SE466481B - ANALGETIC AND ANTI-INFLAMMATORY COMPOSITIONS INCLUDING COFFEE - Google Patents

Description

45ei4s1 now (Ponstelšš and sulind fl <. See also Physicians' Desk Reference, 55th Edition, 1981 and mcfenamic acid The Merck Index, Ninth Edition, Merck & Co., Rahway, New Jersey (1976) for information on the specific non-steroidal anti-inflammatory drugs. See also generally, Wiseman, "Pharmacological Studies with a New Class of Nonsteroidal Anti-Inflammatory Agents - The Oxicams - With Special Reference to Piroxicam (Feldenégš, The American Journal of Medicine, February 16, l982: Z-8 Foley et al., The Management of Cancer Pain, Volume II - The Rational Use of Analgesics in the Management of Cancer Pain, Hoffman ~ LaRoche Inc., 1981; and Cutting's Handbook of Pharmacology, 6th Edition, publisher TZ Czáky, MD , Appleton-Century-Crofts, New York, 1979, Chapter 49; 558-550. _ Narcotic analgesics are often used when pain control with non-narcotic analgesics is ineffective.

Although the drugs in this group vary considerably in terms of chemical structures and pharmacological properties, almost all show the disadvantages of tolerance and possible bending during continued use.

Within the narcotic analgesic group, the drugs can be classified as narcotic agonists or narcotic antagonists. Narcotic agonists include the morphine group, the meperidine group and the methadone group.

While some narcotic antagonists are pure antagonists (which are not analgesics), other narcotic antagonists are agonist antagonists (ie, antagonists with analgesic properties); ßgonist antagonists are generally intended to belong to the category of morphine-like or nalorphine-like). Many narcotic analgesics are not effective orally but are used parenterally. Orally active narcotic analgesics include such compounds as codeine, oxycodone, levorphanol (Levo-Dromoran) meperidine (Demero), propoxyphene hydrochloride (Darvodâš, propoxyphenane napsylate (Darvon-, methadone, propiram, 466 481. buprenorphine), , nalbuphine (Nubuišß), and butorphanol (Stadolg fi.

For more specific information on these compounds, see Physician's Desk Reference, 35th Edition, 1981, and The Merck Index, 9th J1 Edition, Merck & Co., Inc., Rahway, New Jersey (1976).

See also Foley et al reference cited above and Cutting's Handbook of Pharmacology, 6th Edition, publisher T.Z. Czáky, M.D., Appleton-Century-Crofts, New York, 1979, Chapter 50: 551-566.

Caffeine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione has the structural formula Hc 9 çH3 \ NN IAIV 1 CH 3 O 3 This substance has been used separately intravenously in the treatment of headaches and has also been used in combination with selected drugs. Compositions containing one or more of the analgesic agents aspirin, acetaminophen and phenacetin, in combination with varying amounts of caffeine have been marketed previously; In several cases, such non-narcotic combination products of analgesic and caffeine have additionally comprised one of the narcotic analgesic agents codeine, propoxyphene or oxycodone. Examples of these combinations include the products commercially designated Excedrin, SK-6 compound, Darvon compound, Anacišâ, A.P.C. and A.P.C. with codeine, TabloidBL Brand. The non-steroidal analgesic components of these mixtures have the following structural formulas: NH-COCH3 NH-COCHB I çp-cocns Ö q COOH óH _ czns asvirin acetamlnofen (acety salicylic acid) phen fl cetin 466 481 'The three narcotic analgesics that have been temporarily added The aspirin / phenacetin / acetaminophen / caffeine combinations have the following structural formulas: codeine propoxyphene oxycodone S However, it has not previously been suggested that caffeine be added to a narcotic analgesic to contribute to its analgesic effect.

Many researchers have tried to show the effectiveness of the aspirin / phenacetin / acetaminophen / caffeine combination products. A comprehensive review of the literature on caffeine and analgesics has been published ["Over-The-Counter Drugs: Establishment of a Monograph for OTC Internal Analgesic, Antipyretic and Antirheumatic Products", Federal Register, 1977, 42 (131): 35482 -35485] and several other relevant articles have emerged. Most animal studies on caffeine analgesia have been performed on rats, and Williams (Toxicology and Applied Pharmacology, 1959, 12447-453) used experimental pain and found that caffeine exerted analgesic effects only on rats and also in combination with aspirin; the effect appeared additive but not potentiating. Vínegar et al (Proceedings of the Society for Experimental Biology and Medicine, 1976, 1512556-560), found ten years later that rats potentiate caffeine the acute anti-inflammatory and analgesic activity of aspirin.

Siegers (Pharmacology, 1973, 10: 19-27) studied the effect of oral doses of caffeine (10, 50 and 100 mg / kg) 466 481 administered to rats together with acetaminophen and found that caffeine inhibited its absorption and lowered its serum concentration. . He suggested that delayed gastric emptying due to the relaxing effect of caffeine on the smooth abdominal muscle was probably the reason for the decreased absorption of orally administered drugs in the presence of caffeine. Despite this discovery, acetaminophen analgesia was not reduced by caffeine.

In agreement with Williams and Vinegar and his colleagues, Siegers found that caffeine itself had analgesic activity. Only at the lowest dose of caffeine studied, a dose at which analgesia was not observed, was a reduction in acetaminophen-induced analgesia obtained. In a later article, Seegers et al (Arch.

Int. Pharmacodyn., 1981, 251: 237-254) an anti-inflammatory, analgesic effect of caffeine in rats. He also found that the combination of caffeine, aspirin and acetaminophen as well as the combination of caffeine, aspirin and phenacetin gave in low doses anti-inflammatory, analgesic effects, which are at least as great as could be expected on the basis of addition while at high dose results suggested potentiation.

