Analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor

专利摘要:
The invention relates to the use of a combination of an opioid analgesic together with a COX-2inhibitor.
公开号:EP1518555A1
申请号:EP04027114
申请日:1998-09-17
公开日:2005-03-30
发明作者:Ronald M. Burch；Richard S Sackler；Paul D. Goldenheim
申请人:Euro Celtique SA；
IPC主号:A61K45-00

专利说明:
[0001] The invention relates to analgesic pharmaceutical compositions containing anopioid analgesic and a cyclooxygenase-2 (COX-2) inhibitor. The invention also relatesto methods of treating pain comprising administering such pharmaceuticalcompositions to human patients. BACKGROUND OF THE INVENTION
[0002] There is a continuing need for analgesic medications able to provide highefficacy pain relief while reducing the possibility of undesirable effects. Non-steroidalanti-inflammatory drugs ("NSAID'S"), including compounds such as ibuprofen,ketoprofen and diclofenac, have anti-inflammatory actions and are effective on painassociated with the release of prostaglandins and other mediators of inflammation.For example, diclofenac is considered to be extremely potent and effective as ananalgesic and anti-inflammatory agent. Diclofenac is approved in the United States forthe long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis andankylosing spondylitis. It is also considered to be useful for the short-term treatment ofacute musculoskeletal injury, acute painful shoulder, postoperative pain anddysmenorrhea. However, NSAID'S such as diclofenac produce side effects in about20% of patients that require cessation of medication. Side effects include, for example,gastrointestinal bleeding and the abnormal elevation of liver enzymes.
[0003] The opioids are a group of drugs, both natural and synthetic, that are employedprimarily as centrally-acting analgesics and are opium or morphine-like in theirproperties (Gilman et al., 1980, GOODMAN AND GILMAN'S. THEPHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 24:494-534, Pub.Pergamon Press; hereby incorporated by reference). The opioids include morphine andmorphine-like homologs, including, e.g., the semisynthetic derivatives codeine(methylmorphine) and hydrocodone (dihydrocodeinone) among many other such derivatives. Morphine and related opioids exhibit agonist activity at central nervoussystem or CNS (referring to the brain and spinal cord) µ (mu) opioid receptors as wellas showing affinity for the δ and κ opioid receptors, to produce a range of effectsincluding analgesia, drowsiness, changes in mood and mental clouding. In addition topotent analgesic effects, the morphine-related opioids may also cause a number ofundesirable effects, including, for example, respiratory depression, nausea, vomiting,dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary tractpressure, urinary retention and hypotension. The development of tolerance to theopioid drugs and the risk of chemical dependence and abuse for these drugs is anotherundesirable effect.
[0004] Morphine, which has been considered the prototypic opioid analgesic, has beenavailable in many dosage forms, including immediate release oral dosage forms, andmore recently, formulated into 12 hour controlled release formulations (e.g., MSContin® tablets, commercially available from Purdue Frederick Company). Otheropioid analgesics have been available as immediate release oral dosage forms, such ashydromorphone (e.g., Dilaudid®, commercially available from Knoll Pharmaceuticals).More recently, another controlled release opioid analgesic, oxycodone, has becomeavailable ( OxyContin®, commercially available from Purdue Pharma). There are, ofcourse, many other oral formulations of immediate release and sustained releaseopioids which are commercially available throughout the world.
[0005] Prior publications report that analgesic potency may be improved whilereducing undesirable effects by combining an opioid with an NSAID or an analgesicsuch as acetylsalicylic acid or acetaminophen, in such a way as to obtain a synergisticanalgesic effect allowing for a reduction in the total dose of both the NSAID andanalgesic. For example, U.S. patent number 4,569,937, issued to Baker et al. onFebruary 11, 1986, describes a combination of oxycodone with ibuprofen in a ratio ofoxycodone/ibuprofen from 1:6 to about 1:400. U.S. patent number 4,690,927, issued toVoss et al. on September 1, 1987, describes a combination of the NSAID diclofenacand codeine in a weight ratio of diclofenac to codeine of about 1:1 to about 3:1. U.S.patent number 5,190,947, issued to Riess et al. on March 2, 1993, describes adiclofenac-codeine salt ([2-[2,6-dichlorophenyl)-amino]-phenyl]-acetic acid). U.S. patent number 4,844,907, issued to Elger et al. on July 4, 1989, describes a multiphasetablet combining a narcotic analgesic phase and an NSAID phase in separate layers.U.S. patent number 4,587,252, issued to Arnold et al. on May 6, 1986, describes aprocess for treating pain using a combination of hydrocodone and ibuprofen.
[0006] Non-steroidal, anti-inflammatory drugs (NSAID'S) exert most of their anti-inflammatory,analgesic and antipyretic activity and inhibit hormone-induced uterinecontractions and certain types of cancer growth through inhibition of prostaglandin G/Hsynthase, also known as cyclooxygenase.
[0007] Fatty acid cyclooxygenase (COX) was described as the source ofprostaglandins, thromboxanes, and a variety of other arachidonic acid-, and higherdesaturated fatty acid-derived biologically active hydroxylated metabolites. Beginningin the late 1960's, B. Sammuelsson, S. Bergstrom and their colleagues discovered thebiological activity and elucidated the structures of the products of cyclooxygenase. Inthe late 1960's and early 1970's, J. Vane discovered that aspirin and other NSAIDsexert their major biological activities by inhibiting cyclooxygenase. COX is directlyresponsible for the formation of PGG and PGH and these serve as the intermediates inthe synthesis of PGD, PGE, PGF, PGI, and TXA. By the late 1970's and early 1980's,it was appreciated that many hormones and other biologically active agents couldregulate the cellular activity of COX. At first, it was assumed that COX induction wasthe simple result of oxidative inactivation of COX,which happens after only a fewsubstrate turnovers. This is common among enzymes that incorporate molecularoxygen into their substrates ― the oxygen rapidly degrades the enzyme. Such enzymesare sometimes referred to as suicide enzymes. In response to the rapid (within seconds)inactivation of cyclooxygenase, its message is transcribed, and the enzyme is rapidlyinduced to replace that lost due to catalysis. It was noticed by several groups thatcyclooxygenase was induced to a much greated degree than necessary to replace thelost enzyme. Using an oligonucleotide directed to the cloned COX-1 enzyme, a secondband was identified on Northern blots under low stringency. This gene was cloned andidentified as a second COX enzyme, named COX-2, and was found to be largely absentfrom many cells under basal conditions but rapidly induced by several cytokines andneurotransmitters. The expression of this enzyme was found to be largely responsible for the previously-observed excess COX activity in activated cells. The genes for COX-1and COX-2 are distinct, with the gene for COX-1 being 22 kb and the message size2.8 kb whereas the gene for COX-2 is 8.3 kb and the message size 4.1 kb. Whereas theCOX-1 promoter does not contain recognized transcription factor binding sites, theCOX-2 promoter contains sites for NF-κB, AP-2, NF-IL-6 and glucocorticoids (H.R.Herschman, Canc. Metas. Rev. 13: 256, 1994). There are some differences in the activesites of the enzymes. Aspirin inhibits the cyclooxygenase activity of COX-1 but leavesintact its peroxidase activity, whereas aspirin converts COX-2 from a cyclooxygenaseto a 15-lipoxygenase (E.A. Meade et al, J. Biol. Chem. 268: 6610, 1993).
[0008] It has been proposed that the COX-1 is responsible, in many cells forendogenous basal release of prostaglandins and is important in the physiologicalfunctions of prostaglandins which include the maintenance of gastrointestinal integrityand renal blood flow. Inhibition of COX-1 causes a number of side effects includinginhibition of platelet aggregation associated with disorders of coagulation, andgastrointestinal toxicity with the possibility of ulcerations and of hemorrhage. It isbelieved that the gastrointestinal toxicity is due to a decrease in the biosynthesis ofprostaglandins which are cytoprotective of the gastric mucosa.
[0009] A high incidence of side effects has historically been associated with chronicuse of classic cyclooxygenase inhibitors, all of which are about equipotent for COX-1or COX-2, or which are COX-1-selective. While renal toxicity occurs, it usuallybecomes evident in patients who are already exhibit renal insufficiency (D.Kleinknecht, Sem. Nephrol. 15: 228, 1995). By far, the most prevalent and morbidtoxicity is gastrointestinal. Even with relatively nontoxic drugs such as piroxicam, upto 4 % of patients experience gross bleeding and ulcertaion (M.J.S. Langman et al,Lancet 343: 1075, 1994). In the United States, it is estimated that some 2000 patientswith rheumatoid arthritis and 20,000 patients with osteoarthritis die each year due togastrointestinal side effects related to the use of COX inhibitors. In the UK, about 30% of the annual 4000 peptic ulcer-related deaths are attributable to COX inhibitors(Scrip 2162, p.17). COX inhibitors cause gastrointestinal and renal toxicity due to theinhibition of synthesis of homeostatic prostaglandins responsible for epithelial mucusproduction and renal blood flow, respectively.
[0010] The second form of cyclooxygenase, COX-2, is rapidly and readily inducibleby a number of agents including mitogens, endotoxins, hormones, cytokines andgrowth factors.
[0011] It has been proposed that COX-2 is mainly responsible for the pathologicaleffects of prostaglandins, which arise when rapid induction of COX-2 occurs inresponse to such agents as inflammatory agents, hormones, growth factors, andcytokines. A selective inhibitor of COX-2 therefore would have anti-inflammatory,antipyretic and analgesic properties similar to those of a conventional non-steroidalanti-inflammatory drug (NSAID). Additionally, a COX-2 inhibitor would inhibithormone-induced uterine contractions and have potential anti-cancer effects. A COX-2inhibitor would have advantages over NSAID'S such as a diminished ability to inducesome of the mechanism-based side effects. Moreover, it is believed that COX-2inhibitors have a reduced potential for gastrointestinal toxicity, a reduced potential forrenal side effects, a reduced effect on bleeding times and a lessened ability to induceasthma attacks in aspirin-sensitive asthmatic subjects.
[0012] Thus, compounds with high specificity for COX-2 over COX -1, may be usefulas alternatives to conventional NSAID'S. This is particularly the case when NSAIDuse is contra-indicated, such as in patients with peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinallesions; GI bleeding, coagulation disorders including anemia, hypoprothrombinemia,haemophelia or other bleeding problems; kidney disease, and patients about to undergosurgery or taking anticoagulants.
[0013] Once it became clear that COX-1 but not COX-2 is responsible forgastrointestinal epithelial prostaglandin production and a major contributor to renalprostaglandin synthesis, the search for selective COX-2 inhibitors became extremelyactive. This led very quickly to the recognition that several COX inhibitors, includingnimesulide and Dup-697, which were known to cause little or no gastrointestinalirritation, are COX-2-selective.
