NL8320240A - IMPROVED ANALGETIC AND ANTIFLOGISTIC, CAFFEINE-CONTAINING PREPARATIONS AND METHODS FOR USE THEREOF. - Google Patents

Description

832 02 4 0 VO 6171

Improved analgesic and antiphlogistic caffeine-containing preparations and methods for their use.

The present invention relates to new pharmaceutical preparations containing caffeine and one or more analgesic agents, or caffeine and an antiphlogistic agent, and methods of using these preparations to accelerate the occurrence of an analgesic or antiphlogistic response and to enhance a analgesic or antiphlogistic response.

Non-narcotic analgesics, most of which are also known as non-steroidal antiphlogistic drugs (NSAG), are widely administered orally in the treatment of mild to severe pain. Within this class, the compounds exhibit a wide variety of chemical structure and biological profile as analgesics, antiphlogistics and antipyretics. Aspirin, acetaminophen and phenacetin have long been among the most commonly used members of these groups, however, in the more recent past, a large number of alternative non-narcotic agents with differing benefits over the older drugs have been developed. Tolerance or addiction to these drugs is generally not a problem in their continued use in the treatment of pain or in the treatment of acute or chronic inflammatory states (especially rheumatoid arthritis and osteoarthritis); nevertheless, these drugs generally have a higher potential for adverse side effects to occur at the upper limits of their effective dosage ranges. In addition, above the upper limit or ceiling of any drug, the administration of additional drug does not usually enhance the analgesic or anti-phlogistic effect. Among the newer compounds from the non-narcotic analgesic-non-steroidal antiphlogistic group are compounds such as di-flunisal (Dolobid®), summer pirac sodium (Zomax®), ibuprofen (Motrin®), naproxen (Naprosyn®), phenoprofen ( Naif on®), proxicam (Feldene®), fluirbiprofen, mefenamic acid (Ponstel ^) and sulindac. See also

Physicians' Desk Reference, 35th Edition, 1981, and The Merck Index, 9th Edition,

Merck & Co., Rahway, New Jersey (1976), for information on specific non-steroidal antiphlogistic agents. General reference should also be made to 83 2 0 2 4 0 2 to Wiseman, "Pharmacological Studies with a New Class of Nonsteroidal Anti-Inflammatory Agents - The Oxicams - With Special Reference to Piroxicam (Feldene ^), The American Journal of Medicine, Feb. 16, 1982: 2-8; Foley et al., The Management of Cancer Pain, Vol. II - The 5 Rational Use of Analgetics in the Management of Can-er Pain, Hoffman-La Roche Inc., 1981; and Cutting * s Handbook of Pharmacology, 6th ed., ed.

T.Z. Cz £ ky, M.D.,. Appleton-Century-Crofts, New York, 1979, chapter 49: 538 - 550.

Narcotic analgesics are often used when the control of pain with non-narcotic analgesics is ineffective. While the drugs in this group show significant variation in their chemical structure and pharmacological properties, almost all of them suffer from the drawback of tolerance and possible addiction with continued use. Within the narcotic analgesic group, the drugs can be divided into 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 (other than analgesics), other narcotic antagonists are agonist antagonists (i.e.

20 antagonists with analgesic properties); the agonist antagonists are commonly classified as morphine-like or nalorphine-like). Many of the narcotic analgesics are oral, ineffective and are therefore preferred to be used parenterally. The orally active narcotic analgesics include compounds such as codeine, oxycodone, levorphanol 25 (Levo-Dromoran ^), meperidine (Demerol ^), propoxyphene hydrochloride (Darvon ^), propoxyphene napylate (Darvon-N'- '), methadone, propiram , buprenorphine, pentazocine (Talwin®), nalbuphine (Nubain®) and butorphanol (Stadolv - '). For more specific information on these compounds, see Physician's Desk Reference, 35th Edition, 1981, and The 30 Merck Index, 9th Edition, Merck & Co., Inc., Rahway, New Jersey (1976).

In general, reference is also made to the literature cited above by Foley et al. And Cutting's Handbook of Pharmacology, 6th edition, ed. T.Z. Czdky, M.D., Appleton-Century-Crofts, New York, 1979, chapter 50: 551-566.

Caffeine, or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2.67 dione, corresponds to structural formula 1 (formula figures refer to the attached formula sheet). This material was used alone, intravenously, 83202403 in the treatment of headaches, and was also used in combination with selected drugs. One or more of the aspinrine, acetaminophen and phenacetin analgesics in combination with varying amounts of caffeine-containing preparations have been marketed in the past; in several instances, such products comprising a combination of non-narcotic analgesics and caffeine further contain one of the narcotic analgesics, codeine, propoxyphene, or oxycodone. Examples of these combinations include the products commercially known as Excedrin®, SK-65® Compound, Darvon®

Cr) 10 Compound, Anacin ^, A.P.C., and A.P.C.with Codeine, Tabloid "-" Brand.

The non-steroidal analgesic components of these mixtures aspirin (acetylsalicylic acid), acetaminophen, phenacetin, correspond to structural formulas 2, 3 and 4, respectively.

The three narcotic analgesics sometimes added to the aspirin / phenacetin / acetaminophen / caffeine combinations, viz. Codeine, propoxyfen and oxycodone, correspond to the structural formulas 5, 6 and 7, however. The prior art has never suggested adding caffeine to a narcotic analgesic to contribute to the analgesic effect of that narcotic.

Many researchers have attempted to demonstrate 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 25 a Monograph for OTC Internal Analgesic, Antipyretic and Antirheumatic Products," Federal Register, 1977, 42 (131): 35482 - 35485 ] and several relevant further articles have been published. Most animal studies on caffeine analgesia have been conducted in rats. Williams (Toxicology and Applied Pharmacology, 1959, 1: 447-453) used experimental pain and found that caffeine alone had analgesic activity in rats and when combined with aspirin, the activity was found to be additive, but not to be potent. Vinegar et al (Proceedings of the Society for Experimental Biology and Medicine, 1976, 151: 556-560), found ten years later that rats potentiate the acute anti-phlogistic and analgesic activity of aspirin. Siegers (Pharmacology, 1973, 10: 19-27) studied the effect of oral doses of 6320240 4 of caffeine (10, 50 and 100 mg / kg) administered to rats along with acetaminophen and found that caffeine inhibited its absorption and serum concentration decreased. He suggests that delayed gastric emptying due to the relaxing effect of caffeine on the smooth muscle of the stomach was probably responsible for the reduced absorption of orally administered drugs in the presence of caffeine. Despite this finding, the. acetaminophen analgesia not reduced by caffeine. In agreement with Williams and Vinegar and his collaborators, Siegers found that caffeine itself had analgesic activity. Only in the smallest caffeine dose examined, a dose in which analgesia did not occur, was a reduction in the analgesia elicited by acetaminophen. In a more recent publication, Seegers et al. (Arch. Int. Pharmacodyn., 1981 , 251; 237-254) an antiphlogistic analgesic activity of caffeine in rats.

They also found that the combination of caffeine, aspirin and acetamino gene as well as the combination of caffeine, aspirin and phenacetin in small doses had antiphlogistic analgesic effects at least as strong as might be expected from addition, while at higher doses indicated the results in the direction of potentiation. The work of 20 Giertz and Jurna (Naturwissenschaften, 1957, 44: 445), and Fuchs and Giertz (Arzneimittelforsch., 1960, 10: 526-530), observed that caffeine-induced analgesia in mice where inflammation was not concerned, quoting, Seegers argued, "it seems safe to assume that the analgetic activity of caffeine consists of at least 25 two components, one indepentent of and another one dependent on its antiinflammatory activity." (It seems safe to assume that the analgesic activity of caffeine consists of at least two components, one independent of and the other dependent on its antiphlogistic activity.)

