JPS62501630A - Analgesic, anti-inflammatory and skeletal muscle relaxant composition - 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] [Background of the invention] field of invention The present invention generally provides at least one non-steroidal anti-inflammatory drug. 1 cucumber skeletal muscle relaxant, and optionally cyxanthin or xanthine derivatives, e.g. For example, a novel pharmaceutical composition containing in combination with caffeine, and skeletal muscle spasm, Predetermined orthopedic condition (orthop@dic oot+ditlons) , moderate skeletal muscle disorders including intervertebral disc syndrome and low back pain, etc. The present invention relates to methods of using the compositions in the treatment of diseases.

Description of prior art Centrally acting skeletal muscle relaxants5 are usually used as single agents or in combination products. prescribed as an ingredient. The U.S. Food and Drug Administration recommends that these drugs be Additive to rest (r@st) and physical therapy for the relief of musculoskeletal problems allowed to be displayed as. Clinically, the majority of cases involve small muscle contusions ( strain) and mild pain associated with small injuries have a limited course of progression. Follow the path. Most patients usually respond quickly to rest. Tissue damage Anti-inflammatory drugs may be helpful if edema and edema are present. On the other hand, degenerative deformation Significant musculoskeletal disease as a result of osteoarthritis, disc herniation, dorsal spondylitis or transitional resection Strains and sprains, trauma and cervical or lumbar radiculopathy often cause moderate or cause severe and often chronic painful skeletal muscle spasticity. The main symptoms are Increased local pain, correction on palpation, muscle stiffness (eonslst@nay) and restrictions on movement. For these patients, treatment alone or with analgesics Combination skeletal muscle relaxants are often prescribed. The results of one study showed that laxatives and A combination of analgesics and analgesics may be more effective in patients with acute musculoskeletal problems than similar doses of analgesics alone. He suggested that it would bring great benefits.

Table 1 shows some commercial combination products currently available. current city Commercially available laxative formulations include 200 ■ carinprodol and 325 ■ aliquots. Cart@r-Wallac, which contains spirin. Soma Compound made by o, Ino, ) It is. Karinprotol is.

It is a centrally acting laxative that does not directly relax tense skeletal muscles in humans. a Spirin is a common non-narcotic analgesic with anti-inflammatory and antipyretic activity. The most common adverse reactions associated with the use of aspirin in products are nausea, Gastrointestinal symptoms included vomiting, gastritis, occult bleeding, constipation, and diarrhea.

Allergic type reactions associated with aspirin also involve the respiratory tract and skin. Sometimes.

Another commercially available skeletal muscle relaxant composition is Matsukunil 7 Humasutical (Me Paraphone 7# Rute (Par afon Forts■). Nokrahon Forte is 250■ Kuroroki It contains sazon and 300 Da of 7cetaono7ene. Chloroxazone is , a centrally acting drug that does not directly relax tense skeletal muscles in humans. Non-service Acetaminophen, a ricylate analgesic, is a common non-anesthetic drug with antipyretic activity. It is a sexual analgesic.

A. H. Robins Com-pany, I Ropaxal ■ manufactured by Na, ) is 40 (1') Another commercially available articulation laxative containing vamol and 3251n9 as It is a drug combination product. The mechanism of action of methocarbamols in humans has been established. This is probably due to general central nervous system depression. Methocarbamol is It does not directly relax tense skeletal muscles in humans. Related to aspirin in this composition Unfavorable reactions include: nausea and other gastrointestinal discomfort, gastritis. , gastric ulcer, vomiting, constipation, diarrhea, vascular Drops, asthma, rash, itching and hives.

Licker 2 is from Radley's (R1ak*r Laboratories).

In11. ) commercial products Norgesic (Norg・Yama■) and Norjini Norg@sieFort. They are used as laxatives and The product mentioned above contains caffeine as well as aspirin. Sea walk is excellent. Norgesic's specific composition consists of 25 ■ citric acid or 7 Contains Enadrine, 385 ■ Aspirin and 30 ■ Caffeine.