[0014] U.S. Patent No. 5,409,944 (Black, et al.) describes certain novel alkane-sulfonamido-indanonederivatives useful for the treatment of pain, fever, inflammation,arthritis, cancer, and other disease states. Also discussed therein are compositions for the treatment of cyclooxygenase-2-mediated diseases comprising the therein-describednovel alkane-sulfonamidoindanone derivatives together with a pain reliever includingacetaminophen or phenacetin; a potentiator including caffeine; an H2-antagonist,aluminium or magnesium hydroxide, simethicone, a decongestant includingphenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinephrine,naphazoline, xylonetazoline, propylhexedrine, or levo-desoxy ephedrine; an antitussiveincluding codeine, hydrocodone, caramiphen, carbetapentane or dextromethorphan; adiuretic and/or a sedating or non-sedating antihistamine. While Black et al. mention theuse of an antitussive dose of two opioid analgesics (codeine and hydrocodone), they donot describe or suggest the use of their COX-2 inhibitors with analgesically effectiveamounts of any opioid analgesics. SUMMARY OF THE INVENTION
[0015] It is an object of the present invention to provide a method and pharmaceuticalformulation (medicament) which allows for reduced plasma concentrations of an opioidanalgesic, while still providing effective pain management.
[0016] It is a futher object of the present invention to provide a method andpharmaceutical formulation (medicament) for effectively treating patients in pain withan opioid analgesic which achieves prolonged and effective pain management, while atthe same time provides the opportunity to reduce side effects, dependence and tolerancewhich the patients may experience when subjected to prolonged treatment with anopioid.
[0017] It is yet a further object to provide a method and pharmaceutical formulation(medicament) for the effective treatment of pain in patients by augmenting theanalgesic effect of a COX-2 inhibitor.
[0018] The invention is directed to the surprising synergy obtained via theadministration of an opioid analgesic together with a COX-2 inhibitor.
[0019] The present invention is related in part to analgesic pharmaceuticalcompositions comprising a COX-2 inhibitor together with an opioid analgesic. Theopioid analgesic and COX-2 inhibitor can be administered orally, via implant,parenterally, sublingually, rectally, topically, via inhalation, etc. In other embodiments of the invention, the COX-2 inhibitor can be administered separately from the opioidanalgesic, as set forth in more detail below.
[0020] The invention allows for the use of lower doses of the opioid analgesic or theCOX-2 inhibitor (referred to as "apparent one-way synergy" herein), or lower doses ofboth drugs (referred to as "two-way synergy" herein) than would normally be requiredwhen either drug is used alone. By using lower amounts of either or both drugs, theside effects associated with effective pain management in humans are significantlyreduced.
[0021] In certain preferred embodiments, the invention is directed in part to synergisticcombinations of a COX-2 inhibitor in an amount sufficient to render a therapeuticeffect together with an opioid analgesic, such that an an analgesic effect is attainedwhich is at least about 5 (and preferably at least about 10) times greater than thatobtained with the dose of opioid analgesic alone, except for combinations of the Cox-2inhibitor with anti-tussive doses of hydrocodone or codeine. In certain embodiments,the synergistic combination provides an analgesic effect which is up to about 30-40times greater than that obtained with the dose of opioid analgesic alone. In suchembodiments, the synergistic combinations display what is referred to herein as an"apparent one-way synergy", meaning that the dose of COX-2 inhibitor synergisticallypotentiates the effect of the opioid analgesic, but the dose of opioid analgesic does notappear to significantly potentiate the effect of the COX-2 inhibitor. In certainembodiments, the combination is administered in a single dosage form. In otherembodiments, the combination is administered separately, preferably concomitantly. Incertain preferred embodiments, the synergism exhibited between the COX-2 inhibitorand the opioid analgesic is such that the dosage of opioid analgesic would be sub-therapeuticif administered without the dosage of COX-2 inhibitor. In other preferredembodiments, the present invention relates to a pharmaceutical composition comprisingan analgesically effective dose of an opioid analgesic together with a dose of a COX-2inhibitor effective to augment the analgesic effect of the opioid analgesic.
[0022] Although certain embodiments of the invention are directed to synergisticcombinations of a COX-2 inhibitor together with an opioid analgesic, where there is anapparent "one-way synergism", it is believed that in actuality these combinations exhibit two-way synergism, meaning that the COX-2 inhibitor potentiates the effect ofthe opioid analgesic, and the opioid analgesic potentiates the effect of the COX-2inhibitor. Thus, other embodiments of the invention relate to combinations of a COX-2inhibitor and an opioid analgesic where the dose of each drug is reduced due to thesynergism demonstrated between the drugs, and the analgesia derived from thecombination of drugs in reduced doses is surprisingly enhanced. The two-waysynergism is not always readily apparent in actual dosages due to the potency ratio ofthe opioid analgesic to the COX-2 inhibitor (meaning that the opioid generally displaysmuch greater relative analgesic potency).
[0023] In certain preferred embodiments, the invention is directed to pharmaceuticalformulations comprising a COX-2 inhibitor in an amount sufficient to render atherapeutic effect together with a therapeutically effective or sub-therapeutic amount ofan opioid analgesic selected from the group consisting of alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine,propiram, propoxyphene, sufentanil, tilidine, tramadol, salts thereof, complexes thereof;mixtures of any of the foregoing, mixed mu-agonists/antagonists, mu-antagonist combinations,salts or complexes thereof, and the like. In certain preferred embodiments,the opioid analgesic is a mu or kappa opioid agonist. In certain preferred embodiments,the invention is directed to pharmaceutical formulations comprising a COX-2 inhibitorin an amount sufficient to render a therapeutic effect together with a therapeuticallyeffective or sub-therapeutic amount of an opioid analgesic selected from the group consisting of morphine, dihydrocodeine, hydromorphone, oxycodone, oxymorphone,salts thereof, and mixtures of any of the foregoing.
[0024] In certain preferred embodiments, the invention is directed to pharmaceuticalformulations comprising a COX-2 inhibitor in an amount sufficient to render atherapeutic effect together with a dose of codeine which is analgetic if administeredwithout the COX-2 inhibitor. Such a dose of codeine is preferably from about 30 toabout 400 mg.
[0025] In certain preferred embodiments, the invention is directed to pharmaceuticalformulations comprising a COX-2 inhibitor in an amount sufficient to render atherapeutic effect together with a dose of hydrocodone which is analgetic ifadministered without the COX-2 inhibitor. Such a dose of hydrocodone is preferablyfrom about 5 to about 2000 mg, and preferably at least about 15 mg hydrocodone.
[0026] The invention further relates to a method of effectively treating pain in humans,comprising administering to a human patient a therapeutically effective amount of aCOX-2 inhibitor together with a dose of an opioid analgesic, such that the combinationprovides an analgesic effect which is at least about 5 (and preferably at least about 10)times greater than that obtained with the dose of opioid analgesic alone. In certainembodiments, the synergistic combination provides an analgesic effect which is up toabout 30-40 times greater than that obtained with the dose of opioid analgesic alone. Incertain preferred embodiments, the doses of the COX-2 inhibitor and the opioidanalgesic are administered orally. In further preferred embodiments, the doses of theCOX-2 inhibitor and the opioid analgesic are administered in a single oral dosage form.In certain preferred embodiments, the dose of opioid analgesic would be sub-therapeuticif administered without the dose of COX-2 inhibitor. In other preferredembodiments, the dose of opioid analgesic is effective to provide analgesia alone, butthe dose of opioid provides at least a five-fold greater analgesic effect than typicallyobtained with that dose of opioid alone.
[0027] The invention further relates to the use of a pharmaceutical combination of aCOX-2 inhibitor together with an opioid analgesic to provide effective painmanagement in humans.
[0028] The invention further relates to the use of a COX-2 inhibitor in the manufacture of a pharmaceutical preparation containing a COX-2 inhibitor and an opioid analgesicfor the treatment of pain.
[0029] The invention further relates to the use of an opioid analgesic in themanufacture of a pharmaceutical preparation containing a COX-2 inhibitor and anopioid analgesic for the treatment of pain.
[0030] The invention is also directed to a method for providing effective painmanagement in humans, comprising administering an analgesically effective or sub-therapeuticamount of an opioid analgesic; and administering an effective amount of aCOX-2 inhibitor in an amount effective to augment the analgesic effect provided bysaid opioid analgesic. The COX-2 inhibitor can be administered before, simultaneouslywith, or after administration of the opioid analgesic, as long as the dosing interval of theCOX-2 inhibitor overlaps with the dosing interval of the opioid analgesic (or itsanalgesic effects). In other words, according to the method of the present invention, incertain preferred embodiments the COX-2 inhibitor need not be administered in thesame dosage form or even by the same route of administration as the opioid analgesic.Rather, the method is directed to the surprising synergistic and/or additive benefitsobtained in humans, when analgesically effective levels of an opioid analgesic havebeen administered to a human, and, prior to or during the dosage interval for the opioidanalgesic or while the human is experiencing analgesia, an effective amount of COX-2inhibitor to augment the analgesic effect of the opioid analgesic is administered. If theCOX-2 is administered prior to the administration of the opioid analgesic, it is preferredthat the dosage intervals for the two drugs overlap, i.e., such that the analgesic effectover at least a portion of the dosage interval of the opioid analgesic is at least partlyattributable to the COX-2 inhibitor.
[0031] In an additional method of the invention, the surprising synergistic and/oradditive benefits obtained in humans are achieved when analgesically effective levelsof a COX-2 inhibitor have been administered to a human, and, during the dosageinterval for the COX-2 inhibitor or while the human is experiencing analgesia by virtueof the administration of a COX-2 inhibitor, an effective amount of an opioid analgesicto augment the analgesic effect of the COX-2 inhibitor is administered.
[0032] In a further embodiment of the present invention, the invention comprises an oral solid dosage form comprising an analgesically effective amount of an opioidanalgesic together with an amount of a COX-2 inhibitor or pharmaceutically acceptablesalt thereof which augments the effect of the opioid analgesic.
[0033] Optionally, the oral solid dosage form includes a sustained release carrier whichcauses the sustained release of the opioid analgesic, or both the opioid analgesic and theCOX-2 inhibitor when the dosage form contacts gastrointestinal fluid. The sustainedrelease dosage form may comprise a plurality of substrates which include the drugs.The substrates may comprise matrix spheroids or may comprise inert pharmaceuticallyacceptable beads which are coated with the drugs. The coated beads are then preferablyovercoated with a sustained release coating comprising the sustained release carrier.The matrix spheroid may include the sustained release carrier in the matrix itself; or thematrix may comprise a normal release matrix containing the drugs, the matrix having acoating applied thereon which comprises the sustained release carrier. In yet otherembodiments, the oral solid dosage form comprises a tablet core containing the drugswithin a normal release matrix, with the tablet core being coated with a sustainedrelease coating comprising the sustained release carrier. In yet further embodiments,the tablet contains the drugs within a sustained release matrix comprising the sustainedrelease carrier. In yet further embodiments, the tablet contains the opioid analgesicwithin a sustained release matrix and the COX-2 inhibitor coated into the tablet as animmediate release layer.
[0034] In many preferred embodiments of the invention, the pharmaceuticalcompositions containing the COX-2 inhibitors and opioid drugs set forth herein areadministered orally. Such oral dosage forms may contain one or both of the drugs inimmediate or sustained release form. For ease of administration, it is preferred that theoral dosage form contains both drugs. The oral dosage forms may be in the form oftablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, multiparticulate formulations, syrups, elixirs, and the like.
