AT389998B - Process for producing an analgesic and antiinflammatory pharmaceutical preparation - Google Patents

Abstract

The production of novel analgesic and antiinflammatory compositions used to induce an analgesic or antiinflammatory response is described, wherein the compositions contain caffeine together with a steroidal, selected, non-narcotic analgesic non-steroidal, antiinflammatory medicament and a selected, narcotic analgesic. The caffeine used in combination with the selected medicaments enhances the analgesic and/or antiinflammatory response and likewise expedites its onset.

Description

Nf. 309998

The invention relates to a process for the preparation of a pharmaceutical preparation containing once analgesic and anti-inflammatory non-active ingredient and an adjuvant which enhances the effect of the active ingredient, with the additional use of an orally analgesic, nakotic analgesic.

Non-narcotic analgesics, most of which are also known as non-steroidal anti-inflammatory drugs (NSA1D), are often administered orally to treat mild to severe pain. Within this class, the compounds vary widely in their chemical structure and in their biological profiles as analgesics, anti-inflammatory agents and anti-pyretic agents. Acetylsalicylic acid, acctaminophen and phenacetin have long been among the most commonly used compounds in this group under 1cn. Recently, however, a large number of alternative, non-narcotic agents that have a variety of advantages over the known drugs have been developed. Tolerance or addiction is generally not a problem with these drugs when used continuously in the treatment of pain or in the treatment of acute or chronic inflammatory conditions (particularly rheumatic arthritis and osteoarthritis). Nevertheless, these drugs generally have a higher potential for adverse side effects in the upper limits of their effective dose ranges. In addition, the administration of additional medicinal products above the respective upper limit or the limit value of the medicinal product does not result in a significant increase in the alnalgesic or anti-inflammatory effect. Of the newer compounds in the non-narcotic analgesic / non-steroidal, anti-inflammatory group are compounds such as diflunisal. Zomepirac sodium, ibuprofen, naproxen, fenoprofen, piroxicam, flurbiprofen, mefcnamic acid and sulindac, cf. also Physicians' Desk Reference, 35th Edition, 1981, and The Merck Index, 9th Edition, Merck & Co., Rahway, New Jersey (1976), for more information on specific, non-steroidal, anti-inflammatory agents; see. Wiseman, " Pharmacological Studies with a New Class of Nonsteroidal Anti-Inflammatory Agents - The Oxicams · With Special Reference to Piroxicam, The American Journal of Medicine. February 16, 1982: 2-8; 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, edited by T. Z. Cziky, M.D., Appleton-Century-Crofts, New York, 1979, chapters 49.538-550.

Narcotic analgesics are often used when pain control with non-narcotic analgesics is ineffective. Although the drugs in this group vary widely in their chemical structures and pharmacological properties, almost all of them have the disadvantage of being tolerable and potentially addictive when used continuously. Within the narcotic, analgesic group, the drugs can be classified as narcotic agonists or as narcotic antagonists. Narcotic agonists include the morphine group, the meperidine group and the methadone group. Although some narcotic antagonists are pure antagonists (which are not analgesics), other narcotic antagonists are agonist antagonists (i.e., antagonists with analgesic properties). The agonist antagonists are generally classified as morphine-like or nalorphine-like compounds. Many of the narcotic analgesics are ineffective orally and are administered parenterally. The orally active, narcotic analgesics are such compounds as codeine, oxycodine, levorphanol, meperidine, propoxyphene hydrochloride, propoxyphene napsylate, methadone, propiram. Buprenorphine, pentazocine, nalbuphine and butorphanol. For a more detailed explanation of these connections, cf. Physicians' Desk Reference, 35th Edition, 1981, and The Merck Index, 9th Edition, Merck & Co .. Inc., Rahway, New Jersey (1976); see. further generally the Foley et al. and Cuttino's Handbook of Pharmacology, 6th edition, publisher T. Z. Czäky, M.D., Appleton-Century-Crofts, New York, 1979, chapters 50, 551-566.

Caffeine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione has the structural formula

This substance has been used intravenously in the treatment of headache alone and has continued to be used with selected drugs. Means one or more of the analgesics

No. 3S9998

Acetylsalicylic acid, aceemiitophene, and phenacetin, along with various amounts of caffeine, have been widely marketed. Such non-narcotic analgesic / i-caffeine combination products still contain various amounts of one of the narcotic analgesics codsin. Ptopoxyphene or Oxyccdon.

The non steroidal. Analgesic components of these mixtures have the following structural formulas:

NH-COCH3

NH-CGCH 1

OK OC2Hs

Acetylsalicylic acid

Acetaminophen

Phenacetin

The three narcotic analgesics that were occasionally added to the acctylsalicylic acid / phenacetin / acetaminophen / caffeine combinations have the following structural formulas:

CH, Oi- / \

Codeine

Propoxyphene

As far as is known, it has never been suggested that caffeine can be added to a non-anesthetic analgesic to contribute to its analgesic effect.