The first human study in question was reported by Wallenstein (Proceedings of the aspirin symposium, held at the Royal College of Surgeons, London, 1975). Two tablets of a combination, each tablet containing aspirin 210 mg, acetaminophen 150 mg and caffeine 30 mg, clearly and markedly produced stronger analgesia than the combination without caffeine. The dose of one tablet of the combination achieved higher mean points than the B 3 2 0 2 4 0 5 individual components alone, but was no better than the combination without caffeine. Wallenstein speculated that, "dosage may be an important factor, and caffeine may simply be ineffective much below the 60 mg dose." (Dosage may be an important factor, and it is possible that caffeine at a much smaller dose than 60 mg is simply ineffective). Booy (Nederlands Tijdschrift Voor Tandheelkunde, 1972, 79: 69-75) studied the relief of pain on each, from two days after pulling. a tooth. In patients who reported "severe pain" on the first day, the pain was relieved more strongly by 1000 mg acetaminophen 10 plus 100 mg caffeine than by 1000 mg acetaminophen alone. On the second day, this difference was not determined, although on both days all treatments were stronger than those with placebo, him et al. (Clin, Pharmacol. Ther., 1967, £: 521-542) included in their report, regarding a study, experimentally inducing pain in the 15 subjects by bradykinin, where, the combination of aspirin 520 mg and acetaminophen 260 mg administered orally could not be distinguished from placebo, while the same combination in smaller amounts, aspirin 325 mg and acetaminophen 162.5 mg plus caffeine 32.5 mg markedly differed from placebo 15, 60, 75, 105, and 120 minutes after taking the drug. A double-blind, crossover study of 216 patients by Wojcicki et al. [Archivum Immunologiae et Therapeae Experimentalis, 1977, 25 (2): 175-179] compared the activity of 1000 mg acetaminophen plus 100 mg of caffeine with the same amount of acetaminophen alone. One group of 25 patients in the trial suffered from severe and frequent idiopathic headaches and a second group had moderate post-operative orthopedic pain. The authors concluded that the pain relief was much stronger with the caffeine combination than with acetaminophen alone or with aspirin alone. Jain et al. (Clin. Pharmacol. Ther ,, 1978, 24: 69-75) first studied 70 postpartum patients with moderate to severe uterine cramps and / or episiotomy pain, and then a second group of 70 patients whose pain until only severe pain was limited. When comparing 800 mg aspartine plus 64 mg caffeine with 650 mg aspirin alone, these authors concluded that in patients with severe episiotomy pain, the combination is the more effective analgesic.

The use of caffeine in the treatment of headaches has a long history. The FDA Advisory Panel (the Food Food Drug A Administration's advisory panel 8320240 6) reasoned in its consideration of caffeine (Federal Register, 1977, £ 2 (131): 35482-354851, which describes the known biochemical effect of caffeine on the small blood vessels is a plausible explanation for its effectiveness in the treatment of cerebral blood vessel-related headaches Recently Sechzer [Curr. Therapy Research, 1979, 26 (4)], found that intravenous administration of caffeine sodium benzoate quickly relieved pain the majority of patients who had headaches as a result of dural puncture or spinal anesthesia The author, referring to the literature regarding the mechanism of caffeine's action on blood flow in the brain and on vascular tone in the brain, argues from a that of the Panel opposite perspective, which implies the analgesic relief of pain obtained, that an intracranial vascular component ire factor in such 15 headaches.

Mood changes and a general feeling of well-being after the administration of caffeine have been widely reported in the literature. Beginning in the first part of this century, Hollingsworth (Arch. Psychol., 1912, _22: 1) reported favorable motor and mental functioning of 65 to 130 mg of caffeine, and tremor, poor motor performance, and insomnia caused by 390 mg of caffeine. Many studies over the past 70 years confirm these findings. Review articles on the xanthines [Ritchie, J.M., "Central nervous system stimulants. 2. The xanthines," Goodman, L.S. & 25 Gilman, A. (Eds.), The pharmacological basis of therapeutics, 4th edition,

New York: Macmillan Co., 1970; Stepenson, P.E., "Physiologic and psychotropic effects of caffeine on man," J. Amer. Diet. Assoc., 1977, 71 (3): 240-247] report that doses of 50 to 200 mg of caffeine result in enhanced alertness, decreased drowsiness, and decreased fatigue. Doses in the 200 to 500 mg range can cause headaches, tremor, nervousness, and irritability.

After extensive review of the relevant literature, the main contributions of which are summarized above, the FDA Advisory Panel concluded in 1977 that caffeine was safe to use as an analgesic adjuvant when used, but that insufficient data was available to demonstrate that caffeine is contributing. to the action of the analgesic [Federal Register, 1977, 42 (131): 35482-35485].

8320240 7

The panel stated:

Unfortunately, the information and data, submitted, fail to demonstrate conclusively that caffeine in combination is effective as an.analgesic ,, antipyretic and / or antirheuma-5 tic ingredient. The Panel finds.there is. little evidence to show that this ingredient even contributes to these pharmacological. effects.in. the clinical-situation, (unfortunately 'the information and data presented do not unambiguously demonstrate that caffeine in combination is effective as an analgesic, antipyretic and / or anti-rheumatic component.

Panel believes that little evidence is available to demonstrate that this compound even contributes to these pharmacological actions-in-one. clinical situation).

This remains the official position on the question to date. Consequently, many of them. previously available analgesic / caf-felne combination products. no longer on the market.

Except for the few prior art combinations of selected non-narcotic analgesic / cafphinic combinations which are furthermore a. selected narcotic analgesic (which three-component combinations have been discussed above), there are also examples of prior art two-component combinations of selected non-narcotic analgesics with selected narcotic analgesics. Known combinations of this type include Darvon® with ASA ^ (propoxyphene hydrochloride and aspirin), Darvon-N ^ J with ASA ^ (propoxyphene napsylate and aspirin), aspirin with codeine, Talwin® Compound (pentazocine hydrochloride, oxycodone and aspirin), Percodane (oxycodone hydrochloride, terephthalate and aspirin) and nalbuphine with acetaminophen. the latter combination being described in U.S. Patent. No. 4,237,140. The general principle of using a combination of drugs to effect additive analgesic action is well known to those skilled in the art; for example, .. 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, suggest this combination and they point out in particular that 650 mg of aspirin or acetaminophen is regularly added to the standard narcotic dose. often enhances analgesic activity without requiring larger doses of the narcotic. Such additive actions have been previously described by Houde et al., Clin. Pharm. Ther. 1 (2): 163-174 (1960) for intramuscularly administered morphine sulfate given together with orally administered aspirin. As far as the applicant is aware, however, there are no prior art proposals regarding two-co-mixtures of a narcotic analgesic and caffeine, nor. proposals concerning improvement of the analgesic response derived from the co-administration of caffeine and any narco-analgesic.

Surprisingly, the applicant has found that certain non-narcotic analgesic / non-steroidal antiphlogistic drugs, which differ significantly in their chemical structure from aspirin, phenacetin and acetaminophen, and which have markedly different biological profiles, may advantageously be formulated into novel pharmaceutical preparations together with caffeine and administered to mammals, especially humans, not only to produce a more potent analgesic or antiphlogistic response, but also to produce this response more rapidly than is possible by administration of the analgesic or antiphlogistic agent only.

