogeneous mixture, which then It is diluted with an alkaline solution to obtain an aqueous dispersion that can be applied directly on substrates. Acrylic Polymers In other preferred embodiments of the present invention, the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer, including, but not limited to, copolymers of acrylic acid and methacrylic acid, copolymers of methyl methacrylate, methacrylates of ethoxyethyl, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer , poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers. In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonium-methacrylate copolymers. Ammonium-methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of esters of acrylic and methacrylic acids with a low content of quaternary ammonia groups. In order to obtain a dissolution profile desirable, it may be necessary to incorporate two or more ammonium-methacrylate copolymers with different physical properties, such as different molar proportions of the quaternary ammonia groups against the neutral (meth) acrylic esters. Certain methacrylic acid ester type polymers are useful for preparing pH dependent coatings that can be used in accordance with the present invention. For example, there is a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available as Eudragit®, from Rohm Tech, Inc. There are several different types of Eudragit. ®. For example, Eudragit® E is an example of a methacrylic acid copolymer that expands and dissolves in acid media. Eudragit® L is a methacrylic acid copolymer that does not swell at about pH < 5.7, and is soluble at about pH > 6. Eudragit® S does not expand at approximately pH < 6.5, and is soluble at about pH > 7. Eudragit® RL and Eudragit® RS are expanded in water, and the amount of water absorbed by these polymers is pH dependent; however, dose presentations coated with Eudragit® RL and RS are pH independent. In certain preferred embodiments, the coating Acrylic comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trademarks Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with low content of ammonia quaternary groups, where the molar ratio of ammonia groups against the esters (met) neutral acrylics remaining is 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. The average molecular weight is about 150,000. The RL designation codes (high permeability) and RS (low permeability) refer to the permeability properties of these agents. The mixtures of Eudragit® RL / RS are insoluble in water and in digestive fluids. However, the coatings formed thereof are expandable and permeable in aqueous solutions and digestive fluids. The Eudragit® RL / RS dispersions of the present invention can be mixed together at any desirable ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release formulations can be obtained, for example, from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL: 90% of Eudragit® RS. Of course, the connoisseur of the The technique may recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L. Plasticizers In embodiments of the present invention wherein the coating comprises an aqueous dispersion of a hydrophobic material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of a hydrophobic material will further improve the physical properties of the sustained release coating. For example, since ethylcellulose has a relatively high glass transition temperature and does not form films, flexible under normal coating conditions, it is preferable to incorporate a plasticizer in an ethylcellulose coating containing sustained release coatings before using it as a starting material. coating. In general, the amount of plasticizer included in a coating solution is based on the concentration of the film former, ie, generally from about 1 to about 50 percent of the weight of the film former. However, the concentration of the plasticizer can be determined appropriately only after careful experimentation with the particular coating solution and its method of application. Examples of suitable plasticizers for ethylcellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and. triacetin, although it is possible to use other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.). Triethyl citrate is a plasticiser especially preferred for the aqueous dispersions of ethylcellulose of the present invention. Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to, citric acid esters, such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers shown to be suitable for increasing the elasticity of films formed from acrylic films such as Eudragit® RL / RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin. Triethyl citrate is a plasticiser especially preferred for the aqueous dispersions of ethylcellulose of the present invention. It was also discovered that the addition of small amounts of talc reduces the tendency of the aqueous dispersion to stick during the process, and acts as a polishing agent. PROCESSES FOR PREPARING COVERED ACCOUNTS When the aqueous dispersion of the material is used hydrophobic for coating inert pharmaceutical beads such as paired 18/20 beads, a plurality of the resulting stabilized controlled release solid beads can then be placed in a gelatin capsule in sufficient quantity to provide a controlled release dose when ingested and enter contact with a fluid from the environment, that is, gastric fluid or dissolution medium. The sustained release stabilized count formulations of the present invention slowly release the therapeutically active agent, i.e., when ingested and exposed to gastric fluids and then to intestinal fluids. The controlled release profile of the formulations of the present invention can be altered, for example, by varying the amount of coating with the aqueous dispersion of hydrophobic material, altering the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic material, varying the amount of plasticizer in relation to the hydrophobic material, including additional ingredients or excipients, altering the manufacturing method, etc. The dissolution profile of the final product can also be modified, for example, by increasing or decreasing the thickness of the retardant coating. Spheroids or beads coated with a therapeutically active agent are prepared by dissolving the therapeutically active agent in water and then spraying the solution In a substrate, for example, you count a pariel 18/20, using a Wuster insert. Optionally, additional ingredients are also added before the beads are coated, in order to assist in the binding of the opioid to the beads, and / or to color the solution, etc. For example, a product including hydroxypropylmethylcellulose, etc., with or without a dye (for example, Opadry®, commercially available from Colorcon, Inc.) can be added to the solution and mixed (for example, for about 1 hour) before to apply it to the accounts. The resulting coated substrate, which in this example are beads, can then optionally be overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating. An example of a suitable barrier agent is one comprising hydroxypropylmethylcellulose. However, any film former known in the art can be used. It is preferred that the barrier agent does not affect the rate of dissolution of the final product. The beads can then be overcoated with an aqueous dispersion of the hydrophobic material. The aqueous dispersion of the hydrophobic material preferably also includes an effective amount of plasticizer, for example triethyl citrate. Aqueous dispersions preformulated of ethylcellulose, such as Aquacoat® or Surelease®. If Surelease® is used, it is not necessary to separately add a plasticizer. Alternatively, preformulated aqueous dispersions of acrylic polymers such as Eudragit® can be used. The coating solutions of the present invention preferably contain, in addition to the film former, plasticizer and a solvent system (ie, water), a colorant to provide elegance and product distinction. Color can be added to the solution of the therapeutically active agent instead of, or in addition to, the aqueous dispersion of hydrophobic material. For example, color can be added to Aquacoat® through the use of alcohol-based or propylene glycol-based, milled aluminum and opaque color dispersions such as titanium dioxide by adding color with liquid to water-soluble polymer solutions and then using low liquefied with the Aquacoat® plasticized. Alternatively, any suitable method can be used to provide color to the formulations of the present invention. Suitable ingredients for providing color to the formulations when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and pigments, such as iron oxide pigments. However, the incorporation of pigments could increase the delayed effect of the coating. The plasticized aqueous dispersion of material Hydrophobic can be applied on the substrate, comprising the therapeutically active agent, by spraying by any suitable spraying equipment known in the art. In a preferred method, a fluidized bed Wurster system is used in which a jet of air, injected from below, fluidizes the core material and effects drying while spraying the acrylic polymer thereon.

