CN1349423A - Composition comprising tramadol aterial and a selective cox-2 inhibitor drug - Google Patents

Abstract

This invention relates to a pharmaceutical composition comprising tramadol and a selective COX-2 inhibitor, and to the treatment or prevention of pain, inflammation, and certain neurological disorders and cancers. This composition exhibits synergistic effects, utilizes small amounts of each component, and has fewer opioid-like side effects such as abuse liability, tolerance, constipation, and respiratory depression.

Description

Compositions comprising a tramadol substance and a selective COX-2 inhibitor drug

field of invention

The present invention relates to a pharmaceutical composition for treating or preventing pain, inflammation, certain nervous system diseases and cancer. More particularly, the present invention relates to pharmaceutical compositions comprising a tramadol substance and a selective cyclooxygenase-2 (COX-2) inhibitor drug.

Background of the invention

US Patent 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group on the cycloalkyl ring. It specifically discloses the compound (1R,2R or 1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, commonly known as tramadol. In Arzneim. Forsch. (Drug Res.), 28 (I), 114 (1978) published a series of papers related to the pharmacology, toxicology and clinical research of tramadol. Driessen et al., Arch. Pharmacol., 341, R104 (1990) disclose that tramadol produces its analgesic effect through a mechanism that is neither entirely opioid nor non-opioid. The abstract of the VI International Conference on Pain (April 1-6, 1990) disclosed that tramadol hydrochloride is an orally active purely stimulant opioid analgesic. However, clinical experience has shown that tramadol does not produce many of the typical side effects of opioid stimuli, such as respiratory depression (W. Vogel et al., Arzneim. Forsch. (Drug Res.), 28(I), 183(1978)) , constipation (I.Arend et al., Arzneim.Forsch.(Drug Res.), 28(I), 199(1978)), tolerance (L.Flohe et al., Arzneim.Forsch.(Drug Res. .), 28(1), 213(1978)), and liability for abuse (T. Yanagita, Arzneim. Forsch. (DrugRes.), 28(1), 158(1978)). Tramadol, when administered at a dose of 50 mg by bolus intravenous injection, can produce some of the side effects unique to tramadol, including fever and sweating. Despite these side effects, the combination of tramadol's non-opioid and opioid activities makes tramadol a unique drug. Tramadol is currently marketed as a pain reliever.

For many years opioids have been used as analgesics to treat severe pain. However, they produce undesired side effects and therefore cannot be administered repeatedly or in high doses. The problem of these side effects is well documented in the literature. See, e.g., "Goodman and Gilman's, The Pharmacological Basis of Therapeutics" by T. Reisine and G. Pastemak, 9th ed.; Hardman et al.; McGraw-Hill, New York, 1996; Chapter 23; pp. 521-555 Morphine and its congeners, such as codeine, dihydrocodeine and hydroxycodone, are opioid stimulant analgesics exhibiting side effects such as respiratory depression, constipation, tolerance and abuse liability.

To reduce the problem of opioid side effects, opioids have been combined with other drugs, including non-opioid analgesics, such that a lower amount of the opioid must produce a comparable degree of analgesia. Certain such combination products, which also have the advantage of producing a synergistic analgesic effect, have been proposed for patent protection, for example, A. Takemori, Annals New York Acad. Sci., 281, 262 (1976) discloses opioid analgesia Compositions in combination with non-analgesic drugs exhibiting various effects, eg, sub-additive (suppressive), additive or super-additive. R. Taber et al., J. Pharm. Expt. Thera., 169(1), 29 (1969) disclose that the combination of morphine and methadone (another opioid analgesic) exhibits an additive effect. U.S. Patent 4,571,400 discloses a combination of dihydrocodeine (an opioid analgesic) and ibuprofen (a non-opioid analgesic) that, when the components are within a certain ratio, produces super superposition effect. Also US Patent Nos. 4,587,252 and 4,569,937 disclose other ibuprofen opioid compositions. A. Pircio et al., Arch. Int. Pharmacodyn., 235, 116 (1978) reported a 1:125 ratio of cyclidine (another opioid analgesic) and paracetamol (a non opioid analgesics) mixture had a super-additive analgesic effect, while the 1:10 mixture did not show any statistically significant super-additive analgesic effect.