Applicant has also found, quite surprisingly, that orally effective narcotic analgesics (ie, narcotic agonists and narcotic agonist antagonists which are orally effective as analgesics) can also be advantageously formulated into new pharmaceutical compositions along with caffeine and administered to mammals , especially humans, not only to produce a more potent analgesic response, but also to produce this response more rapidly than is possible by administration of the narcotic drug alone. Furthermore, the applicant has found that orally effective narcotic analgesics can advantageously be combined with non-narcotic analgesics and caffeine to form new pharmaceutical compositions which can be administered to mammals, especially humans, to achieve an improved analgesic response to bring.

In one aspect, the present invention thus provides a novel pharmaceutical composition or mixture for use to produce an analgesic or antiphlogistic response, of which compositions have an effective analgesic or antiphlogistic amount of a particular non-narcotic analgesic / non-steroidal antiphlogistic drug as described below and a sufficient amount of caffeine to accelerate the occurrence of the analgesic or antiphlo- gistic response or to prevent this analgesic or anti-phlogistic response. strengthen, be part.

In another aspect, the invention provides a novel pharmaceutical composition for use to elicit an analgesic response, of which composition an effective analgesic amount of an orally analgesically active narcotic agonist or agonist antagonist and a sufficient amount of caffeine to prevent the action of the accelerate analgesic response or to enhance the analgesic response.

In a further aspect, the invention provides a new pharmaceutical composition for use to elicit an analgesic response, of which composition an effective analgesic amount of an orally analgesically active narcotic agonist or agonist antagonist, an amount of a particular non-narcotic analgesic as described below in a sufficient amount to enhance analgesia, and a sufficient amount of caffeine to further enhance analgesia or accelerate its action.

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

In other aspects, the invention provides methods of accelerating the occurrence of an analgesic or antiphlogistic response and methods of establishing an enhanced analgesic or antiphlogistic response in mammals.

The non-narcotic analgesic / non-steroidal antiphlogistic drugs for use in the compositions and methods of the invention may be selected from the following categories: (1) the propionic acid derivatives; 8320240 (2) the acetic acid derivatives; (3) the phenamic acid derivative and; (4) the biphenylcarboxylic acid derivatives; and 5 (5) the oxicams.

While some of these compounds are nowadays mainly used as antiphlogistic agents, and others are mainly used as analgesics, in fact all have them. eye-catching compounds have both analgesic and antiphlogistic activity and can be used in suitable dosages for both purposes in the compositions and methods of the invention. The compounds in groups (1) to (4) typically contain a carboxylic acid function, but these acids are sometimes administered in the form. of their pharmaceutically acceptable salts, for example sodium salts.

The propionic acid derivatives intended for use according to the invention include, but are not limited to, ibuprofen, naproxen, benoxaprofen, flurboprofen, phenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozine, pranoprofen, miroprofen, tioxaprofen, suprofenoprofen , tiaprofenic acid.,. fluprofen and buclo-20. xinic acid. Structurally related propionic acid derivatives with similar analgesic and antiphlogistic properties are also considered to fall within this group. On this. currently preferred members of the propionic acid group include ibuprofen, naproxen, flurbiprofen, phenoprofen, ketoprofen and fenbufen. Representative members of this group are 25 inuprofen (Formula S), naproxen (Formula 9), flurbiprofen (Formula 10), fenbufen (Formula 11), phenoprofen (Formula 12), ibuprofen aluminum (Formula 13), indoprofen (Formula 14) ), ketoprofen (formula 15), fluprofen (formula 16),. and buccloxic acid. (formula 17).

Thus, the "propionic acid derivatives," as defined herein, are non-narcotic analgesic / non-steroidal antiphlogistic drugs, with a free CH2 CH2 COOH or. -CH ^ CH ^ COOH group (which may optionally be in the form of a pharmaceutically acceptable acid group, e.g., -CH (CH.j) COO Na + or -CH2CH2COO Na +), was typically bonded to a ring directly or through a carbonyl function -35 system, preferably to a. aromatic ring system.

The acetic acid derivatives of the invention include, but are not limited to, indomethacin, sulindac, tolmetine, summer pirac, dicophenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tio-pinac, zidometacin, acemetacin, fentiazac, fentiazac. Structurally related acetic acid vessels with similar analgesic and antiphlogistic properties are also considered to fall within this group. Presently preferred members of this acetic acid group include, tolmetin sodium, summer pirac sodium, sulindac and indomethacin. Representative members of this group are: summer pirac (formula 18), tolmetine (formula 19), silindac (formula 20), indomethacin (formula 21), diclofenac (formula 22), alclofenac (formula 23), phenclozin acid (formula 24) ) and ibufenac (formula 25).

Thus, "acetic acid derivatives" as defined herein are non-narcotic analgesic / non-steroidal antiphlogistic drugs with a free -C 2 COOH group (which may optionally be in the form of a pharmaceutically acceptable acid group, for example, -CH 2 COO Na + ), typically bonded directly to a ring system, preferably to an aromatic or heteroaromatic ring system.

The phenamic acid derivatives of the invention include, but are not limited to, mefenamic acid, meclofenamic acid, fluphenamic acid, niflumic acid, and tolfenamic acid. Structurally related phenamic acid derivatives with similar analgesic and antiphlogistic properties are also considered to fall within this group. Presently preferred members of the phenamic acid group include: mefenamic acid and meclofenamate sodium (the sodium salt of meclofenamic acid). Representative members of this group are: mefenamic acid (formula 26), meclofenamic acid (formula 27), and flufenami-. neic acid (formula 28).

Thus, "phenamic acid derivatives," as defined herein, are non-narcotic analgesic / non-steroidal antiphlogistic drugs which are based radically with. have formula 29 which can bear various substituents and in which the free -COOH group may be in the form of a pharmaceutically acceptable salt group, for example -COO Na +.

The biphenylcarboxylic acid derivatives of the invention include, but are not limited to, diflunisal and fluorideal. Structurally related biphenylcarboxylic acid derivatives with similar analgesic and antiphlogistic properties are also considered to fall within this group. Preferred members of this group are diflunisal and fluvinal of formula 30 and 31, respectively.

. Thus, "biphenylcarboxylic acid derivatives", as defined herein, are non-narcotic analgesic / non-steroidal antiphlogistic drugs which are based on it. radical with. have formula 32 which can bear various substituents and wherein the free -COOH group is in. the form. from. a pharmaceutically acceptable salt group, for example - + - - -COO Na.

The oxicams for use according to the invention include, but are not limited to piroxicam, sudoxicam ,. isoxicam and CP-14.304. Structurally related oxicams with similar analgesic and antiphlogistic properties are also considered to fall within this group. A preferred member of this group is piroxicam (Formula 33).

Representative members are piroxicam .. (Formula 33) r sudoxicam (Formula 34), isoxicam (Formula 35) and CP-14,304 (4-hydroxy-1,2-benzothiazine 1,1-dioxide-4- (N-phenyl) -carboxamide] (formula 36).

Thus, the "oxicamen1" described herein are non-narcotic analgesic / non-steroidal antiphlogistic drugs of general formula 37, wherein R represents an aryl or heteroaryl ring system.

More particularly, according to the invention, there are suitably provided pharmaceutical compositions which are suitable and which provide analgesic and antiphlogistic responses in need of such treatment in such a manner as to trigger the occurrence of the response. accelerated and the response is enhanced, of which preparations one. unit dose of an analgesic and antiphlogistically effective amount of an active drug component and a .de. Functioning of. active drug 30 potentiating adjuvant. therefor part of which active drug ibuprofen, naproxen, fenoprofen, indoprofen, diflunisal or a pharmaceutically acceptable salt thereof are part thereof. and the adjuvant essentially consists of an amount of caffeine which accelerates the action of the analgesic and anti-phlogistic action of the active drug and which enhances this action.

