JPS59501459A - Improved analgesic and anti-inflammatory compositions comprising caffeine and methods of use thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Improved analgesic and anti-inflammatory compositions comprising caffeine and methods of use thereof field of invention This invention provides caffeine and one or more analgesics, or caffeine and an anti-inflammatory drug. and for hastening the onset of an analgesic or anti-inflammatory response. and methods of using said compositions to enhance analgesic or anti-inflammatory responses.

Background technology Non-narcotic analgesics are widely administered orally for the treatment of mild to severe pain. The majority of these drugs are also known as non-steroidal anti-inflammatory drugs (N5AIDs). It is. Within this class, the compounds include their chemical structure and analgesic, anti-inflammatory and antipyretic agents. They vary widely in their biological properties as drugs. aspirin, acetaminophen and tsenacetin have long been the most commonly used members of this group. However, there are a number of non-anesthetic drugs that differ from the aforementioned drugs and have many advantages over earlier drugs. Sex drugs are being developed. Tolerance or addiction to these drugs may result in pain treatment or in acute or chronic inflammatory conditions (particularly leelamatiform arthritis and osteoarthritis). There are generally no problems when these drugs are used sequentially in the treatment of arthritis. However, these drugs should nevertheless be administered at the upper end of their effective dosage range. There is a high possibility that undesirable side effects will occur if the product is used in a vacuum. In addition, the upper limits for each drug are In other words, above the dosage limit, administration of additional drugs may not have an analgesic or anti-inflammatory effect. use generally does not increase. New in the group of non-narcotic analgesics/non-steroidal anti-inflammatory drugs Possible compounds include diflunisal rubiglofen, methenamate Compounds such as Stell ■ and Sulindac may be mentioned. Certain non-steroidal For information on anti-inflammatory drugs, visit Physicians’ Desk Refe rence + 35th edition, 1981: and The Merck Index + 9th ed., Merck & Co., Rahe/Niny Chassi (1976).

Furthermore, in general, Wiseman + “Pharmacological Studies with a New C1ass of Non5tero idal Anti-InfLammatory Agents-The O xicama-With 5specialReference to Pir oxicam (Fuerbon■), The American Journa l of Medicine + February 16, 1982.

3 Tonto Sentiley Klovso, New York, 1979, Chapter 49, 538 See ~550.

Narcotic analgesics are often used when pain control with non-narcotic analgesics is ineffective. It is used if This group of drugs differs considerably in their chemical structure and pharmacological properties. However, most of them develop drug resistance and addiction upon continuous use. The disadvantage is that there is a possibility that Within the narcotic analgesic group, drugs are classified as narcotic They can be classified as antagonists or narcotic agonists. Morphine is a narcotic agonist. group, meperidine group, and mesatone group. In contrast, some anesthetic Antagonists are pure antagonists (they are not analgesics); other narcotic antagonists are An agonist-antagonist (i.e., an antagonist that has an analgesic effect); Generally classified as morphin-like or telorpine-like. Many narcotic analgesics are administered orally. It is ineffective orally and is rather used parenterally. Orally active narcotic analgesia Medications include codin, oxycodone, leporphanol (shize-dromoran), Meperidine (Demerol■), Propoxyfoon Hydrochloride (Dalmen■) ), Propoquine phenapsylate (Darbon-N■), Mesatone, Trufano This includes compounds such as stadol (■). Compounds against Kogawara et al. See specifics. Furthermore, in general, Foley et al., cited above; and Cutting’s Handbooks of Pharmacology .

6th edition, edited by T, Z, Czaky, Abretone-Century-Crofu 2nd New York, 1979, Chapter 50:551-566.

Caffeine, i.e. 3,7-nohydro1.3.7-trimethyl-IH-puri -2,6-phono has the following structure H3 This substance is used alone by intravenous administration to treat headaches, and also Used in combination with selected drugs. Aspirin, aceta, an analgesic Combining one or more of minophen and zenacetin with varying amounts of caffeine Compositions containing these substances have been sold in the past. In some cases, non-anesthetized The analgesic/caffeine combination product further includes Codine, an anesthetic analgesic; It contained one of propoquinphene or oxycodone. Examples of these combinations Excedrin■, 5K-65■compound, Dalpon■compound, Anacin■, A, P, C.

and A, P, C, with codin, commercially known when tabloid ■ brand. Includes products that are Non-steroidal analgesic component of these mixtures + primary structure Build for 7 hours.

Added to aspirin/phenacetene/acetaminophene/caffeine compositions The three types of narcotic analgesics that may be used have the following structures:

However, to the best of the knowledge of the inventors, the prior art does not use caffeine as a narcotic sedative. There is no suggestion that anything is added to the pain medication to contribute to its analgesic effect.7 not present.

Many researchers have found that aspirin/fenaceti//acetaminophen/caffeine We have sought to prove the efficacy of the combination. About caffeine and analgesics An extensive review of the literature has been published (0ver-The-Coun. ter　Drugs　:　gstablishmentof　a　Monogr aphfor OTC Internal Analgesic Antipyr etic and Antirheumatie Products r Fair -35485), and several other similar papers exist. caffeine analgesic Most animal studies on have been conducted in rats. Will 1 i amsl: 447-453) uses experimental pain and caffeine , has an analgesic effect on humans alone, and is effective when combined with aspirin. was found to be additive and not synergistic. Vineger et al. 10 years later , in rats, caffeine synergistically enhanced the acute anti-inflammatory and analgesic activities of aspirin. The oral dose of caffeine administered together with the booster (10°8) 01459 (4) 50 and 100 my/kg), and cuff It has been shown that Ein inhibits the absorption of acetaminophen and lowers its serum concentration. I found it. He believes that the relaxing effect of caffeine on the stomach muscles results in stomach emptying. The delay reduces the absorption of orally administered drugs in the presence of caffeine. It was suggested that this may be the cause. Despite this knowledge, acetaminophen's sedation Pain effects were not reduced by caffeine. Wi 1 iams and Vi Like Negar, his collaborator Sieger believes that caffeine It was found that it itself has an analgesic effect. The lowest tested dose of caffeine is This means that acetaminophen-induced The analgesic effect decreased. In a more recent report, Seegers et al. h, Int, Pharmacodyn + 1981 +251: 23 7-254) demonstrated the non-inflammatory analgesic effect of caffeine in rats. he further includes combinations of caffeine, aspirin and acetaminophen, and cuffs. The combination of Ein, aspirin, and zenacetin may be additive at low doses. It exerts an anti-inflammatory analgesic effect at least as high as that expected on the basis of At high doses, the results suggested that they were synergistic. Giertz and J. (observed that caffeine induces analgesic effect when measured in urnas) Citing a study by Seegers, ``caffeine's analgesic activity is at least is also composed of two components, one independent of its anti-inflammatory activity1; It is safe to assume that it is activity dependent. ” he declared.