Citing the work of Giertz and Jurna (Naturwissenschaften, 1957, 44: 445) and Fuchs and Giertz (Arzneiittelforsch, 1960, 10: 5Z6-530) who observed that caffeine induced analgesia in tests on mice which did not include inflammation, Seegers stated that it seemed safe to assume that the analgesic activity of caffeine consisted of at least two components, one independent of and the other dependent activity. the study on humans of its anti-inflammatory The earliest relevant (Proceedings of the at the Royal College of reported by Wallenstein aspirin symposium, held Surgeons, London, 1975). Two tablets of a combination, each tablet containing 210 mg of aspirin, and 466 481 UT 6 150 mg of acetaminophen and 30 mg of caffeine gave clearly and significantly more analgesia than the combination without caffeine.

The dose of one tablet of the combination showed higher mean values than each component alone but was not superior to the combination without caffeine. Wallenstein assumed that the dose could be a significant factor 1 and that caffeine could simply be ineffective at a significantly lower dose than 60 mg. Booy (Nederlands Tijd- ¿schrift Voor Tandheelkinde, 1972, 79: 69-75) studied pain relief on each of the first two days »after tooth extraction. Patients who reported "great pain" on the first day received more pain relief from 1000 mg acetaminophen plus 100 mg caffeine than from 1000 mg acetaminophen alone. On the second day, this difference could not be determined even though the treatments on both days were superior to placebo. Lim et al (Clin. Pharmacol. Ther., 1967, 8: 521-542) observed in reporting a study in which experimental pain was induced in patients by bradykinin, that the combination of 520 mg aspirin and 260 mg acetaminophen administered orally could not differs from placebo as, however, the same combination in smaller amounts, namely 325 aspirin and 162.5 mg acetaminophen plus 32.5 mg caffeine differed significantly from placebo 15, 60, 75, 105 and 120 minutes after taking the drug.

A cross-sectional double-blind study of 216 patients by Wojcicki et al [Archive Immunologiae et Therapeae Experimentalís, 1977, 25 (2): 175-179] compared the activity of 1000 mg of acetaminophen plus 100 mg of caffeine with the same amount of acetaminophen alone . One group of patients in the trial suffered from severe and frequent idiopathic headaches and a second group showed moderate post-operative orthopedic pain. The authors concluded that pain relief was significantly higher with the caffeine combination than with acetaminophen alone or with aspirin alone. Jaín et al (Clin. Get 466 481 Pharmacol. Ther., 1978, 24: 69-75) first studied 70 patients after delivery showing moderate to severe uterine cramps and / or episiotomy pain and then a second group of 70 patients limited to only severe pain. When comparing 800 mg of aspirin plus 64 mg of caffeine with only 650 mg of aspirin, these authors concluded that for patients with severe episiotomy pain, the combination is a more effective analgesic.

The use of caffeine in the treatment of headaches has a long history. In its review of caffeine [Federal Register, 1977, 42 (131): 35482-35485], the FDA Advisory Panel has argued that the known biochemical effect of caffeine on small blood vessels provides a plausible explanation for its effectiveness in treating headaches. associated with cerebral blood vessels. Recently, Sechzer [Curr. Therapy Research, 1979, 26 (4)] found that intravenous administration of caffeine-sodium benzoate rapidly provides relief for the majority of patients who experience headaches due to dural puncture or spinal anesthesia.

Referring to the literature on the mechanism of action of caffeine on cerebral blood flow and cerebral vascular tension, the author argues from the opposite perspective in comparison with the above-mentioned "Panel" that analgesic relief obtained means that an intracranial vascular component is the primary factor for such headaches. .

Changes in mood and the overall feeling of "well-being" after caffeine administration have been widely reported in the literature. Beginning in the early part of this century, Hollingsworth (Arch. Psychol., 1912, Z2: 1) reported beneficial motor and near-effects of 65-130 mg of caffeine and tremor, poor motor condition and insomnia caused by 390 mg of caffeine. '466 481 Manga studies over the last 70 years have confirmed these findings. Review articles on xanthines [Rítchie, J.M., "Central nervous system stimulants, 2. The xanthines", Goodman, L.S. & Gilman, A. (publishers), The pharmacological basis of therapeutics, 4th edition, New York, Macmillan Co., 1970; Stephenson, P.E., "Physiologic and psychotropic effects of caffeine on man", J. Amer. Diet. Assoc., 1977, 71 (3): Z40-247] reports that doses of 50-200 mg of caffeine lead to increased alertness, reduced sleepiness and reduced fatigue. Doses in the range of 200-500 mg may cause headache, tremor, nervousness and irritability.

After extensive review of the relevant literature, the most significant contributions of which are summarized above, the FDA Advisory Panel in 1977 concluded that caffeine when used as an analgesic adjuvant is safe but that there is insufficient data to demonstrate that caffeine contributes in some way to the action of the analgesic [Federal Register, 1977, 42 (131): 35482-35485]. The above-mentioned "Panel" stated that available information and data unfortunately can not reliably show that caffeine in combination is effective as an analgesic, antipyretic and / or antirheumatic ingredient, and further states that they have found that there is little evidence to show that this ingredient even - attracts these pharmacological effects under clinical conditions.

This has remained the official position on this issue to this day. Consequently, many of the previously available combination products of analgesic and caffeine are no longer on the market.

In addition to this few previous cases of selected non-narcotic analgesic / caffeine combinations which also contain a selected narcotic analgesic (which three-component combinations have already been discussed above), there are also examples in the art of two-466 481 S). -component combinations of selected non-narcotic analgesics with selected narcotic analgesics. Known combinations of this type include Darvon with A.SaA@§ (propoxyphenic hydrochloride and aspirin), Darvon-N with A.S.A. (priaoxyphenene napsylate and aspirin), aspirin with codeine, Talwin compound (pentazocine hydrochloride, oxycodone and aspirin), Percodan (oxycodone hydrochloride, terephthalate and aspirin) and nalbuphine with acetaminophen, the latter U.S. Pat. 140. The general principle of using a combination of medicinal effects, means for producing additive analgesics is known to those skilled in the art; for example, Foley et The Management of Cancer Pain, Volume II - The Rational Use of Analgesics in the Management of Cancer Pain, Hoffman-LaRoche Inc., 1981, describes such a combination and specifically states that 650 mg of aspirin or acetaminophen as Regularly added to a standard narcotic dose often increases the analgesic effect without requiring higher doses of the drug. Such additive effects have been previously reported by Houde et al, Clin.