Preferably, a sufficient amount of the aqueous dispersion of hydrophobic material is applied to obtain a predetermined controlled release of the therapeutically active agent when the coated substrate is exposed to aqueous solutions, i.e., gastric fluid, taking into account the physical characteristics of the therapeutically active agent , the manner of incorporation of the plasticizer, etc. After coating it with hydrophobic material, an additional coating of a film former, such as Opadry®, is optionally applied to the beads. If applied, this additional coating works to essentially reduce the agglomeration of the beads. The release of the therapeutically active agent from the controlled release formulation of the present invention can also be influenced, i.e., adjusted to a desired rate, by adding one or more release modifying agents, or by providing one or more passageways. through the coating. The proportion of material Hydrophobic versus water-soluble material is determined by, among other factors, the rate of release required and the solubility characteristics of the selected materials. Release modifiers that function as pore formers can be organic or inorganic, and include materials that can be dissolved, extracted or filtered from the coating in the environment of use. The pore formers may comprise one or more hydrophilic materials, such as hydroxypropylmethylcellulose. The sustained release coatings of the present invention can also include erosion promoting agents, such as starch and gums. The sustained release coatings of the present invention may also include materials useful for making microporous sheets in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid, in which carbonate groups recur in the polymer chain. The release modifying agent may also comprise a semipermeable polymer. In certain preferred embodiments, the release modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates and mixtures of any of the above. The sustained release coatings of the present invention may also include an output device comprising at least one passage, orifice or the like. The passage can be formed by methods such as those disclosed in U.S. Pat. numbers 3,845,770; 3,916,889; 4,063,064 and 4,088,864 (all incorporated herein by reference). The passage can have any shape, which can be round, triangular, square, elliptical, irregular, etc. Formulations of the bead matrix In other embodiments of the present invention, the controlled release formulation is achieved by a matrix having a controlled release coating as specified above. The present invention can also utilize a controlled release matrix that allows in vitro dissolution rates of the opioid within the preferred ranges and that releases the opioid in a pH dependent or pH independent manner. Suitable materials for inclusion in a controlled release matrix will depend on the method used to form the matrix. For example, a matrix in addition to the opioid analgesic and (optionally) the COX-2 inhibitor includes: hydrophilic and / or hydrophobic ISaterials, such as gums, cellulose ethers, acrylic resins, protein derived materials; the list is not intended to be exclusive, and in accordance with the present invention many hydrophobic or hydrophilic pharmaceutically acceptable materials which are capable of imparting a controlled release of the active agent and which melts (or softens to the extent necessary to be extruded) can be used. ). Substituted or unsubstituted, digestible and long chain hydrocarbons (C8-C5o, especially C? 2-C40), such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, oils and vegetable and mineral waxes and stearyl alcohol, and glycols of polyalkylene. Of these polymers, acrylic polymers are preferred, especially Eudragit® RSPO, cellulose ethers, especially hydroxyalkylocelluloses and carboxyalkylocelluloses. The oral dose presentation contains between 1% and 80% (by weight) of at least one hydrophilic or hydrophobic material. When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point of between 25 and 90 ° C. Among the long chain hydrocarbon materials, fatty alcohols are preferred (aliphatic) The oral dose presentation may contain up to 60% (by weight) of at least one long chain digestible hydrocarbon.