JP Kokai No. 56 154 416 (Kakeu) describes the enhancement of the antipyretic analgesic activity of ibuprofen by processing it with an antipyretic analgesic based on an aniline derivative, in particular bucetin and advantageously a caffeine and thiamine hydrochloride. Any reinforcing effects of caffeine, let alone caffeine alone, are not mentioned. The overall disclosure of this reference shows that a prejudice to the action of ibuprofen is essential with the presence of 1. the antipyretic, analgesic aniline derivative (which is structurally very different from caffeine) in combination with changing amounts of 2. a caffeine and 3. a Thiamine hydrochloride is linked.

Many scientists have tried to demonstrate the effectiveness of acetylsalicylic acid / phcnacctin / acciaminophcn and caffeine combinadone products. An extensive review of the literature on caffeine and analgesics has been published (" Ovcr-Thc-Countcr Drugs: Establishaient of a Mor.ograph for OTC Internal Analgesie, Antipyrctic and Anurheumatic Products ". Federal Register. 1977, «2 (131 ): 25482-354851.

Various, relevant, additional articles have been published. Most Ticrun examinations with KofTcin-Analgeuka were performed on the rue. Williams (Toxicology and Applied Pharmacology, 1959,

P00R ηιΐΔΐιτν

No. 389993 1, 447-453) used the experimental pain and found that caffeine alone has analgesic effects in rats and when combined with acetylsalicylic acid, the effects appearing to be additive and not potentiated. Vinegar et al. (Procccdings of the Society for Experimental Biologa and Medicine, 1976, 151,556 * 560) found ten years later that caffeine in the rat potentiates the acute, inflammatory and analgesic activity of acetylsalicylic acid Siegers (Phamt2Co! Ogy, 1973, IQ, 19-27 ) examined the effects of oral caffeine (10.50 and 100 mg / kg) when administered to rats together with acctaminophen and found that caffeine inhibits its absorption and lowers the senim concentration. He suspected that delayed gastric secretion as a result of the reclaxing Effect of caffeine on smooth stomach muscles was probably the cause of decreased absorption of the orally administered drugs in the presence of caffeine. Despite this result, the analgesic effects of acctaminophen were not worsened by caffeine. In agreement with Williams and Vinegar and his co-workers, Siegers found that caffeine itself has analgesic activity. Only in the lowest doses of caffeine investigated, a dose at which there was no analgesic effect, was a reduction in an analgesic effect of acetaminophen found. In a recent publication, Seegers et al. (Arch. Int. Pharmacodyn., 1981.251.237-254) according to the anti-inflammatory, analgesic effect of caffeine in rats. He further found that the combination of caffeine, acetylsalicylic acid and acctaminophen, as well as the combination of caffeine, acetylsalicylic acid and phenacetin, at very low doses, gave anti-inflammatory, analgesic effects that were at least as large as would be expected based on the addition , while at high dose levels the results suggested potentiation. Citing the work of Gierlz and Jurna (Natural Sciences, 1957, £ 4, 445) and Fuchs and Giertz (Medicinal Research, 1960, IQ, 526-530), who observed that caffeine induces the analgesic effect in assays in mice who did not experience inflammation, Seegers ensured that `` it appears to be safe to suggest that the analgesic activity of caffeine consists of at least two components, one of which is independent of and the other of which is dependent on its anti-inflammatory activity ''.

The first relevant human investigation was reported by Wallenstein (Proceedings of the aspirin Symposium, held at the Royal College of Surgcons, London, 1975). Two tablets of a combination, each tablet containing 210 mg acetylsalicylic acid, 150 mg acetaminophen and 30 mg caffeine, clearly and significantly gave a stronger analgesic effect than the combination without caffeine. The one tablet dose of the combination had a higher mean rating than either component alone, but was no better than the combination without caffeine. Wallcnstein speculated that "the dose must be an important factor, and that caffeine is simply ineffective significantly below a 60 mg dose". Booy (Ncdcriands Tijdschrift Voor Tandhcelkindc, 1972,22.69-75) examined the Schmcrzcrleichtening every two days after tooth extraction. Patients who reported "great pain" on the first day showed a greater pain relief with 100 mg acetaminophen plus 100 mg caffeine compared to 1000 mg acctaminophen alone. This difference was not resolved on the second day, although on both days all treatments were better than those with a placebo. Lim et al (Clin. Pharmacol. Ther., 1967, &, 521-542) reported an investigation in which a trial smear was induced in the subjects with bradykinin, and observed that a combination of 520 mg acetylsalicylic acid and 260 mg of orally administered acctaminophen could not be differentiated from the placebo, whereas the same combination in smaller amounts, 325 mg of acetylsalicylic acid and 162.5 mg of acctaminophen plus 32.5 mg of caffeine, differed significantly from the placebo at 15, 60, 75, 105 and 120 minutes after administration of the drug differed. In a Doppcl blind cross-test of 216 patients by Wojcicki et al. [Archivum Immunologiae et Therapeae Expcrimentalis, 1977.25 (2), 175-179] compared the activity of 1000 mg acctaminophen plus 100 mg caffeine against the same amount of acctaminophen alone. One group of patients in this trial had severe and common idiopathic headache, and a second group had moderate post-operative orthopedic pain. The authors concluded that the relief of pain with the caffeine combination is much better. compared to acetaminophen alone or acetylsalicylic acid alone. Jain et al. (Clin. Pharmacol. Ther., 1978, 21, 69-75) first examined 70 postpartumatic diseases with moderate to severe uterine cramps and / or episiotomic pain and then a second group of 70 patients who showed only severe pain. Comparing 800 mg acetylsalicylic acid plus 64 mg caffeine versus 650 mg acetylsalicylic acid alone, these authors concluded that the combination was a more effective analgesic in patients with severe episiotomic pain.