Pharm. Ther. 1 (2): 163-174 (1960) for intramuscularly administered morphine sulfate administered with orally administered aspirin. However, no two-component composition of a narcotic analgesic and caffeine has been suggested; nor have any improvements in analgesic response that can be derived from concomitant administration of caffeine with any narcotic analgesic been proposed.

According to the present invention, it has now surprisingly been found that selected non-narcotic analgesic / non-steroidal anti-inflammatory drugs, which differ significantly in chemical structure from aspirin, phenacetin and acetaminophen, and which exhibit significantly different biological profiles in comparison, can advantageously be formulated into new pharmaceutical compositions together with caffeine and administered to mammals, especially humans, not only to elicit a more potent analgesic or anti-inflammatory response but also to elicit such a response faster than possible by administration of the analgesic or anti-inflammatory agent alone.

According to the present invention, it has also surprisingly been found that orally effective narcotic analgesics (ie narcotic agonists and narcotic agonist antagonists, which are effective orally as analgesics) can also be advantageously formulated into new pharmaceutical compositions together with caffeine and administered to mammals. , especially humans, for eliciting not only a stronger analgesic response but also for eliciting such an response more rapidly than is possible by administering the narcotic drug alone.

It has further been found that orally effective narcotic analgesics can be advantageously combined with non-narcotic analgesics and caffeine to form new pharmaceutical compositions which can be administered to mammals, especially humans, to elicit an improved analgesic response.

Accordingly, in one embodiment, the present invention provides a novel pharmaceutical material composition designed to induce accelerated onset and enhanced analgesic and anti-inflammatory response in a mammalian organism in need of such treatment, characterized in that the composition is a unitary dose of an analgesically and anti-inflammatory effective amount of an active drug component and an active drug potentiating adjuvant therefor, which active drug is naproxen (2- (6-methoxy-2-naphthyl) propionic acid), phenopropene (2- (3-phenoxyphenyl) propionic acid), indoprofen (p- (1-oxo-2-isoindolinyl) hydratropic acid), diflunisal (2 ', 4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid) or a pharmaceutically acceptable salt thereof, and which adjuvant 466 481 11 vans consists essentially of caffeine (3,7-dihydro-1,3,7-trimethyl) -1H-purine-2,6-dione) in an amount which accelerates the initiation of and enhances analgesic and anti-inflammatory effect of it ak the drug.

According to another embodiment of the present invention, the composition comprises a three-component composition consisting of (1) the active drug component consisting of naproxen, phenopropene, indoprofen, diflunisal or a pharmaceutically acceptable salt thereof, (2) a narcotic analgesic for oral administration and ( 3) the adjuvant which essentially consists of caffeine.

Typically, the active ingredients in the compositions of the invention are further combined with a non-toxic, pharmaceutically acceptable inert carrier therefor.

The present invention also means that methods for accelerating the initiation of an analgesic and anti-inflammatory response and methods for eliciting an enhanced analgesic and anti-inflammatory response in mammals may be developed.

The non-narcotic analgesic / non-steroidal anti-inflammatory drugs that can be used in the compositions of the present invention belong to the following categories: (1) propionic acid derivatives; and (2) biphenylcarboxylic acid derivatives.

While some of these compounds are currently used primarily as anti-inflammatory agents and others are primarily used as analgesics, in fact, all of the intended compounds have both analgesic and anti-inflammatory activity and can be used at appropriate dose levels for each of these objects in the compositions and methods of the present invention. The compounds of groups (1) - (2) typically contain a carboxylic acid functional group; however, such acids are sometimes administered in the form of their pharmaceutically acceptable salts, for example sodium salts. 4- Propionic acid derivatives that can be used include naproxen, phenoprofen and indoprofen. At present, naproxen and phenoprofen are preferred. Structural formulas of the above compounds are set forth below: PROPION ACID DERIVATIVE WB HCOOH naproxen CH3O oø fl phenoprofen í 3 CHCOOH o H3 K ::]: f & ï - «<::>» cHcooH These "propionic acid derivatives" are non-narcotic anal-non-dopoprene get -steroidal anti-inflammatory drugs, which have a free -CH (CH 3) COOH group (which may optionally be in the form of a pharmaceutically acceptable salt, for example -cHcoo 'Ne +>, which is directly attached to an aromatic ring system.

The biphenyl carboxylic acid derivative that can be used is diflunisal whose structural formula is given below: BIPHENYL CARBOXYLIC ACID DERIVATIVE COOH diflunisal F O O OH It is very advantageous that according to the present invention, pharmaceutical compositions are conveniently provided. 466 481 13 of materials adapted to elicit an enhanced analgesic and anti-inflammatory response with accelerated activation in the mammalian organism in need of such treatment, which compositions comprise a unit dose of an analgesically and anti-inflammatory effective amount of an active drug component and an active drug-potentiating adjuvant therefore, which active drug is naproxen, phenoprofen, indoprofen, diflunisal or pharmaceutically acceptable salt thereof and which adjuvant consists essentially of caffeine in an amount which accelerates the initiation of and enhances analgesic and anti-inflammatory action.

Accordingly, there is also provided an advantageous method of eliciting an enhanced analgesic and anti-inflammatory response with accelerated initiation in a mammalian organism in need of such treatment by administering to the mammal a unit dose of an analgesically and anti-inflammatory effective amount. a pharmaceutical composition of material comprising an active drug component and an active drug potentiating adjuvant thereof, which active drug is naproxen, phenoprofen, indoprofen, diflunisal or pharmaceutically acceptable salt thereof, and which adjuvant consists essentially of caffeine in an amount that accelerates and accelerates analgesic and anti-inflammatory effect of an active drug.