Preferably, the oral dose presentation contains up to 60% (by weight) of at least one polyalkylene glycol. The hydrophobic material is preferably selected from the group consisting of alkylcelluloses, polymers and copolymers of acrylic and methacrylic acid, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil or mixtures thereof. In certain preferred embodiments of the present invention, the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including, but not limited to, copolymers of acrylic acid and methacrylic acid, methyl methacrylate, copolymers of methyl methacrylate, ethoxyethyl methacrylates, methacrylate cyanoethyl, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid-alkyl-amine copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers. In other embodiments, the hydrophobic material is selected from materials such as hydroxyalkylocelluloses such as hydroxypropylmethylcellulose and mixtures of the foregoing. The preferred hydrophobic materials are insoluble in water with hydrophilic tendencies and / or hydrophobic more or less pronounced. Preferably, the hydrophobic materials useful in the present invention have a melting point of between 30 to about 200 ° C, preferably from about 45 to about 90 ° C. Specifically, the hydrophobic material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably ketostearyl alcohol), fatty acids, including, but not limited to, fatty acid esters, fatty acid glycerides (mono-, di- and triglycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials that have hydrocarbon main chains. Soluble fats include, for example, beeswax, glycol wax, carnauba wax and castor wax. For purposes of the present invention, a waxy substance is defined as any material which is normally solid at room temperature and which has a melting point of between 30 to about 100 ° C. Hydrophobic materials that can be used in accordance with the present invention include substituted or unsubstituted, digestible and long chain hydrocarbons (Cs-C50 especially Ci = -C40), such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, and natural waxes and synthetic Hydrocarbons with a melting point of between 25 and 90 ° C are preferred. Of the long chain hydrocarbon materials, fatty alcohols (aliphatic) are preferred in certain embodiments. The oral dose presentation may contain up to 60% (by weight) of at least one long chain digestible hydrocarbon. Preferably, a combination of two or more hydrophobic materials is included in the formulations of the matrices. If any additional hydrophobic material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and mixtures thereof. Examples include beeswax, carnauba wax, stearic acid and stearyl alcohol. The list is not intended to be exclusive. A particularly suitable matrix comprises at least one water-soluble hydroxyalkyl cellulose, at least one C 2 -C 36 aliphatic alcohol, preferably Ci 4 -C 22 r optionally, at least one polyalkylene glycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy (Ci to Cd) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. The amount of the at least one hydroxyalkyl cellulose in the present oral dose presentation will be determined, inter alia, by the precise rate of opioid release required.