Norjinijitsukforte is 50■orphenadrine citrate, 770■as Contains Pirin and 601n9 caffeine. Orphenadri citric acid 2-dimethylaminoethyl 2-methylbenzhydryl ether citrate It is. Common Side Effects and Concerns Associated with Aspirin Use Norgesic This also occurs when using Norzhinizikkforte.

Skeletal muscle relaxant composition containing acetaminophen, which is currently one of the commercially available products Thing A? Parajon Forte withdraws its new drug application approval in the near future in 1985 The subject of a hearing granted by the Commissioner of Food and Drug Administration in response to a request made by It will be.

Federal Rs + Gister.

FDA in a notice published in 1982, 47 F.R. 22599. Director of Pharmaceutical Convex Zhou, he has scientific training and training to prove the effectiveness of Parahon Forte. An assignment performed by a professional qualified by knowledge and experience (omitted). The authors concluded that they were unaware of the contents of a proper and well-controlled clinical study. food The current opinion of the Secretary of State for Pharmaceutical Affairs is as follows [Federal Register (F. ederal Register@r), 1984, 49(200): 482 12-48214): This NDA permission is granted to Parajon Forte on its label. To have ... (omitted) under the prescribed, recommended or suggested conditions of use. It will be withdrawn if there is no clear evidence of clinical efficacy.

All of the skeletal muscle relaxant-narcotic analgesic combination products mentioned above are non-narcotic analgesics. Please note that this product contains aspirin or acetaminophen. However, there are now a variety of superior non-narcotic analgesic and antipyretic agents available. Several alternative non-narcotic agents have been developed that exhibit the advantage of these A new non-steroidal anti-inflammatory drug.

Widely used to treat mild to severe pain, as well as rheumatoid and osteoarthritis Administered orally in the treatment of distinct diseases including. In this type of drug, The compound is an analgesic, anti-inflammatory and antipyretic due to its chemical structure and biological characteristics varies widely in The main advantages of these new non-steroidal anti-inflammatory drugs is clinically superior to aspirin, acetamin-7ene or zenacetin. Contains analgesic and anti-inflammatory activity, but not those experienced with conventional drugs. In particular, the gastrointestinal ulceration and gastrointestinal ulceration experienced with aspirin. It also reduces bleeding and liver toxicity caused by the use of large amounts of 7cetaminophen. Contains.

Additionally, xanthine or xanthine inducers are present in these novel skeletal muscle relaxant compositions. A particularly favorable reaction is obtained by including a conductor, e.g. caffeine. It was discovered that it can be done. The central nervous system stimulant effect of caffeine is It is advantageous to counteract the sedative effects often caused by the use of relaxants. deer While combining xanthine or xanthine derivatives with non-steroidal anti-inflammatory drugs The increased effect observed by increasing the concentration is even more significant. increased analgesic or an anti-inflammatory response is achieved, and a better alternative for the same analgesic or anti-inflammatory effect. Small amounts of selected non-steroidal anti-inflammatory drug effects are required.

Aspirin and acetamin-7ene have been used in conventional compositions, but improve the appearance of the body, reduce the incidence of side effects and thereby prevent musculoskeletal disorders. To achieve effective treatment, skeletal muscle relaxants and xanthine or Santhin derivatives, e.g. any novel non-steroid in combination with caffeine anti-inflammatory drugs (i.e., aspirin, aceto7mino7ene, and zenacetin) It has not previously been proposed to use

[Summary of the invention]

Surprisingly, the inventors have now found that substantially aspirin, acetamin 7 7-enacetene and 7-enacetene, and their chemical structure is significantly different from them. A novel non-steroidal anti-inflammatory drug with unique chemical properties has been developed to advantageously and optionally together with cyxanthin and xanthine derivatives in novel compositions. It has been administered to mammals, especially humans, to reduce pain and is preferred. We have found that it is possible to reduce side effects without any problems.