Narcotic analgesics that can be used in accordance with the present invention are orally active narcotic agonists and narcotic agonist antagonists (ie antagonists with analgesic properties). Suitable narcotic agonists that may be used include orally analgesically active members of the morphine group, the meperidine group 466 481 14 and the methadone group, especially codeine, oxycodone, hydromorphone, levorphanol, meperidine, propoxyphene and methadone. Suitable agonist antagonists that may be used include orally analgesically active morphine-type antagonists, especially propiram and buprenorphine; and orally analgesically active nalorphine-type antagonists, especially pentazocine, nalbufine and butorphanol.

Another suitable agonist-antagonist is meftazinol. In many cases administered narcotic analgesics that can be used in the form of pharmaceutically acceptable acid addition salts, for example kodeínsulfat, codeine phosphate, oxycodone hydrochloride, oxycodone terephthalate, hydromorphone hydrochloride, levorphanol tartrate, meperidinhydroklorid, propoxyphene hydrochloride, propoxyphene napsylate, methadone hydrochloride, propiram fumarate, buprenorphine hydrochloride, nalbuphine hydrochloride and meptazinol hydrochloride . Structural formulas for representative free bases are given below: codeine oxycodone levorphanol meperidine methadone meptazinol propoxyphene 466 481 CH CH ZCH-N \\\ CH C H5-CO - C-CH 2 OH 2 5 H CH 3/3 QH - 0- -CHCH -N \\ 2 s 2 ä H2 466 481 16 propiram buprenorphine pentazocin nalbufin butorphanol “FHS C CH3CH2COï-CHCHZN _ / N. \ 'Ca x-cH2c fi = c1: __ cn CH3 3 H3 HO 466 481 17 hydromorphone O HO The term "caffeine" is used to mean not only caffeine as the anhydrous powder, but also any salt or derivative of caffeine or any mixed mixture thereof which is non-toxic, pharmaceutically acceptable and which may accelerate and enhance an analgesic or anti-inflammatory agent. -inflammatory response in use as described herein. See, for example, The Merck Index, 9th Edition, Merck & CO., Inc.

Rahway, New Jersey (1976), pages 207-208, for a description of caffeine salts, derivatives and mixtures which may prove useful in the compositions of the present invention. Nevertheless, caffeine is currently preferred as the anhydrous powder base material, and when specific amounts of caffeine are given below, such amounts are given in mg of the anhydrous base material. The term "selected NSAID" is used to mean any non-narcotic, analgesic / non-steroidal anti-inflammatory compound of the compounds listed above. The term "selected narcotic analgesic" is intended to mean any orally analgesically active narcotic. analgesic, whether an orally active narcotic agonist or a narcotic antagonist exhibiting oral analgesic activity.The terms "selected NSAID" and "selected narcotic analgesic" are used for simplicity in the following discussion.

When a selected NSAID is combined with caffeine in accordance with the present invention, the following unexpected results are obtained: (1) The analgesic or anti-inflammatory effect of selected NSAIDs on mammals is more rapidly induced; (2) lower amounts of selected NSAIDs are required for the same analgesic or anti-inflammatory effect; and (3) higher analgesic or anti-inflammatory response is achieved over all doses.

For patients suffering from pain, the time from administration of medication to initiation of effective relief is of course of paramount importance.

According to the present invention, it has been found that caffeine significantly shortens the start-up time (ie significantly speeds up the start-up) for analgesia, which is consequently very significant; moreover, this was completely unexpected § For patients suffering from inflammation, for example due to rheumatoid arthritis or osteoarthritis, likewise, the significant shortening of the onset time provided according to the present invention is of utmost importance not only because it provides faster pain relief but also because this provides faster relief with respect to other aspects of the inflammatory disease, such as morning stiffness.

In addition, the ability of caffeine to enhance analgesia or to enhance the anti-inflammatory response, i.e. to significantly reduce the amount of selected NSAIDs required to elicit a given analgesic or anti-inflammatory response is also an unexpected and very significant aspect of the invention. This unexpected and significant finding allows the use of the selected NSAID in amounts that are significantly lower than the doses currently proposed as an analgesic or anti-inflammatory agent in humans. The use of lower doses should in turn reduce the incidence and / or severity of failure. 466 481 19 desirable side effects. In addition, at a given dose level, higher analgesic or anti-inflammatory response. More specifically, it is believed that the onset time for analgesia or for the anti-inflammatory response is on average about 1/4 to about 1/3 faster. A composition of the invention is used instead. for when the selected NSAID was used alone. Approximately 1/5 to 1/3 less amount of the selected NSAID can also be used in the caffeine combination to achieve the same analgesic or anti-inflammatory drug fissile misalignment obtained using only the selected NSAID; in other words, the addition of caffeine reduces the amount of selected NSAIDs to about 2/3 to 4/5 of the conventional amount to achieve the same effect. However, these conditions may vary depending on the patient's individual response, the selected dose level of the active ingredients, etc.

The exact amount of non-narcotic analgesic / non-steroidal anti-inflammatory drug for use in the present compositions varies, for example, depending on the particular drug selected, the condition for which the drug is administered, and the size and type of mammal. In general, selected NSAIDs can be used in any amount known to be an effective analgesic or anti-inflammatory amount, as well as in doses that are 1/5 to 1/3 less than the usual amounts.

For humans, typically effective analgesic amounts of currently preferred NSAIDs for use in the unit dose compositions of the invention are about 125-500 mg of diflunisal, phenoprofen. is about 125-500 mg naproxen and about 50-200 mg However, larger amounts can be used if desired. The amount of caffeine in the analgesic composition is an amount sufficient to shorten the onset time and / or increase analgesia. 466 481 - 3J For humans, an analgesic unit dose composition typically contains from about 60 to about 200 mg (preferably about 65 to about 150 mg) of caffeine; this dose level of caffeine is generally sufficient to both shorten the onset time and increase analgesia. However, some NSAIDs are particularly long lasting and do not need to be administered as often as the usual frequency of every four to six hours; for example, diflunisal and naproxen are typically administered only twice daily. When such long-acting drugs are used, it is often desirable to include an additional analgesic-enhancing amount of caffeine in the sustained-release formulation composition; thus, the composition typically contains from about 60 to about 200 (preferably about 85 to about 150) mg of immediate release caffeine to accelerate initiation and enhancement of analgesia and an additional (or possibly more) doses of 60-200 (preferably 65-150). mg caffeine for delayed release for continued increase in analgesia. The daily analgesic dose in humans varies depending on the selected NSAID and may, of course, be as low as the amount ingested in a single dose unit as indicated above. The daily dose for use in the treatment of mild to moderate pain preferably does not exceed 1500 mg diflunisal or 1000 mg naproxen or 2400 mg phenoprofen, plus 1000 mg caffeine, for use in the treatment of mild to moderate pain, although larger amounts may be used if such. tolerated by the patient.