The at least one aliphatic alcohol can be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. However, in particularly preferred embodiments of the present oral dose presentation, the at least one aliphatic alcohol is cetyl alcohol or ketostearyl alcohol. The amount of the at least one aliphatic alcohol in the present oral dose presentation will be determined, as in the previous case, by the precise rate of opioid release that is required. It will also depend on whether at least one polyalkylene glycol is present or absent in the oral dose presentation. In the absence of at least one polyalkylene glycol, the oral dose presentation preferably contains between 20 and 50% by weight of at least one aliphatic alcohol. If at least one polyalkylene glycol is present in the oral dose presentation, then the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol preferably constitutes between 20 and 55% of the weight of the total dose. In one embodiment, the ratio of, for example, the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol / polyalkylene glycol determines, to a large extent, the opioid release rate of the formulation. A proportion of the at least one hydroxyalkyl cellulose is preferred against the at least one aliphatic alcohol / polyalkylene glycol of between 1: 2 and 1: 4, and a ratio of between 1: 3 and 1: 4 is particularly preferred. The at least one polyalkylene glycol can be, for example, polypropylene glycol or, which is preferable, polyethylene glycol. The average molecular weight of the at least one polyalkylene glycol is preferably between 1,000 and 15,000, especially between 1,500 and 12,000. Another suitable controlled release matrix would comprise an alkylceiulose (especially ethylcellulose), a C12 to C3β aliphatic alcohol and, optionally, a polyalkylene glycol. In another preferred embodiment, the matrix includes a pharmaceutically acceptable combination of at least two hydrophobic materials. In addition to the above ingredients, a controlled release matrix can also contain suitable amounts of other materials, for example diluents, lubricants, binding agents, granulation aids, dyes and flavors conventional in the pharmaceutical art. PROCESSES FOR PREPARING MATRIX-BASED ACCOUNTS In order to facilitate the preparation of a solid oral release and controlled release according to the present invention, it can be used any method of preparing a family matrix formulation for those skilled in the art. Incorporation into the matrix can be effected, for example, by (a) the formation of granules comprising at least one hydroxyalkyl cellulose soluble in water and an opioid and an opioid salt; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C? 2 aliphatic alcohol to C3d; and (c) optionally compressing and forming the granules. Preferably, the granules are formed by wet granulation of the hydroxyalkyl opioid / cellulose with water. In a particularly preferred embodiment of the present process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the opioid. In yet other alternative embodiments, a spheronizing agent can be spheronized to form spheroids. Microcrystalline cellulose is preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments, in addition to the active ingredient and the spheronizing agent, the spheroids may contain a binder. Suitable binders, such as low viscosity water soluble polymers, are familiar to those skilled in the pharmaceutical art. However, the lower hydroxyalkyl cellulose soluble in water, such as hydroxypropyl cellulose. Additionally (or alternatively), the spheroids may contain a water-insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a copolymer of methacrylic acid-ethyl acrylate, or ethyl cellulose. In such embodiments, the sustained release coating will generally include a hydrophobic material such as (a) a wax, either alone or mixed with a fatty alcohol; or (b) shellac or zein. Fusion extrusion matrix Sustained-release matrices can also be prepared by melt-granulation or melt-extrusion techniques. Generally, melt granulation techniques involve melting a normally solid hydrophobic material, for example a wax, and incorporating a powdered drug therein. To obtain a sustained release dosage presentation, it may be necessary to incorporate an additional hydrophobic substance, for example ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic material. Examples of sustained release formulations prepared by melt granulation techniques can be found in U.S. Pat. No. 4,861,598, assigned to the assignee of the present invention and incorporated in its entirety to this by reference. The additional hydrophobic material may comprise one or more water-insoluble thermoplastic waxy substances, possibly mixed with one or more thermoplastic waxy substances less hydrophobic than the first, or waxy substances more insoluble in water. In order to achieve constant release, the individual waxy substances in the formulation must be essentially non-degradable and insoluble in gastrointestinal fluids during the initial release phases. Useful water-insoluble waxy substances may be those with a solubility in water of less than about 1: 5,000 (w / w). In addition to the above ingredients, a sustained release matrix can also contain suitable amounts of other materials, for example diluents, lubricants, binders, granulation aids, dyes and flavorings conventional in the pharmaceutical art. The amounts of these additional materials should be sufficient to provide the desired effect for the desired formulation. In addition to the above ingredients, a sustained release matrix incorporating melt extruded multiparticles may also contain adequate amounts of other materials, for example diluents, lubricants, binders, granulation aids, conventional dyes and flavors in the pharmaceutical art, in amounts of up to about 50% of the weight of the particles, if desired. In the Pharmaceutical excipients Handbook of the United States Pharmaceutical Association (1986), incorporated by reference herein, specific examples of pharmaceutically acceptable excipients and vehicles that can be used to formulate oral dose presentations are described. Multiparticles by melt extrusion The preparation of a melt extrusion matrix suitable for the present invention may, for example, include the steps of mixing the opioid analgesic, together with at least one hydrophobic material and preferably the additional hydrophobic material to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude it. The resulting homogeneous mixture is then extruded to form yarns. The extrudate is preferably cooled and cut into multiparticles • by any device known in the art. The threads are cooled and cut into multiparticles. The multiparticles are then divided into unit doses. The extrudate preferably has a diameter of between 0.1 to about 5 mm and provides a sustained release of the therapeutically active agent for a period of about 8 to about 24 hours. An optional process for preparing the melt extrusions of the present invention includes directly dosing a hydrophobic material in an extruder, a therapeutically active agent and an optional binder; heat the homogeneous mixture; extruding the homogeneous mixture to thereby form salts; cool the threads containing the homogeneous mixture; Cut the strands into particles with sizes between 0.1 mm to about 12 mm, and divide these particles into unit doses. In this aspect of the present invention, a relatively continuous manufacturing process is performed. The diameter of the extruder opening or outlet port can also be adjusted to vary the thickness of the extruded wires. In addition, the exit part of the extruder does not necessarily have to be round: it can be oblong, rectangular, etc. The threads can be reduced to particles using a hot cutter, guillotine, etc. The melt-extruded multiparticulate system can be, for example, in the form of granules, spheroids or lamellae, depending on the exit orifice of the extruder. For purposes of the present invention, the terms "melt extruded multiparticles", "melt extruded multiparticulate systems" and "extruded particles" "melt" refer to a plurality of units, preferably within a range of similar sizes or shapes, and containing one or more active agents and one or more excipients, preferably including a hydrophobic material as described in FIG. In this regard, the multiparticulates extruded by fusion will be in a range of length between 0.1 to approximately 12 mm, and will have a diameter of between 0.1 to approximately 5 mm.