The first similar study in humans was by Wallenstein (Royal C. oCo11e of Surgeons + London, 4975 Proce edings of the aspirin symposium) Reported. 210 mV aspirin, 150 mV acetaminophene and 30 mV Two combination tablets containing mg of caffeine are combined with a combination containing no caffeine. It exerted a clear and significantly higher analgesic effect than saccharine. One tablet dosage of the combination is Showed a higher average score than any of the individual ingredients, but does not contain caffeine It was no more than a combination. Wallenstein says, ``Dosage is an important factor.'' Acid, and caffeine is ineffective at doses significantly less than 60m7. It was assumed that Booy (Nederlands) tVoor Tandheelkinde + 1972 + 79:69- 75) studied pain relief for 2 days after tooth extraction. On the first day, she said, ``It hurts a lot.'' 1000 mg of acetaminophen was also administered to patients who complained of 00mg of acetaminophen + 100mg of caffeine provides greater pain relief Brought. This difference was not observed on the second day. However, all The treatment was a placebo (1967.8:521-542), in which subjects were given pradeikinin. reported a study in which experimental pain was induced, and oral aspirin 520 mg and aceta The combination with Minofen 260 ~ was indistinguishable from the placebo, but a smaller dose of the same combination Combined: 325 kg of aspirin and 162.5 kg of acetaminophen and 10 caffeine. 32.5■ is 15,60.75,105. after administering this drug. and 120 minutes We observed that the results were significantly different from the placebo. Double-blind trial of 216 patients In the experiment, 1000 mg of acetaminophene + 100 mg of caffeine and , compared with the same amount of acetaminophen.

The first group of patients in the study had severe and frequent spontaneous headaches, and the second group had mild He had mild postoperative surgical pain. The presenter believes that acetaminophen can reduce pain. Dogs are much more likely to be treated with the combination of caffeine than with aspirin or aspirin alone. concluded.

69-75), first of all, moderate to severe uterine spasms and/or perineal side 70 postpartum patients with incisional pain, followed by a second group of 7 patients with severe pain only. Researched on 0 people. 800mg of As e6 lJ + 6.1■ Caffeine and 650 ■ aspirin, and these presenters reported severe perineal incision. We conclude that konai is a more effective analgesic in patients with pain.

The use of caffeine in the treatment of headaches has a long history. FDA advisory committee , the known biochemical effects of caffeine on caffeine are related to cerebral blood vessels. provides a plausible explanation for the effects of caffeine in the treatment of headaches. he claimed.

Recently, 5echzer (Curr, Therapy Re5earch + 1979+26(4)], intravenous administration of caffeine sodium benzoate Provides relief in patients experiencing headaches caused by dural puncture or spinal anesthesia. I discovered that This presenter will explain how Café affects cerebral blood flow and cerebrovascular tone. In view of opposing the advisory panel, citing the literature on the mechanism of action of In. , the obtained analgesic relief suggests that the intracranial vascular component is the primary factor in such headaches. claimed to mean.

Mood changes and an overall sense of ``well-being'' after administering caffeine are widely reported in the literature. has been done. Advantageous mobility and psychological effects arising in this century, and the 390 ■ cuff They reported tremors, poor movement, and insomnia caused by the effect. past 7 Numerous studies over 0 years have confirmed these findings. General information about xanthine Paper CRitchie J, M, +r Centralnervous sy stem stimulants, 2. The xanthines J Kumilan Publishing, 1970: 5tephenson P, E, +r Phy siologic and psychotropic effects of coffee on man + r J, Amer, Diet, As5 oc, +1977+71(3):240-2473 has cuffs from 50 to 200. They report that they feel less fatigued. A dose of 200 to 500 μm can cause headaches and tremors. Irritability, irritability, and sensitivity may occur.

After a broad overview of the relevant literature (the most significant points of which are summarized above), the FDA In 1977, an advisory panel concluded that caffeine is safe when used as an analgesic. Yes, but caffeine has some effect on the effects of analgesics. Unfortunately, there is insufficient data to demonstrate that the information provided and data indicate that caffeine may be used as an analgesic, hypopyretic, and/or antirheumatic drug in combination. Fortunately, we have not attempted to conclusively prove that it is effective as an ingredient.

The committee believes that this component contributed to these pharmacological effects in the Lin-Song dynasty. We find that there is almost no evidence that this is the case.

This is the official position on this issue to date. Therefore, it is already possible to obtain Many of the existing pain relief/caffeine combination products are no longer on the market.

Adding the selected narcotic analgesic to the selected non-narcotic analgesic/caffeine combination In addition to a few prior art examples (the combination of the three components has already been mentioned above) and, further, a two-component combination of a selected non-narcotic analgesic and a selected narcotic analgesic. There are examples of this. Known combinations of this type include Darbon ■ and A, S, A■ (purple). Lopogisifen hydrochloride and aspirin), Darzano N■ and A, S, A■ (Prohoki/)Sun Napunrate and Aspirin), Aspirin and Kodi compounds (pentazo/n hydrochloride, oxycottone and a Subiri 7), bar’: j Tan■ (oxycodone hydrochloride, tele phthalates and aspirin), as well as nalbuphine and acetaminophen. , the last mentioned combination is disclosed in U.S. Pat. No. 4.237], 40 . The general principles of using drug combinations to obtain additive analgesic effects are well within the skill of those skilled in the art. known to. Example 7 Noh Inc., 1981, suggests such a combination, and Specifically, 65 Q my of aspirin was added regularly to the standard anesthetic dose. Phosphorus or acetaminophenophenols provide analgesia without the need for higher doses of anesthetics They point out that it will often enhance the effect. Such an additive effect is , Houde et al., CHn.

Orally by Pharm, Ther 1(2):163-174 (196B) Morphine sulfa-1 Ni administered intramuscularly with aspirin administered b, has already been reported from an early stage. However, as far as the inventor knows, However, the prior art does not suggest any two-component composition of a narcotic analgesic and caffeine. is not induced by co-administration of caffeine and any narcotic analgesic. showed no improvement in analgesic response15 I didn't suggest it.

Summary of the invention Surprisingly, the inventors have now discovered that aspirin, zenacetate, and Chin and acetaminophen and parenchymal sandbags, and their significantly different biological sex. Caffeine and selected narcotic analgesics/non-steroidal anti-inflammatory drugs with high quality Both can be advantageously formulated into novel pharmaceutical compositions and are suitable for use in animals, especially humans. compared to administering only analgesics or only anti-inflammatory drugs. Not only can it induce a strong analgesic or anti-inflammatory response, but also We have discovered that it is possible to more rapidly induce such a reaction.

The inventors further discovered that, quite surprisingly, oral narcotic analgesics (e.g. For example, narcotic agonists and narcotic agonist-antagonists that are orally effective as analgesics. can be advantageously formulated with caffeine into novel drug compositions, And by administering it to animals, especially humans, compared to administering anesthetics alone. Not only can it induce a more powerful analgesic response, but also We found that it is possible to induce the effects more rapidly. The inventors further Advantageously combining orally effective narcotic analgesics with non-narcotic analgesics and caffeine This 1 GTft Table 1985-501459 (6) Toyoshi, administration to animals, especially humans. to form novel pharmaceutical compositions capable of eliciting an improved analgesic response. Find out what you can do.

Accordingly, in one aspect, the invention provides The present invention provides novel pharmaceutical compositions for use in drug therapy, which compositions are effective for analgesic or anti-inflammatory purposes. amounts of selected non-narcotic analgesics/non-steroidal anti-inflammatory drugs as defined below; To hasten the onset of pain or anti-inflammatory responses or to enhance analgesic or anti-inflammatory responses Contains sufficient amount of caffeine.