Therefore, the main objective of the present invention is to induce an analgesic or anti-inflammatory and musculoskeletal relaxation response. A novel pharmaceutical composition for use in administering an analgesic or anti-inflammatory effective amount of a novel non-steroidal anti-inflammatory drugs, effective amounts of skeletal muscle relaxants, and any necessary analgesic or is one example of xanthine or xanthine derivative in an amount sufficient to increase the anti-inflammatory effect For example, an object of the present invention is to provide the above pharmaceutical composition containing caffeine. In standard terms , the active ingredient is further combined with a non-toxic pharmaceutically acceptable inert carrier for the ingredient. are combined.

A further object of the present invention is to treat various skeletal muscle disorders in mammals, such as skeletal muscle spasms. A treatment method for certain orthopedic conditions, intervertebral disc syndrome, lower back pain, etc. , a preselected dose of the non-steroidal anti-inflammatory drug in the mammal, the skeletal muscle administering a relaxant and, if necessary, the xanthine or xanthine derivative. An object of the present invention is to provide the above-mentioned treatment method.

Another object of the invention is an effective amount of a non-steroidal anti-inflammatory drug, an effective amount of a skeletal muscle relaxant. , and optionally an effective amount of xanthine or xanthine derivative. It is possible to provide a suitable unit dosage form of the composition.

A further object of the invention is to provide xanthine or xanthine derivatives such as caffeine A novel pharmaceutical composition containing the drug can be administered to mammals, particularly humans, to determine its effectiveness. The use of skeletal muscle relaxants as well as eliciting strong analgesic or anti-inflammatory responses often The aim is to reduce the sedative effects that often occur.

[Detailed description of the invention]

More specifically, one applicant surprisingly found that.

Certain new non-steroidal anti-inflammatory drugs include aspirin or acedosanophen. compared to the analgesic, anti-inflammatory and by increasing antipyretic activity and reducing the incidence of untoward side effects. Skeletal muscle relaxants and optionally cyxanthins or xanthine derivatives, e.g. It has been found to be ideally suited for use in formulations with feins.

A novel non-steroid in a comparative study with aspirin and acetaminophen. The superiority of various non-narcotic analgesics belonging to the class of inflammatory anti-inflammatory drugs has been demonstrated in the literature. are fully demonstrated.

-/4- (Coop@r) launched ibuprofen 400■ in 1977. Spirin 650 has a higher peak effect and longer duration of action. I found it. Cooper, Nis, Ni, (Cooper, S, A,), Ni -dol, knee, e, (N...di..., A, E,), Krueger, g, oh, (Krug@r, G, 0.) 1977.

"An analgesic relativistic potency assay conveyor Aspirin, Ibuprofen and φ Placego (Analges) icRelative Potency A@aay Comparing A splrin.

Ibuprofen and Placebo) J Jay, oral competition mackerel - In another 1982 study, 400 pounds of ibuprofen was compared to 650 pounds. Aspirin was found to be more effective. Ku/arm, varnish, knee.

Engle, J-(Eng@l*J-)% Radog, M.

(Ladov, M,), Preci, Le, H* (Pr@eh@ur.

H,), Rosenheck, Nie, (Rosenh@ck, A*), Lau Chi, De 4-m (Rauch gD *) 198'2, "Anal Jessi Red An-Its Clofen-Codeine Combination (AnalgesicEfflaacy of an Ibuprofen- codslne　Con+binat1on) J Pharmacotherapy (Phar maeoth@rapy) 2: pp. 162-167. Sunshine (5u et al. showed that ibuprofen was effective in reducing pain after episiotomy. It was found that it was significantly superior to spirin.

Sunshine, Knee, (5unshlns, A*), etc., clinical Pharmacology and Therapy 24:254-250, 1983 Year.