In addition, it should be understood that melt extruded multiparticles can have any geometric shape within this range of sizes. Alternatively, the extrudate can be simply cut into desired lengths and divided into unit doses of the therapeutically active agent, without the need for the spheronization step. In a preferred embodiment, oral dose presentations are prepared to include an effective amount of multiparticular extruded by fusion within a capsule. For example, a plurality of melt extruded multiparticles may be placed in a gelatin capsule in an amount sufficient to provide an effective dose of sustained release upon ingestion and contact with the gastric fluid. In another preferred embodiment, a suitable amount of multiparticulate extrudate is compressed into an oral tablet using tablet equipment using conventional techniques. In Remington Pharmaceutical Sciences (edited by Arthur Olson), 1553-1593 (1980), incorporated herein by reference, describes techniques and compositions for forming tablets (compressed and molded), capsules (hard and soft gelatin) and pills. In yet another preferred embodiment, the extrudate can be molded into tablets as specified in U.S. Pat. No. 4,957,681 (Klimesch et al.), previously described in additional detail and incorporated herein by reference. Optionally, melt extruded multiparticulate sustained release systems or tablets may be coated, or the gelatin capsule may be further coated, with a sustained release coating such as the sustained release coatings described above. Such coatings preferably include a sufficient amount of hydrophobic material to obtain a weight gain level of between about 2 to about 30 percent, although overcoating may be greater, depending on the physical properties of the particular opioid analgesic compound being used. and the desired release rate, among other things. The melt extruded unit dose presentations of the present invention further include combinations of melt extruded multiparticles containing one or more of the therapeutically active agents previously disclosed before being encapsulated. In addition, unit dose presentations may also include an amount of an immediate release therapeutically active agent for an early therapeutic effect. The immediate release therapeutically active agent can be incorporated as separate granules within a gelatin capsule, or it can be coated on the surface of the multiparticulates upon preparation of dosage forms (i.e., controlled release coatings or matrices). The unit dose presentations of the present invention may also contain a combination of controlled release beads and multi-particle arrays to achieve a desired effect. Sustained-release formulations of the present invention preferably slowly release the therapeutically active agent, i.e., when ingested and exposed to gastric fluids, and then to intestinal fluids. The sustained release profile of the melt extruded formulations of the present invention can be altered, for example, by varying the amount of retarder, ie, hydrophobic material, by varying the amount of plasticizer relative to the hydrophobic material, by inclusion of additional ingredients or excipients, altering the manufacturing method, etc. In other embodiments of the present invention, the melt extrudate is prepared without the inclusion of the therapeutically active agent, which is subsequently added to the extrudate. Typically, in such formulations the therapeutically active agent will be mixed with the extruded matrix material, and then the mixture is tableted in order to provide a slow release formulation. Such formulations can be beneficial, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures necessary to soften the hydrophobic material and / or the retardant material. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The following examples illustrate various aspects of the present invention. They should not be interpreted in any way as limiting the appended claims. EXAMPLES 1-2 Evaluation of the combination of morphine and nabumetone (example 1) and morphine and meloxicam (example 2) In examples 1-2, the COX-2-opioid inhibitor synergy was examined by examining nabumetone (example 1) and meloxicam ( example 2) in a stretching test (convulsions) of phenylquinone (PPQ). Nabumetone is not intrinsically COX-2-selective, but it is evaluated here because its use is associated with an extremely low ulcerogenesis. Nabumetone is a prodrug, which produces the true COX-2 inhibitor, acid 6-methoxy-2-naphthylacetic (6-MNA) (see Table 1). The low ulcerogenic potential of nabumetone could be due to the pH-dependent formation of 6-MNA. This does not occur at low pH, such as those that appear in the gastric mucosa. Therefore, the COX-2 selectivity appears to be functional. In clinical studies, it was discovered that nabumetone is effective, with extremely little ulcerogenesis. In a study of patients with osteoarthritis, nabumetone was compared with diclofenac. It was found to be as effective as diclofenac (it is extremely impotent, and requires 1,500 mg daily). However, none of the 382 patients treated with nabumetone experienced gastrointestinal toxicity (S.H. Roth et al., J. Rheumatol., 21: 1118, 1994). In a report of a 1-year follow-up of patients treated with nabumetone, the incidence of ulcers was only 0. 5% (PDR 1995, p.2396). Methods: An isobolographic analysis of drug interaction in male ICR mice was performed. In time = 0, p.o. meloxicam, nabumetone or vehicle. At time (T) = 9 minutes, p.o. morphine or vehicle.