Also, in accordance with this, there is provided a favorable method for effecting an accelerated and enhanced analgesic and antiphlogistic response in response to a mammalian organism in need of such treatment, comprising the administering to such an organism an analgesic and antiphlogistically effective amount of a pharmaceutical composition comprising an active drug component and an active drug-enhancing adjuvant therefor of which active drug ibuprofen, naproxen, phenofprofen, indoprofen, diflunisal or a pharmaceutically acceptable salt forms part thereof and the adjuvant consists essentially of an accelerating and enhancing amount of caffeine which enhances the analgesic and antiphlogistic action of the active drug.

The narcotic analgesics for use in accordance with the invention are orally active narcotic agonists and narcotic agonist antagonists (i.e., antogonists with analgesic properties). Suitable narcotic agonists for use according to the invention include orally analgesically active members of the morphine group, the meperine group and the methadone group, especially codeine, oxycodone, hydromorphone. levorphanol, meperidine, propoxyphene and methadone. Suitable agonist-20 antagonists for use according to the invention include orally analgesically active antagonists of the morphine type, in particular propiram and buprenorphine and predominantly analgesically active antagonists of the morphine type, in particular pentazocine, nalbuphine and butorphanol. Another suitable agonist antagonist is meptazinol. In many cases, the narcotic analgesics intended for use in the invention are administered in the form of their pharmaceutically acceptable acid addition salts, for example codeine sulfate, codeine phosphate, oxycodone hydrochloride, oxycodone terephthalate, hydromorphone hydrochloride, levorphanol tartrate, meperidine hydrochloride, propoxyphene hydrochloride, propoxyphene nasylate, methadone hydrochloride, propiramfumarate, buprenorphine hydrochloride, nalbuphine hydrochloride and meptazinol hydrochloride. Representative free bases are: codeine (formula 38), oxycodone (formula 39), levorphanol (formula 40), meperidine (formula 41), methadone (formula 42), meptazinol (formula 43), propoxyphene (formula 44), propiram ( formula 45), buprenorphine (formula 46), pentazocine (formula 47), nalbuphine (formula 48), butorphanol (form 83202414 14 mule 49) and hydromorphone (formula 50).

The term "caffeine" as used herein is considered to be not only caffeine as an anhydrous powder, but any salt or derivative of caffeine or any composite mixture thereof, which is non-toxic, pharmaceutically acceptable, and capable of providing an analgesic or anti- phlogistic response, when used in accordance with the invention, to accelerate or enhance. See, e.g., The Merck Index, 9th ed., Merck & Co., Inc. Rahway, New Jersey (1976), p. 207-208, for a description of caffeine salts, derivatives, and mixes, which may be useful in the compositions of the invention.

However, caffeine as the base in the form of anhydrous powder is currently preferred, and when specific amounts of caffeine are mentioned below, these amounts are given in mg of the anhydrous base.

The term "selected or determined NSAG" used herein is understood to have the meaning of any non-narcotic analgesic / non-steroidal antiphlogistic compound falling within one of the five structural categories indicated above. Likewise, the term "selected or determined narcotic analgesic" is intended to mean any orally analgesically active, narcotic analgesic, whether or not it is an orally active narcotic agonist or a narcotic antagonist with oral analgesic activity. The terms "selected or determined NSAG" and "selected or determined narcotic analgesic" are used for simplicity in the following description.

When a particular NSAG is combined with caffeine according to the invention, the following unexpected results occur: (1) the analgesic or antiphlogistic effect of the selected NSAG on the mammal begins to occur much earlier; (2) smaller amounts of the chosen NASG are required for the same analgesic or antiphlogistic effect, and (3) a stronger analgesic or antiphlogistic response is achieved over all doses.

35 For patients suffering from pain, the time lag from drug administration to the onset of effective relief is clearly of prime importance. Applicants' finding that caffeine significantly shortens the time to the onset of analgesia (i.e. significantly hastens the onset) is therefore of great significance, and is also quite unexpected. Likewise, in patients suffering from inflammation, for example, by rheumatoid arthritis or osteoarthritis, the marked reduction of the duration of action provided by the invention is extremely important, not only because it provides faster pain relief, but also because rapid relief is provided. is obtained in connection with other aspects of the inflammatory condition, for example, morning stiffness.

Furthermore, the ability of caffeine to enhance analgesia or enhance the anti-phlogistic response, ie to significantly reduce the amount of the chosen NSAG required to effect a given analgesic or anti-phlogistic response, is also unexpected and very important aspect of this invention. This unexpected and important benefit allows the chosen NSAG to be used in significantly smaller amounts than those currently proposed as an analgesic or antiphlogistic agent for humans. The use of smaller doses, in turn, should reduce the occurrence and / or severity of unwanted side effects. In addition, at a given dosage level, a stronger analgesic or anti-phlogistic response can be achieved.

More specifically, the applicant assumes that the time of occurrence of analgesia or the antiphlogistic response can be achieved on average about one-fourth to about one-third earlier when using a preparation according to the invention and that this is not the case when the selected NSAG is used alone. Also, about one-fifth to one-third less of the chosen NSAG can be used in combination with caffeine to achieve the same analgesic or antiphlogistic effect obtained by using the chosen NSAG alone, in other words, the addition of caffeine, the amount of the chosen NSAG decreases to about two-thirds to four-fifths of the usual amount to achieve the same effect, however, these proportions may vary depending on the individual response of the patient, 8320240 16 the chosen dose level at the active ingredients etc.

Which. amount of non-narcotic analgesic / non-steroidal antiphlogistic drug for use in exactly the formulations of the invention is used, for example, if function of which drug in particular is selected, varies the function against which the drug is administered and the size and type of the mammal. Generally speaking, the chosen NSAG can be used in any amount known to be an effective analgesic or antiphlogistic amount, as well as in doses one fifth to one third smaller than the usual amounts. .

For humans, typical effective analgesic amounts of the presently preferred NSAGs for use in dosage units of the compositions of the invention are about 125 to 500 mg of diflunisal, about 25 to 100 mg of summer pirac sodium, about 50 up to 400 mg ibuprofen, approx. 125 to 500 mg naproxen, approx. 25 to 50 mg flurbiprofen, approx. 50 to 200 mg phenoprofen, approx. 10 to 20 mg piroxi-cam, approx. 125 to 250 mg mefenamic acid, approx. 100 up to 400 mg fenbufen or about 25 to 50 mg ketoprofen; although larger amounts may be used if desired. The amount of caffeine in the analgesic preparation should be sufficient to shorten the time to analgesia and / or enhance analgesia. For humans, a unit dose of an analgesic composition of the invention will typically contain about 60 to about 200 mg (preferably about 65 to about 150 mg) of caffeine, which dosage level for caffeine is generally sufficient to both shorten the time to analgesia and enhance analgesia. However, some NSAGs have a particularly long-lasting effect and need to be administered less often than the usual 4 to 6 hours; for example, diflunisal and naproxen are typically administered only twice a day and piroxicam only once a day. When such long-acting drugs are used, it is often desirable to incorporate a traditional, analgesia-enhancing amount of caffeine into the composition in a form in which it is released over a longer period of time, and thus the composition typically contains approx.

60 to about 200 (preferably about 65 to about 150) mg of caffeine for immediate 8 3 1 0? A o 17 immediate release to accelerate the occurrence and to enhance the analgesia and an (or possibly more) additional dose (or doses) of 60 to 200 (preferably 65 to 150) mg of caffeine for the. long-term release to continue enhancing analgesia. The daily analgesic dose in humans varies according to the NSAG chosen and may, of course, be as small as the amount contained in a single unit dose, as described above. The daily dose before application; in the treatment of mild to moderate pain, preference should not exceed 1500 mg diflunisal or 600 mg 10-summer pirac sodium or 2400 mg ibuprofen or 1000 mg naproxen or 150 mg flurbiprofen or 2400 mg phenoprofen or 20 mg piroxicam or 1000 mg mefenamic acid or 2400 mg fenbufen or 300 mg ketoprofen, plus 1000 mg caffeine, for use in the treatment of mild to moderate pain, although larger amounts could be used if tolerated by the patient.