Compositions of non-opioid analgesics have also been prepared to avoid the side effects associated with opioids, and it has been noted that these compositions have the advantage of requiring fewer components to produce a superadditive effect. G. Stacher et al., Int.J.Clin.Pharmacol.Biopharmacy, 17, 250 (1979) reported that a combination of non-opioid analgesics such as toluoyl pyrrole acetic acid (another NSAID) and paracetamol can significantly Reduces the amount of toluoylpyrrole acetate required to produce analgesic effects. In addition, U.S. Patent No. 4,260,629 discloses an orally administered combination of acetaminophen and chlorphenacyldimethylpyrrole acetic acid (a non-opioid analgesic) that produces a pain relief effect on mammalian pain within a specific weight ratio range. Mitigates the effects of superstacking. Furthermore, U.S. Patent 4,132,788 discloses that 5-aroyl-1-(lower)alkylpyrrole-2-acetic acid derivatives (non-opioid analgesics) exhibit superadditive antiarthritic properties when combined with paracetamol or aspirin. active. However, there have been warnings against the daily consumption of opioid analgesic mixtures and the consumption of single non-opioid analgesic drugs in large quantities or over prolonged periods. (See, D. Woodbury and E. Fingl, p. 349). In addition, ibuprofen, aspirin, and some other NSAIDs can cause gastrointestinal side effects, especially if used repeatedly. See, e.g., M.J.S. Langman, Am.J.Med.84(Suppl.2A):15-19, 1988; P.A. Insel "Goodman and Gilman's, The Pharmacological Basis of Therapeutics", 9th ed.; Hardman et al.; McGraw -Hill, New York, 1996; Chapter 27; pp. 617-657.

It has now been found that tramadol can also be used in combination with other drugs such as compositions showing a synergistic effect in analgesia. Specifically, US Patent No. 5,516,803 discloses the combination of tramadol and a non-steroidal anti-inflammatory drug, especially ibuprofen. US Patent 5,468,744 discloses tramadol in combination with any of hydroxycodone, codeine or dihydrocodone and US Patent 5,336,691 discloses tramadol in combination with acetaminophen.

Arachidonic acid metabolites such as prostaglandin E ₂ (PGE ₂ ), prostaglandin G ₂ (PGG ₂ ), prostaglandin H ₂ (PGH ₂ ), prostaglandin I ₂ (PGI ₂ ) and thromboxane B ₂ (TXB ₂ ), which play a major role in the inflammatory process. Highly selective COX-2 inhibitors and compounds that prevent the resulting production of prostaglandins have been identified (Vane et al., Ann. Rev. Pharmacol. Toxicol. 38, 97 (1998)). Furthermore, it has been established that such compounds, when inhibiting the COX-2 enzyme, have analgesic and anti-inflammatory effects (Seibert et al., Proc. Natl. Acad. Sci, USA, 91(12) 12013 (1994).

U.S. Patent 5,994,381 discloses a family of heteroaryl oxazole compounds as highly efficient and selective COX-2 inhibitor drugs, specifically, compound JTE-522 (5-(4-aminosulfonyl-3-fluorophenyl)-4 -cyclohexyl-2-methyloxazole).

WO99/13799 has described a pharmaceutical composition comprising an opioid analgesic and a COX-2 inhibitor drug. Tramadol, listed as an opioid analgesic, claims patent protection for the pharmaceutical composition described. However, only morphine:nabumetone combinations comprising a ratio of 1:1000 based on their respective _ED50 values and combinations of morphine:meloxicam in a ratio of 1:10 are disclosed as synergistic analgesic combinations.

WO 98/50075 describes combinations of non-toxic N-methyl-D-aspartate receptor antagonists, COX-2 inhibitor drugs and other pharmaceutically active substances as analgesic potentiators. Further, patents are claimed for non-toxic and narcotic analgesics as pharmaceutically active substances. Claiming patent protection for the inclusion of the non-toxic analgesic, Tramadol, for the described combination. However, only acetaminophen, aspirin and ibuprofen are disclosed as potentiators of non-narcotic analgesics.

Thus, there is no reference to date disclosing a pharmaceutical composition comprising centrally acting analgesic tramadol and a selective COX-2 inhibitor drug, and suggesting that such a composition has a synergistic effect when each component is used in relatively small amounts. More specifically, compounds involving tramadol hydrochloride and the selective COX-2 inhibitor 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole have not been described previously. A combined pharmaceutical composition.