At T = 29 minutes, i.p. PPQ (phenyl-p-benzylquinone), 2 mg / kg. At T = 36 minutes, the amount of Abdominal stretches for each mouse for one minute.

At T = 40 minutes the stretches were counted again for 1 minute. There were 6 to 8 mice per dose. The morphine concentrations used for the dose reaction were 0.5, 1, 2 and 5 mg / kg. The concentrations of nabumetone used for its reaction to the dose were 20, 50, 100 and 300 mg / kg. The concentrations of meloxicam used for its reaction to the dose were 1, 3, 10 and 50 mg / kg. % Inhibition of stretching test (convulsions) PPQ was calculated as follows: = 1 -. { [# total stretches in two counts with drug] / [# total stretches in two counts with vehicle]} * 100 The ED50 (dose of the drug that caused a 50% inhibition) was determined by non-linear regression. When combinations of morphine and meloxicam or nabumetone were administered, the ratio was always set at 1:10 or 1: 1,000, respectively. For the combination studies, the following were used: morphine / nabumentone was 0.036 / 36, 0.072 / 72, 0.1 / 100 and 0.144 / 144 mg / kg, morphine / meloxicam was 0.18 / 1.8, 0.36 / 3.6, 0.72 / 7.2 and 1.44 / 14.4 mg / kg. The ED50 for each drug in the combination was determined by simple calculation of the amount of each in the combination in the ED50 combination dose. The ED50 results for example 1 (nabumetone) against morphine appear below: nabumetone: ED50 morphine = 1.86 mg / kg po (confidence interval 1.39-2.5) ED50 nabumetone = 92.1 mg / kg po (slight extrapolation) With dose reaction combination using morphine: nabumetone 1: 1,000 ED.50 morphine = 0.06 (confidence interval 0.02 to 0.17) ED50 nabumetone = 64.5 As can be seen from the ED50 results, nabumetone significantly increased the potency of morphine. While morphine did not affect the potency of nabumetone in a statistically significant way, it did change ED50 results in a measure suggesting that increasing the ratio of nabumetone to morphine could result in bidirectional synergy. In view of such a result, the combination of a much more potent COX-2 inhibitor, such as celecoxib, will provide a statistically significant bidirectional synergy. In such combination, it will be seen that the opioid will significantly enhance the analgesic efficacy of celecoxib. The ED50 results for example 2 (meloxicam) appear below: meloxicam: ED50 morphine = 1.86 mg / kg po ED50 meloxicam = 15.2 mg / kg po (slight extrapolation) With reaction to the combination dose using morphine: meloxicam 1:10 ED50 morphine = 0.62 ED50 meloxicam = 6.22 As can be seen from the results ED50, meloxicam significantly increased the potency of morphine, while morphine did not affect the potency of meloxicam. However, morphine allowed meloxicam to have a better efficacy: inhibition of 72% against 45%. The data obtained from Examples 1-2 are represented in Figure 1, which is a graph showing the percentage of inhibition (ED50) plotted against the dose (mg / kg). Figure 1 includes graphs of dose-response data for nabumetone, meloxicam and morphine by themselves, and for combinations of nabumetone + morphine and meloxicam + morphine. As can be seen from the results shown in Figure 1, morphine did not change the reaction to the dose of nabumetone or meloxicam. However, nabumetone and meloxicam both changed the reaction to the dose for morphine (indicated by arrows). The interaction of orphine and flusolide can be demonstrated by an isobologram (See, for example, S.