[0035] The pharmaceutical compositions containing the COX-2 and/or the opioid drugsset forth herein may alternatively be in the form of microparticles (e.g., microcapsules,microspheres and the like), which may be injected or implanted into a human patient,or other implantable dosage forms known to those skilled in the art of pharmaceutical formulation. For ease of administration, it is preferred that such dosage forms containboth drugs.
[0036] Additional pharmaceutical compositions comtemplated by the invention furtherinclude transdermal dosage forms, suppositories, inhalation powders or sprays, andbuccal tablets.
[0037] The combination of COX-2 inhibitor and opioid analgesic may further beadministered by different routes of administration.
[0038] It should be understood that for purposes of the present invention, the followingterms have the following meanings:
[0039] The term "effective analgesia" is defined for purposes of the present inventionas a satisfactory reduction in or elimination of pain, along with the process of atolerable level of side effects, as determined by the human patient.
[0040] The term "effective pain management" means for purposes of the presentinvention as the objective evaluation of a human patient's response (pain experiencedversus side effects) to analgesic treatment by a physician as well as subjectiveevaluation of therapeutic treatment by the patient undergoing such treatment. Theskilled artisan will understand that effective analgesia will vary according to manyfactors, including individual patient variations.
[0041] The term "opioid analgesic" is defined for purposes of the present invention asthe drug in its base form, or a pharmaceutically acceptable salt or complex thereof.
[0042] The term "COX-2 inhibitor " is defined for purposes of the present invention asthe drug in its base form, or a pharmaceutically acceptable salt or complex thereof.
[0043] The term "sustained release" is defined for purposes of the present invention asthe release of the drug (opioid analgesic) from the transdermal formulation at such arate that blood (e.g., plasma) concentrations (levels) are maintained within thetherapeutic range (above the minimum effective analgesic concentration or "MEAC")but below toxic levels over a period of time of about 12 hours or longer.
[0044] The term "steady state" means that the blood plasma concentration curve for agiven drug has been substantially repeated from dose to dose.
[0045] The term "minimum effective analgesic concentration" is defined for purposesof this invention as the minimum effective therapeutic blood plasma level of the drug at which at least some pain relief is achieved in a given patient. It will be well understoodby those skilled in the medical art that pain measurement is highly subjective and greatindividual variations may occur among patients. DETAILED DESCRIPTION
[0046] The COX-2 inhibitors which are useful in the present invention will havesimilar anti-inflammatory, antipyretic and analgesic properties as compared toconventional non-steroidal anti-inflammatory drugs and in addition will inhibithormone-induced uterine contractions and have potential anti-cancer effects, but willhave a diminished ability to induce some of the mechanism-based side effects. Inparticular, such COX-2 inhibitors should have a reduced potential for gastrointestinaltoxicity, a reduced potential for renal side effects, a reduced effect on bleeding timesand a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.COX-2 inhibitors have been reported in the art and many chemical structures areknown to produce inhibition of cyclooxygenase-2. For purposes of the presentinvention, the term "COX-2 inhibitor" is defined as all compounds which wouldpossess COX-2 inhibitory activity and which preferably have at least 9-fold greaterspecificity for COX-2 over COX-1, either in-vitro (as determined, e.g., by IC50measurements) or in-vivo (as determined, e.g., by ED50 measurements). Such COX-2inhibitors will be useful in conjunction with the present invention and are considered tobe encompassed by the appended claims. Preferably, the COX-2 inhibitors used in thepresent invention demonstrate an in-vitro IC50 and/or in-vivo ED50 ratio for COX-1 toCOX-2 of approximately 20-fold or greater, more preferably 100-fold or greater, ormost preferably in certain embodiments 1000-fold or greater.
[0047] Certain preferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), Vioxx(MK-966), nabumetone (prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215,T-614; or combinations thereof.
[0048] There are a number of COX-2 inhibitors in development as of mid-1998.These include meloxicam (commercially available in the U.K. as of 1996 fromBoerhinger-Ingelheim); nimesulide (launched in 1985 in Europe from Hesinn); nabumetone (6-MNA is active metabolite) (commercially available as Relafin™ in theU.S.); celecoxib (SC-58635) (NDA filing by Searle estimated in September 1998);Vioxx (MK-966, L745337) (NDA filing by Merck estimated in November 1998); D-1367(Chiroscience; in Phase I in the U.K.); T-614 (Toyama; in Phase II in Japan andPhase I in the U.K.); and SC-57666 (Monsanto; in Phase I in the U.S.).
[0049] In trials discussed at the 1996 annual meeting of the American College ofRheumatology, celecoxib was demonstrated to be efficacious in patients and devoid ofgastrointestinal side effects in normal volunteers (Scrip 2175, 25 October, 1996, p. 15).In studies in normal volunteers, 128 subjects received celecoxib, 100 mg or 200 mgtwice a day, or naproxen, or placebo, for one week. In the celecoxib groups andsubjects who received placebo, there were no gastrointestinal signs or symptoms,whereas in the naproxen group, 20 % of subjects experienced gastrointestinal signs andsymptoms. Further, in normal volunteers, celecoxib caused no alterations in plateletfunction. In a study in patients, 293 patients, with osteoarthritis received celecoxib, 40mg, 100 mg, or 200 mg, or placebo twice a day for two weeks. Celecoxib reducedsymptoms significantly, and drop-out rates in the higher dose celcoxib groups werelower than for placebo. Patients with rheumatoid arthritis received celecoxib 100 mg,200 mg, or 400 mg, or placebo,twice a day for four weeks. As in patients withosteoarthritis, symptom scores were improved in patients receiving celecoxib comparedto placebo, and drop-out rates were lower in patients taking celecoxib.COX-2 inhibitors have been reported in the art and many chemical structures areknown to produce inhibition of cyclooxygenase-2.
[0050] COX-2 inhibitors are described in U.S. Patent Nos. 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 of which are incorporated byreference. Many COX-2 inhibitors may be described chemically as aryl sulfonamides.Indeed, both celecoxib and Vioxx, which are considered to be "super-selective", arearyl sulfonamides, and more specifically, benzenesulfonamides. These compounds willbe useful in the methods and compositions of the present invention. However, oneskilled in the art will appreciate that many additional COX-2 inhibitors have beenidentified in the art and would be useful in conjunction with the methods and compositions of the present invention.
[0051] The use of structure-activity relationships in evaluating COX inhibitors isproblematic because these COX inhibitors are suicide enzymes. Thus, when analyzedin an in-vitro assay, the IC50 value will change over time. For this reason, publishedIC50's for common COX inhibitors have been reported as values varying by more thantwo orders of magnitude from laboratory to laboratory. This makes it difficult tocompare the value for COX-1 inhibition obtained from one laboratory to the value forCOX-2 inhibition obtained from another laboratory. (See, for example D.E. Griswoldand J.L. Adams, Med. Res. Rev. 16: 181-206). Thus, it is preferable that whenstudying COX inhibitors to compare their relative potencies, comparisons only be madeusing results from the same assay, conducted at the same time. When using previouslygenerated data it is preferable to take data only from lists of several compounds thathave been generated by one group so that the relative potencies may be determined.Table 1 below provides representative data for representative NSAIDs and certainCOX-2 inhibitor compounds. The data have been collected from a number of differentsources, and were chosen from available laboratories, using references which report onseveral compounds in the same paper, and which contain data that are relativelycompatible to data obtained from certain other laboratories (i.e., within a reasonablerange of variation, with the understanding that results from different laboraties can varyup to three orders of magnitude for agents that act as suicide enzymes). It should bekept in mind that most of the values reported in Table 1 are from in-vitro assays (exceptwhere potency is reported as mg/kg). The literature confirms that ratios of COX-1/COX-2potency are generally kept in-vivo, but this is not always true. For example,indomethacin is always COX-I-selective in-vitro and in-vivo, but naproxen, which isCOX-1-selective in-vitro, is often (but not always) COX-2-selective in-vivo. In part,this is due to the highly artificial in-vitro assay conditions used. The first two structuralseries were recognized as COX inhibitors that exhibited remarkably little ulcerogenicactivity. These early compounds included the aryl sulfonamides nimesulide, NS-398,and CGP 23238 and the 1,2-diarylheterocycles Dup-697 and SC-58125. Griswold andAdams describe structure activity relationships in some detail (Med. Res. Rev. 16: 282-206,1996). Selectivity of selected cyclooxygenase inhibitors for COX-1 and Cox-2Drug COX-1 IC50, pM COX-2 IC50. µM COX-1/COX-2 Ref Aspirin 1.67 278 0.004 l 32.4 mg/kg 198 mg/kg 0.16 m Salicylate 254 725 0.36 l Ibuprofen 4.85 72.8 0.067 l 9.2 18.3 0.5 n Naproxen 4.8 28.4 0.17 a 0.6 2.0 0.3 b 6.6 3.9 1.7 c 15.6 28 0.56 n Diclofenac 0.04 0.1 0.4 d 2.7 20.5 0.13 a 1.5 1.05 1.4 c 0.018 0.012 1.5 c Indomethacin 0.1 0.9 0.11 d 13.5 > 1000 < 0.013 a 0.0015 0.0089 0.15 e 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 Piroxicam 17.7 > 500 < 0.035 a 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 > 1000 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 CGP 28238 (flosulide) 72.3 0.015 5000 E SC-58125 > 100 0.09 > 1100 j 38.7 0.27 143 Celecoxib (SC-58635) 15 0.04 375 o Vioxx (L 745.337) 369 1.5 246 n Dup-697 0.8 0.01 80 d a O. Laneuville et al, J. Pharmacol. Exp. Ther. 271: 927, 1994 b J. Barnett et al Biochim. Biophys. Acta 1209: 130, 1994 c J. R. Vane and R. M. Bolting. 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.. Natl. Acad, Sci. USA 91: 11202, 1994 h E.A. Mead et al, J. Biol. Chem. 268: 6610, 1993 i P. 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 l J. A. Mitchell et al Proc. Natl. 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
[0052] For example, as reported by Famaey JP, Inflamm Res 1997 Nov;46(11):437-446,nimesulide, a sulfonanilide compound with anti-inflammatory properties,possessed a pharmacological profile suggesting that it might be a selective inhibitor ofCOX-2. In several in vitro assays using either purified COX-2 and COX-1 preparationsor cell preparations (both from animal and human origins) expressing COX-1 or COX-2,ten out of eleven different groups demonstrated that nimesulide selectively inhibitsCOX-2. The COX-2/COX-1 inhibitory ratio was reported to vary, according to theassay preparation, from about 0.76 to 0.0004 i.e. a 1.3 to 2,512-fold higher selectivityfor COX-2 than for COX-1. Further, an in-vivo whole blood assay performed onhealthy volunteers demonstrated a significant fall in COX-2 PGE2 production withoutany effect on COX-1 TXB2 production (subjects treated with nimesulide 00 mg b.i.d.for 2 weeks) versus no effect on COX-2 PGE2 and an almost total suppression of COX-1TXB2 in subjects treated with aspirin (300 mg t.i.d. for 2 weeks). Nimesulide canthus be considered a relatively selective COX-2 inhibitor. At the recommended dosageof 100 mg b.i.d., it is as effective an analgesic and anti-inflammatory agent as classicalNSAIDs, and a well-tolerated drug with few side-effects according to large-scale openstudies and a global evaluation of a large number of controlled and non-controlledcomparative trials.