The use of caffeine in the treatment of headaches has a long history. The FDA advisory committee, in its summary of caffeine [Federal Register, 1977, 42, (131): 35482-35485], argued that the known biochemical effects of caffeine on small blood vessels provide a plausible explanation for its effectiveness in treating Is a headache associated with cerebral blood vessels. Recently Scchzcr [Curr. Thcrapy Research, 1979.2Q (* ·)] found that intravenous administration of caffeine sodium benzoate quickly provides relief to the variety of patients suffering from headaches due to dural puncture or spinal anesthesia. The author, referring to the literature, the mechanism of action of caffeine on cerebral blood flow and on -4-

No. 389998 describes the cerebral, vosulous tone, argues, argued from the opposite side of the committee, that the analgesic relief that is obtained implies that an inuacranial, vascular component is the main factor in such headache. Change in overall mood in the " wellbeing " after administration of caffeine are often described in the literature. Beginning in the early part of this century, Hollingsworth (Aich. Psychol., 1912, 22, 1) reports favorable motor and mental effects when 65 to 130 mg of caffeine are administered, and tremors, poor motor performance, and insomnia when administered of 390 mg of kofifein. Many studies over the past 70 years have confirmed these results. Summaries of Xanthine [Ritchie, J.M. Central nervous System stimulants. 2, The xanthines, L. S. Goodman and A. Gilman (ed.), The pharmacological basis of therapeutics, 4th edition, New York, Macmillan Co., 1970; P.E. Stephenson, Physiologie an psychotropic effects of caffeine on man, J. Amer. Diet. Assoc., 1977, 11 (3), 240-247] indicate that doses of 50 to 200 mg of caffeine result in increased alertness, reduced fatigue and reduced dreaminess. Doses in the range of 200 to 500 mg can cause headache, tremor, nervousness and irritability.

After carefully examining the relevant literature, the most important of which was mentioned above, the FDA Advisory Committee concluded in 1977 that caffeine when used as an analgesic adjuvant was safe, but that the levels were insufficient to show that caffeine contributes anything to the effects of the analgesic [Federal Register, 1977, 42, (131): 35482-35485], the Committee states: "Unfortunately, the information and values provided do not conclusively demonstrate that caffeine is effective in a combination preparation , analgesic, antipyretic and / or anti-rheumatic additive The Committee notes that there is little evidence that this ingredient contributes to the pharmacological effects of this Alt in a clinical trial "

This is the official response to the question asked above to this day. As a result, many of the analgesic / caffeine combination ion products that were previously sold are no longer on the market.

In addition to the few known cases of selected non-narcotic analgesic / caffeine combinations that additionally contain a selected narcotic analgesic (these three-component combinations have already been discussed above), there are also examples of two-component combinations from selected non-narcotic analgesics with selected narcotic analgesics. Known combinations of this type include propoxyphenhydrochloride with acetylsalicylic acid, propoxyphennapsyiate with acetylsalicylic acid, acetylsalicylic acid with codeine, pentazocin hydrochloride and oxycodone with acetylsalicylic acid, oxycodone hydrochloride and tcrcphthalate with acetylsalphonic acid; the latter combination is described in U.S. Patent 4,237,140. The general principle of using a combination of drugs with the formation of additive, analgesic effects is familiar to the person skilled in the art; e.g. B. 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. There, such a combination is proposed, and in particular it is designed that 650 mg Acetylsalicylic acid or acctaminophen, added regularly to the standard anesthetic dose, often enhances the analgesic effect without the need for higher doses of the anesthetic. Such additive effects were discovered very early on by Houde et al. Clin. Pharm. Thcr. 1 (2), 163-174 (1960) for intramuscularly administered morphine sulfate, which was administered together with orally administered acetylsalicylic acid. As far as is known, however, no Zwci-component compounds from a narcotic analgesic and caffeine are proposed in the literature. There is also no indication in the literature of how the analgesic response can be improved when caffeine and a narcotic analgesic are administered at the same time.