In another aspect, the invention provides a novel medical drug for use in eliciting an analgesic response. providing a pharmaceutical composition, the composition orally providing an analgesic analgesic response in an amount effective for analgesia; Contains a sufficient amount of caffeine to hasten the onset of pain or to enhance the analgesic response. It consists of

In another aspect, the invention provides a novel medical drug for use in producing analgesic effects. A pharmaceutical composition is provided, the composition having orally analgesic activity in an effective amount for analgesia. a narcotic agonist or agonist-antagonist, in an amount sufficient to enhance the analgesic effect, as described below. Selected non-narcotic analgesics and to enhance or hasten the onset of analgesic action Contains sufficient amount of caffeine.

7 Typically, the active ingredient of the compositions of this invention will be a non-toxic pharmaceutical agent for this ingredient. in combination with an acceptable inert carrier.

In another aspect, the invention provides rapid onset of analgesic or anti-inflammatory responses in salivary mammals. The present invention provides a method for inducing an enhanced analgesic or anti-inflammatory response. Non-narcotic analgesic/non-steroidal anti-inflammatory for use in compositions and methods of Symptomatic agents can be selected from the following ranges:

(1) Zolopionic acid derivative; (2) Acetic acid derivative: (3) Phenamic acid derivative; (4) Biphenyl carnic acid derivatives: (5) Oxicams.

Some of these compounds are currently used primarily as anti-inflammatory agents, others Although the compound is primarily used as an analgesic, in fact all compounds considered has both analgesic and anti-inflammatory activity, and in the compositions and methods of this invention. Should it be used at appropriate dosage levels for any purpose? acid functional group However, these acids are sometimes combined with their pharmaceutically acceptable salts, e.g. Administered in the form of Jium salts.

The propionic acid derivatives used for this invention include ibuzolofen (1 bup rofen), naproxen (naprOXen)% penoxaprofe benoxaprofen, flurbizolofen (flurbipro) fen), fenozolofen (fenoprofen), fenbufen ( fenbufen), ketoprofen, India Zolofen (1ndoprofen), Pirnolofen (pirprofe) n), (oxaprozin), pranoprofen (pranoprofen) ), miloprofen (m1roprofen), thioxazolofen (ti oxaprofen), suprofen (5purofen), aluminozolo Alminoprofen nic acid), fluzolofen (fluprofen), and book These include, but are not limited to, bucloxicid.

Structurally related zolopionic acid derivatives with similar analgesic and anti-inflammatory properties also It is intended to be included in this group. Currently preferred members of the propionic acid group include Ibuzolofen, naproxen, flurbizolofen, phenozolofen, keto Includes profen, and hifuenbufen.

The structure of a typical group tank member is shown below.

9 CH3 That is, the "propionic acid derivative" defined in this specification is typically attached directly or via a carbonyl function to a ring system, preferably an aromatic ring system. free -CH(CH5)COOH or -CH2CH2COOH groups (these are optionally in the form of pharmaceutically acceptable salts, e.g. -CH(CH3)Coo-N a+ or -CH2CH2COONa)/ It is a non-steroidal anti-inflammatory drug.

The other acetic acid derivatives used in this invention include indomethacin (indomethacin). , hacin), sulindac (5ulindac), tolmetin (tol metin), Zomepirac (Zomepirac), Nokrophenanoch ( diclofenac), fenclofenac ), alcofenac, ibzena, ri (1bufe nac), Isoxenoguri (1soxepac), Flofenac ( furofenac), tiopinac, cytomethacin (zidometacin), acemethacin, feline fentiazac, clidanac and oxpinac, but are not limited to these. . Structurally related acetic acid derivatives with similar analgesic and anti-inflammatory properties are also included in this group. is intended to be included in The current preference for the acetic acid group is,! , members include Tormechi sodium, zomepirac sodium, sulindac, and indomesan. included. The structure of a typical group tank member is shown below]1 3 C.I. That is, an "acetic acid derivative" as defined in this specification typically directly refers to a ring system, preferably a or a free -cH2cooH group attached to an aromatic or heteroaromatic ring system (this is , optionally in pharmaceutically acceptable salt form, e.g. -CH2C00-Na+ It is a non-narcotic analgesic/non-steroidal anti-inflammatory drug that has the following properties:

Phenamic acid derivatives for use in this invention include methenamic acid (mefe qamic acid), meclofenamic acid (meclofenamic acid) acid), flufenamic acid, nif niflumic acid, and tolfenamic acid (tolfe). namic acid), but are not limited to these. similar pain relief and Structurally related phenamic acid derivatives with anti-inflammatory properties are also included in this group. . Presently preferred members of the phenamic acid group include methenamic acid, and meclophenic acid. Contains sodium namate (sodium salt of meclofenamic acid). Typical The structural formula of the group tank member is shown below.

Phenamine/acid derivatives C0OHH2OCH3 5 That is, the "fenamic acid derivative" defined in this specification has various substituents. and the free −〇〇H group is in the form of a pharmaceutically acceptable salt, e.g. The following basic structure, which may be -Coo Na+, OOH It is a non-narcotic analgesic/non-steroidal anti-inflammatory agent containing

The biphenylcarboxylic acid derivatives used in this invention include noflunisal (dif lunisal) and flufenisal. These include, but are not limited to: Structurally related with similar analgesic and anti-inflammatory properties Biphenylcarboxylic acid derivatives are also intended to be included in this group. this group The preferred members are Hanoflunisal and Flufenyl-Jll-T, which are Their structural formulas are shown below.

biphenylcarbon e derivative 4 In other words, there are various ways to derive biphenylcarboxylic acid as defined in this specification. and the free -COOH group is pharmaceutically acceptable. The following basic structure, which may be in the form of a salt, for example -Coo Na, It is a non-narcotic analgesic/non-steroidal anti-inflammatory agent containing

The oxicams used in this invention include piroxicam, sudoxicam, ink soxicam) and Contains CP-1430427 but not limited to. It has similar analgesic and anti-inflammatory properties and is structurally related. Oxicams such as oxicams are also intended to be included in this group. This group is currently preferred Its members are Pyroquincum. Representative music member, i.e., defined in this Meikyusho An "oxicam" has the following general formula, where R is an aryl or heteroaryl ring system: It is a non-narcotic analgesic/non-steroidal anti-inflammatory drug.

Further advantageously, in accordance with the present invention, early onset of treatment is achieved in a mammal in need of treatment. Pharmaceutical compositions applied to elicit and enhance analgesic and anti-inflammatory responses The composition is easily provided and the composition is effective for analgesic and anti-inflammatory purposes in a unit dose. an amount of the active drug ingredient and an auxiliary agent to enhance the active drug; is ibuprofen, naproxen, fenoprofen, indozolofen, nof Contains no lunisal or their pharmaceutically acceptable salts9 and said auxiliary agents hasten the onset of analgesia and anti-inflammatory action of the active drug and It essentially comes from a boosting amount of caffeine.

Additionally, this results in earlier onset and faster onset in mammals in need of treatment. An advantageous method of eliciting an enhanced analgesic and anti-inflammatory response is provided, the method (provides a unit dose of a medicament, composition effective for analgesia and anti-inflammation to said organism) administering, the pharmaceutical composition comprising an active pharmaceutical ingredient and an active pharmaceutical composition fortified with the active pharmaceutical composition. The active agent is ibuprofen, naproxen, phenol. Zolofen, Indoprofen, Noflunisal, or any of these pharmaceutically acceptable drugs and this auxiliary agent initiates the analgesic and anti-inflammatory action of the active agent. If you start early, you will actually lose weight from the increasing amount of caffeine.