Therefore, an object of the present invention is the preparation of a combination product containing tramadol substances with improved properties. Another object of the present invention is the preparation of a combination product comprising a tramadol substance and a selective COX-2 inhibitor drug, wherein the pharmaceutical composition is formulated to have a synergistic effect when used in small amounts of each component. Another project of the present invention is to prepare tramadol hydrochloride and selective COX-2 inhibitor drug 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxaline Combination products of azoles wherein the pharmaceutical composition has a synergistic effect when each ingredient is used in small amounts, thereby reducing the number and severity of side effects associated with each agent. It is a further object of the present invention to provide a method of treating and preventing pain, inflammation and certain neurological diseases and cancers in mammals.

invention disclosure

Briefly, according to the present invention, there is provided a pharmaceutical composition containing a tramadol substance and a selective COX-2 inhibitor drug, wherein the content ratio of the tramadol substance and the selective COX-2 inhibitor drug is based on their respective 50 Fractional values of % effective dose ( _ED50 ) are based on ratios between about 1:1 to about 1:300 or about 1:1 to about 300:1.

The present invention further provides a method of treating and preventing pain, inflammation and certain neurological diseases and cancers in a mammal comprising administering to the mammal a therapeutically effective amount of a drug comprising a tramadol substance and a selective COX-2 inhibitor drug Combined pharmaceutical composition for the treatment and prevention of pain, inflammation and certain nervous system diseases and cancers, wherein the content ratio of tramadol substance and selective COX-2 inhibitor drug is 50% of their respective effective doses (ED ₅₀ ) Fractional values are based on a ratio between about 1:1 to about 1:300 or about 1:1 to about 300:1.

Further, the pharmaceutical composition according to the present invention is used for treating or preventing pain and inflammation including but not limited to osteoarthritis or rheumatoid arthritis and certain nervous system diseases and including but not limited to Alzheimer's disease, Cancer of the colon or polyps of the large intestine.

Detailed description of the invention

The present invention generally relates to pharmaceutical compositions comprising a tramadol substance and a selective COX-2 inhibitor drug. A tramadol substance is any of (1R,2R or 1S,2S)-2[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol (tramadol) , its N-oxide derivative ("tramadol N-oxide"), and its O-desmethyl derivative ("O-desmethyltramadol") or mixtures thereof. It also includes the respective stereoisomers, mixtures of stereoisomers, including racemates, salts of pharmaceutically acceptable amines, eg hydrochloride, solvates and polymorphs of tramadol. Tramadol is commercially available from Grunenthal and is prepared according to the method described by US Patent 3,652,589, which is incorporated herein by reference.

Tramadol N-oxide is prepared as the free base by treatment with an oxidizing agent such as hydrogen peroxide (30%) in an organic solvent such as methanol or isopropanol with heat, but preferably without heat. See, "Reagents For Organic Synthesis", 1, 471, Fieser & Fieser eds., Wiley NY; (1987), B. Kelentey et al., Arzneim. Forsch., 7, 594 (1957). Under the condition of heating, the reaction takes about 1 hour, whereas the reaction takes about 3 days without heating. Following oxidation, the mixture is treated with a reagent such as _PtO2 or preferably Pt/C for about 1 day to destroy excess hydrogen peroxide. The mixture is filtered, the filtrate evaporated and the residue recrystallized in an organic solvent mixture such as dichloromethane/ethyl acetate.

Tramadol is used as a free base under O-demethylation reaction conditions, for example, heated to reflux with a strong base such as NaOH or KOH, thiophenol and diethylene glycol (DEG), to prepare O-desmethyl tramadol. See, Wildes et al., J. Org. Chem., 36, 721 (1971). The reaction took about 1 hour, after cooling the reaction mixture was quenched in water. The quenched mixture is acidified, extracted with an organic solvent such as diethyl ether, basified and then extracted with a halogenated organic solvent such as dichloromethane. The extract is then dried and the solvent evaporated to yield the O-demethylated product, which can then be converted into the corresponding salt by short-path distillation, for example by treatment with an acidified solution (HCl/ethanol), and prepared from an organic solvent mixture such as Ethanol/ether recrystallization.

Selective COX-2 inhibitor drugs according to the present invention are analgesic and anti-inflammatory agents known as selective COX-2 inhibitor drugs. The most relevant assay to determine selectivity is considered to be the inhibition of recombinant human COX-1 and COX-2 enzymes. Alternatively, enzymes contained in human blood can be used (JR Vane et als, Ann Rev Pharmacol Tox 38:97-120, 1998).