[0053] A non-limiting list of opioid analgesic drugs which may be utilized in thepresent invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, salts thereof, complexes thereof;mixtures of any of the foregoing, mixed mu-agonists/antagonists, mu-antagonist combinations,salts or complexes thereof, and the like. In certain preferred embodiments,the opioid analgesic is a mu or kappa opioid agonist. In additional preferredembodiments, the opioid analgesic is a selective kappa agonist.
[0054] 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.
[0055] The present invention provides for analgesic preparations for oral administrationthat provide a combination of a COX-2 inhibitor or a pharmaceutically acceptable saltthereof and an opioid analgesic or a pharmaceutically acceptable salt thereof. Thecombination preferably provides a synergistic or at least additive effect for analgesicdosages.
[0056] Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg to about140 mg per kilogram of body weight per day are therapeutically effective incombination with an opioid analgesic. Alternatively, about 0.25 mg to about 7 g perpatient per day of a COX-2 inhibitor is administered in combination with an opioidanalgesic. For example, inflammation may be effectively treated by the administrationof from about 0.005 to 50 mg of the COX-2 inhibitor per kilogram of body weight perday, or alternatively about 0.25 mg to about 3.5 g per patient per day.
[0057] The amount of COX-2 inhibitor that may be combined with the carrier materialsto produce a single dosage form having COX-2 inhibitor and opioid analgesic incombination will vary depending upon the patient and the particular mode ofadministration. For example, a formulation intended for the oral administration ofhumans may contain from 0.25 mg to 5 g of COX-2 inhibitor compounded with anappropriate and convenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Unit dosages will generally contain betweenfrom about 0.5 mg to about 1500 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 1000 mg, etc., up to1500 mg.
[0058] In one embodiment, the COX-2 inhibitor is provided in a sustained release oral dosage form with hydromorphone as the therapeutically active opioid in an amountfrom about 2 mg to about 64 mg hydromorphone hydrochloride. Alternatively, thedosage form may contain molar equivalent amounts of other hydromorphone salts or ofthe hydromorphone base. In another embodiment, the opioid analgesic comprisesmorphine, and the sustained release oral dosage forms of the present invention includefrom about 2.5 mg to about 800 mg morphine, by weight. In yet another embodiment,the opioid analgesic comprises oxycodone and the sustained release oral dosage formsinclude from about 2.5 mg to about 800 mg oxycodone. The opioid analgesic maycomprise hydrocodone, and the sustained release oral dosage forms may includeanalgesic doses from about 8 mg to about 50 mg of hydrocodone per dosage unit. Theopioid analgesic may comprise tramadol and the sustained release oral dosage formsmay include from about 25 mg to 800 mg tramadol per dosage unit. The dosage formmay contain more than one opioid analgesic to provide a substantially equivalenttherapeutic effect.
[0059] Preferred combinations of the invention comprise an effective amount of aCOX-2 inhibitor selected from the group consisting of nimesulide, melorican, andflosulide, and an effective amount of an opioid analgesic selected from the groupconsisting of tramadol, hydromorphone, morphine, oxycodone, hydrocodone anddihydrocodeine in the ratios set forth in Table I. In certain preferred embodiments, theratio of the afore-mentioned opioids to the afore-mentioned COX-2 inhibitors is setforth in Table I. Ratios of Opiates to COX-2 Inhibitors COX-2 INHIBITORSOPIATES CELECOXIB FLOSULIDE MELOXICAM NABUMETONE NIMESULIDE T614 MK966 MORPHINE 0.001-1 0.001-1 0.05-50 0.0005-1 0.001-5 0.001-1 0.001-10 METHADONE 0.0001-1 0.0001-1 0.01-10 0.0001-1 0.001-1 0.0001-1 0.001-1 MEPERIDINE 0.01-100 0.001-1 0.001-50 0.004-1 0.01-1 0.01-10 1.100 LEVORPHANOL 0.004-1 0.0001-1 0.001-1 0.00001-0.01 0.0002-1 0.0001-1 0.0001-1 HYDROMORPHONE 0.0003-3 0.0001-1 0.00001-1 0.0001-0.1 0.0001-1 0.0001-1 0.0001-1 OXYCODONE 0.001-10 0.0001-1 0.0001-1 0.0001-1 0.0001-1 0.0001-1 0.0001-1 HYDROCODONE 0.001-10 0.0001-1 0.00011 0.0001-1 0.0001-1 0.0001-1 0.0001-1 CODEINE 0.005-50 0.001-4 0.001-20 0.001-1 0.001-10 0.001-1 0.001-10
[0060] In other words, Table I describes test of ratios of morphine:celecoxib fromabout 0.001:1to about 1:1; for methadone to flosulide the ratio is from about 0.0001:1to about 1:1, and so on.
[0061] In certain preferred embodiments according to the present invention, an oraldosage form is preferred which includes the following opioid/COX-2 inhibitorcombinations: Morphine 40 mg plus 40 mg flosulide; morphine 40 mg plus 6 mgnimesulide; oxycondone 20 mg plus 20 mg flosulide; oxycodone 40 mg plus 4 mgnimesulide; hydromorphone 5 mg plus 20 mg flosulide; or hydromorphone 5 mg plus 4mg nimesulide.
[0062] The dosage administered will, of course, vary depending upon known factorssuch as the pharmacodynamic characteristics of each agent of the combination and itsmode and route of administration and upon the age, health and weight of the patient.The dosage will also depend upon the nature and extent of symptoms, concurrenttreatment, if any, frequency of treatment and the desired result. A compositioncomprising any of the above-identified combinations of opioid analgesics and COX-2inhibitors may be administered in divided doses ranging from 2 to 6 times per day or ina sustained release form that will provide a rate of release effective to attain the desired results.
[0063] The optimal COX-2 inhibitor and opioid analgesic ratios are determined bystandard assays well known in the art for determining opioid and analgesic activity.For example, the phenyl-p-benzoquinone test may be used to establish analgesiceffectiveness. The phenyl-p-benzoquinone induced writhing test in mice (H. Blumberget al., 1965, Proc. Soc. Exp. Med. 118:763-766) hereby incorporated by reference; andknown modifications thereof) is a standard procedure which may be used for detectingand comparing the analgesic activity of different classes of analgesic drugs with a goodcorrelation with human analgesic activity. Data for the mouse, as presented in anisobologram, can be translated to other species where the orally effective analgesic doseof the individual compounds are known or can be estimated. The method consists ofreading the percent ED50 dose for each dose ratio on the best fit regression analysiscurve from the mouse isobologram, multiplying each component by its effectivespecies dose, and then forming the ratio of the amount of COX-2 inhibitor and opioidanalgesic. This basic correlation for analgesic properties enables estimation of therange of human effectiveness (E.W. Pelikan, 1959, The Pharmacologist 1:73; herebyincorporated by reference).
[0064] Application of an equieffective dose substitution model and a curvilinearregression analysis utilizing all the data for the individual compounds and various doseratios for the combinations establishes the existence of unexpectedly enhancedanalgesic activity of combinations of COX-2 inhibitor and opioid analgesic, i.e., theresulting activity is greater than the activity expected from the sum of the activities ofthe individual components.
[0065] The present invention encompasses immediate release dosage forms of aneffective analgesic amount of a COX-2 inhibitor and opioid analgesic combination. Animmediate release dosage form may be formulated as a tablet or multiparticulate whichmay be encapsulated. Other immediate release dosage forms known in the art can beemployed.
[0066] Compositions of the invention present the opportunity for obtaining relief frommoderate to severe pain with or without inflammation. Due to the synergistic and/oradditive effects provided by the inventive combination of opioid analgesic and COX-2 inhibitor, it may be possible to use reduced dosages of each of COX-2 inhibitor andopioid analgesic. By using lesser amounts of other or both drugs, the side effectsassociated with each may be reduced in number and degree. Moreover, the inventivecombination avoids side effects to which some patients are particularly sensitive.
[0067] The present invention encompasses a method of inhibiting COX-2 and treatingCOX-2 mediated diseases comprising administering to a patient in need of suchtreatment a non-toxic therapeutically effective amount of the COX-2 inhibitor andopioid analgesic combination of the present invention. These diseases includemoderate to severe pain arising from many different etiologies, including but notlimited to cancer pain and post-surgical pain, fever and inflammation of a variety ofconditions including rheumatic fever, symptoms associated with influenza or other viralinfections, common cold, low back and neck pain, dysmenorrhea, headache, toothache,sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoidarthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis,bursitis, bums, and injuries. Further, the combination of COX-2 inhibitor and opioidanalgesic is useful as an alternative to conventional non-steroidal anti-inflammatorydrugs or combinations of NSAID'S with other drugs particularly where such non-steroidalanti-inflammatory drugs may be contra-indicated such as in patients withpeptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with arecurrent history of gastrointestinal lesions; GI bleeding, coagulation disordersincluding anemia such as hypoprothrombinemia, haemophilia or other bleedingproblems; kidney disease; those prior to surgery or taking anticoagulants.
[0068] The sustained release dosage forms of the present invention generally achieveand maintain therapeutic levels substantially without significant increases in theintensity and/or degree of concurrent side effects, such as nausea, vomiting ordrowsiness, which are often associated with high blood levels of opioid analgesics.There is also evidence to suggest that the use of the present dosage forms leads to areduced risk of drug addiction.
[0069] The combination of COX-2 inhibitor and oral opioid analgesics may beformulated to provide for an increased duration of analgesic action allowing once-dailydosing. These formulations, at comparable daily dosages of conventional immediate release drug, are associated with a lower incidence in severity of adverse drug reactionsand can also be administered at a lower daily dose than conventional oral medicationwhile maintaining pain control.
[0070] The combination of COX-2 inhibitor and an opioid analgesic can be employedin admixtures with conventional excipients, i.e., pharmaceutically acceptable organic orinorganic carrier substances suitable for oral, parenteral, nasal, intravenous,subcutaneous, enteral, or any other suitable mode of administration, known to the art.Suitable pharmaceutically acceptable carriers include but are not limited to water, saltsolutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols,gelate, carbohydrates such as lactose, amylose or starch, magnesium stearate talc, silicicacid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides,pentaerythritol fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.The pharmaceutical preparations can be sterilized and if desired mixed with auxiliaryagents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure buffers, coloring, flavoring and/or aromatic substancesand the like. They can also be combined where desired with other active agents, e.g.,other analgesic agents. For parenteral application, particularly suitable are oily oraqueous solutions, as well as suspensions, emulsions, or implants, includingsuppositories. Ampoules are convenient unit dosages. For oral application, particularlysuitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets andgelcaps. The compositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or more agentsselected from the group consisting of inert, non-toxic pharmaceutically excipientswhich are suitable for the manufacture of tablets. Such excipients include, for examplean inert diluent such as lactose; granulating and disintegrating agents such ascornstarch; binding agents such as starch; and lubricating agents such as magnesiumstearate. The tablets may be uncoated or they may be coated by known techniques forelegance or to delay release of the active ingredients. Formulations for oral use mayalso be presented as hard gelatin capsules wherein the active ingredient is mixed withan inert diluent.