Narcotic analgesics for use in this invention include oral narcotics/CfFr5 narcotic agonists. drugs and narcotic agonist-antagonists (ie, antagonists with analgesic properties). this invention Suitable narcotic agonists for use in Members of the satone group that have orally analgesic activity, especially codeine ), oxycodon, hydromorphone rphone), leporphanol (levorphanol), non (meperidine), zolopoxy7fen (propoxyphen) e), and methadone. used for this invention Appropriate action of sedatives - antagonists include morphine-type antagonists with orally analgesic activity. Drugs, especially propyram, and prnorphine (bupr) enorphine), as well as Oorphine-type oral analgesic activity. Antagonists, especially pentazocine, nalbuphine lbuphine) and butorphanol. be caught. Another suitable agonist-antagonist is mesotazinol. In many cases, the narcotic analgesic for use in this invention is in the form of a suitable acid addition salt, for example codine sulfate, codine sulfate, etc. Imphosphate, oxycod/hydrochlori P1 oxycodone terephthalate , hydromorphone hydrochloride, leporphanol tartrate, meperidine Hydrochloride, Propoquinphen Hydrochloride, Proboxyphene Napsile -1., mesatone hydrochloride, propylam fumarate, buprenorphine 1 kochlochloride, nalpfine hydrochloride, and meptanonolhydride Administered as lido. The 11/I formula of a typical free base is shown below.

1 1 H3 3 O As used herein, the term "caffeine" refers to caffeine as an anhydrous powder. Not only caffeine but also any salt or derivative of caffeine, or any mixture thereof. a compound that is non-toxic and pharmaceutically acceptable and as described herein. It can also hasten and enhance analgesic or anti-inflammatory responses when used as is also intended to include. For example, caffeine salts used in the compositions of this invention. For derivatives and mixtures that are known to be able to 1976), pp. 207-208. Nevertheless, anhydrous powder base Caffeine as anhydrous base is presently preferred, and the specific amount of caffeine is It is shown closed.

In this specification, the ``selected N5AID J'' Any non-narcotic analgesic/non-steroidal anti-inflammatory belonging to one of the structural categories of intended to mean a compound. Similarly, as used herein, "selection" The term "narcotic analgesic" refers to any orally active narcotic analgesic as an analgesic. intended to mean a drug, which is an orally active narcotic agonist or an oral analgesic It is an active narcotic antagonist. ``Selected NSA DJ and ``Selected The term "narcotic analgesic" is used in the above discussion for simplicity.

When the selected N5AID is combined with caffeine according to this invention, the following You will get unexpected results like this.

(1) The analgesic or anti-inflammatory effects of selected N5AIDs on mammals are more rapid. occurs in

(2) the selected amount of N5AIDO required for the same analgesic or anti-inflammatory effect; is less.

(3) A greater analgesic or anti-inflammatory response is achieved at all doses.

For patients with pain, the time from treatment administration to effective relief is unclear. Obviously very important. Caffeine shortens the onset time of analgesia (i.e. The inventors' discovery of substantially halving the onset of Furthermore, this was completely unexpected. Similarly, inflammation, e.g. In patients with arthritis or osteoarthritis, the onset time afforded by this invention A substantial shortening of is very important. Not only does it provide faster pain relief, but This is because it provides rapid relief from other aspects of inflammatory diseases, such as morning stiffness.

Additionally, caffeine's ability to enhance analgesia or enhance anti-inflammatory responses, i.e. A selected amount of N5AIDO is required to elicit a specific analgesic or anti-inflammatory response. The ability to substantially reduce the This is a great point of view. This unexpected and important finding suggests that analgesic or anti-inflammatory agents in humans selected N at substantially lower doses than currently suggested as 5 Use AID 7 make it possible to By using a lower dose, the unwanted The frequency and/or severity of side effects should be reduced. Additionally, given dosage levels A greater analgesic or anti-inflammatory response can be achieved in the

More specifically, rather than using only the selected N5AID, When using a bright composition, the onset time for an analgesic or anti-inflammatory response is It is shortened by about 1/4 to about ]/3 on average. Furthermore, the use of only selected N5AIDs selected to achieve an analgesic or anti-inflammatory effect comparable to that obtained by N5AID can be used in combination with caffeine in approximately 1/15 to 1/3 lower amount. I can do it. In other words, to achieve the same effect, the addition of caffeine is The amount of selected N5AID is reduced to about 2/3 to 4 A of the normal amount. but However, this rate will depend on the patient's individual response, the selected dosage level of the active ingredient, etc. It will continue to exist and change.

Non-narcotic analgesic/non-steroidal anti-inflammatory used in the composition of this invention The exact amount of the drug will depend on, for example, the particular drug selected, the conditions under which the drug is administered, It will vary depending on the size and species of mammal. Generally speaking, choice N5AID is known to be effective as an analgesic or an anti-inflammatory drug. In any amount that can be used.

For humans, the presently preferred N for use in the unit dosage compositions of this invention is Typical effective analgesic doses for SA■D are approximately 125-50 Tng of diflunisal, Mepila, about 25 to 100 kg of cunadium, about 50 to 400 mg of ibuprofen, Nazoloxene approx. 125-500■, Flurbiprofen approx. 25-50■, Pheno Profen approximately 50-200 ■, Piroxicam approximately 10-20 ■, Metzenamic acid approximately 125 to 250 ■, Fenbufen approximately 100 to 400 ■, or Ketozolofen approximately The amount is from 25 to 50, but a larger amount can be used if desired. pain relief group The amount of caffeine in the composition shortens the onset time and/or enhances the analgesic effect. That would be enough. For humans, unit dosage compositions typically contain about Contains 60 to about 200 μg (preferably about 65 to about 150 μg) of caffeine. Probably. In general, this dose of caffeine shortens onset time and increases analgesia. Enough to strengthen. However, some N5AIDs are particularly long-acting. , and may need to be administered less frequently than the usual 4 to 6 hourly intervals; for example, Flunisal and nazoloxene are typically administered only twice a day and pyroxene Sicam is administered only once a day. When using such long-acting drugs, an additional analgesic-enhancing amount of caffeine in extended release form in the composition. is desirable.

The composition is therefore quickly released into the cuff to hasten and enhance the onset of pain relief. about 60 to about 200 mg (preferably about 65 to about 150 mg), and sustained one (or more) additional doses 60 to 200 to maintain enhanced analgesia due to released release. It will typically contain 1 (preferably 65 to 150) of caffeine. Hi The daily analgesic dosage in patients varies depending on the N5AID selected, and Of course, the amounts contained in the aforementioned unit doses may be as low as possible. mild to medium The daily dose for use in the treatment of severe pain is preferably diflunisal 1 500■, or zomevirac sodium 6oom9, or ibuprofen 240 0■, or naproxen 1oomg, or flurbizolofen 150mg, or is fenoprofen 2400mg, or piroxicam 2o~, or hamefemanin acid 1000■, or fenbufen 2400■, or ketozolo7ene 300~, and caffeine preferably does not exceed 1000 mg. However, if the patient tolerates Higher amounts can be used if necessary.