Selective COX-2 inhibitor drugs according to the present invention are those compounds which inhibit the COX-2 enzyme at least 10 to 100 times more effectively against the COX-2 enzyme than the COX-1 enzyme. Examples of compounds known to be highly selective COX-2 inhibitors are: ^Celebrex® celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] -benzenesulfonamide), ^Vioxx® rofecoxib (4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone), JTE-522 (5-(4-aminosulfonyl) Acyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole) and JTE-522 (5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclo Hexyl-2-methyloxazole) difluoro analogs. These compounds are known to be effective in the treatment or prevention of pain, inflammation and certain neurological disorders and cancers.

In the pharmaceutical compositions of the invention, the selective COX-2 inhibitor drug portion of the composition may be either a single selective COX-2 inhibitor drug or a combination of one or more selective COX-2 inhibitor drugs. Thus, as used herein, a pharmaceutical composition comprising a tramadol substance and a selective COX-2 inhibitor drug includes all possibilities. Pharmaceutical compositions comprising combinations of tramadol substances and selective COX-2 inhibitor drugs as active ingredients in synergistic ratios based on their respective ED ₅₀ score values, and methods of preparing the prepared compositions in synergistic ratios also include within the present invention.

According to the compositions of the present invention, the tramadol substance and the selective COX-2 inhibitor drug content ratio can vary from about 1: ₁ to about 1:300 or, reversibly, from about 1:1 varies to approximately 300:1, depending on the desired outcome. Preferably, the compositions of the present invention comprise a majority of the tramadol substance.

Compositions comprising tramadol substances and selective COX-2 inhibitor drug combinations within these ratios show synergy. Pharmaceutical compositions according to the present invention comprise an effective amount of a tramadol substance in combination with a selective COX-2 inhibitor drug for the treatment or prevention of pain, inflammation and certain neurological and cancerous conditions in mammals. Preferably, the formulated composition comprises tramadol hydrochloride and 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole.

Pharmaceutical compositions comprising a tramadol substance and a selective COX-2 inhibitor drug as active ingredients in intimate admixture and a pharmaceutical carrier can be prepared according to conventional pharmaceutical mixing techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, eg, intravenous, oral or parenteral. Such compositions may also be administered by aerosol. In preparing the composition for oral dosage form any of the usual pharmaceutical media may be employed. For example, in the case of oral liquid preparations (such as suspensions, elixirs, and solutions), water, glycols, oils, ethanol, flavoring agents, preservatives, coloring agents, and the like may be employed. In the case of oral solid preparations (such as powders, capsules and tablets, for example), carriers such as starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants and the like can be used. Because of their ease of administration, tablets and capsules represent the most beneficial oral dosage units, in which case solid pharmaceutical carriers are obviously employed. Tablets may, if desired, be sugar-coated or enteric-coated by standard techniques. For parenteral drugs, the carrier usually comprises sterile water, although other ingredients may also be included, for example for solubility aiding or preservation purposes. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. Where one or more other pharmaceutically active compounds are added to the composition in combination with the tramadol substance and the selective COX-2 inhibitor drug, these ingredients can be added in amounts known in the art and can be added at the rate of these ingredients Regular dose administration. The pharmaceutical composition of the present invention is generally in the form of dosage units, such as tablets, capsules, powders, injections, teaspoonfuls and the like, wherein the preferred amount of each contained active ingredient is determined by the aforementioned ratio.

Dosage units are calculated based on the amount of active ingredient in a single dose administered to a 70 kg human body. The formulated pharmaceutical compositions can be administered at a daily dose of about 0.1 mg/day to about 800 mg/day of the active ingredient, preferably about 0.3 to 200 mg/day of the active ingredient. However, depending on the particular tramadol substance and selective COX-2 inhibitor drug used and the aforementioned ratios, it will be appreciated that the precise dosage of the active ingredients will vary depending on the relative amounts of each active compound employed. Thus, for example, a formulation exhibiting synergistic activity may comprise from about 0.6 mg to about 60 mg of a tramadol substance and from about 2 mg to about 20 mg of a selective COX-2 inhibitor drug, such as 5-(4-aminosulfonyl-3 -fluorophenyl)-4-cyclohexyl-2-methyloxazole. Likewise, the tramadol substance and the selective COX-2 inhibitor drug need not be in the same formulation to achieve the effects described herein. They can be administered at about the same time separately or in a single tablet.