Loewe, Pharm. Rev. 9: 237 (1957) in regard to the preparation and base of an isobologram; incorporated herein by reference). Figure 2 is an isobologram for nabumetone in interaction with morphine (95% confidence intervals are included). The diagonal line joining the ED50 values of the two drugs administered separately represents the simple additivity of effects at different component proportions. The ED50 values that fall under the curve (between the line and the origin) indicate superadditivity. As can be seen in Figure 2, the combination of nabumetone and morphine presented a synergy that supports the proportions of the combinations of these drugs set forth in Table II. Figure 3 is an isobologram for meloxicam in interaction with morphine (95% confidence intervals included). As can be seen in Figure 3, the combination of nabumetone and morphine presented a synergy that supports the proportions of the combinations of these drugs set forth in Table II. It is known in the art that the data for mice, as presented in an isobologram, can be translated into other species where the effective oral analgesic dose of the individual compounds is known or can be estimated. Therefore, the person skilled in the art will appreciate that this basic correlation of properties Analgesics allows an estimation of the ranges of human effectiveness. Conclusion Although the present invention was described and illustrated with reference to certain preferred embodiments, those skilled in the art will appreciate that obvious modifications can be made to the present invention without thereby departing from the spirit and scope of the present invention. For example, effective doses and specific pharmacological reactions may vary depending on the proportions of the opioid in particular against the inhibitor.

COX-2 in particular that were used, as well as the formulation and mode of administration. Such variations are contemplated within the scope of the appended claims.

Claims (13)

1. A pharmaceutical composition comprising a combination of a COX-2 inhibitor in an amount sufficient to produce a therapeutic effect in conjunction with an opioid analgesic, except for combinations of the COX-2 inhibitor with an antitussive dose of hydrocodone or codeine.

2. The pharmaceutical composition according to claim 1, wherein an analgesic effect is obtained that is at least 5 times greater than that obtained with the dose of opioid analgesic alone.

3. The pharmaceutical composition according to claim 1, wherein the dose of opioid analgesic would be subtherapeutic if administered without the COX-2 inhibitor.

4. The pharmaceutical composition according to claim 1, wherein the opioid analgesic and the COX-2 inhibitor are administered orally, by implant, parenterally, sublingually, rectally, topically or by inhalation.

5. The pharmaceutical composition according to claim 1, wherein the therapeutically effective or subtherapeutic amount of an opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodin, anileridin, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihidrornorfina, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxafetilbutirato, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, phenadoxone, phenazocine, phenomorphan, phenoperidine, fentanyl etonitazene, heroin, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levalorphan, levorphanol, levofenacillmorph, lofentanil, meperidine, eptazinol, metazocine, methadone, metopon, morphine, mirofin, nalbuphine, narcein, nicomorphine, norlevorphanol, normetadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, piminodine, piritramide, profeptazine, promedol, properidin, propiram, propoxyphene, sufentanil, tilidine, tramadol, salts of these, complexes of these and mixtures of any of the foregoing.

6. The pharmaceutical composition according to claim 1, wherein the opioid analgesic is selected from the group consisting of mu-agonists, kappa-agonists, mixtures of mu-agonists / antagonists, combinations of mu-antagonists, salts thereof, complexes of these and mixtures of these.

7. The pharmaceutical composition according to claim 1, selected from the group consisting of a tablet, a multiparticulate formulation for oral administration, a solution, suspension or elixir for oral administration, an injectable formulation, an implantable device, a topical preparation, a suppository, a buccal tablet or a formulation for inhalation.