For humans, typical effective anti-phlogistic amounts of currently preferred NSAGs for use in unit doses of compositions of the invention are about 10 to 20 mg piroxicam, about 250 to 500 mg diflunisal, about 25 to 50 mg indomethacin, about 150 to 200 mg sulindac, about 200 to 400 mg tolmetine sodium, about 50 mg meclofenamate sodium ,. about 65 to 600 mg ibuprofen, about 250 to 500 mg naproxen, about 800 to 1200 mg fenbufen, about 50 to 100 mg ketoprofen, or about 200 to. 600 mg of fenoprofen; but larger amounts can be used if desired. The amount of caffeine in the antiphlogistic composition should be an amount sufficient to shorten the time course to occur of the antiphlogistic response and / or to enhance this response. For humans, a unit dose of the antiphlogistic composition typically contains about 60 to 200 mg (preferably 65 to 150 mg) of caffeine; This dose level is generally sufficient both to shorten the time course to onset of the antiphlogistic response and to enhance it. Also in this case, the long-acting NSAGs, ie those administered less often than three or four times a day in the treatment of inflammation (eg piroxicam, diflunisal, sulindac, tolmetin sodium and naproxen) may be formulated with higher amounts of caffeine in the dosage unit, wherein an 8320240 portion of the caffeine is in a sustained release form. Such formulations typically contain about 60 to 200 (preferably about 65 to 150) mg of immediate release caffeine to accelerate the occurrence and enhance the antiphlogistic response and one or more additional doses of 60 to 200 (preferably 65 up to 150 mg sustained release caffeine to enhance the enhancement of the antiphlogistic response. The daily anti-phlogistic dose in humans varies as a function of the chosen NSAG. For example, the daily dose for use in the treatment of inflammatory conditions, for example rheumatoid arthritis, osteoarthritis and degenerative diseases of the joints, is generally about 10 to 20 mg piroxicam, about 250 to 1500 mg di-flunisal, ca. 75 to 200 mg indomethacin, ca. 200 to 600 mg su-lindac, Ca. 600 to 2000 mg tolmethine sodium, approx. 200 to 400 mg meclo-15 fenamate sodium, approx. 1600 to 3000 mg ibuprofen, approx. 250 to 1000 mg naproxen, approx. 3200 to 4800 mg fenbufen, approx. 150 to 400 mg of ketoprofen or about 1600 to 2400 mg of fenoprofen, plus 1000 mg of caffeine, although larger amounts could be used if tolerated by the patient.

When a particular narcotic analgesic is combined with caffeine according to the invention, the following unexpected results occur: the analgesic effect of the chosen narcotic analgesic is produced more quickly, (2) smaller amounts of the chosen narcotic analgesic are required for a and the same analgesic effect, and (3) a stronger analgesic response is achieved across all doses.

For patients in pain, and more particularly for patients in severe pain, the time lag from drug administration to the onset of effective relief is of temporary importance. Applicants' finding that caffeine markedly shortens the time to analgesia occurrence (i.e., significantly accelerates the occurrence of analgesia) when combined with a particular narcotic analgesic is therefore very significant and, moreover, quite unexpected.

Furthermore, the ability to enhance caffeine analgesia, i.e. the amount of the chosen narcotic analgesic required to effect a given analgesic response, is also and unexpectedly a very important aspect of this invention. This unexpected and important finding provides the opportunity to use. the chosen narcotic analgesic in considerably smaller amounts than the presently proposed doses as an analgesic for humans. The use of smaller doses, in turn, should prevent the occurrence and / or severity of. reduce unwanted side effects, including a reduction in potential addiction. In addition, at a given dose level, a stronger analgesic response can be achieved.

More specifically, the applicant assumes that the time of occurrence of analgesia can be reached on average about one-fourth to about one-third earlier when a particular narcotic analgesic / caffeine preparation according to the invention is used than when the narcotic analgesic is used alone. . Also about one fifth to. one third less of the chosen narcotic analgesic are used in the caffeine combination to achieve the same analgesic effect as achieved using the narcotic analgesic alone. In other words, the addition of caffeine reduces the amount of the chosen narcotic analgesic to two-thirds to four-fifths of the usual amount to achieve the same effect. However, these ratios may vary depending on the individual response of the patient, the chosen dosage level of the active ingredients, etc.

The chosen narcotic analgesic / caffeine preparations according to the invention are also beneficial in that caffeine counteracts the sedative action of the chosen narcotic analgesic, so that the patient is more alert, sprightly, has better motor skills and a stronger feeling of. is more than happy when administering the narcotic analgesic alone.

Exactly how much of a particular narcotic analgesic is used in the narcotic analgesic / caffeine compositions of the invention will vary as a function of, for example, the drug specifically selected, the size and the. species of the mammal and the condition for which the drug is administered. Generally speaking, the chosen narcotic analgesic can be used in any amount known to be an orally effective analgesic amount, as well as in doses about one-fifth to one-third less than the usual amounts.

For humans, typical effective analgesic amounts of currently preferred narcotics for use in unit doses of narcotic analgesic / caffeine compositions of the invention administered as needed every 4 to 6 hours are from about 1 to 5 mg of hydromorphone hydrochloride, about 15 to 60 mg of codelesulfate or phosphate, about 2.5 to 5 mg of oxycodone hydrochloride 10 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), approx. 1 to 3 mg levorphanol tartrate, approx. 50 mg meperidine hydrochloride, approx. 65 mg propoxyphene hydrochloride, approx. 100 mg propoxyphene napsylate, approx. 5 to 10 15 mg methadone hydrochloride, approx. 25 to 60 mg propiram fumarate, approx. 8 to 10 mg buprenorphine hydrochloride about 25 to 50 mg pentazocine hydrochloride, about 10 to 30 mg nalbuphine hydrochloride, about 4 to 8 mg butor fanol tartrate or about 100 to 500 mg meptazinol hydrochloride. The amount of caffeine in the analgesic preparation is an amount sufficient to shorten the time course to the onset of analgesia and / or to enhance this analgesia. For humans, a unit dose analgesic composition typically contains about 60 to about 200 mg (preferably about 65 to 150 mg) of caffeine? this caffeine dosage level is generally sufficient both to shorten the time to the onset of analgesia and to enhance the analgesia. The daily analgesic dose in humans varies according to the narcotic analgesic chosen, and may, of course, be as small as the amount contained in a single unit dose, as described above. The daily dose for use in the treatment of moderate to severe pain is preferably not greater than 30 mg of hydromorphone hydrochloride, or 360 mg of codelesulfate 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 propoxyphene nasylate, or 60 mg of methadone hydrochloride, or 300 mg of propiram fumarate, or 60 mg of buprenorphine hydrochloride , or 300 mg pentazocine hydrochloride, or 180 mg nalbuphine hydrochloride 8320240 21 de, or 48 mg butorphanol tartrate ,. or 3000 mg of meptazinol hydrochloride, and 100 mg of caffeine, although larger amounts could be used if tolerated by the patient.