The pharmaceutical composition of the present invention is used for the treatment or prevention of pain, inflammation and certain neurological diseases and cancers in mammals by administering a composition comprising a combination of a tramadol substance and a selective COX-2 inhibitor drug. Those skilled in the art of treating pain in mammals know that the type of pain experienced by mammals varies. Examples of pain in mammals include, but are not limited to, central indirect pain, peripheral indirect pain, pain associated with structural or soft tissue injury, pain associated with progressive disease, and neuropathic pain states, all of which include acute pain such as severe injury, Induced by trauma or surgery; chronic pain such as neurologic symptoms, diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, post-impact pain syndrome, or from episodic or migraine headaches. Examples of inflammation include, but are not limited to, sequelae from osteoarthritis, rheumatoid arthritis or disease, severe injury or trauma. The formulated compositions are also useful in the treatment or prevention of certain neurological disorders, including, but not limited to, the deterioration of nervous system cells due to Alzheimer's disease, and certain cancers, including, but not limited to, Colon cancer and colorectal polyps.

Pharmaceutical compositions comprising a tramadol substance and a selective cyclooxygenase-2 (COX-2) inhibitor drug can be evaluated for efficacy by employing one or more of the following tests. As will be appreciated by those skilled in the art, the following experimental examples describe the invention in particular and are intended to be by way of illustration but not limitation. Further, the efficacy of the pharmaceutical composition of the present invention can be determined by statistically comparing the results obtained with the formulated pharmaceutical composition with those obtained without it. Alternatives are also available.

Example 1

Formulation of Tramadol and Selective COX-2 Inhibitor Pharmaceutical Dosage Combinations

Including various ratios of combinations of tramadol substances and selective COX-2 inhibitor drugs such as 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole Formulation of the composition can be achieved by preparing a concentrated or suspension solution having an expression in mg of active drug per 10 mL of distilled water or in mg of active drug per 10 mL of a 0.5% hydroxypropylmethylcellulose suspension in distilled water. For example, 40 mg of a tramadol substance such as tramadol hydrochloride as a free base is added to 10 mL of a suspension of 0.5% hydroxypropylmethylcellulose in distilled water. Next add an appropriate scalar amount of the selective COX-2 inhibitor drug 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole to an appropriate volume of tramamate hydrochloride Multi-solution (in this case, 40 mg/10 mL) to give 10 mL based on tramadol hydrochloride: 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxaline A 1:1 ratio suspension of azole (40mg:40mg) fractional values of the respective _ED50 . Doses for each range of test ratios were prepared individually in the same manner. Thus, pharmaceutical compositions comprising tramadol substance and selective COX-2 inhibitor drug in other ratios can be similarly prepared in various concentrations.

Example 2

Mouse Abdominal Stimulation Test

A method very relevant to human efficacy in testing and comparing the analgesic activity of various analgesics is the inhibition of acetylcholine-induced abdominal contractions in mice (H.Collier, et al., Br.J.Pharmacol., 1968, 32 , 295).

animal

The analgesic effect associated with the compositions of the invention was measured using male CD1 mice (body weight 18-24 g).

animal dose

Mice were treated with a combination composition comprising tramadol hydrochloride (in bases) and a selective COX-2 inhibitor drug (in bases), or each agent was dissolved in distilled water or dissolved in 0.5% hydroxyl Combination of propylmethylcellulose in suspension in distilled water for oral administration. The dosing volume was 2 mL/kg.

Analgesic effect

Mice were then injected intraperitoneally with a challenge dose of acetylcholine bromide. Acetylcholine was completely dissolved in distilled water at a concentration of 5.5 mg/kg and injected at a ratio of 0.20 mL/20 g. For assessment purposes, "abdominal contraction" was defined as contraction of the abdominal musculature with arching of the back and extension of the limbs. After receiving an acetylcholine dose, following administration of orally administered tramadol hydrochloride alone, a COX-2 inhibitor drug administered alone, combined doses of tramadol hydrochloride and a selective COX-2 inhibitor drug, or vehicle , Immediately began to observe the mice for 10 minutes, whether there was an abdominal contraction response, and each mouse was only used once.