For humans, currently preferred for use in the unit dosage compositions of this invention Typical effective anti-inflammatory doses of N5AIDs are approximately 10 to 20 doses of piroxicam, soflu Nisar approx. 250-500~, Indomethacin approx. 25-50~, Surindak approx. 150-200■, tolmetin sodium approximately 200-4oom9, meclofena Sodium mate approx. 50~, ibuprofen approx. 65~600m9, naproxen Approx. 250-500η, Fenbufen approx. 800-1200■, Ketozolofen approx. 50-100~, or fenoprofen about 200-600~, but optionally Even larger amounts can be used. The amount of caffeine in the anti-inflammatory composition starts The amount is sufficient to shorten the time and/or enhance the anti-inflammatory response. to humans As such, unit dose anti-inflammatory compositions typically contain about 60-200 μg (preferably approximately 65 to 15 oz) of caffeine, and this dosage level is generally sufficient to shorten the time and enhance the anti-inflammatory response. In this case too, the long-acting In the treatment of inflammation, N5AID M is used less frequently than 3 to 4 times a day. (e.g., piroxicam, diflunisal, sulindac, tormet) Naproxen) contain large amounts of caffeine in the dosage unit. They can be formulated together to provide a portion of the caffeine in sustained release form. like this compositions that are typically released quickly to hasten the onset and enhance the anti-inflammatory response. about 60 to 200mg of caffeine (preferably about 65 to 150mg), and and one or more additional agents to continue to enhance the anti-inflammatory response through sustained release. Will contain 60 to 200 ■ (preferably 65 to 150) of caffeine . The daily anti-inflammatory dosage in humans varies depending on the N5AID selected, e.g. in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis and degenerative joint diseases. The daily dosage for use is generally about 10-20 mg of piroxicam, noflunisa The distance is about 250-1500 m’! , indomethatine approximately 75-200■, Surinda Approximately 200-600mg of Tolmetin Sodium, Approximately 600-2000mg of Tolmetin Sodium, Meku Lofenamate sodium approx. 200-400 ~, ibuprofen approx. 1600-3 000■, naproxen approximately 250-11000rn, fenbufen approximately 3200rn ~4800 mW, about 150-400 mg of ketozolo-7ene, or fenoprofe The amount of caffeine is about 1,600 to 2,400, and the caffeine is about 1,000 to 1,000.

However, larger amounts can be used if tolerated by the patient.

When a selected narcotic analgesic is combined with caffeine according to this invention: Unexpected results such as

(1) The analgesic effect of the selected narcotic analgesic occurs more rapidly.

(2) Less amount of the selected analgesic drug is required for the same analgesic effect.

(3) Greater analgesic effect is achieved across all doses.

For patients with pain, and especially those with severe pain, from therapeutic administration The time to onset of effective mitigation is clearly very important. Therefore, cafe This caffeine can cause headaches when combined with selected narcotic analgesics. The inventors' discovery of substantially shortening start time (i.e., earlier start) is extraordinary. It's always meaningful, but this is completely unexpected.

Additionally, caffeine's ability to potentiate analgesia, i.e., eliciting a defined analgesic response. The ability to substantially reduce the amount of selected narcotic analgesics required for This is unexpected and is a very important aspect of this invention. This unexpected , and an important finding is that the doses currently suggested for analgesics in humans are It also allows the use of selected narcotic analgesics in substantially lower amounts. low By using lower dosages, we can in turn reduce the development of undesirable side effects, including the possibility of addiction. The frequency and/or intensity of episodes should decrease. In addition, at a given dose level A greater analgesic response than High C1 can be achieved.

More specifically, it is important to note that this invention's preferred method is not to use narcotic analgesics alone. When using narcotic analgesic/caffeine compositions, the onset of analgesia is reduced by an average of 1/4 Achieved 1/3 faster. Also, only narcotic analgesics when combined with caffeine Approximately 115~/3 to achieve an analgesic effect equivalent to that obtained by using Small amounts of selected narcotic analgesics may be used. In other words, The addition of phene will reduce the amount of narcotic analgesic drug selected to achieve the same effect. Reduce it to 2/3~4A of the normal amount.

However, these rates depend on the patient's individual response, the selected dosage level of the active ingredient. It will vary depending on the file etc.

The selected analgesic/caffeine composition of this invention is 1, in which the use of caffeine is selected. Neutralize the sedative effects of selected narcotic analgesics and administer narcotic analgesics alone Patients were more active, had better mobility, and had an improved sense of well-being compared to It has the advantage of

Selected narcotic properties of the drugs used in the narcotic analgesic/caffeine compositions of this invention The exact amount of analgesic will depend on, for example, the particular drug selected, the size and type of mammal. , as well as the conditions under which the drug is administered. Generally speaking - C1 selection The selected narcotic analgesic may be administered in any amount known to be an orally effective analgesic dose, or can be used in an amount 115 to 1/3 less than the usual amount.

For use in the unit dose narcotic analgesic/caffeine compositions of this invention for humans. Typical effective analgesic doses for currently available analgesics are administered every 4 to 6 hours as needed. When administered to about 1 to 5 days of hydromorphone hydrochloride, codinsulf about 15-60 mQ of ate or phosphate, oxycodone hydrochloride or A mixture of oxycodone hydrochloride and oxycodone tetraphthalate about 2.5 ~5 mg (e.g. 4.50 mg of oxycodone hydrochloride + oxycodone hydrochloride Traphthalate 038■ or oxycone hydrochloride 225mg + oxy Codontetraphthalate 019■), leporphanol tartrate approximately 1-3~ , mebellinone hydrochloride approx. 50cm, propoxyphene hydrochloride approx. 65cm ■, Proboxyphennazosylate approximately 100■, Mesatone hydrochloride approximately 5 ~ 10mg, zolopyram fumarate approx. 25-60cm, pullenorphine hydrochloride About 8 to 1 omp of Lido, about 25 to 50 mg of pentazozone hydrochloride, Narpf About 10 to 30 mq of inhydrochloride, about 4 to 8 mq of butorph gamma nortartrate m7, or about 100 to 500 my of mezotanonol hydrochloride. pain relief The amount of caffeine in the composition is sufficient to stiffen and/or enhance the onset time of analgesia. It's quite spectacular. For humans, unit dose analgesic compositions typically contain about 60 to about 2 Contains 00 mg (preferably about 65~], 50 mq) of caffeine, and This dosage level of phene is generally sufficient to accelerate onset time and enhance analgesia. It's a minute. The daily analgesic dose in humans depends on the selected narcotic analgesic. and, of course, will be as low as the amount contained in said unit dose. . The daily dose used to treat moderate to severe pain should be adjusted to suit the needs of the patient. 30 mq of morphone hydrochloride, or codeine sulfate-1 or phosph ate 360my, or ox/codone hydrochloride, or hydrochloride / prephthalate mixture 6 omti, or leporphanol tartrate 1.8 m! , or linone hydrochloride 600”lF, or propoxyphene 390 mg of hydrochloride, or zolopoquin fennapsire 1-1-6oo, or mesatone hydrochloride 60~, or propylam fumarate 300mg, or is purnorphine human 80 chloride 60rq, or pentazinone hydrochloride 300m? , or nalbufine hydrochloride 180 mg, or butorphano Lutartarate 48mg or meptanonol hydrochloride 3000rrq , and caffeine], not exceeding OOOmg. However, if the patient tolerates it, the amount can be used. selected N5AII) and selected N5AII as defined in this specification. Enhanced analgesia occurs when selected narcotic analgesics are combined and are In Bell, the analgesic effect of the combination is the selected N5AID or the selected anesthesia. In the case of sexual analgesics alone, this is a problem. Therefore, reduce the amount of one of the analgesics and to achieve the same level of analgesia as with even higher doses of the analgesic alone. It is possible to do so. In general, the side effects of selected narcotic analgesics were selected Narcotic analgesia selected as it is considered less preferable than that of N5AIDs It may be more preferable to lower the dosage of the drug. Selected narcotics By lowering the dosage of pain medication, the frequency of associated side effects decreases, and The intensity decreases, and the potential for addiction decreases as well. Generally speaking, selection By adding the selected N5AID, the amount of the selected narcotic analgesic can be adjusted to achieve the same effect. It is possible to reduce the normal amount to 2/3 to 415 to achieve. but However, these rates vary depending on the specific drug selected and the patient's 47 This will vary depending on the individual response and the selected dosage level of active ingredient. moreover, Retain normal doses of selected narcotic analgesics and benefit from enhanced analgesic response can be obtained. Selected narcotic analgesics and selected N5AIDs are Furthermore, when combined with caffeine according to this invention, this combination All of the narcotic analgesic/caffeine combinations discussed in detail above Has unexpected results (earlier start, etc.) and all advantages. Furthermore, the selected The selected narcotic analgesic/selected N5AID/caffeine combination was It contributes to the enhancement of analgesia that would be produced by a combination of different types of analgesics. Cafe The resulting composition is especially suitable for intense Advantageous as an effective daytime oral analgesic against pain, attentive and active Can be used on patients who must be present.