When a particular NSAG and a particular narcotic analgesic as described herein are combined, enhanced analgesia results. At a given dose level, the analgesic effect of the combination is stronger than that of either the chosen NSAG or the chosen narcotic analgesic alone *. It is therefore possible to reduce the amount of one of the analgesics and achieve the same degree of analgesia as with a larger dose of that analgesic alone. In general, it is considered more desirable to reduce the dosage of the chosen narcotic analgesic, since its side effects are considered more undesirable than that of the chosen NSAG. The dose reduction of the chosen narcotic analgesic results in its accompanying side effects becoming less frequent and less severe, and potential addiction becoming less likely. Generally speaking, the addition of a particular NSAG may be expected to reduce the required amount of the chosen narcotic analgesic to two-thirds to four-fifths the usual amount for the. achieve the same effect. However, these ratios may vary depending on which particular drugs are selected, the individual response of the patient and the chosen dose levels. of the active ingredients. In addition, it is possible to maintain the usual amount of the chosen narcotic analgesic and to take advantage of the limited analgesic response. When a certain narcotic analgesic and a certain NSAG are further combined with vaffeine according to the invention, the combination yields all expected results (accelerated occurrence of analgesia, etc.) and has all of the above detailed benefits of the chosen narcotic discussed in detail. analgesic / caffeine combination. In addition, the chosen narcotic analgesic / chosen NSAG / caffeine combination shares the enhancement of analgesia, which is made possible by the combination of two different types of analgesics. Since the presence of caffeine counteracts the selective properties of the narcotic, the resulting preparation is of particular interest as an oral analgesic 8320240 22 for daytime administration, which is effective, against severe pain, and which can be used in patients who have. must remain alert and active.

It is believed that caffeine enhances the analgesic activity of not only the chosen narcotic analgesic, but also the chosen NSAG in the three-component combination, and that caffeine accelerates the occurrence of analgesia elicited by the two drugs. is likely to produce a more potent analgesic response than that not only by the chosen narcotic analgesic alone or the chosen NSAG alone, but also by the chosen NSAG / caffeine, chosen narcotic analgesic / caffeine, and chosen narcotic analgesic / chosen NSAG combination is established. However, it is not generally recommended that the. amounts of chosen narcotic analgesic. and selected NSAG in the. caffeine 15 formulation is further reduced from those used in the chosen narcotic analgesic / chosen. NSAG combination, on the contrary, the three-component formulation is intended to take advantage of the further enhanced and faster acting angesy obtained by the presence of caffeine. Thus, for use in the treatment of humans, the analgesically effective amount of the chosen narcotic analgesic in one. unit dose of one. three-component formulation are typical as described above for the two-component narcotic analgesic / caffeine formulations of the invention. The amount of a particular NSAG in a unit-2 dose of a three-component formulation is an amount sufficient to enhance analgesia. For humans it contains a unit dose of a three-component formulation. typically an amount of the selected NSAG, which is well tolerated by itself when used for the treatment of mild to moderate pain and is sufficient to enhance analgesia in combination with the chosen narcotic analgesic; these amounts are the same as those described above as effective analgesic amounts when discussing the two-component preparations consisting of the selected NSAG and caffeine. The amount of caffeine in the three-component formulation is such that it is sufficient to further enhance or accelerate analgesia. In humans, this amount is typically about 60 8320240 23 to about 200 mg (preferably 65 to 150 mg); which amount is generally sufficient to prevent the occurrence of analgesia. speed up and strengthen it. The daily analgesic dose in man for each analgesic in the three-component formulation will generally not exceed their daily analgesic doses as described above in connection with. the two component mixtures, while the daily dose of caffeine once again over it. generally will not exceed 1000 mg. Obviously, larger amounts may be used if tolerated by the patient.

The presently preferred narcotics described above for use in the narcotic analgesic / caffeine preparations are also preferred, for use in the three component preparations. Over there. These preferred narcotics are typically administered every 6 to 4 hours, particularly preferred NSAGs for use in the three-component formulations are selected from those preferred NSAGs described above for use in the NSAG / caffeine formulations, but are also effective for periods of 4 to 6 hours (summer pirac sodium, ketoprofen, ibuprofen, flurbiprofen, phenoprofen, mefenamic acid and the like). Is a narcotic analgesic with a longer duration of action, or when the chosen narcotic analgesic is. formulated in a sustained release form, one of the longer lasting NSAGs may be combined therewith and optionally an additional amount of caffeine may be included in a sustained release form. Optionally, all three components could be formulated to be delayed or slow release, in which case much larger amounts of each would be included in an individual dosage unit.

Although the. preparations according to the invention are preferably intended for oral use, they can also be formulated and administered according to others for. the administration of analgesics known methods, for example, in the form of suppositories. Furthermore, the preferred human dosage levels indicated above are intended for use in adults; pediatric preparations are said to contain relatively less of the active ingredients.

The compositions of the invention are very suitably administered to mammals by any route of administration suitable for the selected NSAG and / or the selected narcotic analgesic component, for example, oral or rectal. Preferably, the combination is formulated 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. For the non-expert. referred to the text under the title "REMMINGTON1s; PHARMACEUTICAL SCIENCES" (14th edition), 1970. In a typical preparation for oral administration, for example, a tablet or capsule, the selected NSAGs are in an effective analgesic or antiphlogistic amount and caffeine in a sufficient amount to limit or accelerate the analgesic or antiphlogistic response, or the chosen narcotic analgesic in an effective analgesic amount, and caffeine in an amount sufficient to enhance or accelerate the analgesic response, or the chosen narcotic analgesic in an effective analgesic amount together with a selected NSAG in an amount sufficient to enhance the analgesic response and caffeine in an amount sufficient to further enhance the analgesic response or accelerate its occurrence. Combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar. In addition, if necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be included. Typical binders include starch, gelatin, sugars such as sucrose, molasses and lactose, natural and synthetic gums such as acacia gum, sodium alginate, Irish moss extract, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolodone, polyethylene glycol, ethyl cellulose and waxes. Typical lubricants for use in these 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, methyl cellulose, agar, bentonite, cellulose, wood products, alginic acid, guar gum, citrus pulp, carboxymethyl cellulose, and sodium lauryl sulfate. If desired, a conventional pharmaceutically acceptable dye can be included in the dosage unit. 40, i.e. any of the standard FD&C dyes, Sweeteners and flavors and preservatives may also be included, especially when formulating a liquid dosage form, for example an elixir, suspension or syrup. Furthermore, a dosage form, when it is a capsule, may contain, in addition to the materials of the aforementioned type, a liquid carrier, such as a fatty oil. Various other materials may be present as an envelope agent to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules can be skinned with shellac, sugar or both. Preferably such preparations should contain at least 0.1% active ingredients; generally, the amount of the active ingredients makes up from about 2% to about 60% of the weight of the unit.

Examples of typical unit dosage forms are 15 tablets or capsules containing the amounts indicated in the table below. It should be noted that it (x) indicates that the amount indicated therein applies to the sustained release form; for example, "130 mg + - 130 mg" means that the first 130 mg refers to an immediate release formulation, while the second 130 mg refers to the form in which the active ingredients are released over a longer period of time.