8. The pharmaceutical composition according to claim 1, which is an oral solid dosage form formulated as a tablet or capsule. The pharmaceutical composition according to claim 1, comprising a therapeutically effective or subtherapeutic amount of an opioid analgesic selected from the group consisting of morphine, methadone, meperidine, levorphanol, codeine, hydrocodone, dihydrocodeine, hydromorphone, oxycodone, oxymorphone, salts of these and mixtures of any of the above. The pharmaceutical composition according to claim 1, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, Vioxx (L 745,337), 6-methoxy-2-naphthylacetic acid (6-MNA), MK-966, nabumetone, nimesulide, NS-398, SC-5766. SC-58215, T-614, and mixtures thereof. 11. The pharmaceutical composition according to claim 1, comprising a COX-2 inhibitor in sufficient quantity to produce a therapeutic effect together with a dose of hydrocodone which is analgesic if it is administered without the COX-2 inhibitor. 12. The pharmaceutical composition according to claim 11, where the dose of hydrocodone is preferably between 15 to about 2,000 mg. The pharmaceutical composition according to claim 1, comprising a COX-2 inhibitor in an amount sufficient to produce a therapeutic effect together with a dose of codeine which is analgesic if administered without the COX-2 inhibitor. 1 . The pharmaceutical composition according to claim 13, wherein the dose of codeine is between 30 to about 400 mg. The pharmaceutical composition according to claim 1, comprising an opioid analgesic selected from the group consisting of morphine, methadone, meperidine, levorphanol, hydrocodone, hydromorphone, oxycodone, and codeine, together with a COX-2 inhibitor selected from the group consisting in celecoxib, flosulide, meloxicam, nabumetone, nimesulide, T614 and MK966, in the proportions specified in Table 1. 16. The pharmaceutical composition according to claim 1, wherein the dose of COX-2 inhibitor synergistically potentiates the effect of the analgesic. opioid, but the dose of opioid analgesic does not seem to significantly enhance the effect of the COX-2 inhibitor. 17. The pharmaceutical composition according to claim 8, wherein the oral solid dosage form includes a sustained release vehicle that causes sustained release of the COX-2 inhibitor, the opioid analgesic, or the opioid analgesic and the COX- inhibitor. 2 simultaneously, when the dosage form comes into contact with gastrointestinal fluids. 18. A method for effectively treating pain in humans and other mammals, comprising administering to the patient a therapeutically effective amount of a COX-2 inhibitor together with a dose of opioid analgesic. The method of claim 18, wherein the combination provides an analgesic effect that is at least 5 times greater than that obtained with the dose of opioid analgesic alone. The method of claim 18, wherein the dose of COX-2 inhibitor and the opioid analgesic is administered orally. The method of claim 18, wherein the dose of COX-2 inhibitor and the opioid analgesic is administered in a single oral dosage form. 22. The method of claim 18, wherein the dose of opioid analgesic would be subtherapeutic if administer without the dose of COX-2 inhibitor. The method of claim 18, wherein the dose of opioid analgesic is effective on its own to provide analgesia, but the dose of opioid analgesic provides an analgesic effect at least five times greater than that typically obtained with the dose of opioid analgesic by Yes, alone. 24. The use of a pharmaceutical combination of a COX-2 inhibitor together with an opioid analgesic to provide effective pain management in humans. 25. The use of a COX-2 inhibitor in the manufacture of a pharmaceutical preparation containing a COX-2 inhibitor and an opioid analgesic for the treatment of pain. 26. The use of an opioid analgesic in the manufacture of a pharmaceutical preparation containing a COX-2 inhibitor and an opioid analgesic for the treatment of pain. The method of claim 18, wherein the COX-2 inhibitor is administered before, simultaneously with or after the administration of the opioid analgesic, such that the dosage range of the COX-2 inhibitor overlaps with the dosage range of the opioid analgesic. . 28. A method for reducing the amount of opioid analgesic required to treat a pain-affected patient, which comprises coadministering with the opioid analgesic an effective amount of a COX-2 inhibitor, to increase the analgesia attributable to the opioid analgesic during at least a portion of the opioid analgesic dosage range. 2

9. A method for reducing the amount of COX-2 inhibitor required to treat a pain-affected patient, comprising co-administering with the COX-2 inhibitor an effective amount of an opioid analgesic, to increase the analgesia attributable to the COX-2 inhibitor. during at least a portion of the dosage range of the COX-2 inhibitor.