Caffeine, in a three-component composition, has only the analgesic effect of selected narcotic analgesics. but also enhances the analgesic effects of selected N5AIDs, and caffeine Both drugs are believed to hasten the onset of analgesia.

This three-component combination may be used for selected narcotic analgesics alone or for selected N5AIs. Not only the analgesic response due to D alone, but also selected! '&5AID / Caffeine, Selected 48 Special Publications 1984-501459 (14) Narcotic Analgesics/Caffeine and selected narcotic analgesics/selected N5AID combinations. It appears to induce a stronger analgesic response than a pain response.

Nevertheless, selected narcotic analgesics and and the selected N5AIDO amount to the selected narcotic analgesic/selected N5AII ) is generally not recommended. Not possible. Rather, the three-component composition provides a boost in the amount of caffeine provided by the three-component composition. Additionally, it is intended to obtain the advantage of rapid analgesic effect. Therefore, 4, human Analgesia of selected narcotic analgesics in unit dose three-component compositions when used therapeutically Effective amounts are typically for the two-component narcotic analgesic/caffeine compositions of this invention. This is the same as described above. Selected N5AIDOs in unit dose three-component compositions The amount is sufficient to enhance analgesia. For humans, the unit dose is a three-component composition. The product is typically used to treat mild to moderate pain. In amounts that are well tolerated alone and in combination with selected narcotic analgesics. The selected N5AID will contain a sufficient amount of the selected N5AID to enhance analgesia.

Such amounts are determined by consideration of the selected N5AID/caffeine binary composition. The effective analgesic amount is the same as the amount described above. 3 ingredients 9 The amount of caffeine in the composition is sufficient to further enhance or hasten the onset of analgesia. In humans, this amount typically ranges from about 60 to about 200 μm (preferably or 65 to 150 ■), i.e., generally sufficient to hasten the onset and enhance analgesia. That's a good amount.

3. The daily analgesic amount for humans for each analgesic in the component composition is generally determined by a mixture of the two components. Do not exceed these daily analgesic doses previously disclosed for compounds, and again without caffeine. The daily dose generally will not exceed 1000 my. Of course, patient Kamisue Even larger amounts can be used if

The presently preferred methods described above for use in narcotic analgesic/caffeine compositions Anesthetics are also preferred for use in the 35-year composition. these in a three-component composition where the preferred anesthetic is typically administered every 4 to 6 hours. A particularly preferred N5AID to use is The preferred N5AID, also effective for 4-6 hours, described above for use ( Zomepirac Sodium, Ketoprofen, Ibuprofen, Flurbiprofe selected from among will be done. If longer-acting narcotic analgesics are used or If selected narcotic analgesics are formulated in extended free form, longer-acting one of the N5AIDs is combined with the narcotic analgesic and optionally additional Additional caffeine can be included in sustained free form. Instead of this method, 3 All of the ingredients can be formulated for sustained release, in which case the unit Very large amounts of each component can be introduced in a dose.

Although the compositions of this invention are preferably for oral use, they may also be used to administer analgesics. be formulated and administered by other methods known to You can also. Additionally, the above preferred human dosage levels are for adults. However, pediatric compositions can contain relatively few active ingredients. .

Compositions of this invention include selected N5AIDs and/or selected narcotic analgesics. to the mammal by a route of administration appropriate for the component, e.g., orally or rectally. Conveniently administered. Preferably, the composition comprises any suitable non-toxic pharmaceutical agent. Formulated with acceptable inert carrier materials. Such carrier materials are used in pharmaceutical manufacturing. Well known to those skilled in the art.

For those who are not skilled in the art, [MINGTON'SPHARMACEUTIC] Reference is made to the text entitled AL 5CIENCES (14th edition) 1970 . In typical convex administration formulations, such as tablets or capsules, effective analgesic or anti-inflammatory doses of selected N5AIDs, and enhance analgesic or anti-inflammatory responses. or an amount of caffeine sufficient to hasten its onset; or the selection of an effective analgesic amount. narcotic analgesics, and sufficient drugs to enhance or accelerate the onset of the analgesic response. sufficient amount of caffeine; or sufficient amount of selected N5A to enhance analgesic response. Selected narcotic analgesics in effective analgesic doses along with ID and further enhance analgesic response or a sufficient amount of caffeine to hasten its onset; Pharmaceutically acceptable inert carriers such as lactose, starch (pharmaceutical grade), Combined with dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar Let me do it. In addition, if necessary, suitable binders, lubricants, disintegrants and colorants are included. You can also have it. Typical binders include starch, gelatin, sugars such as --Crose, molasses and lactose, natural and synthetic gums such as acacia gum, Sodium alginate, Cotonoconium extract, Cal? oxymethylcellulose , methylcellulose, polyvinylpyrrolidone, polyethylene glycol, ethyl Contains cellulose and wax. Lubricants for use in these dosage forms is boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and Including, but not limited to, polyethylene glycols. A suitable disintegrant , starch, methylcellulose, agar, bentonite, cellulose, wood, algi acid, guar gum, citrus pulp, cal? quinmethylcellulose, and lauryl May include, but are not limited to, sodium sulfate. If necessary, regular Bringing pharmaceutically acceptable dyes i.e. any FD & C dyes into unit dosage form can be entered. Especially in liquid dosage forms, without sweeteners, flavors and preservatives, e.g. It can be introduced when producing elixirs, suspensions or tablets. difference Additionally, when the dosage form is a capsule, in addition to materials of the above type, a liquid carrier, For example, fatty oils can be included. Various other materials as coatings , or can be used to alter the physical form of the dosage unit. for example, Tablets, pills or capsules may be coated with shellac, sugar or both. can. These compositions preferably have at least 0. ], Contains % of active ingredients. and generally the active ingredient will be from about 2% to about 60% by weight of the dosage unit.