[0071] Aqueous suspensions contain the above-identified combination of drugs and that mixture has one or more excipients suitable as suspending agents, for examplepharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose ornatural gums. Oily suspensions may be formulated by suspending the above-identifiedcombination of drugs in a vegetable oil or mineral oil. The oily suspensions maycontain a thickening agent such as beeswax or cetyl alcohol. A syrup, elixir, or the likecan be used wherein a sweetened vehicle is employed. Injectable suspensions may alsobe prepared, in which case appropriate liquid carriers, suspending agents and the likemay be employed. It is also possible to freeze-dry the active compounds and use theobtained lyophilized compounds, for example, for the preparation of products forinjection.
[0072] The method of treatment and pharmaceutical formulations of the presentinvention may further include one or more drugs in addition to a COX-2 inhibitor andan opioid analgesic, which additional drug(s) may or may not act synergisticallytherewith. Examples of such additional drugs include non-steroidal anti-inflammatoryagents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin,acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid,flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam or isoxicam, and the like. Other suitable additional drugs which may beincluded in the dosage forms of the present invention include acetaminophen, aspirin,and other non-opioid analgesics. CONTROLLED RELEASE DOSAGE FORMS
[0073] The COX-2 inhibitor and opioid analgesic combination can be formulated as acontrolled or sustained release oral formulation in any suitable tablet, coated tablet ormultiparticulate formulation known to those skilled in the art. The sustained releasedosage form may optionally include a sustained released carrier which is incorporatedinto a matrix along with the opioid, or which is applied as a sustained release coating.
[0074] The sustained release dosage form may include the opioid analgesic in sustained release form and COX-2 inhibitor in sustained release form or in immediate releaseform. The COX-2 inhibitor may be incorporated into the sustained release matrix alongwith the opioid; incorporated into the sustained release coating; incorporated as aseparated sustained release layer or immediate release layer; or may be incorporated asa powder, granulation, etc., in a gelatin capsule with the substrates of the presentinvention. Alternatively, the sustained release dosage form may have the COX-2inhibitor in sustained release form and the opioid analgesic in sustained release form orimmediate release form.
[0075] An oral dosage form according to the invention may be provided as, forexample, granules, spheroids, beads, pellets (hereinafter collectively referred to as"multiparticulates") and/or particles. An amount of the multiparticulates which iseffective to provide the desired dose of opioid over time may be placed in a capsule ormay be incorporated in any other suitable oral solid form.
[0076] In one preferred embodiment of the present invention, the sustained releasedosage form comprises such particles containing or comprising the active ingredient,wherein the particles have diameter from about 0.1 mm to about 2.5 mm, preferablyfrom about 0.5 mm to about 2 mm.
[0077] In certain embodiments, the particles comprise normal release matrixescontaining the opioid analgesic with or without the COX-2 inhibitor. These particlesare then coated with the sustained release carrier in embodiments where the COX-2inhibitor is immediately released, the COX-2 inhibitor may be included in separatenormal release matrix particles, or may be co-administered in a different immediaterelease composition which is either enveloped within a gelatin capsule or isadministered separately. In other embodiments, the particles comprise inert beadswhich are coated with the opioid analgesic with or without the COX-2 inhibitor.Thereafter, a coating comprising the sustained release carrier is applied onto the beadsas an overcoat.
[0078] The particles are preferably film coated with a material that permits release ofthe opioid (or salt) and if desired, the COX-2 inhibitor, at a sustained rate in an aqueousmedium. The film coat is chosen so as to achieve, in combination with the other statedproperties, a desired in-vitro release rate. The sustained release coating formulations of the present invention should be capable of producing a strong, continuous film that issmooth and elegant, capable of supporting pigments and other coating additives,non-toxic, inert, and tack-free. COATINGS
[0079] The dosage forms of the present invention may optionally be coated with one ormore materials suitable for the regulation of release or for the protection of theformulation. In one embodiment, coatings are provided to permit either pH-dependentor pH-independent release, e.g., when exposed to gastrointestinal fluid. A pH-dependentcoating serves to release the opioid in desired areas of the gastro-intestinal(GI) tract, e.g., the stomach or small intestine, such that an absorption profile isprovided which is capable of providing at least about twelve hour and preferably up totwenty-four hour analgesia to a patient. When a pH-independent coating is desired, thecoating is designed to achieve optimal release regardless of pH-changes in theenvironmental fluid, e.g., the GI tract. It is also possible to formulate compositionswhich release a portion of the dose in one desired area of the GI tract, e.g., the stomach,and release the remainder of the dose in another area of the GI tract, e.g., the smallintestine.
[0080] Formulations according to the invention that utilize pH-dependent coatings toobtain formulations may also impart a repeat-action effect whereby unprotected drug iscoated over the enteric coat and is released in the stomach, while the remainder, beingprotected by the enteric coating, is released further down the gastrointestinal tract.Coatings which are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate(PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid estercopolymers, zein, and the like.
[0081] In certain preferred embodiments, the substrate (e.g., tablet core bead, matrixparticle) containing the opioid analgesic (with or without the COX-2 inhibitor) iscoated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylicpolymer; or (iii) mixtures thereof. The coating may be applied in the form of anorganic or aqueous solution or dispersion. The coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desiredsustained release profile. Such formulations are described, e.g., in detail in U.S. PatentNos, 5,273,760 and 5,286,493, assigned to the Assignee of the present invention andhereby incorporated by reference.
[0082] Other examples of sustained release formulations and coatings which may beused in accordance with the present invention include Assignee's U.S. Patent Nos.5,324,351; 5,356,467, and 5,472,712, hereby incorporated by reference in their entirety. Alkylcellulose Polymers
[0083] Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to the invention.Simply by way of example, one preferred alkylcellulosic polymer is ethylcellulose,although the artisan will appreciate that other cellulose and/or alkylcellulose polymersmay be readily employed, singly or in any combination, as all or part of a hydrophobiccoating according to the invention.
[0084] One commercially-available aqueous dispersion of ethylcellulose is Aquacoat®(FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat® is prepared by dissolvingthe ethylcellulose in a water-immiscible organic solvent and then emulsifying thesame in water in the presence of a surfactant and a stabilizer. After homogenization togenerate submicron droplets, the organic solvent is evaporated under vacuum to form apseudolatex. The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it is necessary tointimately mix the Aquacoat® with a suitable plasticizer prior to use.
[0085] Another aqueous dispersion of ethylcellulose is commercially available asSurelease® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during the manufacturingprocess. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleicacid) is prepared as a homogeneous mixture, which is then diluted with an alkalinesolution to obtain an aqueous dispersion which can be applied directly onto substrates. Acrylic Polymers
[0086] In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the controlled release coating is a pharmaceutically acceptableacrylic polymer, including but not limited to acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acidanhydride), and glycidyl methacrylate copolymers.
[0087] In certain preferred embodiments, the acrylic polymer is comprised of one ormore ammonio methacrylate copolymers. Ammonio methacrylate copolymers are wellknown in the art, and are described in NF XVII as fully polymerized copolymers ofacrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
[0088] In order to obtain a desirable dissolution profile, it may be necessary toincorporate two or more ammonio methacrylate copolymers having differing physicalproperties, such as different molar ratios of the quaternary ammonium groups to theneutral (meth)acrylic esters.
[0089] Certain methacrylic acid ester-type polymers are useful for preparing pH-dependentcoatings which may be used in accordance with the present invention. Forexample, there are a family of copolymers synthesized from diethylaminoethylmethacrylate and other neutral methacrylic esters, also known as methacrylic acidcopolymer or polymeric methacrylates, commercially available as Eudragit® fromRöhm Tech, Inc. There are several different types of Eudragit®. For example,Eudragit® E is an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit® L is a methacrylic acid copolymer which does not swell atabout pH < 5.7 and is soluble at about pH > 6. Eudragit® S does not swell at about pH< 6.5 and is soluble at about pH > 7. Eudragit® RL and Eudragit® RS are waterswellable, and the amount of water absorbed by these polymers is pH-dependent,however, dosage forms coated with Eudragit® RL and RS are pH-independent.
[0090] In certain preferred embodiments, the acrylic coating comprises a mixture oftwo acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30Dand Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a lowcontent of quaternary ammonium groups, the molar ratio of ammonium groups to theremaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 inEudragit® RS30D. The mean molecular weight is about 150,000. The codedesignations RL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures are insoluble inwater and in digestive fluids. However, coatings formed from the same are swellableand permeable in aqueous solutions and digestive fluids.
[0091] The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain a sustained releaseformulation having a desirable dissolution profile. Desirable sustained releaseformulations may be obtained, for instance, from a retardant coating derived from100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit®RL:Eudragit® 90% RS. Of course, one skilled in the art will recognize that otheracrylic polymers may also be used, such as, for example, Eudragit® L. Plasticizers
[0092] In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of an effective amount of aplasticizer in the aqueous dispersion of hydrophobic material will further improve thephysical properties of the sustained release coating. For example, because ethylcellulosehas a relatively high glass transition temperature and does not form flexible filmsunder normal coating conditions, it is preferable to incorporate a plasticizer into anethylcellulose coating containing sustained release coating before using the same as acoating material. Generally, the amount of plasticizer included in a coating solution isbased on the concentration of the film-former, e.g., most often from about 1 to about 50percent by weight of the film-former. Concentration of the plasticizer, however, canonly be properly determined after careful experimentation with the particular coatingsolution and method of application.
[0093] Examples of suitable plasticizers for ethylcellulose include water insolubleplasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethylcitrate is an especially preferred plasticizer for the aqueous dispersions of ethylcellulose of the present invention.
[0094] Examples of suitable plasticizers for the acrylic polymers of the presentinvention include, but are not limited to citric acid esters such as triethyl citrate NFXVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Otherplasticizers which have proved to be suitable for enhancing the elasticity of the filmsformed from acrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethylcellulose of the present invention.
[0095] It has further been found that the addition of a small amount of talc reduces thetendency of the aqueous dispersion to stick during processing, and acts as a polishingagent. PROCESSES FOR PREPARING COATED BEADS
[0096] When the aqueous dispersion of hydrophobic material is used to coat inertpharmaceutical beads such as nu pariel 18/20 beads, a plurality of the resultantstabilized solid controlled release beads may thereafter be placed in a gelatin capsule inan amount sufficient to provide an effective controlled release dose when ingested andcontacted by an environmental fluid, e.g., gastric fluid or dissolution media.
[0097] The stabilized controlled release bead formulations of the present inventionslowly release the therapeutically active agent, e.g., when ingested and exposed togastric fluids, and then to intestinal fluids. The controlled release profile of theformulations of the invention can be altered, for example, by varying the amount ofovercoating with the aqueous dispersion of hydrophobic material, altering the mannerin which the plasticizer is added to the aqueous dispersion of hydrophobic material, byvarying the amount of plasticizer relative to hydrophobic material, by the inclusion ofadditional ingredients or excipients, by altering the method of manufacture, etc. Thedissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.