It has now surprisingly been found that a selected nichi-narcotic analgesic amine-non-steroid drug, namely ibuprofen, whose chemical structure differs significantly from acetylsalicylic acid, phenacetin and acctaminophen and which has a significantly different biological profile with advantage to new, pharmaceutical preparations together with oral narcotic analgesics (ie narcotic agonists and narcotic agonists · antagonists, which are oral analgesics and can be processed with caffeine and can be administered to mammals, preferably humans. These preparations not only result in a stronger, analgesic or anti-inflammatory Responses, but also cause this response to occur more quickly than when administering an analgesic or anti-inflammatory agent alone.

The invention is based on the object of specifying a method of the type mentioned at the outset which leads to a pharmaceutical preparation which not only provides an effective analgesic or anti-inflammatory response, but which responds faster than when NSAID is administered alone.

The process for producing a pharmaceutical preparation containing an analgesic and anti-inflammatory non-steroidal active substance and an adjuvant which enhances the effect of the active substance,

No. 389998 with the additional use of an orally analgesic, narcotic analgesic according to the invention consists in that as an analgesic and anti-inflammatory, non-active ingredient 50 to 24C0 mg of ibuprofen or a pharmaceutically acceptable salt thereof together with one narcotic analgesic per 60 to 1000 mg of caffeine as an adjuvant and optionally a carrier, the adjuvant enhancing the active ingredient accelerating the onset of the analgesic, anti-inflammatory effect of the active drug and enhancing the analgesic and anti-inflammatory effect.

Preferred embodiments of the invention are the subject of the subordinate claims.

The non-narcotic analgesic non-steroidal anti-inflammatory drug used in the preparations obtainable according to the invention is a propinic acid derivative, namely ibuprofen with the formula: (ch3) 2chch2

CHCOOH

This compound indeed has both analgesic and anti-inflammatory activity and can be used in suitable dose amounts for any purpose in the process according to the invention.

Iboprofen contains a carboxylic acid function. However, this compound is sometimes used in the form of one of its pharmaceutically acceptable salts, e.g. B. as a sodium salt.

It is particularly advantageous with the preparations obtainable according to the invention that they accelerate the start of the analgesic and anti-inflammatory response in the organism of a mammal which requires such treatment, and intensify the analgesic and anti-inflammatory response. These formulations contain a dose unit of an analgesic and anti-inflammatory amount of a drug ingredient and an adjuvant for potentiating the drug ingredient, the drug ingredient consisting of ibuprofen or one of its pharmaceutically acceptable salts and the adjuvant consisting of an amount of caffeine sufficient to begin with accelerate and intensify the analgesic and anti-inflammatory effects.

The narcotic analgesics that are additionally used in the present invention are orally active, narcotic agonists and narcotic agonist antagonists (i.e. antagonists with analgesic properties). Suitable narcotic agonists that can be used in the present invention include orally administrable, analgesically active members of the morphine group, the meperidine group and the methadone group, in particular codeine, oxycodone, hydromorphone, levorphanol, meperidine, propoxyphene and methadone. Suitable agonist antagonists which can be used in the present invention include orally administrable, analgesically active antagonists of the morphine type, in particular propiram and buprenorphine: and orally administrable, analgesically active antagonists of the nalorphine type, in particular pentazocin, nalbuphin and butorphanol. Another suitable agonist antagonist is meptazinol. In many cases, the narcotic analgesics used in the present invention are in the form of their pharmaceutically acceptable acid addition salts, e.g. B. listed as codcin sulfate, codcin phosphate, oxycodone hydrochloride, oxycodone terephthalate, hydromorphone hydrochloride, levorphanol tartrate, meperidine hydrochloride, propoxyphenhydrochloride, propoxyphene napsylate, methadone hydrochloride, propiram fumarate, buprenorphine hydrochloride, structure, and morphine chloride, nalbuphine,

Code in -6-

No. 389998

Oxycodone

Meperidine

CH 3

Methadone

Meptazinal

-7-

No. 389998

Propoxyphene

Propiram

Pentazocin

The term " caffeine " as used in the present context encompasses caffeine as an anhydrous powder, salts or derivatives of caffeine or a mixture thereof, which is non-toxic, pharmaceutically acceptable and which accelerates or enhances the analgesic or anti-inflammatory response, if is used as described; see. see The Merck Index, 9th edition, Merck & Co .. Inc., Rahway. New Jersey (1976), pages 207-208, for a description of caffeine salts, derivatives and mixtures useful in the preparations of the invention. Independently of this, caffeine is preferred as the anhydrous base in powder form, and if certain amounts of caffeine are listed below, such amounts are given in mg of the anhydrous mass.