For humans, typical effective anti-inflammatory amounts of currently preferred NSAIDs for use in unit dose compositions of the invention are about 250-500 mg diflunisal, about 250-500 mg naproxen or about 200-600 mg phenoprofen; however, larger amounts can be used if desired. The amount of caffeine in the anti-inflammatory composition is an amount sufficient to shorten the onset time and / or increase the anti-inflammatory response. For humans, a unit dose of anti-inflammatory composition typically contains from about 60-200 mg (preferably 65-150 mg) of caffeine; this dose level is generally sufficient to both shorten the start-up time and increase the anti-inflammatory response. Again, long-acting NSAIDs, i.e. those administered less often than three or four times a day in the treatment of inflammation (eg diflunisal and naproxen) can be formulated with larger amounts of caffeine in the dosage unit, with some of the caffeine being in sustained release form. Such compositions typically contain from about 60 to 200 (preferably about 65-150) mg of immediate release caffeine to accelerate initiation and enhancement of the anti-inflammatory response and one or more additional doses of 60-200 (preferably 65-150). ) mg of caffeine for delayed release for further enhancement of the anti-inflammatory response. The daily anti-inflammatory dose in humans varies depending on the selected NSAID; for example, the daily dose for use in the treatment of inflammatory conditions, for example rheumatoid arthritis, osteoarthritis and degenerative joint disease, is generally about 250-1500 mg diflunisal, about 250-1000 mg naproxen or about 1600-2400 mg phenoprofen. , plus 1000 mg of caffeine, although larger amounts could be used if tolerated by the patient.

When a selected narcotic analgesic is combined with caffeine in accordance with the present invention, the following unexpected results are obtained: (1) the analgesic effect of the selected narcotic analgesic is more rapidly produced; (2) lower amounts of the selected narcotic analgesic are required for the same analgesic effect; (3) a higher analgesic response is achieved over all doses. 466 481 '2D g35 22 Of course, for patients suffering from pain, and especially for patients suffering from severe pain, the time from administration of the medicine to the onset of effective relief is of utmost importance.

The discovery of the present invention that caffeine significantly shortens the onset time (ie, significantly accelerates the onset) of analgesia when combined with a selected narcotic analgesic is consequently highly significant; moreover, it is totally unexpected.

In addition, the ability of caffeine to enhance analgesia, i.e., to significantly reduce the amount of selected narcotic analgesic required to elicit a given analgesic response, is also an unexpected and very significant aspect of the present invention. This unexpected and significant discovery allows the use of selected narcotic analgesics in amounts substantially less than the doses currently proposed as analgesics for humans. The use of lower doses should in turn reduce the incidence and / or severity of undesirable side effects, including reducing the risk of addiction. In addition, a higher analgesic response can be achieved at a given dose level.

More specifically, it is believed that the onset time of analgesia can on average be about 1/4 to about 1/3 faster when a selected narcotic analgesic / caffeine composition of the invention is used in place of when only the narcotic analgesic is used. In addition, about 1/5 to 1/3 less amount of the selected narcotic analgesic may be used in the caffeine combination to achieve the same analgesic effect than that obtained by using the narcotic analgesic alone; in other words, the addition of caffeine reduces the amount of the selected narcotic analgesic to 2/3 to 4/5 of the conventional amount to achieve the same effect. However, these conditions may vary depending on the patient's individual response, the selected dose level of the active ingredients, etc.

The selected narcotic analgesic / caffeine compositions of the present invention are also beneficial because the use of caffeine counteracts sedative effects of the selected narcotic analgesic so that the patient becomes more lively, exhibits better mobility and can obtain an improved sense of well-being compared to when the narcotic analgesic is administered alone.

The exact amount of selected narcotic analgesic for use in the present narcotic analgesic / caffeine compositions varies, for example, depending on the specific drug selected, the type and size of the mammal, and the condition for which the drug is administered. In general, the selected narcotic analgesic can be used in any amount known to be an orally effective analgesic amount and in doses that are about 1/5 to 1/3 lower than the conventional amounts.