Example 3

Rat Abdominal Stimulation Test

A method very relevant to human efficacy in testing and comparing the analgesic activity of various analgesics is the inhibition of acetylcholine-induced abdominal contractions in rats (Von Voigtlander and Lewis, Drug Dev. Res., 2:577, 1982) .

animal

Male Sprague-Dawley rats (Charles River Laboratories), weighing 80-120 g, were housed 5-10 per cage for at least 5 days prior to testing in a climate-controlled, virus-free environment. Food and water were available ad libitum until the time of the experiment. Animals were individually weighed and allowed to acclimate prior to testing.

animal dose

The test drug was dissolved in distilled water (vehicle) and administered in a volume of 2 mL/kg.

Analgesic effect

The air-induced abdominal stimulation test in rats was used here as described by Von Voigtlander, et al., with minor modifications. Other stimuli may be employed by those skilled in the art. 2 mL/kg, 30 minutes after oral administration of the test drug, the animals were injected intraperitoneally with 10 ml of air. Each rat was placed in a plastic observation box to observe the development of the abdominal stimulation response for a maximum of 30 minutes (as described under the acetylcholine-induced abdominal stimulation test). The percent inhibition of this reaction was calculated as follows:

Inhibition %=

100 x (number of non-responders)/number of animals in the group)

The anti-nociceptive response activity in the abdominal stimulation test in rats was evaluated one hour after administration of each drug. At the doses tested (30 mg/kg for rofecoxib; 10, 30, 60 and 100 mg/kg for celecoxib), none of the compounds showed antinociceptive activity.

Example 4

Carrageenan paw hyperalgesia test

A well-relevant method used in testing and comparing the anti-inflammatory activity of various anti-inflammatory drugs in humans is the carrageenan paw hyperalgesia test (Dirig, et al., J. Pharmacol Expt Therap. 1998, 285, 1031).

animal dose

Male Sprague-Dawley rats (Charles River Laboratories) were housed in a climate-controlled, virus-free environment for at least 5 days prior to testing. Food and water were available ad libitum until the time of the experiment.

animal dose

Test rats were injected subcutaneously with an irritant (eg, 0.1 ml of 0.3-1.0% carrageenan in 0.9% saline solution) into the plantar tissue of one of the hind paws to stimulate an acute inflammatory response. Control rats received the same saline injection.

In a composition comprising a combination of tramadol hydrochloride (by base) and a selective COX-2 inhibitor drug (by base), either dissolved in distilled water or dissolved in 0.5% hydroxypropylmethylcellulose Distilled water suspensions of each agent were orally administered to rats at a defined time after carrageenan injection. The dosing volume was 2 mL/kg. The hyperalgesic response of the animals is subsequently assessed at a later time determined.

hyperalgesia measurement

Hyperalgesia is assessed by measuring responses to thermal or mechanical stimuli. Thermal hyperalgesia measurements were performed with standard laboratory hot plate equipment, where the surface temperature of the hot plate was precisely measured and kept uniform. Alternatively, hyperalgesia was assessed with a commercially available Hargreaves device that selectively increases the temperature of individual paws (Dirig, et al., J Neurosci Methods, 1997, 76, 183). With either device, hyperalgesia is measured as a reduced reaction time to the response compared to that of untreated or vehicle-treated animals, and the analgesic effect of the test compound is seen as a restoration of the (local) reaction time to normal (Dirig, et al., J Pharmcol Expt Therap, 1998, 285, 1031). Responses were defined as any shaking, licking or retraction of the handled paw.

Assessment of hyperalgesia mechanically is achieved with a device designed to apply precisely calibrated forces to the paw. Hyperalgesia is measured as the reduction in force required to cause paw withdrawal or vocalisation, measured in grams (Randall and Selitto, Arch Int Pharmacodyn, 1957, 4, 409). The analgesic effect of the test compound is seen to (locally) induce force restoration towards normal responses.

Example 5

Synergy analysis

Synergy between the tramadol substance and the selective COX-2 inhibitor drug was determined at precise dose ratios of tramadol hydrochloride and the selective COX-2 inhibitor drug. The effect of each selected combination of multiple (usually 4-6) numbered doses was studied using an experimental design that allowed random selection of individual dose forms to complete the trial.

analyze

The analysis of the possible synergistic effect of each composition in defined ratios was determined as published by RJ Tallarida, et al., Life Sci., 1989, 45, 947. This method involves determining the total amount of the mixture required to produce a demonstrated synergistic antiallodynic effect at the 50% dose level (in other words, _ED50mix or _Zmix ), and the corresponding total amount desired under simple addition ( _ED50add or _Zadd ) . For specifically determined ratios, it has been established that Z _mix < Z _add , and then the combination is determined to be synergistic. The amount of ED _50mix and ED _50add was varied randomly. ED _50mix is determined from a dose-response curve that specifically determines the proportion of components; ED _50add is calculated from the ED ₅₀ values of individual drugs. Then Z _mix was compared with Z _add by the researcher's experiment.