In 1982, Dlonn et al. Ibuprofen is more effective than acetaminophen in delaying I discovered that. Dlonne, RlA, Campbell, R.A., Cooper, Varnish, knee,.

Hall, D, L, (Hall, DmL&), Packingham, B* (Bueklnghum, B,) r Sagledge.

n og post operatig pain pie greoperatig atomy Ni storage, n og ibuprofen in con i yari shin toku pla Cibo, Acetaminophen and Acetaminophen Glass 9 Codeine (5uppr・5alon of Post Op@ratlv* Pa1n b y　Preop@rative　Adminlst-ratlon　of　Ib upprof@n in Comparison to Plae@bo.

Ac@tamlnoph@n and Aestaminophen Plus Coding) JJ, Clin, Pharmacol, (J, 011n).

Phthrmaeol m) (in press).

Comparing Nafloxen Sodium 550■ to 650■ Aspirin, it was found that Spirin has been shown to provide faster and better pain relief. Founded by Chi, (5ave11us, H,) Nargesic Effekt Og Naproxen Sodium, Aspirin Fist A Comparative Analgesic Eff@c laof Naproxen Sodlum, Aspirln and P 1ac@bo) J-Ken 50■ and 100■ flurbinolofen are both Flurbinolofen 25 was significantly more effective than aspirin 6001n9. The effectiveness of Asviri and N600 was slightly lower. Sunshine.

Olson, N., 4-0.

2), Laaka, E, M- (Laaka 6 E * M @), Zui Gulboam, Ie (Zigh@lbo1m Ie) s Decast o, x-, (DsCastro, A*), Desaraji y, Sea a (Desarrazi'n, C*), Farfco. Chill.

(Pharmaeo Th@r,) 3: I 77-181 negative, "7 Narjie Shitsuku Effect of Dareibuidban Doshi's Og e Full Rubiprofe Ana1g@sie　Eft@a t of Gradad Dosss of Flurbiprof@n in Posteplslotmy pain in treatment ranging from moderate pain to severe pain Suflofen (5uprof@n) 2001R9 is used to relieve aspiritis. We have found that it is more effective than 65019. Silverman, H.E. Mu, (Sllber. □, H, M,) r multi-blue dose compalycin φ og supro 2 en, aspirin φ and glassy?・In the Treat Ment of Masculoskeletal Pain (Multlple-Dogs Comparison of 5uprofen, Aspirin and Placeb.

In the Treatment of Museuloskeletal Pa1n) J Fu 1:30 G (Pharmaeology) 27 : S 1.65-73 (1983).

Significant analgesic and anti-inflammatory properties compared to aspirin or acetaminophen Due to their excellent properties, non-steroidal anti-inflammatory drugs are effective in treating acute and chronic pain. treatment and treatment of severe rheumatoid arthritis and osteoarthritis. As standalone agents, these novel non-narcotic analgesics have a wide range of promoted acceptance and use; However, xanthine or xanthine derivatives The use of these nonsteroidal anti-inflammatory drugs in skeletal muscle relaxant compositions with It hadn't been thought of.

Non-steroidal anti-inflammatory i used in the pharmaceutical composition of the present invention and its method of use (N5AID) can be selected from the following categories: (1) ropionic acid derivatives, (2) acetic acid derivative, (3) f@namic acid derivative, (4) biphenyl Carboxylic acid derivatives and (5) oxleam.

Therefore, r　N5AID　J means aspirin, acetaminol, falls into one of the five structural categories above, excluding 7ene and zenacetin. Any non-narcotic analgesic non-steroidal anti-inflammatory compound and its pharmaceutical Refers to salts with an acceptable number of orders of magnitude.