Examples of amorphous unit dosage forms are tablets or capsules containing the amounts shown in the following table: . An asterisk (*) indicates that the amount shown next to it is in sustained release form, e.g. ri30q+ 1.30 rrq J is formulated for immediate release of the previous 7.30 my The latter 130 mg means that it is in extended release form.

table 125mg130mg+130mF* 250m7 130mg+13(Cv*500m7 130η+13CIIf* 25m1 65 or 130■ 50■ 65 or 130■ 100mg 65 or 130mg ibuprofen 50mg 65 or 130■ 100■ 65 or 130■ 200 ■ 65 or 130m9 300η 65 or 130~ 400■ 65 or 130■ 500■ 65 or 130■ 600mq 65 or 130rq Nazoloxene 125q 130++v+130q” 250■　130m1130■1 250 ■ 65 ■ + 65 ■ 8 500■　130■＋130η8 flurhyprofen 25■ 130■ 50mv 130mg Table (continued) 50 ■ 65 or 130 ~ 100m2 130~ 200m! i+ 65 or 130■ 300rrq 13 (Cv 600m7 130mg Pyroquincum 10Tn9130～+130mid”20mg130～+130my* 20■ 130～ 2Qmg 130■+260mg” tolmetin sodium 200m’1 130#Ig 400"lli' i3omir' 400■ 130mg 30mg metsue Namin mg 65 or 130Tng 250mp 65 or 130’7g indomethacin 25m7 130■ 50mg130■ Ketoprofen 25~65 or 130++v 50 ■ 65 or 130 ~ Table (continued) 200η 65 or 130~ 400mf 65 or 130mg 800m7 65 or 130mfl slindak 1507Y 1301nfI+ 130 ■*200mF 130my+130 +y*meklofenami Sodium phosphate 50η 65 or 130~ hydromorphone hydrochloride 1~130■ 2 ■ 130 rng 3■ 130～ 15 ■ 130~ 30mg130～ 45■ 130■ 60 ■ 130~ 5～130mg Table (continued) 200m7 65 or L30■ 4.5~70.38m1 130■ 2.25mq1019mf 1307q3+++9 1301ng 50■ 130m9 65■ 130mg 100!　130mg mesatone hydrochloride 5～130～ 10mg 130mf propylum fumarate 35η 65 or 130mg 50～130～ Table (continued) '13mg 130m9 10~130mg 25η 65 or 130mg 50~130mg 10m7 130m1i1 15 mg65 or 130 mq 30Tng130mg 4-130 mg 8 ■ 65 or 130Ing 15 ■ 200 or 400 ~ 130 ■! robiram fumarate ibuprofen 35 ■ 200 or 400mg 130 ■ 50η 200 or 400 ~ 130 ■35～200 or 400 my 65 mg50■ 200 or 400■ 65■ pentazoshinhi Drochloride Ibuprofen 25η 200 or 400mg 130■Table (continued) 8～4oomg1:3omg Glopyram fumarate Zomepira, Cusodium 50 ■ 50 or 100 ~ 1 30■ 35mg 50 or -00mg130mg0mg130mg Zorohoki/Fen Fenoprofen 65 ■ 200 ■ 130 ~ 100mf 200q 130W Glopyram fumarate Fenbufen 35 or 50 kg 400 li 130/n g35 or 50~800q 130mg35 or 50”+F 4.OO”f 65Tng Provirum Fumarej・Metsenamate 35m'! 250mV 130W 30■ 250■ 130■ 30 ■ 125 ■ 130 Takumi Norobilam Fumarate Ketozorofen 35mg 25 or 50++v 130 mg200m! I 25 or 50 ■ 1.30 m’! 200 ■ 25 or 50 m965my If desired, the compositions of this invention can be formulated for parenteral use by known methods. can do.

The selected narcotic analgesic/caffeine two-component composition can be used for drug therapy by oral administration. It is especially valuable in patients with severe pain that cannot be tolerated.

The oral compositions of this invention are prepared in such a way that the narcotic analgesic is extracted from the composition and administered parenterally. It can also be formulated in such a way that the potential for misuse is significantly reduced. This thing is , the drug can be made water-insoluble by combining it with an insoluble excipient, such as methylcellulose. This can be achieved by forming it into a soluble dosage form. Such water-insoluble substances The oral dosage form contains at least some of the anesthetics themselves, such as zolopyram fumarate and mesato. Hydrochloride is already known.

The analgesic and anti-inflammatory effects of the compositions of this invention were demonstrated in animals in the tests described below. can be quantitatively evaluated.

Anti-phenylquinone agony test This test is the standard method for detecting and comparing analgesic activity and is commonly The results are in good agreement with the effects in humans.

Mice are first treated with the medication being tested. Medication used involves caffeine Selected N5AID with or without % Selected with or without caffeine selected narcotic analgesics with or without caffeine Two dose levels each of drug + selected N5AID. Then the mouse was i.p. Challenged by the thrown phenyl-p-benzoquinone and the characteristic elongation Observe for symptoms of prolonged agony. Lack of agony constitutes a positive response. degree of analgesic protection Degree can be calculated based on suppression of writhing compared to control animals on the same day. can. Time response data is also obtained. This test was carried out by Sigmund et al. and Blu. mberg et al. (Sigmund, E, Cadmus + R, and Lu lG, + Proc, Soc, Bxp, Biol, and M ed, 95 + 729.

Inflammation last paw test - pressure induced stimulation Modifications of the Randall-5elitto method using W i n t e r etc. By applying increasing pressure to the left hind paw, which was caused to become inflamed by the yeast, Check the limit of the avoidance reaction that occurs. Perform drug treatment. The medication being tested is Café Selected NSA, ID at two dose levels with and without infusion. to the feet Apply constantly increasing force and observe and record the "escape reaction" (Ran dal + II, 409-419, 1957; Winter, C, A, Til-flick test in L and L'S+ mice was performed with tail control. This is done as a modification of σAmour and Sm1th by applying high-intensity heat. normal ma mice and drug-treated mice are observed and reaction times are measured. The drug used is A selection of two doses of the Hafty Tea Lou Pinch Method (H Using a modification of the Ta1l-Pinch Hafner method, rats were To confirm the effect of the drug on the aggressive response evoked by the pressure stimulus of pinching the tail of a Ru. Clamps were placed on each rat's paw prior to drug treatment and at specific times after treatment. Attach the clamp again in between. Overt aggression and biting behavior directed at stimulation Observe the time it takes to occur. The medications tested include caffeine-containing and C-like 2 doses of the selected narcotic analgesic without concomitant. (Haffner, F. , : Experimentelle Prufung Schmerzsti ttender Mittel, Deutsch med, Wshr, A modification of the method of rWo o 1 f e and MacDonald is used.