Claims (26)

1. pharmaceutical composition that comprises the combination of tramadol material and selective COX-2-inhibitor 2 medicine, wherein tramadol material and selective COX-2-inhibitor 2 medicament contg ratio is based on they ED separately ₅₀Fractional value, ratio is from about 1: 1 to about 1: 300 or from about 1: 1 to about 300: 1.

2. the pharmaceutical composition of claim 1, wherein for each composition based on ED ₅₀The ratio of fractional value be about 1: 1 to about 1: 30 and from about 1: 1 to about 30: 1

3. the pharmaceutical composition of claim 1, wherein the tramadol material is a tramadol hydrochloride.

4. the pharmaceutical composition of claim 3, wherein tramadol hydrochloride is a racemic modification.

5. the pharmaceutical composition of claim 3, wherein tramadol hydrochloride is an enantiomer.

6. the pharmaceutical composition of claim 1, the wherein ED of tramadol hydrochloride ₅₀Fractional value be about 0.0001 to about 0.75.

7. the pharmaceutical composition of claim 1, the wherein ED of tramadol hydrochloride ₅₀Fractional value be about 0.001 to about 0.05.

8. the pharmaceutical composition of claim 1, the wherein ED of tramadol hydrochloride ₅₀Fractional value be about 0.0015 to about 0.025.

9. the pharmaceutical composition of claim 1, the wherein ED of tramadol hydrochloride ₅₀Fractional value be about 0.0025 to about 0.01.

10. the pharmaceutical composition of claim 1, the wherein ED of tramadol hydrochloride ₅₀Fractional value be about 0.005 to about 0.0075.

11. the pharmaceutical composition of claim 1, wherein selective COX-2-inhibitor 2 medicine be selected from down the group at least a:

The difluoride of celecoxib, rofecoxib, valdecopxib, parecoxib, JTE-522, JTE-522, their salt, their complex and aforesaid any mixture.

12. the pharmaceutical composition of claim 1, wherein selective COX-2-inhibitor 2 medicine is the combination of two or more selective COX-2s-inhibitor 2 medicine.

13. the pharmaceutical composition of claim 1, wherein selective COX-2-inhibitor 2 medicine is single cox 2 inhibitor medicine.

14. the pharmaceutical composition of claim 1, wherein selective COX-2-inhibitor 2 medicine is JTE-522.

15. the pharmaceutical composition of claim 1 further comprises pharmaceutically acceptable carrier.

16. the mammiferous method for the treatment of or preventing to have pharmacology's symptom comprises giving the pharmaceutical composition that mammal is treated the claim 1 of effective dose.

17. the method for claim 16, wherein the treatment effective dose of pharmaceutical composition is about 0.1mg/ days to approximately 800mg/ days.

18. the method for claim 16, wherein the treatment effective dose of pharmaceutical composition is about 0.3mg/ days extremely approximately 200mg/day.

19. the method for claim 16, wherein the tramadol material is distinguished administration with selective COX-2-inhibitor 2 medicine in about identical time.

20. the method for claim 16, wherein tramadol material and selective COX-2-inhibitor 2 medicine is with single tablet administration.

21. the method for claim 16, wherein the tramadol material is a tramadol hydrochloride, and selective COX-2-inhibitor 2 medicine is JTE-522.

22. the method for claim 16, wherein pharmacology's symptom is selected from pain, inflammation, nervous system disease or cancer.

23. the method for claim 16, wherein pain is selected from the indirect pain of maincenter, the pain that pain, structure or soft tissue harm are relevant indirectly, pain, the neuropathic pain that PD is relevant on every side, the severe pain that is caused by violent damage, wound or surgery is by the peripheral neuropathy of neurological symptom, diabetes, herpes later stage neuralgia, nervi trigeminus neuralgia, bump back pain syndrome or from collection property or inclined to one side the chronic pain pain that headache causes.

24. the method for claim 16, wherein inflammation is selected from osteoarthritis, rheumatic arthritis or disease, the acutely damage or the sequela of wound.

25. the method for claim 16, wherein nervous system disease is an alzheimer's disease.

26. the method for claim 16, wherein cancer is selected from colon cancer or colorectal polyp.