Compounds determined to fall within the above definition of non-steroidal anti-inflammatory drugs used in the present invention are: Their chemical structure, biological activity, side effects and usual dosage ranges are well known to those skilled in the art. References may be made to various references for the following. For example, Huizo Shan Phy+1eian'a Dask Refer ence) s 8438 edition, 1984 and De Melk Index ( Th@M@rck　Ind@x　9th edition, Merck & Company (Me rck and Company), o-way (Rahvay), Twos--Chassis (1967) and Cuttinges Handbook Og. ・Pharmacology (Cutting’s Handbook of Phar) maeology), 6th edition, T, Z, Kusaki (T, Z, Cmak y), M, D, (M, D,) and B, Knee, Pans (B, A, B arnes), Abreton-Senna, Riichiri o7tsu (Appleston) -Century -Crofts)%2 JL-York, 1984, No. See Chapter 49: pages 604-638.

Some of these compounds are currently used primarily as anti-inflammatory drugs, while others It is primarily used as an analgesic, and in fact, the intended compound has both analgesic and anti-inflammatory activity and is useful in the compositions and methods of the present invention. It can be used at dosage levels appropriate for the intended purpose.

Compounds in groups (1) to (4) contain carboxylic acid groups; ! ! ! It may be administered in the form of a structurally acceptable salt, e.g. the sodium salt. be.

The propionic acid derivatives used in the present invention include the following. but not limited to: ifloaen, naproxen, nazoloxenate Rium, flurbiprofen, phenozolofen, 7emp7en, ketocrov En, pirprofen, carclofen, oxaglodin, zolanoflofen, i-lobroaene, thio-M-pro7ene, supro-7ene, al-inoflofen, Tiaprofen acid (th1aprof*nic acid), fluprofen and bucloxic acid. similar analgesic and Structurally related propionic acid derivatives with anti-inflammatory properties are also included in this group. It is intended that Representative members of this propionic acid group include: In: Ibuprofen, naproxen, flurpiglofen%7enf7g , fenopro7ene, ibuprofen aluminum, ketoprofen, flupro Phen and pucuroxic acid. The structural formulas of members of these representative groups are shown below. profen aluminum Therefore, "cropionic acid derivatives" as defined herein typically directly or a free group in which Cal is attached to a ring system, preferably an aromatic ring system, via a nyl group. -CH(CH3)C0OH group or -CM2CH2COOH group (if necessary, Pharmaceutically acceptable salt groups, such as -0M(CH3)Coo-Na+ or -C H2CH2Coo-Na+). It is a roidal anti-inflammatory drug.

The acetic acid derivatives used in the present invention include, but are not limited to, primary ones. Not included: indomethacin, sulindac, tolmetin, diclo7enac, Fenclofenac, Arclo 7 Enatsuku, Ibufenac, Ink 7 pack (iso:cepac), flofenac, tiobinac (tloplnac) , zldometain, acemethacin, fentiade oxpinac, clidanac, and oxspinac.

Structurally related acetic acid derivatives with similar analgesic and anti-inflammatory properties are also included in this group. intended to be included. Representative members of this acetic acid group include: Contains: Tolmetin, Surinjiri, Indomethacin, Dicro7enac, Alc Rofenac, fencrosic acid (f@nclozie acid) and Eve Fenac. Structural formulas of members of these representative groups are shown below.

Acetic acid derivative Therefore, an "acetic acid derivative" as defined herein typically refers directly to a ring system, Free -CH,COOH preferably bonded to an aromatic or heteroaromatic ring system groups (optionally, pharmaceutically acceptable salt groups, such as -CH2C00-Na+) It is a non-narcotic analgesic/non-steroidal anti-inflammatory drug, which may be in the form of

The seven-functional namic acid derivatives used in the present invention include, but are limited to, the following: Not: mefenamic acid, meklo7enamic acid, flufenamic acid, nif lumic acid (nlflum1c acld) and tolu7enamic acid. similar analgesic properties and structurally related fenamic acid derivatives with anti-inflammatory properties are also encompassed by this group. intended to be included. Representative members of this group of fenamic acids are fenamic acid, meclofenamic acid sodium salt (meclofenamic acid, sodium salt) and flufenamic acid. The structural formulas of the members of these representative groups are It is shown below.

fenamic acid derivatives Therefore, the "7-Namic acid conductor" defined in this specification has various substituents. The basic structure below can be: (The free -COOH group in the formula is a pharmaceutically acceptable salt group, for example, -Coo"Na non-narcotic analgesics/non-steroidal anti-inflammatory drugs containing It is.