If a selected narcotic analgesic is mixed or combined with caffeine and the selected NSAID (ibuprofen) for the production of a pharmaceutical preparation according to the invention, the following unexpected results are obtained: (1) the analgesic effect of the selected narcotic analgesic occurs more quickly: (2) lower amounts of atKgewshhcm. narcotic analgesics are required for the same analgesic treatment; and (3) greater analgesic response is obtained at all dose levels.

In patients who experience pain, and especially in patients who experience severe pain, the -8-

No. 389993

Time from the administration of the drug to the onset of effective relief is clearly of great importance. The discovery by the inventors of the present application that caffeine significantly shortens (i.e., significantly speeds up) the onset of analgesics when used with a selected narcotic analgesic is therefore of major importance. Furthermore, it is completely unexpected.

Caffeine's ability to enhance analgesic effects, i.e. H. the amount of selected narcotic analgesic required to elicit a given analgesic response is also an unexpected and very important feature of the present invention. This unexpected and important result permits the use of selected, narcotic analgesics in amounts that are significantly lower than the dose levels currently used in human analgesics. The use of lower dose amounts in turn enables the occurrence and / or the undesired occurrence. Reduce side effects including a decrease in addiction potential. Furthermore, a larger or more pronounced analgesic response can be achieved with a given dose amount.

More specifically, the onset of analgesic activity is believed to be 1/4 to 1/3 faster on average when a selected narcotic analgesic and caffeine preparation of the present invention is used compared to when using a narcotic analgesic alone becomes. Furthermore, 1/5 to 1/3 less of the selected narcotic analgesic in the caffeine combination can be used to achieve the same analgesic effect as achieved using the narcotic analgesic alone, in other words, the addition of caffeine will decrease the amount of chilled, narcotic analgesic to 2/3 to 4/5 the usual amount with which the same effect is achieved. However, these ratios can vary depending on the patient's individual response, the selected dose amount of the active ingredient, etc.

The partial combinations obtainable according to the invention for further processing with ibuprofen from selected narcotic analgesic / caffeine are also advantageous since the use of caffeine counteracts the sedative effects of the selected narcotic analgesic, so that the patient is more alert, shows better motor skills and has an improved well-being compared to the case where the narcotic analgesic is administered alone.

The exact amount of selected narcotic analgesic used in the partial narcotic analgesic / caffeine combinations available according to the invention will vary depending on, for example, the specific drug selected, the size and type of mammal and the condition for which the drug is being administered becomes. Generally speaking, the selected narcotic analgesics can be administered in any amount known to be an orally effective analgesic amount, as well as in dose amounts that are 1/5 to 1/3 lower than the usual amounts.

In humans, typical, effective, analgesic amounts of the anesthetics used are in a dose ratio of the pharmaceutical preparation produced according to the invention, which are administered every 4 to 6 hours as required, 1 to 5 mg hydromorphone hydrochloride, 15 to 60 mg codcin sulfate or phosphate, 2.5 to 5 mg oxycodone hydrochloride or a mixture of oxycodone hydrochloride and oxycodone terephthalate (e.g. 4.50 mg oxycodone hydrochloride + 0.38 mg oxycodone tcrcphthalate or 2.25 mg oxycodone hydrochloride + 0 , 19 mg oxycodone terephthalate), 1 to 3 mg levorphanol tartrate, approx. 50 mg Mcpcridin hydrochloride, 65 mg propoxyphcnhydrochloride, 100 mg propoxyphen napsylate, 5 to 10 mg Mclhadon hydrochloride, 25 to 60 mg propiramfumarai, 8 to 10 mg buprenorphine hydrochloride , 25 to 50 mg Pcntazocin hydrochloride, 10 to 30 mg nalbuphine hydrochloride, 4 to 8 mg butorphanol tartrate or 100 to 500 mg mcptazinol hydrochloride.

The amount of caffeine in the analgesic medicament obtainable according to the invention will be an amount sufficient to shorten the initial time and / or to increase the analgesic effect. In humans, a unit dose of the analgesic preparation will typically contain 60 to 200 mg (preferably 65 to 150 mg) of caffeine. This dose of caffeine is generally sufficient both to shorten the initial time and to increase the analgesic effect. The daily human analgesic dose will vary according to the selected narcotic analgesic and, of course, can be as low as the amount contained in a single dose, as set out above. The daily dose for use in the treatment of moderate to severe pain is preferably 30 mg hydromorphone hydrochloride or 360 mg codcin sulfate or phosphate or 60 mg oxycodone hydrochloride or hydrochloride / tcrphthalate mixture or 18 mg levorphanol tartrate or 600 mg mcpcridin hydrochloride or 390 mg propoxyphcn hydrochloride or 600 mg propoxyphene napsylate or 60 mg Mclhadon hydrochloride or 300 mg propiramfumarai or 60 mg buprenorphine hydrochloride or 300 mg Pcntazocin hydrochloride or 180 mg nalbuphin hydrochloride or 48 mg buiorphanoliartrate or 3000 mg meptazinol hydrochloride and not exceed 1000 mg of caffeine, although larger amounts can be used if tolerated by the patient.