This method consists of applying a controlled thermal stimulus to the mouse's paw. drug in treatment group administer the drug. When the animal comes into contact with the hot plate and the standard disease reaction, i.e. The latency period between fast matting and/or observation of one or both hindpaws. Measure. Medications tested include selected narcotic sedatives with or without caffeine. Two doses of pain medication. (Wo o l f e + G, + in rats Adjuvant arthritis is a widely used model of rheumatoid arthritis in humans. be.

This basically involves cell-mediated immunity against the injected bacterial substances. It is caused by an immune reaction. The reaction is systemic, but primarily occurs in the limbs as polyarthritis. Ru. Visually assess the degree of arthritis in the hind paws or 21 days after injection of adjuvant. Evaluated by adding the volume of the daily bar Swelling measured on day 16 constitutes the second response. The drug is given as an unbanded injection. Administer orally daily starting 1 day in advance. The medication used may be with or without caffeine. Two dose levels of N5AID were selected.

Results are expressed as inhibition relative to control. (WalzpRheum, Dis,, 30, 303-306 (1971)).

In order to confirm the effectiveness of the composition of this invention in humans, moderate to severe pain Options with or without caffeine for patients with pain who require oral analgesia. narcotic analgesics or N5AIDs, or with or without caffeine. Administer no selected narcotic analgesic + selected N5AID, while inflammatory or degenerative joint diseases such as leelamatiform arthritis, osteoarthritis, gout or acute For patients with musculoskeletal disorders who require oral anti-inflammatory agents, use with or without caffeine The selected N5AID can be administered without concomitant. To determine the analgesic effect The nursing observer should interview the patient regarding the level of pain or stiffness and subsequent swelling. come into contact with Ask patients to subjectively estimate the time it takes for relief to begin with medication. average Thus, the compositions of this invention with caffeine have a short onset time and a positive effect. It can be shown by appropriate statistical methods that the

(La5ka, E, Gormely + M, + 5unshine r A, + Be1leville + J, W,, Kantov, T, + Forest 1w, LISiegel + G, + and Meisner , M, :’″A Bioassay Computer Program for Analgesis C11nical Trials”+D,R,+ “Regression Motels and Life T&bles ”　rJournal　Royal　5tatitical　5ociety , 5eries B.

Volume 34: 187-202. (1972). Inflammation and degenerative joint diseases Evaluation of effectiveness in patients is based on the degree of pain, duration of morning stiffness, general feeling, and behavior. by the patient's self-assessment of the ease of Swelling, number of painful joints, as well as various functional tests, such as locomotor strength, walking speed, This is accomplished by a physician's assessment of chest expansion and finger approximation to the floor.

From the foregoing description, one skilled in the art can easily ascertain the essential features of this invention and Changes and/or modifications may be made to this invention without departing from its spirit and scope. child Thus, these changes and/or modifications are properly, legitimately, and within the scope of the following claims. is intended to be within sufficient equivalence of .

international search report PCT/US83101121 Lexis and Chemical Absmrac Rens, --Jo1.　 97Pronanamide, N-1m5-2-(1-=piperidiny l) eehyn-N-2-pyridinyl.

Morphinan-3,6,14-riot, 17(cyclobu-ren y1 mee=hyl), 4.5-epoxy-, (5, 6) Continued from page 1 (A61K 31152 31/435) (A61K 31152 0 shots clearer Russ Riki Nijin M New York 10538, USA Larchmont Dante Street 34

Claims (1)

[Claims] 1. Because the onset is accelerated and an enhanced analgesic and anti-inflammatory response is elicited. A pharmaceutical composition for use in mammals in need of such treatment, comprising: The composition includes an analgesic and anti-inflammatory effective amount of the active pharmaceutical ingredient and It contains an active agent potentiator for this action, and the active agent is ibuprofen. Nazoloxene, Fenoprofen, Indoprofen, Noflunisal or pharmaceutically acceptable salts thereof, and said auxiliary agents are active agents of the active agent. Substantially acidic composition from an amount of caffeine that accelerates and enhances the onset of analgesia and anti-inflammatory effects thing. 2. The active agent comprises ibuprofen or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1. 3. The active agent comprises nazoloxene or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1. 4. The active agent comprises fenoprofen or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, comprising: 5. The active agent comprises indoprofen or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, comprising: 6. The active agent comprises noflunisal or a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to claim 1, comprising: 7. The pharmaceutical composition according to claim 1, comprising about 60 to about 200 caffeine. Pharmaceutical composition. 8. The method according to claim 7, comprising about 65 to about 150 m7 of caffeine. Pharmaceutical composition. 9 About 125 to about 500 mg of diflunisal and about 65 to about 150 mg of cafe 7. A pharmaceutical composition according to claim 6, comprising: 10 Nofurnisal from about 250 to about 500 and a cafe from about 65 to about 15 Qy 7. A pharmaceutical composition according to claim 6, comprising: 11 Claim No. 1 comprising about 50 to about 400 rrbtz of ibuprofen Pharmaceutical composition according to item 2. 12, from about 100 to about 600 μg of ibuprofen. Pharmaceutical compositions. 13. About 125 to about 500 ■ Naproxen and about 65 to about 150 ■ Caffeine 4. A pharmaceutical composition according to claim 3, comprising: 14. Nazoloxene of about 250 to about 500 and caffeine of about 65 to about 150 4. A pharmaceutical composition according to claim 3, comprising: 15, about 5Q to about 2oo■ 7 enoprofen 68 5. A pharmaceutical composition according to claim 4, comprising: 16. Claim No. 1 comprising about 200 to about 600 μ of fenoprofen 1 Pharmaceutical composition according to item 4. 17. Claim 1 further comprising a non-toxic pharmaceutically acceptable carrier. Pharmaceutical compositions as described. 18. The medicament according to claim 17, wherein the composition is adapted for oral administration. Composition. 19. Claim 18, wherein the composition is formulated as a tablet or capsule. Pharmaceutical compositions. 20. The medicament according to claim 17, wherein the composition is adapted for rectal administration. Composition. 21. The pharmaceutical composition according to claim 20, wherein the composition is formulated as a crude drug. thing. 22. The pharmaceutical composition according to claim 18, which is in sustained release form. 23. further comprising an orally analgesic active narcotic analgesic in an amount effective for analgesia; A pharmaceutical composition according to claim 1, comprising: 24 The above-mentioned narcotic analgesic! Claim 23 comprising robiram fumarate. The pharmaceutical composition described in Section 1. 25 The above-mentioned narcotic analgesics crabbutane hydrochloride, nalbuphine hydrochloride Lorido, butorphanol tartrate or mezotazole hydrochlori 69' 91 Table ■59-501459 (2) Things. 26. The narcotic analgesic comprises Norofuxifene human. Pharmaceutical composition. 27. Such treatments provide an accelerated onset and enhanced analgesic and anti-inflammatory response. A method of raising an active drug ingredient and an active drug in a mammal in need thereof. A unit dose of a pharmaceutical composition comprising an agent-enhancing agent is an analgesically and anti-inflammatoryly effective amount. said active agent is ibuzolofen, nazolofen, etc. Loxene, fenoprofen, indopro-7ene, diflunisal or these containing a pharmaceutically acceptable salt; How to extract essential nutrients from caffeine in amounts that speed up and enhance the onset of inflammation. 28. The pharmaceutical composition contains an analgesically effective amount of a narcotic sedative having orally analgesic activity. 28. The method of claim 27, further comprising a pain medication.