The biphenylcarenic acid derivatives used in the present invention include diflunisal and flufurnisal. including, but not limited to, monkeys. Similar analgesic and Structurally related compounds with anti-inflammatory and anti-inflammatory properties also belong to this group. is intended to be encompassed by. The representative members of this organization are Schiff A/N. and flufenisal. Their structural formulas are shown below.

biphenyl carbon etss body Therefore, "biphenylcarganic acid derivatives" defined in this document 8A#l are: The following basic structure can have various substituents: (The free -〇〇H group in the formula is a pharmaceutically acceptable salt group, such as -Coo-Na non-narcotic analgesics/non-steroidal anti-inflammatory drugs containing It is.

The oxicams used in the present invention are piroxicam, stoxicam (sudoxicam), cm), ink zicam (isozicmm) and CP-14,304 including but not limited to. Similar analgesic and anti-inflammatory properties Structurally related oxicams having ing. Representative members of this group are shown below.

oxicam CP-14,304 ? Ki 1 "t do" Accordingly, "oxicam" as defined herein has the following general formula: (In the above formula 1, R is aryl or heloaryl) It is an analgesic/non-steroidal anti-inflammatory drug.

Among the tetrapionic acid derivatives used in the present invention, a particularly preferred compound is bunolofen, nazoloxene, nafloxen sodium, flurbinolofen, Fenoprofen, Ketoprofen, Suflofen, Fenbufen and Flu I can mention Pro 7 En.

Tolmetin sodium and sulinda are currently preferred members of the acetic acid derivatives. and indomethacin.

Mefenamic acid and mekaminic acid are particularly preferred compounds among the 7-namic acid derivatives. Sodium enamate can be mentioned.

Among the biphenylcarboxylic acid derivatives used in the present invention, the preferred compound is -) flunisal and flufenisal.

Particularly advantageous oxicams include piroxicam, stoxicam and isoxicam. I can name the cam.

In carrying out a preferred embodiment of the present invention, among the aforementioned non-steroidal anti-inflammatory drugs, Most preferred are ibuzolofen and nazoloxene.

Regarding the dosage of non-steroidal anti-inflammatory drugs in the formulations of the present invention, the particular dosage Although it varies depending on the person's age and weight, the severity of symptoms, the incidence of side effects, etc. Presently preferred N5A for use in unit dosage compositions of the invention for humans Typical analgesically effective doses of ID (1!!9) are shown in Table 2. But long If desired or necessary, larger or smaller amounts can be used. Ru. For unit dose formulations, please contact Remington's Pharmaceutical Sciences. Rsmington's PharmaceutlcalSeien The description can be found in ca m →, 15th edition, pages 1698-9.

With respect to said compounds falling into the category of zolopionic acid derivatives, those compounds Suitable dosage ranges are generally within the range of approximately 12.5 to 900 μ for each unit dose. It is. The general dosage range for said compounds that fall under the category of acetic acid derivatives is Dosage width approximately 25cm~4001n? It is. It falls into the category of 7-Namic acid visiting conductor. Typical dosage ranges for such compounds are each unit dose range of about 50 to 5001 W.

Typical dosage ranges for said compounds that fall into the category of biphenylcarboxylic acid conductors. The width of each unit dose is approximately 125 to 10,009 cm. In the category of oxicams Typical dosage ranges for such compounds are each unit dose range of about 10 to 40 inches.