TABLE

Chosen narcotic Chosen NSAG Caffeine analgeticum_ _ _ diflunisal 25 125 mg 130 mg + 130 mg * 250 mg 130 mg + 130 mg *

500 mg 130 mg + 130 mgS

summer pirac sodium 25 mg 65 or 130 mg 50 mg 65 or 130 mg 100mg 65 or 130 mg ibuprofen 50 mg 65 or 130 mg 100 mg 65 or 130 mg 200 mg 65 or 130 mg 35 300 mg 65 or 130 mg 400 mg 65 or 130 mg 500 mg 65 or 130 mg 600 mg 65 or 130 mg 83 202 * 0 26 TABLE (Continued)

Chosen narcotic Chosen NSAG Caffeine analgesic _ _ _ naproxen 125 mg 130 mg + 130 mg * 5 250 mg 130 mg + 130 mg3 * 250 mg 65 mg + 65 mg 500 mg 130 mg + 130 mg flurbiprofen 25 mg 130 mg 10 50 mg 130 mg fenoprofen 50 mg 65 or 130 mg 100 mg 130 mg 200 mg 130 mg15 600 mg 130 mg piroxicam 10 mg 130 mg + 130 mg

20 mg 130 mg + 130 mgM

20 mg 130 mg 20 20 mg 130 mg + 260 mg tolmetine sodium 200 mg 130 mg 400 mg 130 mg ibuprofen-aluminum 400 mg 130 mg mef enamic acid 125 mg 65 or 130 mg 250 mg 65 or 130 mg 30 indomethacin 25 mg 130 mg 50 mg 130 mg ketoprofen 25 mg 65 or 130 mg 35 50 mg 65 or 130 mg fenbufen 200 mg 65 or 130 mg 400 mg 65 or 130 mg 800 mg 65 or 130 mg 40 sulindac 150 mg 130 mg +130 mg 200 mg 130 mg + 130 mg3 * meclofenamate sodium 50 mg 65 or 130 mg 45t 8320240 27 TABLE (Continued)

Chosen narcotic Chosen NSAG Caffeine analgesic _ _ _ hydromorphone hydrochloride 5 1 mg 130 mg 2 mg 130 mg 3 mg 130 mg 4 mg 130 mg 5 mg 130 mg 10 codeine sulfate or phosphate 15 mg 130 mg 30 mg 130 mg 45 mg 130 mg 15 60 mg 130 mg oxycodone hydrochloride 2.5 mg 130 mg 5 mg 130 mg 20 meptazinol hydrochloride 200 mg 65 or 130 mg oxycodcn hydrochloride 25 terephthalate mixture 4.5 mg / 0.38 mg 130 mg 2.25 mg / 0.19 mg 130 mg levorphanol tartrate 1 mg 130 mg 30 2 mg 130 mg 3 mg 130 mg meperidine hydrochloride 50 mg 130 mg 35 propoxyphene hydrochloride 65 mg 130 mg propoxyphene napsylate 40 100 mg 130 mg methadone hydrochloride 5 mg 130 mg 10 mg 130 mg 45 propiram fumarate 35 mg 65 or 130 mg, 50 mg 130 mg 8320240 TABLE (Continued) 28

Chosen narcotic Chosen NSAG Caffeine analgesic _ _ _ buprenorphine hydrochloride 5 8 mg 130 mg 10 mg 130 mg pentazocine hydrochloride 25 mg 65 or 130 mg 10 50 mg 130 mg nalbuphine hydrochloride 10 mg 130 mg 15 mg 65 or 130 mg 15 30 mg 130 mg butorphano1-tartrate 4 mg 130 mg 8 mg 65 or 130 mg nalbuphine- hydrochloride ibuprofen 15 mg 200 or 400 mg 130 mg propiram fumarate ibuprofen 35 mg 200 or 400 mg 130 mg 50 mg 200 or 400 mg 130 mg 25 35 mg 200 or 400 mg 65 mg 50 mg 200 or 400 mg 65 mg pentazocine hydrochloride ibuprofen 25 mg 200 or 400 mg 130 mg 30 butorphanol tartrate ibuprofen 8 mg 400 mg 130 mg propiram fumarate summer pirac sodium 50 mg 50 or 100 mg 130 mg 35 mg 50 or 100 mg 130 mg 35 propoxyphenophenoprofen hydrochloride 65 mg 200 mg 130 mg propoxyphene napsylate fenoprofen 100 mg 200 mg 130 mg 40 propiram fumarate fenbufen 35 or 50 mg 400 mg 130 mg 35 or 50 mg 800 mg 130 mg 35 or 50 mg 400 mg 65 mg propiram fumarate mefenamic acid, 45 35 mg 250 mg 130 mg 8 3 2 0 2 A 0 29 TABLE (Continued)

Chosen Narcotic Chosen NSAG Caffeine analgesic _ _ _ codeine sulfate or phosphate mefenamic acid 30 mg 250 mg 130 mg 30 mg 125 mg 130 mg propiram fumarate ketoprofen 35 mg 25 or 50 mg 130 mg meptazinol ketoprofen 10 hydrochloride 200 mg 25 or 50 mg 130 mg 200 mg 25 or 50 mg 65 mg

If desired, the compositions of the invention can be formulated for parenteral use by known methods.

The two-component narcotic analgesic and caffeine preparation is particularly valuable in the case of severely painful patients who cannot tolerate oral administration of such drugs.

It is also possible to formulate the oral compositions of the invention such that the possibility that the narcotic analgesic could be extracted therefrom and subsequently misused parenterally is significantly reduced. This can be done by combining the drugs with insoluble excipients, such as methyl cellulose, to form a dosage form that is insoluble in water. Such water-insoluble oral administration forms are already known for at least some of the narcotics themselves, for example for propiram fumarate and methanone hydrochloride.

The analgesic and antiphlogistic effects of the compositions according to the invention can be quantitatively evaluated in animals in the experiments described below: Anti-phenylquinone coiled test

This test is a standard protocol for assessing and comparing analgesic activity and generally has a good correlation with efficacy for humans.

35 Mice are first administered the investigated medicaments. The indication occurs at two dose levels of a particular NSAG with and without caffeine, or a certain narcotic analgesic with a without caffeine, or a certain narcotic analgesic plus a selected NSAG with and without caffeine. The mice are then raised to react with phenyl-β-benzoquinone administered intraperitoneally and the characteristic pull-twirl syndrome is observed. The absence of squiggles means a positive response.

The degree of analgesic protection can be calculated from the squirm suppression relative to a comparison animal test on the same day. Time response data are also obtained. The trial is an altered form of the methods of Sigmund 10 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. Med. 118, 763-766, 1965).

The inflamed rat paw test - Pressure-induced stimuli.

Randall-Selitto's method, modified according to Winter et al., Is used to determine the threshold of the escape response, which results from increasing pressure on the left hind leg inflamed by yeast. The drug is administered. The medications studied were at two dose levels of a given NSAG with and without caffeine. A steadily increasing force is applied to the leg and the "flight response" is observed and recorded (Randall, LQ, and Selitto, JJ: Arch. Int. Pharmacodyn., II, 409-419, 1957; Winter, CA and Lars, F .; J. Pharmacol.

Exp. Therap., 148, 373-379, 1965).

The mouse tail swinging sample The study of tail swinging in mice is modified according to D'Amour and Smith using tail intensity controlled heat applied to the tail. Normal and drug treated mice are observed and the reaction time is measured. Drugs used consisted of two doses of a particular narcotic analgesic with and without caffeine (D'Amour, E. and Smith, L., J. Pharmacol., 72, 74 - 79, 1941).

Haffner's tail pinch method

A modified form of Haffner's prescription was used to assess drug effect on the aggressive attack responses elicited by a pressure stimulus in the form of squeezing a rat's tail. A clamp 8320240 31 is located on the root of the tail of each rat prior to drug treatment and again at specified intervals after treatment. The time required to establish a clear attack and bite behavior directed at the stimulus is observed. The medications examined consisted of two doses of a particular narcotic analgesic with and without caffeine. (Haffner, F.: Experimentelle Prüfung Schmerzstillender Mittel. Deutsche Med. Wschr., 55, 731-732, 1929).