[0098] Spheroids or beads coated with a therapeutically active agent are prepared, e.g.,by dissolving the therapeutically active agent in water and then spraying the solutiononto a substrate, for example, nu pariel 18/20 beads, using a Wuster insert. Optionally,additional ingredients are also added prior to coating the beads in order to assist thebinding of the opioid to the beads, and/or to color the solution, etc. For example, aproduct which includes hydroxypropylmethylcellulose, etc. with or without colorant(e.g., Opadry®, commercially available from Colorcon, Inc.) may be added to thesolution and the solution mixed (e.g., for about 1 hour) prior to application of the sameonto the beads. The resultant coated substrate, in this example beads, may then beoptionally overcoated with a barrier agent, to separate the therapeutically active agentfrom the hydrophobic controlled release coating. An example of a suitable barrieragent is one which comprises hydroxypropylmethylcellulose. However, any film-formerknown in the art may be used. It is preferred that the barrier agent does notaffect the dissolution rate of the final product.
[0099] The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic material preferablyfurther includes an effective amount of plasticizer, e.g. triethyl citrate. Pre-formulatedaqueous dispersions of ethylcellulose, such as Aquacoat® or Surelease®, may be used.If Surelease® is used, it is not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit® can be used.
[0100] The coating solutions of the present invention preferably contain, in addition tothe film-former, plasticizer, and solvent system (i.e., water), a colorant to provideelegance and product distinction. Color may be added to the solution of the therapeuticallyactive agent instead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color be added to Aquacoat® via the use of alcohol orpropylene glycol based color dispersions, milled aluminum lakes and opacifiers such astitanium dioxide by adding color with shear to water soluble polymer solution and thenusing low shear to the plasticized Aquacoat®. Alternatively, any suitable method ofproviding color to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxidepigments. The incorporation of pigments, may, however, increase the retard effect ofthe coating.
[0101] The plasticized aqueous dispersion of hydrophobic material may be appliedonto the substrate comprising the therapeutically active agent by spraying using anysuitable spray equipment known in the art. In a preferred method, a Wursterfluidized-bed system is used in which an air jet, injected from underneath, fluidizes thecore material and effects drying while the acrylic polymer coating is sprayed on. Asufficient amount of the aqueous dispersion of hydrophobic material to obtain apredetermined controlled release of said therapeutically active agent when said coatedsubstrate is exposed to aqueous solutions, e.g. gastric fluid, is preferably applied, takinginto account the physical characteristics of the therapeutically active agent, the mannerof incorporation of the plasticizer, etc. After coating with the hydrophobic material, afurther overcoat of a film-former, such as Opadry®, is optionally applied to the beads.This overcoat is provided, if at all, in order to substantially reduce agglomeration of thebeads.
[0102] The release of the therapeutically active agent from the controlled releaseformulation of the present invention can be further influenced, i.e., adjusted to a desiredrate, by the addition of one or more release-modifying agents, or by providing one ormore passageways through the coating. The ratio of hydrophobic material to watersoluble material is determined by, among other factors, the release rate required and thesolubility characteristics of the materials selected.
[0103] The release-modifying agents which function as pore-formers may be organic orinorganic, and include materials that can be dissolved, extracted or leached from thecoating in the environment of use. The pore-formers may comprise one or morehydrophilic materials such as hydroxypropylmethylcellulose.
[0104] The sustained release coatings of the present invention can also include erosion-promotingagents such as starch and gums.
[0105] The sustained release coatings of the present invention can also includematerials useful for making microporous lamina in the environment of use, such aspolycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.
[0106] The release-modifying agent may also comprise a semi-permeable polymer.
[0107] In certain preferred embodiments, the release-modifying agent is selected fromhydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of theforegoing.
[0108] The sustained release coatings of the present invention may also include an exitmeans comprising at least one passageway, orifice, or the like. The passageway may beformed by such methods as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,889;4,063,064; and 4,088,864 (all of which are hereby incorporated by reference). Thepassageway can have any shape such as round, triangular, square, elliptical, irregular,etc. Matrix Bead Formulations
[0109] In other embodiments of the present invention, the controlled releaseformulation is achieved via a matrix having a controlled release coating as set forthabove. The present invention may also utilize a controlled release matrix that affordsin-vitro dissolution rates of the opioid within the preferred ranges and that releases theopioid in a pH-dependent or pH-independent manner. The materials suitable forinclusion in a controlled release matrix will depend on the method used to form thematrix.
[0110] For example, a matrix in addition to the opioid analgesic and (optionally) COX-2may include:
[0111] Hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers,acrylic resins, protein derived materials; the list is not meant to be exclusive, and anypharmaceutically acceptable hydrophobic material or hydrophilic material which iscapable of imparting controlled release of the active agent and which melts (or softensto the extent necessary to be extruded) may be used in accordance with the presentinvention.
[0112] Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fattyacids, mineral and vegetable oils and waxes, and stearyl alcohol; and polyalkyleneglycols.
[0113] Of these polymers, acrylic polymers, especially Eudragit® RSPO - the celluloseethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses, are preferred.The oral dosage form may contain between 1% and 80% (by weight) of at least onehydrophilic or hydrophobic material.
[0114] When the hydrophobic material is a hydrocarbon, the hydrocarbon preferablyhas a melting point of between 25 and 90 C. Of the long chain hydrocarbon materials,fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 60%(by weight) of at least one digestible, long chain hydrocarbon.
[0115] Preferably, the oral dosage form contains up to 60% (by weight) of at least onepolyalkylene glycol.
[0116] The hydrophobic material is preferably selected from the group consisting ofalkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein,hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof. In certainpreferred embodiments of the present invention, the hydrophobic material is apharmaceutically acceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acidalkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers. In other embodiments, the hydrophobic material is selectedfrom materials such as hydroxyalkylcelluloses such as hydroxypropylmethylcelluloseand mixtures of the foregoing.
[0117] Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends. Preferably, the hydrophobicmaterials useful in the invention have a melting point from about 30 to about 200 C,preferably from about 45 to about 90 C. Specifically, the hydrophobic material maycomprise natural or synthetic waxes , fatty alcohols (such as lauryl, myristyl, stearyl,cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fattyacid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats,hydrocarbons, normal waxes, stearic aid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones. Suitable waxes include, forexample, beeswax, glycowax, castor wax and carnauba wax. For purposes of thepresent invention, a wax-like substance is defined as any material which is normallysolid at room temperature and has a melting point of from about 30 to about 100 C.
[0118] Suitable hydrophobic materials which may be used in accordance with thepresent invention include digestible, long chain (C_8-C₅₀, especially C₁₂-C₄₀),substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glycerylesters of fatty acids, mineral and vegetable oils and natural and synthetic waxes.Hydrocarbons having a melting point of between 25 and 90 C are preferred. Of thelong chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in certainembodiments. The oral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.
[0119] Preferably, a combination of two or more hydrophobic materials are included inthe matrix formulations. If an additional hydrophobic material is included, it ispreferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, andmixtures of the same. Examples include beeswax, camauba wax, stearic acid andstearyl alcohol. This list is not meant to be exclusive.
[0120] One particular suitable matrix comprises at least one water soluble hydroxyalkylcellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂, aliphatic alcohol and, optionally,at least one polyalkylene glycol. The at least one hydroxyalkyl cellulose is preferably ahydroxy (C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. The amount ofthe at least one hydroxyalkyl cellulose in the present oral dosage form will bedetermined, inter alia, by the precise rate of opioid release required. The at least onealiphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearylalcohol. In particularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. Theamount of the at least one aliphatic alcohol in the present oral dosage form will bedetermined, as above, by the precise rate of opioid release required. It will also dependon whether at least one polyalkylene glycol is present in or absent from the oral dosageform. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20% and 50% (by wt) of the at least one aliphatic alcohol.When at least one polyalkylene glycol is present in the oral dosage form, then thecombined weight of the at least one aliphatic alcohol and the at least one polyalkyleneglycol preferably constitutes between 20% and 50% (by wt) of the total dosage.
[0121] In one embodiment, the ratio of, e.g., the at least one hydroxyalkyl cellulose oracrylic resin to the at least one aliphatic alcohol/ polyalkylene glycol determines, to aconsiderable extent, the release rate of the opioid from the formulation. A ratio of theat least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkyleneglycol of between 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 beingparticularly preferred.
[0122] The at least one polyalkylene glycol may be, for example, polypropylene glycolor, which is preferred, polyethylene glycol. The number average molecular weight ofthe at least one polyalkylene glycol is preferred between 1,000 and 15,000 especiallybetween 1,500 and 12,000.
[0123] Another suitable controlled release matrix would comprise an alkylcellulose(especially ethyl cellulose), a C₁₂ to C₃₆ aliphatic alcohol and, optionally, apolyalkylene glycol.
[0124] In another preferred embodiment, the matrix includes a pharmaceuticallyacceptable combination of at least two hydrophobic materials.
[0125] In addition to the above ingredients, a controlled release matrix may alsocontain suitable quantities of other materials, e.g. diluents, lubricants, binders,granulating aids, colorants, flavorants and glidants that are conventional in thepharmaceutical art. PROCESSES FOR PREPARING MATRIX - BASED BEADS
[0126] In order to facilitate the preparation of a solid, controlled release, oral dosageform according to this invention, any method of preparing a matrix formulation knownto those skilled in the art may be used. For example incorporation in the matrix may beeffected, for example, by (a) forming granules comprising at least one water solublehydroxyalkyl cellulose and opioid or an opioid salt; (b) mixing the hydroxyalkylcellulose containing granules with at least one C₁₂ - C₃₆ aliphatic alcohol; and (c) optionally, compressing and shaping the granules. Preferably, the granules are formedby wet granulating the hydroxyalkyl cellulose/opioid with water. In a particularlypreferred embodiment of this process, the amount of water added during the wetgranulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5times, the dry weight of the opioid.
[0127] In yet other alternative embodiments, a spheronizing agent, together with theactive ingredient can be spheronized to form spheroids. Microcrystalline cellulose ispreferred. A suitable microcrystalline cellulose is, for example, the material sold asAvicel PH 101 (Trade Mark, FMC Corporation). In such embodiments, in addition tothe active ingredient and spheronizing agent, the spheroids may also contain a binder.Suitable binders, such as low viscosity, water soluble polymers, will be well known tothose skilled in the pharmaceutical art. However, water soluble hydroxy lower alkylcellulose, such as hydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially an acrylic polymer, anacrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethylcellulose. In such embodiments, the sustained release coating will generally include ahydrophobic material such as (a) a wax, either alone or in admixture with a fattyalcohol; or (b) shellac or zein. Melt Extrusion Matrix
[0128] Sustained release matrices can also be prepared via melt-granulation or melt-extrusiontechniques. Generally, melt-granulation techniques involve melting anormally solid hydrophobic material, e.g. a wax, and incorporating a powdered drugtherein. To obtain a sustained release dosage form, it may be necessary to incorporatean additional hydrophobic substance, e.g. ethylcellulose or a water-insoluble acrylicpolymer, into the molten wax hydrophobic material. Examples of sustained releaseformulations prepared via melt-granulation techniques are found in U.S. Patent No.4,861,598, assigned to the Assignee of the present invention and hereby incorporatedby reference in its entirety.