Wcr.n uaS CuiSgCwahiW »N5AID Cul uuS ^ CV» uitilc-S, Γιοι kuu & ctiüö AlUli & CUKimi, such as t JVUl UCUllieii, 1111 diuue def

Production of a pharmaceutical preparation according to the invention can be combined with caffeine, an increased analgesic effect is obtained at a given dose amount, and the analgesic effect of the combination is greater than that of the selected NSAID or the selected narcotic analgesic -9-

No. 389998 alone. Consequently, it is possible to reduce the amount of one of the analgesics and achieve the same analgesic effect compared to a higher dose of the analgesic alone. In general, it is more preferred to lower the dose of selected narcotic analgesic because its side effects are considered to be more undesirable than those of the selected MS AID. Lowering the dose of the selected narcotic analgesic leads to less occurrence and less severe accompanying side effects and to a reduction in the risk of addiction. Generally speaking, the addition of the selected NSAID can be expected to decrease the amount of anesthetic analgesic chosen and to be only 2/3 to 4/5 of the usual amount to achieve the same effect. However, these ratios may vary depending on the particular drug selected, the patient's individual response, and the selected dose amount of the active ingredient. It is also possible to use the usual amount of selected narcotic analgesic and to take advantage of the improved analgesic response.

When a selected narcotic analgesic and ibuprofen are further combined with caffeine according to the present invention, the combination has the advantage of accelerated onset of action and enhancement of the analgesic effect. Since the presence of caffeine counteracts the sedative properties of the narcotic, the preparation obtainable according to the invention is of particular interest as an oral analgesic during the day, which acts against severe pain and can be used in patients who need to remain alert and active.

It is believed that caffeine enhances the analgesic effect not only of the selected narcotic analgesic, but also that of ibuprofen in the Drci-component combination, and that caffeine enhances the onset of analgesic activity for both of these drugs. This is likely to result in a stronger analgesic response than that obtained not only by the selected narcotic analgesic alone or by ibuprofen alone, but also by ibuprofen / caffeine or the selected narcotic analgesic / caffeine and the selected narcotic analgesic / ibuprofen Combination Nevertheless, it is not generally recommended that the amounts of selected narcotic analgesic and ibuprofen in the caffeine preparation be further reduced compared to those used in the combination of selected narcotic analgesic / ibuprofcn, but in the Drci component. Combination uses the advantage of a further intensified and faster analgesic effect, which is obtained by the presence of caffeine. The amount of ibuprofen in a dose unit of the Drci component preparation that can be produced according to the invention will be an amount sufficient to enhance the analgesic effect. In humans, the dosage component of the Drci component supplement will typically contain an amount of ibuprofen which is well tolerated when used alone to treat mild to moderate pain and which is sufficient to enhance the analgesic effect when used in conjunction with the selected narcotic analgesic is combined. The amount of caffeine in the three-component preparation will be an amount sufficient to further enhance the analgesic effect or accelerate its onset. In humans, this level will typically be 60 to 200 mg (preferably 65 to 150 mg), an amount which is generally sufficient to both accelerate the onset and enhance the analgesic effect. The daily human analgesic dose for each analgesic in the Drci component supplement will generally not exceed the daily analgesic dose as previously discussed in connection with the Zwci component supplement, while the daily dose of caffeine will generally be 1000 mg will not exceed. Of course, larger amounts can be used if they are tolerated by the patient.

If a longer-acting narcotic analgesic is used or if the selected nno-co-analgesic is formulated in a delayed release form, then additional caffeine in a delayed release form should be miicingcarbcitci. Alternatively, all three components can be formulated for delayed release, with larger amounts of each component being worked into an individual dose.

The preparations obtainable according to the invention are preferably intended for oral use. However, they can also be formulated so that they can be used for other methods of administration known for the administration of analgesics, such as, for example, as supposiloricn. The preferred dose levels listed above for humans are for adults. Children should contain proportionately fewer active ingredients.

The formulations obtainable according to the invention are used in mammals according to any method. which is suitable for ibuprofen and the selectable, narcotic, analgesic component, e.g. B. administered orally or rectally. Preferably the combination is prepared with any suitable, non-toxic, pharmaceutically acceptable, inert carrier.