The mouse hot plate assay (thermal stimuli) 10 'A modified form of the Woolfe and MacDonald method is used and involves the administration of a controlled heat stimulus to the legs of mice. Drug is administered to the treatment group. The latency period between, the time of contact of the animal with the hot plate and the observation of the standard pain response, jumping and / or rapid tapping of one or both hind legs is measured. The medications examined consisted of two doses of a particular narcotic analgesic with and without caffeine. (Woolfe, G. and MacDonald, A.D .: J. Pharmacol. Exp. Ther., 80, 300-307, 1944). Adjuvant Arthritis Test 20 Adjuvant arthritis in rats is a widely used model for human rheumatoid arthritis. Basically, it is an immunological response involving a cellular immune response to an injected bacterial adjuvant. The response is systemic, but mainly develops in the limbs as a polyarthritis. The degree of hind limb arthritis is assessed either visually or by measuring the volume of the foot on the 21st day after adjuvant injection.

A single subcutaneous injection of 1 mg Mycobacterium butyricum suspended in 0.1 ml mineral oil is injected into the rats' right hind legs. The swelling of the injected hind leg, measured on day 16, is the secondary response. Medicines are administered perorally, starting 1 day prior to adjuvant injection. The medications consisted of two dose levels of a given NSAG with and without caffeine. Results 35 are expressed as a percentage of the control animal's suppression. [Walz, D.T., Di Martino, M.J. and Misher, A .: Ann. Rheum.

8320240 32

Dis., 30, 303-306 (1971)].

For the determination of the effectiveness of the compositions of the invention in humans, patients with moderate to severe pain requiring an oral analgesic may use a given narcotic analgesic or NSAG with and without caffeine or a given narcotic analgesic plus a selected NSAG with and without caffeine, while patients suffering from an inflammatory or degenerative disease of the joints, for example rheumatoid arthritis, osteoarthritis, gout or an acute musculoskeletal disorder, requiring an oral antiphlogistic agent , as certain NSAG with and without caffeine are administered. For the determination of analgesic effectiveness, a nurse observer questions the patients regarding their pain level or stiffness and swelling at later times. Patients are asked to subjectively estimate the time when the medication provides relief. Appropriate statistical methods can be used to demonstrate that, on average, caffeine preparations start to work earlier and are more effective. (Laska, E., Gormely, M., Sunshine, A., Belleville, JW, Kantor, T., Forrest, WH, Siegel, C., and Meisner, M .: "A Bioassay Computer Program for Analge-20 sic Clinical Trials ", Clin. Pharmacol. Ther. 8: 658, 1967, Cox, DR," Regression Models and Life Tables ", Journal Royal Statistical Society, Series B, vol 34: 187-202, 1972). The evaluation of effectiveness in inflammatory and degenerative joint diseases is made by the patient's own assessment of the degree of pain, the duration of the morning stiffness, and the general feeling and ease of movement by the patient, and based on the assessment. by the physician of objective measures, such as tenderness, swelling, the number of the sore joints, plus various function tests, such as the strength of the grip, gait speed, chest expansion and finger on the floor.

From the foregoing description, the ordinary artisan can easily determine the essential features of the present invention, and without departing from its scope, can make various changes and / or modifications to the invention to adapt it to various uses and conditions. As such, these changes and / or modifications are properly and lawfully considered to fall within the full equivalence area of the following claims.

8 3 2 D 2 4 0

Claims (28)

A pharmaceutical composition suitable for and accelerated its performance and to elicit an enhanced analgesic and antiphlogistic response in a mammalian organism in need of such treatment, with. characterized in that the composition consists of a. unit dose of an analgesic and antiphlogistically effective amount of an active drug component and an active drug-potentiating adjuvant therefor, which active drug consists of ibuprofen, naproxen, fenoprofen, indoprofen, diflunisal or a pharmaceutically acceptable salt therefor, and which ad-10 juvans consists essentially of an increase in the activity of the analgesic and antiphlogistic effect induced by the active drug and an enhancing effect of this effect, which enhances this effect. Pharmaceutical preparation according to claim 1, characterized in that the active medicament consists of inuprofen or a pharmaceutically acceptable salt thereof. Pharmaceutical preparation according to claim 1, characterized in that the active medicament consists of naproxen or a pharmaceutically acceptable salt thereof. Pharmaceutical preparation according to claim 1, characterized in that the active medicament consists of phenoprofen or a pharmaceutically acceptable salt thereof. Pharmaceutical preparation according to claim 1, characterized in that the active medicament consists of indoprofen or a pharmaceutically acceptable salt thereof. Pharmaceutical preparation according to claim 1, characterized in that the active medicament consists of diflunisal or a pharmaceutically acceptable salt thereof. Pharmaceutical preparation according to claim 1, characterized in that it contains about 50 to about 200 mg of caffeine. Pharmaceutical preparation according to claim 7, characterized in that it contains about 65 to about 150 mg of caffeine. Pharmaceutical preparation according to claim 5, characterized in that it contains from about 125 to about 500 mg of diflunisal and from about 55 to about 150-8,320-240 mg of caffeine. Pharmaceutical preparation according to claim 6, characterized in that it contains about 250 to about 500 mg of diflunisal and about 65 to about 150 mg of caffeine. Pharmaceutical preparation according to claim 2, characterized in that it contains about 50 to about 400 mg ibuprofen. Pharmaceutical preparation according to claim 2, characterized in that it contains about 100 to about 600 mg inuprofen. Pharmaceutical preparation according to claim 3, characterized in that it contains about 125 to about 500 mg naproxen and about 65 to about 150 mg caffeine. Pharmaceutical preparation according to claim 3, characterized in that it contains about 250 to about 500 mg naproxen and about 65 to about 150 mg caffeine. Pharmaceutical preparation according to claim 4, characterized in that it contains about 50 to about 200 mg of phenoprofen. Pharmaceutical preparation according to claim 4, characterized in that it contains about 200 to about 600 mg of phenoprofen. Pharmaceutical preparation according to claim 1, characterized in that it contains a non-toxic pharmaceutically acceptable carrier. Pharmaceutical preparation according to claim 17, characterized in that the preparation is suitable for oral administration. Pharmaceutical preparation according to claim 18, characterized in that the preparation is formulated as a tablet or capsule. Pharmaceutical preparation according to claim 17, characterized in that the preparation is suitable for rectal administration. Pharmaceutical preparation according to claim 20, characterized in that the preparation is formulated as a suppository. Pharmaceutical preparation according to claim 18, characterized in that it is in such a form. that the active ingredients are released over a longer period of time. Pharmaceutical composition according to claim 1, characterized in that it further contains an analgesically effective amount of an orally analgesically active narcotic analgesic. Pharmaceutical preparation according to claim 23, characterized in that the narcotic analgesic consists of propiram fumarate. 8320240 Λ ft ν Pharmaceutical preparation according to claim 23, characterized in that the narcotic analgesic consists of pentazicine hydrochloride, nalbuphine hydrochloride, butorphanol tartrate or meptazinol hydrochloride. Pharmaceutical composition according to claim 23, characterized in that the narcotic analgesic consists of propoxyphene hydrochloride, propoxyphene napsylate, codeine sulfate or codeine phosphate. 27. Method 'for inducing an accelerated and action-enhanced analgesic and antiphysic response in a mammalian organism in need of such treatment, characterized in that it consists of administration to this organism, of a unit dose of an analgesic and antiphlogistically effective amount. a pharmaceutical composition comprising an active drug component and an active drug potentiating adjuvant therefor, said active drug consisting of ibuprofen, naproxen, phenoprofen, indoprofen, difunisal or pharmaceutically acceptable salts thereof, and which adjuvant essentially consists in accelerating the action of the analgesic and antiphlogistic effect induced by the active drug and enhancing this effect enhancing amount of caffeine. A method according to claim 27, characterized in that of the pharmaceutical preparation for an analgesic. effective amount of an oral analgesic active narcotic analgesic is included. 8320240