For humans, typical effective analgesic amounts of currently preferred drugs for use in the narcotic analgesic / caffeine unit dose compositions of the present invention are to be administered every four to six hours as needed. Approximately 1-5 mg of hydromorphone hydrochloride, about -60 mg codeine sulphate or phosphate, about 2.5-5 mg oxycodone hydrochloride or a mixture of oxycodone hydrochloride and oxycodone terephthalate (eg 4.50 mg oxycodone hydrochloride + 0.38 mg oxycodone terephthalate, or 2.25 mg oxycodone hydrochloride + 0.19 mg oxycodone terephthalate ), about 1-3 mg levorphanol tartrate, about 50 mg meperidine hydrochloride, about 65 mg propoxyphene hydrochloride, about 100 mg propoxyphenapsylate, about -10 mg methadone hydrochloride, about 25-60 mg propiram fumarate, about 8-10 mg buprenorphine hydrochloride, about -50 mg pentazocine hydrochloride, about 10-30 mg nalbu-g fine hydrochloride, about 4-8 mg butorphanol tartrate or about 100-500 mg meptazinol hydrochloride. The amount of caffeine in the analgesic composition is an amount sufficient to shorten the onset time and / or increase analgesia. For humans. contains an analgesic unit dose composition typically from about 60 to about 200 mg (preferably about 65-150 mg) of caffeine. This dose level of caffeine is generally sufficient both to shorten the start-up time and increase analgesia. The daily analgesic dose in humans varies with the selected narcotic analgesic and can, of course, be as low as the amount contained in a single unit dose as indicated above. The daily dose for use in the treatment of moderate to severe pain preferably does not exceed 30 mg of hydromorphone hydrochloride or 360 mg of codeine sulphate or phosphate or 60 mg of oxycodone hydrochloride or hydrochloride / terephthalate mixture, or 18 mg of levorphanol tartrate or 600 mg of meperidine hydrochloride or 390 mg of propoxyphene hydrochloride or 600 mg of propoxyphenapsylate or 60 mg of methadone hydrochloride, or 300 mg of propiram fumarate or 60 mg of buprenorphine hydrochloride or 300 mg of pentazocine hydrochloride or 180 mg of nalbuphine hydrochloride or 48 mg of butorphanol tartrate or 3000 mg of meptaphinol however, larger amounts may be tolerated by the patient. selected NSAIDs and a selected narcotic as defined herein combine receiving analgesia; at a given dose level it is When an analgesic is read, the increased analgesic effect of the combination is greater than for both the selected NSAID and for the selected narcotic analgesic alone. Consequently, it is possible to lower the amount of an analgesic and to achieve the same degree of analgesia as with a higher dose of the analgesic 466 -4'81 alone. In general, it is considered more desirable to lower the dose of the selected narcotic analgesic as its side effects are considered more undesirable than those of the selected NSAID. Decreasing the dose of the selected narcotic analgesic leads to a lower incidence and less severity of its concomitant side effects and less likelihood of addiction. In general, the addition of a selected NSAID can be expected to reduce the amount of the selected narcotic analgesic required to 2/3 to 4/5 of the conventional amount to achieve the same effect. However, these conditions may vary depending on the particular drugs selected, the patient's individual response, and the selected dose level of the active ingredients. In addition, it is possible to maintain the conventional amount of the selected narcotic analgesic and to utilize the enhanced analgesic response. When a selected narcotic analgesic and selected NSAID are further combined with caffeine in accordance with the present invention, the combination exhibits all unexpected results (accelerated initiation, etc.) and exhibits all the benefits discussed further above for selected narcotic analgesic / caffeine. the combination. In addition, the selected narcotic analgesic / selected NSAID / caffeine combination shares the increase in analgesia made possible by the combination of two different types of analgesic. Because the presence of caffeine counteracts the sedative properties of the drug, the resulting composition is of particular interest for an oral analgesic to be used during the day and which is effective against severe pain that can be exploited by patients who must remain awake and active.

It is believed that caffeine enhances the analgesic effect not only for the selected narcotic analgesic but also for the selected NSAID in the three-component combination; and that caffeine increases the onset of analgesia for both of these drugs. This is likely to lead to a higher analgesic response than that achieved not only by the selected narcotic analgesic alone or the selected NSAID alone but also by selected NSAIDs / caffeine, selected narcotic analgesic caffeine and selected narcotic analgesic / selected NSAID combinations. . However, it is not generally recommended that the amounts of selected narcotic analgesic and selected NSAIDs in the caffeine composition be further reduced compared to those used in the selected narcotic analgesic / selected NSAID combination; the purpose of the three-component composition is rather the utilization of further elevated and faster analgesia provided by the presence of caffeine. Accordingly, for use in the treatment of humans, the analgesically effective amount of selected narcotic analgesic in a unit dose three-component composition will typically be one previously indicated for the narcotic analgesic / caffeine two-component compositions of the invention. The amount of NSAID selected in a unit dose three component composition will be an amount sufficient to enhance analgesia.

For humans, a unit dose three-component composition will typically contain an amount of selected NSAIDs which are well tolerated when used in the treatment of mild to moderate pain and which are sufficient to enhance analgesia in combination with the selected narcotic analgesic; such amounts are the same as those set forth above as effective analgesic amounts in the discussion of the selected NSAID / caffeine two component compositions. The amount of caffeine in the three-component composition will be an amount sufficient to further increase analgesia or accelerate its onset; for humans 466 481 27 this amount will typically be from about 60 to about 200 mg (preferably 65 to 150 mg), which is an amount generally sufficient for both accelerated onset and elevated analgesia. The daily analgesic dose in humans of each analgesic in the three-component composition generally does not exceed the daily analgesic dose thereof as described above in connection with the two-component mixtures, while the daily dose of caffeine again usually does not exceed exceeds 1000 mg. Of course, larger amounts may be used if tolerated by the patient.

Currently preferred drugs as described above for use in the narcotic analgesic / caffeine compositions are also preferred for use in the three component compositions. Since these preferred drugs are typically administered every four to six hours, especially preferred NSAIDs for use in the three component compositions are selected from those preferred NSAIDs described above for use in the NSAID / caffeine compositions which are also effective for 4- to 6-hour hours. periods (phenoprofen and the like). If a narcotic analgesic with a longer-lasting effect is used or if the selected narcotic analgesic is prepared in a delayed release form, one of the NSAIDs with a longer-lasting effect could be combined therewith and, if desired, additional caffeine could be included in a delayed release form. Alternatively, all three components may be prepared for sustained release, in which case much larger amounts of each could be enclosed in an individual unit.