Such carrier materials are familiar to the person skilled in the art for pharmaceutical preparations. Compare " Rcmington's Pharmacutical Sciences " (14th edition), 1970. In a typical preparation for oral administration, e.g. For tablets or capsules, to produce a Drci-Kcmponcntcn-Zubcrcitung the selected, narcotic analgesic in an effective, analgesic amount together with ibuprofen in an amount sufficient to enhance the analgesic response and caffeine in an amount that is sufficient to intensify the analgesic response or to accelerate its onset, in each case as an active ingredient -10-

No. 339998 mixed with an orally non-toxic, pharmaceutically acceptable, inert carrier such as I-actose, starch (pharmaceutical grade), dicalcium phosphate, calcium ralfate, kaolin, maize nitrite and powdered sugar. In addition, binders, lubricants, disintegration agents and dyes can also be processed if necessary. Typical binders are starch, gelatin, sugar, such as sucrose, molasses and lactose, natural and synthetic gums, such as Acccia, sodium alginate, extract of Irish moss, corboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, ethyl cellulose and waxes. Examples of lubricants that can be used in these dosage forms are boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and polyethylene glycol. Examples of disinfection waste are starch, methyl cellulose, agar, bentonite, cellulose, wood products, alginic acid, guar gum, citric pulp or citrus pulp, carboxymethylccllulose and sodium lauryl sulfate. If necessary, a known, pharmaceutically acceptable dye can be cingearbsitcted into the Dosiscinkcitsfcrm z. B. any of the standard FD & C dyes. Sweeteners and flavorings as well as preservatives can also be included, especially when preparing a liquid dosage form, e.g. B. an elixir, a suspension or a syrup. Furthermore, the dosage form, when in a capsule form, may contain a liquid carrier such as a fatty oil in addition to the materials of the above type. Various other materials can be present as coatings or to otherwise modify the physical form of the dose unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Such preparations should preferably contain at least 0.1% of active ingredients. In general, the active ingredients will total between 2 and 60% by weight of the unit.

table

Selected anesthetic anesthetic Selected NSAID flbuorofenl caffeine nalbuphine hydrochloride 15 mg 200 or 400 mg 130 mg propiram fumarate 35 mg 200 or 400 mg 130 mg 50 mg 200 or 400 mg 130 mg 35 mg 200 or 400 mg 65 mg 50 mg 200 or 400 mg 65 mg pentazocin hydrochloride 25 mg 200 or 400 mg 130 mg butorphanol tartrate 8 mg 400 mg 130 mg

If necessary, the preparations for parenteral use obtainable according to the invention can be formulated according to methods known per se.

It is also possible to formulate the oral preparations obtainable according to the invention in such a way that the possibility that the narcotic analgesic is extracted therefrom and then subject to parenteral abuse is substantially reduced. This can be achieved by combining the drugs with insoluble diluents such as methyl cellulose to form a dosage form that is insoluble in water.

The analgesic and anti-inflammatory effects of the preparations or partial preparations obtainable according to the invention for further processing with the third component can be determined quantitatively in animals in the tests described below.

Antiphenequinone curvature test or cramp test for Writhine test)

This test is a standard method for the detection and comparison of analgesic activity and is generally very good in relation to the effectiveness in humans.

The mice are first administered the medication to be examined. The drugs are administered in two doses to a selected NSAID with and without caffeine or the selected narcotic analgesic with and without caffeine or with a selected narcotic analgesic + selected -11 -

No. 389398

NSAID administered with and without caffeine. The mice then graze with phonyl-p-benzoquinone, which is administered intraperitoneally, and then the characteristic strain-syndrome syndrome bcobachtcL

Lack of crimping is a positive response. The level of analgesic protection can be determined based on the cramping suppression relative to the comparative tics examined on the same day. Time-claim dates are still received. This trial is a medication of the Sigmund et al. and Blumberg et al. (E. Sigmund, R. Cadmus and G. Lu, Ploc. Soc. Exp. Biol. And Med. 25.729-731, 1957; H. Blumberg et al., Proc. Soc. Exp. Biol. Med. IIS, 763 -766, 1965). 10 Inflammated Ratofoten Test - Pressure Induced Stimulation

Randall-Selitto's method, modified according to Winter et al., Is used to determine the escape response throttle response that results when increased pressure is applied to the left hind paw inflamed with yeast.

Treatment with the drug follows. The drugs are examined at two dose levels of 15 selected NSAIDs with and without caffeine. A constantly increasing force is applied to the paw and the " escape reaction " is observed and recorded; (L. Q. Randall and J. J. Selitto, Arch. Int. Pharmacodyn., II. 409-419, 1957; C. A. Winter and F. Lars, J. Pharmacol. Exp. Therap., 148. 373-379, 1965). 20 tail-twitch test in the mouse

Mouse tail twitch testing is tested according to D'Amour and Smith using controlled high intensity heat applied to the tail. Normal and drug-treated mice are examined and response time is measured. The drugs used are two doses of selected, narcotic analgesic with and without caffeine (E. D'Amour and 25 L. Smith, J. Pharmacol., U. 74-79, 1941).

Tail-pinching or clamping method according to Haffncr

A modification of Haffncr's method is used to establish the effectiveness of the drugs in an aggressive attack response created by stimulative squeezing under pressure from the rat's tail. A clip is placed at the end of the tail of each rat before treatment with the drug and again at specified intervals after treatment. The time required to initiate a clear attack and bite behavior directed against the simulant is measured. The investigated medicinal products are two dose quantities of selected, narcotic analgesic with and without caffeine (F. Haffncr, Experimental Examination Painkillers, 35 Deutsche Med. Wschr., 55.731-732, 1929).