[0129] The additional hydrophobic material may comprise one or more water-insolublewax-like thermoplastic substances possibly mixed with one or more wax-likethermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances. In order to achieve constant release, the individual wax-likesubstances in the formulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Useful water-insoluble wax-likesubstances may be those with a water-solubility that is lower than about 1:5,000 (w/w).
[0130] In addition to the above ingredients, a sustained release matrix may also containsuitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids,colorants, flavorants and glidants that are conventional in the pharmaceutical art. Thequantities of these additional materials will be sufficient to provide the desired effect tothe desired formulation.In addition to the above ingredients, a sustained release matrix incorporating melt-extrudedmultiparticulates may also contain suitable quantities of other materials, e.g.diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% by weight of theparticulate if desired.
[0131] Specific examples of pharmaceutically acceptable carriers and excipients thatmay be used to formulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986), incorporatedby reference herein. Melt Extrusion Multiparticulates
[0132] The preparation of a suitable melt-extruded matrix according to the presentinvention may, for example, include the steps of blending the opioid analgesic,together with at least one hydrophobic material and preferably the additionalhydrophobic material to obtain a homogeneous mixture. The homogeneous mixture isthen heated to a temperature sufficient to at least soften the mixture sufficiently toextrude the same. The resulting homogeneous mixture is then extruded to form strands.The extrudate is preferably cooled and cut into multiparticulates by any means knownin the art. The strands are cooled and cut into multiparticulates. The multiparticulatesare then divided into unit doses. The extrudate preferably has a diameter of from about0.1 to about 5 mm and provides sustained release of the therapeutically active agent fora time period of from about 8 to about 24 hours.
[0133] An optional process for preparing the melt extrusions of the present inventionincludes directly metering into an extruder a hydrophobic material, a therapeuticallyactive agent, and an optional binder; heating the homogenous mixture; extruding thehomogenous mixture to thereby form strands; cooling the strands containing thehomogeneous mixture; cutting the strands into particles having a size from about 0.1mm to about 12 mm; and dividing said particles into unit doses. In this aspect of theinvention, a relatively continuous manufacturing procedure is realized.
[0134] The diameter of the extruder aperture or exit port can also be adjusted to varythe thickness of the extruded strands. Furthermore, the exit part of the extruder neednot be round; it can be oblong, rectangular, etc. The exiting strands can be reduced toparticles using a hot wire cutter, guillotine, etc.
[0135] The melt extruded multiparticulate system can be, for example, in the form ofgranules, spheroids or pellets depending upon the extruder exit orifice. For purposes ofthe present invention, the terms "melt-extruded multiparticulate(s)" and "melt-extrudedmultiparticulate system(s)" and "melt-extruded particles" shall refer to a plurality ofunits, preferably within a range of similar size and/or shape and containing one or moreactive agents and one or more excipients, preferably including a hydrophobic materialas described herein. In this regard, the melt-extruded multiparticulates will be of arange of from about 0.1 to about 12 mm in length and have a diameter of from about0.1 to about 5 mm. In addition, it is to be understood that the melt-extruded multiparticulatescan be any geometrical shape within this size range. Alternatively, theextrudate may simply be cut into desired lengths and divided into unit doses of thetherapeutically active agent without the need of a spheronization step.
[0136] In one preferred embodiment, oral dosage forms are prepared to include aneffective amount of melt-extruded multiparticulates within a capsule. For example, aplurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in anamount sufficient to provide an effective sustained release dose when ingested andcontacted by gastric fluid.
[0137] In another preferred embodiment, a suitable amount of the multiparticulateextrudate is compressed into an oral tablet using conventional tableting equipmentusing standard techniques. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also describedin Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.
[0138] In yet another preferred embodiment, the extrudate can be shaped into tablets asset forth in U.S. Patent No. 4,957,681 (Klimesch, et. al.), described in additional detailabove and hereby incorporated by reference.
[0139] Optionally, the sustained release melt-extruded multiparticulate systems ortablets can be coated, or the gelatin capsule can be further coated, with a sustainedrelease coating such as the sustained release coatings described above. Such coatingspreferably include a sufficient amount of hydrophobic material to obtain a weight gainlevel from about 2 to about 30 percent, although the overcoat may be greater dependingupon the physical properties of the particular opioid analgesic compound utilized andthe desired release rate, among other things.
[0140] The melt-extruded unit dosage forms of the present invention may furtherinclude combinations of melt-extruded multiparticulates containing one or more of thetherapeutically active agents disclosed above before being encapsulated. Furthermore,the unit dosage forms can also include an amount of an immediate releasetherapeutically active agent for prompt therapeutic effect. The immediate releasetherapeutically active agent may be incorporated, e.g., as separate pellets within agelatin capsule, or may be coated on the surface of the multiparticulates afterpreparation of the dosage forms (e.g., controlled release coating or matrix-based). Theunit dosage forms of the present invention may also contain a combination of controlledrelease beads and matrix multiparticulates to achieve a desired effect.
[0141] The sustained release formulations of the present invention preferably slowlyrelease the therapeutically active agent, e.g., when ingested and exposed to gastricfluids, and then to intestinal fluids. The sustained release profile of the melt-extrudedformulations of the invention can be altered, for example, by varying the amount ofretardant, i.e., hydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients or excipients, byaltering the method of manufacture, etc.
[0142] In other embodiments of the invention, the melt extruded material is prepared without the inclusion of the therapeutically active agent, which is added thereafter tothe extrudate. Such formulations typically will have the therapeutically active agentblended together with the extruded matrix material, and then the mixture would betableted in order to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agent included in theformulation is sensitive to temperatures needed for softening the hydrophobic materialand/ or the retardant material. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0143] The following examples illustrate various aspects of the present invention.They are not to be construed to limit the claims in any manner whatsoever. EXAMPLES 1 - 2 Evaluation of Combination of Morphine and Nabumetone(Example 1) and Morphine and Meloxicam (Example 2)
[0144] In Examples 1-2, COX-2 inhibitor-opiate synergy were examined by examiningnabumetone (Example 1) and meloxicam (Example 2) in a Phenylquinone (PPQ)stretching (writhing) test.
[0145] Nabumetone is not intrinsically COX-2-selective, but is evaluated here becauseits use is associated with extremely low ulcerogenesis. Nabumetone is a prodrug,giving rise to the actual COX-2 inhibitor, 6-methoxy-2-naphthylacetic acid (6-MNA).(see Table 1). The low ulcerogenic potential of nabumetone may be due to the pH-dependentformation of 6-MNA. This does not occur at low pH values, such as thosefound in the gastric mucosa. Thus, COX-2 selectivity appears to be functional. Inclinical trials, nabumetone has been found to be quite efficacious, with extremely littleulcerogenesis. In a trial in patients with osteoarthritis, nabumetone was compared todiclofenac. It was found to be as efficacious as diclofenac (it is extremely impotent,requiring 1500 mg daily), however, none of the 382 patients treated with nabumetoneexperienced gastrointestinal toxicity (S.H. Roth et al, J. Rheumatol. 21: 1118, 1994). Ina report of 1-year follow-up of patients treated with nabumetone, the incidence of ulcers was only 0.5 % (PDR 1995, p. 2396).Methods: Isobolographic analysis of drug interaction was performed in male ICR mice.At time = 0, meloxicam or nabumetone or vehicle was administered p.o. At time (T) =9 minutes, morphine or vehicle was administered p.o. At T = 29 minutes, PPQ(phenyl-p-benzylquinone), 2 mg/kg, was injected i.p. At T = 36 minutes, the number ofabdominal stretches was counted for each mouse for 1 minute. At T = 40 minutes,stretches were again counted for 1 minute. There were 6 - 8 mice per dose.The concentrations of morphine used for its dose-response were 0.5, 1, 2, and 5 mg/kg.The concentrations of nabumetone used for its dose-response were 20, 50, 100, and300mg/kg. The concentrations of meloxicam used for its dose-response were 1, 3, 10,and 50 mg/kg.The % inhibition of PPQ stretching (writhing) test was calculated as follows:= 1 - {[total # stretches at two countings with drug]/[total # stretches at two countingswith vehicle]} X 100ED50 (the dose of drug that caused an inhibition of 50 %) was determined by nonlinearregression. When combinations of morphine and meloxicam or nabumetone wereadministered, the ratio was always set at 1:10 or 1:1000, respectively. For thecombination studies, the following were used: morphine/nabumetone were 0.036/36,0.072/72, 0.1/100, and 0.144/144 mg/kg, morphine/meloxicam were 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 wasdetermined by simple calculation of the amount of each in the combination at the ED50combination dose. The ED50 results for Example 1 (nabumetone) versus morphine areset forth below: nabumetone: morphine ED50 = 1.86 mg/kg po (confidence interval 1.39 - 2.5)nabumetone ED50 92.1 mg/kg po (slight extrapolation) with combination dose-response using morphine:nabumetone 1:1000ED50 morphine = 0.06 (confidence interval is 0.02 to 0.17)ED50 nabumetone = 64.5.
[0146] As can be seen from the ED50 results, nabumetone significantly increased thepotency of morphine. While morphine did not affect the potency of nabumetone in astatistically significant manner, it did shift the ED50 results to an extent which suggeststhat increasing the ratio of nabumetone to morphine may result in two-way synergy. Inview of this result, the combination of a much more potent COX-2 inhibitor such ascelecoxib will provide statistically significant two-way synergy. In such a combination,the opioid will be seen to significantly potentiate the analgesic effecticacy of celecoxib.
[0147] The ED50 results for Example 2 (meloxicam) are set forth below: meloxicam: morphine ED50 = 1.86 mg/kg pomeloxicam ED50 15.2 mg/kg po (slight extrapolation)with combination dose-response using morphine:meloxicam 1:10ED50 morphine = 0.62ED50 meloxicam = 6.22.
[0148] As can be seen from the ED50 results, meloxicam significantly increased thepotency of morphine, whereas morphine did not affect the potency of meloxicam.Morphine did however, allow meloxicam to reach better efficacy - 72 % vs 45 %inhibition.
[0149] The data obtained from Examples 1-2 are further represented in Figure 1, whichis a graph depicting the percent inhibition (ED50) plotted against the dose (mg/kg).Figure I includes plots of dose-response data for nabumetone, meloxicam andmorphine alone, and for combinations of nabumetone + morphine and meloxicam +morphine. As can be seen from the results set forth in Figure 1, morphine did not shift the dose-response for nabumetone or meloxicam. However, nabumetone andmeloxicam both shifted the dose-response for morphine (indicated by the arrows).
[0150] The interaction of morphine and flusolide can be demonstrated via anisobologram. (See, e.g., S. Loewe, Pharm. Rev., 9; 237 (1957)) regarding thepreparation and basis of an isobologram; hereby incorporated by reference).
[0151] Figure 2 is an isobologram for nabumetone in interaction with morphine(included are 95 % confidence intervals). The diagonal line joining the ED₅₀ values ofthe two drugs given separately represents the simple additivity of effects at differentcomponent ratios. ED₅₀ values falling under the curve (between the line and the origin)indicate superadditivity. As can be seen from Figure 2, the combination ofnabumetone and morphine exhibited synergism supporting the ratios of thecombinations of these drugs set forth in Table II.