Although the compositions of the invention are preferably for oral use, they may also be formulated for and administered by other methods known for the administration of analgesics, for example as suppositories. In addition, the preferred human dose levels indicated above are for use in adults; pediatric compositions would contain proportionately less of the active ingredients. The compositions of the present invention are conveniently administered to mammals by any route of administration suitable for selected NSAIDs and / or selected narcotic pelvis orally or rectally. Preferably, the combination is prepared with any suitable non-toxic pharmaceutically acceptable inert carrier material. Such carrier materials are well known to those skilled in the art of pharmaceutical formulations. analgesic component, exem- For those who are not skilled, reference is made to a work entitled "REMINGTON'S PHARMACEUTICAL SCIENCES" (1416 uppagan), 1970. According to a typical preparation for oral administration, for example tablet or capsule, selected NSAIDs are combined in an effective analgesic or anti-inflammatory amount and caffeine in an amount sufficient to enhance the analgesic or anti-inflammatory response or accelerate its initiation, or the selected narcotic analgesic in an effective analgesic amount and caffeine in an amount which is sufficient to enhance the analgesic response or to accelerate its initiation, or the selected narcotic analgesic in an effective analgesic amount together with a selected NSAID in an amount sufficient to enhance the analgesic response and caffeine in an amount sufficient to further increase the analgesic response or accelerate initiation thereof, with any oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulphate, kaolin, mannitol and powdered sugar. If necessary, suitable binders, lubricants, explosives and dyes can also be included. includes starch, molasses and lactose, Typical binders gelatin, sugars such as sucrose, natural and synthetic gums such as acacia, sodium alginate, extracts of Irish moss, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol. Typical lubricants for use in such dosage forms may include, but are not limited to, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, and polyethylene glycol. Suitable disintegrants may include, but are not limited to, starch, methylcellulose, agar, bentonite, cellulose, wood products, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, and sodium lauryl sulfate. If desired, a conventional pharmaceutically acceptable dye may be included in the unit dosage form, i.e., any of the standard FD&C dyes. Sweetening and flavoring agents and preservatives may also be included, especially when preparing a liquid dosage form, for example, an elixir, a suspension or a syrup. In addition, when the dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be included as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both. Such compositions preferably contain at least 0.1% of active components; in general, the active ingredients constitute between about 2% and about 60% by weight of the unit.

Illustrative of typical unit dosage forms are tablets or capsules containing the amounts indicated in the table below. In this case, the asterisk (*) indicates that the adjacent amount is in delayed-release form. For example, "130 mg + 130 mg *" means that the first 130 mg are prepared for immediate release while the subsequent 130 mg is in sustained release form. 466 481 Table, Selected narcotic Selected NSAID K0ffGí analgesic in diflunisal, * I 125 mg 130 mg + 130 mg * 250 mg 130 mg + 130 mg * 500 mg 130 mg + 130 mg naproxen * 125 mg 130 mg + 130 mg * 250 mg 130 mg + 150 m8 * 250 mg 65 mg + 65 mg 500 mg 130 mg + 130 mg * phenoprofen 50 mg 65 or 130 mg 100 mg 130 mg 200 mg 65 or 130 mg 300 mg 130 mg 600 mg 130 mg propoxyphene hydrochloride feH ° PT ° fen 65 mg 200 mg 130 mg .f _ gšggçïaten fenoprofen 100 mg 200 mg 130 mg If desired, compositions of the present invention may be prepared for parenteral use by known methods.

It is possible to prepare the oral compositions according to the invention in such a way that the possibility that the narcotic analgesic can be extracted therefrom and then administered parenterally is significantly reduced. This can be accomplished by combining the drugs with insoluble excipients, such as methylcellulose, so that they form a dosage form that is insoluble in water. Such water-insoluble oral dosage forms are already known for at least some drugs per se, for example for propiram fumarate and methadone hydrochloride.

The analgesic and anti-inflammatory effects of the compositions of the present invention can be quantitatively evaluated in animals by the following tests: The antiphenylquinone torsion test: This test is a standard procedure for detecting and comparing analgesic activity and generally shows good correlation with human effect.

Mice are first given doses of the medicine being studied. The medications used are two dose levels of a selected NSAID with and without caffeine, or of a selected narcotic analgesic with and without caffeine or of a selected narcotic analgesic and a selected NSAID with and without caffeine. The mice were then exposed to phenyl-β-benzoquinone administered intraperitoneally and observed for the characteristic stretch-twist syndrome. Lack of rotation is a positive answer. The degree of analgesic protection can be calculated on the basis of suppression of rotation in relation to control animals examined on the same day. Time response data were also obtained. The test is a modification of the method of Sigmund et al and Blumberg et al (Sigmund, E., Cadmus, R., and Lu, G., Proc. Soc.

Exp. Biol. and Med. 95, 729-731, 1957; Blumberg, H. et al., Proc. Soc. Exp. Biol. With. 118, 763-766, 1965).

Test with inflamed rat paw: - Pressure-induced stimuli.

The Randall-Selitto method, modified according to Winter et al., Was used to determine the escape response threshold, which arose due to the application of increasing pressure to the yeast-inflamed left hind paw. Drug treatment was performed. The medications studied were 466 481 32 were two dose levels of a selected NSAID with and without caffeine. A constant increasing force was applied to the paw and the "escape reaction" was observed and recorded (Randall, L.Q., and Selitto, J.J .: Arch. Int.

Pharmacodyn., II, 409-419, 1957; Winter, C.A., and J. Pharmacol. Exp. Therap., 148, 373-379, des.

Lars, F .: (1965).

Mouse tail flick test: Tail flick testing in mice was modified according to D'Amour and Smith using controlled high-intensity heat applied to the tail. Normal and drug-treated mice were observed and the reaction time was measured. The drugs used were two doses of a selected narcotic analgesic with and without caffeine.

(D'Amour, E., and Smith, L., J. Pharmacol., 72, 74-79, 1941).

Tail clamping method according to Haffner: A modification of the method according to Haffner was used to determine drug effects on aggressive attack response caused by pressure stimulus clamping of the tail of a rat. A clamp is placed at the base of each straight tail before drug treatment and then again at specified intervals after treatment. The time required for induction of clear attack and biting behavior in the direction of the used stimulus was observed. The drugs studied were two doses of a selected drug (Haffner, F .: mentelle Prüfung Schmerzstillender Mittel. Deutsch med. Wschr., 55, 731-732, 1929).

Hot plate test on mouse (thermal stimulation): analgesic with and without caffeine. Experiment A modification of the Woolfe and MacDonald method was used, including the application of controlled thermal stimulation of the paws of mice. Drugs were administered to each treatment group.

The latency between the time of the animal's contact with the hot plate and the observation of standard pain responses, jumps and / or rapid blows with one or both hind paws were measured. The drugs studied were two doses of a selected narcotic analgesic with and without caffeine. (Woolfe, G., and MacDonald, A.D .: J. Pharmacol. Exp. Ther., 80, 300-307, 1944).