Hot plate mouse mouse (thermal stimulant)

A modification of the Woolfe and MacDonald method is used and involves the application of a controlled heat stimulant to the mouse paws. The drug is administered to treatment group 40. The latency between the time the animal comes into contact with the hotplate and the observation of standard pudding, bouncing and / or rapid tapping of one or both hind paws is measured. The medications examined are two doses of a selected, narcotic analgesic with and without caffeine (G. Woolfe and A. D. MacDonald, J. Pharmacol. Exp. Thcr., 2Q, 300-307, 1944).

Afliuyans-Arthnüstgst The adjuvant arthritis test in the rat is often used as a model! used for human rheumatoid annriiis. It is fundamentally an immunological reaction and comprises the cellular immune response to an injected bacterial adjuvant. The response is systemic, but mainly develops in the limbs as polyarthritis. The degree of arthritis in the hind legs is determined either visually or by measuring the foot volume on the 21st day after the adjuvant injection. A simple, subcutaneous injection of 1 mg Mycobacterium butyricum, suspended in 0.1 ml mineral oil, is injected into the right hind paws of the rats. The swelling of the injected hind legs, measured on day 16, represents the secondary response. The drugs are p. daily, starting one day before the adjuvant injection. Two medications with two dose levels of cm NSAID with and without caffeine are used. The results are expressed as% suppression based on the comparison. [D. T. Walz, M.J. Di Martino and A. Mishcr, Ann. Rhcum. Dis., IQ, 303-306 (1971)]. To determine the effectiveness of the preparations according to the invention available in humans, patients with moderate to severe pain who need an oral analgesic are given a selected, narcotic analgesic or NSAID with and without caffeine or a selected, narcotic analgesic + a selected NSAID with and without caffeine , while patients suffering from an inflammatory or degenerative joint disease, e.g. B. rheumatoid arthritis, osteoarthritis, gout or acute, muscular 45 50 55 -12- • 60

Claims (10)

No. 389998 S & elcu disease, suffering and in need of an oral anti-inflammatory agent, a selected NSAID is administered with and without caffeine. To determine the analgesic efficacy, interviews with the patient's observing nurse regarding the type or Severity of pain or stiffness and swelling at successive times. Patients are subjectively interviewed 5 to determine at what point in time the medication provides relief. Appropriate statistical methods can be used to show that the preparation with caffeine has an average shorter start and is more effective (E. Laskas, M. Gormcly, A. Sunshine, JW Belleville, T. Kantor, W. H, Formst, C. Siegel and M. Meisner, A Bioassay Computer Program for Analgesia Clinical Trials, Clin. Pharmacol. Thcr. Fi, 658, 1967; DR). 10 PATENT CLAIMS 15 1. Process for the preparation of a pharmaceutical preparation containing an analgesic and 20 anti-inflammatory non-steroidal active ingredient and an adjuvant which enhances the effect of the active ingredient, with the additional use of an orally analgesic, narcotic analgesic, characterized in that an analgesic and anti-inflammatory nonsteroidal active ingredient 50 to 2400 mg of ibuprofen or a pharmaceutically acceptable salt thereof, together with a narcotic analgesic per 60 to 1000 mg of caffeine, is used as an adjuvant and, if appropriate, a carrier, the adjuvant enhancing the active ingredient accelerating the onset of the analgesic, anti-inflammatory effect of the active drug and the analgesic and anti-inflammatory effect. 2. The method according to claim 1, characterized in that one uses 65 to 150 mg of caffeine as an adjuvant. 30th 3. The method according to claim 2, characterized in that as an analgesic and anti-inflammatory non-steroidal active ingredient 50 to 400 mg ibuprofen per 65 to 150 mg caffeine as an adjuvant einctzL 4. The method according to claim 1, characterized in that the pharmaceutical preparation is further admixed with a non-toxic, pharmaceutically acceptable carrier. 5. The method according to claim 4, characterized in that one prepares the preparation for oral administration 6. The method according to claim 5, characterized in that one prepares the preparation in the form of tablets or capsules. 7. The method according to claim 5, characterized in that one prepares the preparation with delayed delivery 45. 8. The method according to claim 1, characterized in that one as a narcotic analgesic propiram fumarate 9. The method according to claim 1, characterized in that as an anesthetic analgesic Pcntazocin hydrochloride, nalbuphine hydrochloride, butorphanol taruate or Mcptazinol hydrochloride einctzL 10. The method according to claim 1, characterized in that as a narcotic analgesic propoxyphcn hydrochloride, propoxyphcnnapsylate, codcin sulfate or codeine phosphate EinsctzL 55 -13-