[0152] Figure 3 is an isobologram for meloxicam in interaction with morphine(included are 95 % confidence intervals) . As can be seen from Figure 3, thecombination of nabumetone and morphine exhibited synergism supporting the ratios ofthe combinations of these drugs set forth in Table II.
[0153] It is known to the art that data for the mouse, as presented in an isobologram,can be translated to other species where the orally effective analgesic dose of theindividual compounds are known or can be estimated. Therefore, one of ordinary skillin the art will appreciate that this basic correlation for analgesic properties enablesestimation of the range of human effectiveness. Conclusion
[0154] While the invention has been described and illustrated with reference to certainpreferred embodiments thereof, those skilled in the art will appreciate that obviousmodifications can be made herein without departing from the spirit and scope of theinvention. For example, effective dosages and the specific pharmacological responsesmay vary depending upon the ratios of the particular opioid to particular COX-2inhibitor used, as well as the formulation and mode of administration. Such variationsare contemplated to be within the scope of the appended claims.

权利要求:
Claims (30)
[1] A pharmaceutical composition comprising an analgesically effectivecombination, which comprises
a) at least one COX-2 inhibitor and/or a pharmaceutically acceptable salt thereofand
b) at least one opiod analgesic and/or a pharmaceutically acceptable salt thereof,except for combinations of the COX-2 inhibitor with an anti-tussive dose ofhydrocodone or codeine, and    except for single pharmaceutical dosage forms comprising an analgesic combinationwhich comprises (a) at least one COX-2 inhibitor and/or a pharmaceutically acceptable saltthereof and (b) oxycodone or morphine, and/or at least one pharmaceutically acceptable saltthereof; said COX-2 inhibitor having at least 9-fold greater specificity for COX-2 over COX-1either in-vivo (as determined by ED50 measurements) and/or in-vitro (as determined byIC50 measurements).
[2] The pharmaceutical composition according to claim 1, wherein an analgesiceffect is attained which is at least about 5 times greater than that obtained with the dose ofsaid opioid analgesic alone.
[3] The pharmaceutical composition according to any of claims 1 or 2, wherein thedose of said opioid analgesic would be subtherapeutic, if administered without said COX-2inhibitor.
[4] The pharmaceutical composition according to any of claims 1 to 3, whereinsaid opioid analgesic and said COX-2 inhibitor are administered orally, via implant, parenterally, sublingually, rectally, topically, or via inhalation.
[5] The pharmaceutical composition according to any of the preceding claims,wherein said opioid analgesic is selected from the group consisting of alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol,dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone,nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil,tilidine, tramadol, salts thereof; complexes thereof; and mixtures of any of the foregoing.
[6] The pharmaceutical composition according to any of claims 1 to 4, whereinsaid opioid analgesic is selected from the group consisting of mu-agonists, kappa-agonists,mixed mu-agonists/antagonists, mu-antagonist combinations, salts thereof; complexesthereof; and mixtures thereof.
[7] The pharmaceutical composition according to any of the preceding claims inthe form of a tablet; a multiparticulate formulation for oral administration; a solution,suspension or elixer for oral administration; an injectable formulation; an implantable device;a topical preparation; a suppository; a buccal tablet; or an inhalation formulation.
[8] The pharmaceutical composition according to any of claims 1 to 3 and 5 to 6,which is a solid oral dosage form formulated as a tablet or a capsule.
[9] The pharmaceutical composition according to any of the preceding claims,comprising a therapeutically effective or sub-therapeutic amount of said opioid analgesicselected from the group consisting of morphine, methadone, meperidine, levorphanol,codeine, hydrocodone, dihydrocodeine, hydromorphone, oxycodone, oxymorphone, saltsthereof; and mixtures of any of the foregoing.
[10] The pharmaceutical composition according to any of the preceding claims,wherein said COX-2 inhibitor is selected from the group consisting of celecoxib, 5-bromo-s-(4-fluorophenyl)-3-[4-(methylsufonyl)phenyl]thiophene, flosulide , meloxicam, rofecoxib ,6-methoxy-2 naphthylacetic acid , nabumetone, nimesulide, N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide, 1-fluoro-4-[2-[4-(methylsufonyl)phenyl]-1-cyclopenten-1-yl]benzene, 5-(4-fluorophenyl)-1-[4-(methylsufonyl)phenyl]-3-trifluoromethyl 1H-pyrazole,N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] methanesulfonamide, mixturesthereof, and pharmaceutically acceptable salts thereof.
[11] The pharmaceutical composition according to claim 1 to 2 and 4 to 10,comprising said COX-2 inhibitor in an amount sufficient to render a therapeutic effecttogether with a dose of hydrocodone, which is analgetic if administered without the COX-2inhibitor.
[12] The pharmaceutical composition according to claim 11, wherein the dose ofhydrocodone is preferably from about 15 to about 2000 mg.
[13] The pharmaceutical composition according to claim 1 to 2 and 4 to 10,comprising said COX-2 inhibitor in an amount sufficient to render a therapeutic effect together with a dose of codeine which is analgetic if administered without the COX-2inhibitor.
[14] The pharmaceutical composition according to claim 13, wherein the dose ofcodeine is from about 30 to about 400 mg.
[15] The pharmaceutical composition according to any of the preceding claims,wherein said opioid analgesic is selected from the group consisting of morphine, methadone,meperidine, levorphanol, hydromorphone, oxycodone, hydrocodone, codeine, andpharmaceutically acceptable salts thereof, and said COX-2 inhibitor is selected from thegroup consisting of celecoxib, flosulide, meloxicam, nabumetone, nimesulide, N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]methanesulfonamide, rofecoxib, andpharmaceutically acceptable salts thereof, in the ratios and/or equivalent amounts of thepharmaceutically acceptable salts thereof, as set forth in Table I.
[16] The pharmaceutical composition according to any of the preceding claims,wherein the dose said COX-2 inhibitor synergistically potentiates the effect of said opioidanalgesic, but the dose of opioid analgesic does not appear to significantly potentiate theeffect of the COX-2 inhibitor.
[17] The pharmaceutical composition according to claim 8, wherein the oral soliddosage form includes a sustained release carrier.
[18] The use of an analgesically effective combination in the manufacture of apharmaceutical preparation for the treatment of pain, said combination comprising
a) at least one COX-2 inhibitor and/or a pharmaceutically acceptable salt thereofand
b) at least one opiod analgesic and/or a pharmaceutically acceptable salt thereof,    except for combinations of the COX-2 inhibitor with an anti-tussive dose ofhydrocodone or codeine, andexcept for single pharmaceutical dosage forms comprising an analgesic combination whichcomprises (a) at least one COX-2 inhibitor and/or a pharmaceutically acceptable salt thereofand (b) oxycodone or morphine, and/or at least one pharmaceutically acceptable salt thereof;said COX-2 inhibitor having at least 9-fold greater specificity for COX-2 over COX-1 eitherin-vivo (as determined by ED50 measurements) and/or in-vitro (as determined by IC50measurements).
[19] The use of a COX-2 inhibitor and/or a pharmaceutically acceptable salt thereofin the manufacture of a pharmaceutical preparation for the treatment of pain, comprising ananalgesically effictive combination, which comprises
a) at least one COX-2 inhibitor and/or a pharmaceutically acceptable salt thereofand
b) at least one opiod analgesic and/or a pharmaceutically acceptable salt thereof,    except for combinations of the COX-2 inhibitor with an anti-tussive dose ofhydrocodone or codeine, andexcept for single pharmaceutical dosage forms comprising an analgesic combination whichcomprises (a) at least one COX-2 inhibitor and/or a pharmaceutically acceptable salt thereofand (b) oxycodone or morphine, and/or at least one pharmaceutically acceptable salt thereof;said COX-2 inhibitor having at least 9-fold greater specificity for COX-2 over COX-1 eitherin-vivo (as determined by ED50 measurements) and/or in-vitro (as determined by IC50measurements).
[20] The use of an opiod analgesic and/or a pharmaceutically acceptable salt thereofin the manufacture of a pharmaceutical preparation for the treatment of pain, comprising ananalgesically effictive combination, which comprises
a) at least one COX-2 inhibitor and/or a pharmaceutically acceptable salt thereofand
b) at least one opiod analgesic and/or a pharmaceutically acceptable salt thereof,    except for combinations of the COX-2 inhibitor with an anti-tussive dose ofhydrocodone or codeine, andexcept for single pharmaceutical dosage forms comprising an analgesic combination whichcomprises (a) at least one COX-2 inhibitor and/or a pharmaceutically acceptable salt thereofand (b) oxycodone or morphine, and/or at least one pharmaceutically acceptable salt thereof;said COX-2 inhibitor having at least 9-fold greater specificity for COX-2 over COX-1 eitherin-vivo (as determined by ED50 measurements) and/or in-vitro (as determined by IC50measurements).
[21] The use according to any of claims 18 to 20, wherein said combinationprovides an analgesic effect which is at least about 5 times greater than that obtained with thedose of said opioid analgesic alone.
[22] The use according to any of claims 18 to 21, wherein said pharmaceuticalpreparation is provided to be administered orally.
[23] The use according to any of claims 18 to 22, wherein said pharmaceuticalpreparation is administered in a single oral dosage form.
[24] The use according to claims 23, wherein said single oral dosage form includesa sustained release carrier.
[25] The use according to any of claims 18 to 24, wherein the dose of said opioidanalgesic would be sub-therapeutic if administered without the dose of said COX-2 inhibitor.
[26] The use according to any of claims 18 to 24, wherein the dose of said opioidanalgesic is effective to provide analgesia alone, but the dose of opioid provides at least afive-fold greater analgesic effect than that obtained with the dose of opioid alone.
[27] The use according to any of claims 18 to 26, wherein said COX-2 inhibitor isadministered before, simultaneously with, or after administration of said opioid analgesic,such that the dosing interval of the COX-2 inhibitor overlaps with the dosing interval of theopioid analgesic.
[28] The use according to any of claims 18 to 26, wherein the amount of opioidrequired to treat a patient affected with pain is reduced, comprising co-administering with saidopioid analgesic an effective amount of a COX-2 inhibitor, to augment the analgesiaattributable to said opioid analgesic during at least a portion of the dosage interval of saidopioid analgesic.
[29] The use according to any of claims 18 to 26, wherein the amount of a COX-2 inhibitorrequired to treat a patient affected with pain is reduced, comprising co-administering with saidCOX-2 inhibitor an effective amount of an opioid analgesic, to augment the analgesiaattributable to said COX-2 inhibitor during at least a portion of the dosage interval of saidCOX-2 inhibitor.
[30] The use of the pharmaceutical composition according to any one of claims 1 to17 to manufacture a pharmaceutical preparation designed to provide effective painmanagement in humans.

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优先权:

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申请号 | 申请日 | 专利标题

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US5919597P| true| 1997-09-17|1997-09-17||

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US59195P||1997-09-17||

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EP98947135A|EP1014886B1|1997-09-17|1998-09-17|Synergistic analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor|SI9830926T| SI1518555T1|1997-09-17|1998-09-17|Analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor|

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CY20101100587T| CY1110160T1|1997-09-17|2010-06-25|ANALYTIC COMBINATION OF OPTIONAL ANALYTIC AND CYCLOGENIC INHIBITOR-2|