Adjuvant Arthritis Test: Adjuvant arthritis in the rat is a widely used model for human rheumatoid arthritis. It is basically an immunological reaction involving a cellular immune response to an injected bacterial adjuvant. The response is systemic but is mainly induced in the joints such as polyarthritis. The degree of arthritis in the hind paws is estimated either visually or by measuring the foot volume on the Z1 day after injection of the adjuvant.

A single subcutaneous injection of 1 mg Mycobacterium butyricum suspended in 0.1 ml of mineral oil was injected into the right hind paws of rats. The swelling of the injected hind paw measured on the 16th day constitutes the secondary response. Drugs were administered orally daily starting on the first day before injection of adjuvant. The drugs used were two dose levels of selected NSAIDs with and without caffeine. The results are expressed as a percentage suppression of the control. [Walz, D.T., Di Martino, M.J., and Misher, A .: Ann. Rheum. Dís., 30, 303-306 (l971)].

To determine the efficacy of the compositions of the present invention in humans, patients with moderate to severe pain requiring an oral analgesic may be administered a selected narcotic analgesic or NSAID with and without caffeine or a selected narcotic analgesic and a selected NSAID. with and without caffeine, while patients suffering from inflammatory or degenerative joint disease, such as rheumatoid arthritis, osteoarthritis, gout d '466 481 34 or acute musculoskeletal disease requiring an oral anti-inflammatory agent, may be administered a selected NSAID with and without caffeine. To determine the analgesic efficacy, an observatory nurse interviewed patients for the degree of pain or stiffness and swelling at subsequent time periods. Patients were asked to estimate the time subjectively at which the medication began to provide relief. Appropriate statistical methods can be used to demonstrate that, on average, the caffeine compositions have a shorter onset and are more effective. (Laska, E., Gormely, M., Sunshine, A., Belleville, J.W., Kantor, T., Forrest, W.H., Siegel, C.

Meisner, M .: and "A Bioassay Computer Program for Analgesic Clin. Ther. 8: 658, 1967; Cox, DR," Regression Models and Life Tables ", Journal Royal Statistical Society, Series B, Volume 34: 187-202, Clinical Trials ", Pharmacol. 1972). Evaluation of the effectiveness of inflammatory and degenerative joint disease was obtained by the patient's own assessment of the severity of pain, the duration of morning stiffness, general feeling and ease of movement; and through the physician's evaluation of objective measurements, such as tenderness, swelling, number of painful joints, and various tests of function, such as grip strength, walking speed, breast augmentation, and ability to bring the fingers to the floor.

From the above description, the person skilled in the art can easily determine essential characteristics of the present invention and can within the scope of the invention carry out various changes and / or modifications for adaptation to different areas of use and conditions.

Accordingly, such changes and / or modifications are also encompassed by the present invention.

Claims (2)

W1 466 481 35 Patent claim A pharmaceutical composition designed to induce accelerated initiation and enhanced analgesic and anti-inflammatory response in a mammalian organism in need of such treatment, characterized in that the composition is a unit dose of an analgesic and anti-inflammatory agent. theoretically effective amount of an active drug component and an active drug potentiating adjuvant therefore, which active drug is naproxen (2- (6-methoxy-2-naphthyl) propionic acid phenoprofen (2- (3-phenoxyphenyl) propionic acid), indoprofen (p- ( 1-oxo-2-isoindolinyl) hydratropic acid), diflunisal (2 ', 4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid) or a pharmaceutically acceptable salt thereof, and which adjuvant consists essentially of caffeine (3,7-dihydro- 1,3,7-trimethyl) -1H-purine-2,6-dione) in an amount that accelerates the initiation of and enhances the analgesic and anti-inflammatory effect of the active drug. 2. A composition according to claim 1, characterized in that the active drug is naproxen or a pharmaceutically acceptable salt thereof. 3. A composition according to claim 1, characterized in that the active medicament is phenoprofen or a pharmaceutically acceptable salt thereof. 4. A composition according to claim 1, characterized in that the active drug is indoprofen or a pharmaceutically acceptable salt thereof. 5. A composition according to claim 1, characterized in that the active medicament consists of diflunisal or a pharmaceutically acceptable salt thereof. 6. A composition according to claim 1, characterized in that it comprises from 60 to 200 mg of caffeine. 7. A composition according to claim 6, characterized in that it comprises from 65 to 150 mg of caffeine. 8. A composition according to claim 5, characterized in that it consists of from 125 to 500 mg of diflunisal and from 65 to 150 mg of caffeine. 9. A composition according to claim 5, characterized in that it consists of from 250 to 500 mg of diflunisal and from 65 to 150 mg of caffeine. 10. A composition according to claim 2, characterized in that it consists of from 125 to 500 mg of naproxen and from 65 to 150 mg of caffeine. 11. A composition according to claim 2, characterized in that it is contaminated with from 250 to 500 mg of naproxen and from 65 to 150 mg of naproxen and from 65 to 150 mg of caffeine. 12. A composition according to claim 3, characterized in that it comprises from 50 to 200 mg of phenoprofen. 13. A composition according to claim 3, characterized in that it comprises from 200 to 600 mg of phenoprofen. The composition of claim 1, characterized in that it comprises a non-toxic pharmaceutically acceptable carrier. A composition according to claim 1, characterized in that it consists of a three-component composition consisting of (1) the active drug component consisting of naproxen, phenoprofen, indoprofen, diflunisal or a pharmaceutically acceptable salt thereof, (2) a narcotic analgesic for oral administration and (3) the adjuvant which consists essentially of caffeine. 16. A composition according to claim 15, characterized in that the narcotic analgesic is propiram fumarate. Composition according to Claim 15, characterized in that the narcotic analgesic is pentazocine hydrochloride, nalbuphine hydrochloride, butorphanol tartrate or meptazinol hydrochloride. 18. A composition according to claim 15, characterized in that the narcotic analgesic is propoxyphene hydrochloride, propoxyphenapsylate, codeine sulphate or codeine phosphate.