Table 2 species containing an acceptable analgesically effective amount for use in the unit dosage compositions of the invention. A complete description of each N5AID can be found in our U.S. Pat. No. 4,486,436. Also found in the specification and US Pat. No. 4,522,826.

As used herein, "skeletal muscle relaxant" refers to any compound that has skeletal muscle relaxing properties. refer to things Any skeletal muscle relaxant is useful in the practice of this invention.

Skeletal muscle relaxants can be divided into those that act directly on skeletal muscles and those that act at the level of the central nervous system. It can be broadly classified into. Arthrodialgic drugs that act on the central nervous system mainly affect the dorsal spinal cord. At the level of , the intervention of the multi-synergic reflex arc 2. Ru. About this.

a flexor muscle that has one or more interpositions between the sensory and motor fibers and evidenced by the absence of decreased cross extensor reflexes. single synagetic anti This type of protoalgal reflex reaction that acts through the radiation system and therefore does not have an intervening Not affected by similar drugs.

These drugs also have mild depressant properties on the CNS, and their primary effect is The sites are the brainstem and subpolar regions. Ascending (as) that receives and transmits certain sensory stimuli e@ndlng) The reticular formation communicates and maintains a state of arousal. The path of stimulation is the ascending network. When blocked at the level of the body, the response to sensory stimulation decreases, leading to a transition from sedation to sensory withdrawal. Suppression in the range up to an@ith·−1 m may occur. dorsal spinal cord level The inhibition of polysynaptic reflexes is not sufficient to explain the inhibition of the arousal system.

The majority of clinically useful centrally acting skeletal muscle relaxants fall into the following chemical groups: Glyceryl monoethers and derivatives, oxazoles,! converted alkanediol, Benzazole, benzodiazepine, 1,3-dioxalane and others. All Therefore, it is appropriate to easily classify all skeletal muscle relaxants in this way. There are no other categories, so other categories are also needed.

The skeletal muscle relaxing composition of the present invention includes, in addition to non-steroidal anti-inflammatory drugs, the above-mentioned chemical substance group. Contains at least one active ingredient selected from. of drugs contained within each chemical group A typical example is the following.

S, glyceryl monoether and derivative me7enesine Menenesin Carbamate Mephenesic acid succinate Methocarbamol Chlorphenesin Carbamate b, oxazole Mefenoxalon metaxalone C0-substituted alkanediol meglobamate Karinprodol d, benzazole Mr. Oxazola Chloroxazone ...Benzodiazepines Chlordiazepoxide hydrochloride Diazepam f, other analexif (anal@xin) cyclobendegrine hydrochloride (cyelob snzaprine) orphenadrine citrate Several centrally-acting laxatives are classified by their chemical structure, dosage form, and typical unit dosage. The dosage is shown in Table 3.

Mephenesin is the most widely studied skeletal muscle relaxant. today Although rarely used, mephenesin has similar pharmacological effects. It is the basic type of other skeletal muscle relaxants. These other skeletal muscle relaxants include carisopro Dole, chlorphenesin carbamate, chloroxazone, metaxalone, meth Contains tocarbamol and orphenadrine citrate. Methocarbamo and orphenadrine citrate may be administered orally or intravenously. can. In the latter case, acute and local origin caused by inflammation or trauma Used to relieve severe muscle spasms. Mephene in pharmacological mode of action Other clinically useful skeletal muscle relaxants that differ from the benzodiazepines (e.g. diazepam), baclofen and cyclobenzaprine. diazepam and and other benzodiazepines can cause various types of convulsions1! (spamtlc) for status However, it can be most useful for painful spasticity of the flexor muscles.

These drugs have a positive effect on dorsal spinal cord (5plnal)-mediated 2,-ron activity. It seems to have a selective effect on the reticular neuronal mechanism that controls the meat condition. Although it would seem, mephenesin-like drugs do not exhibit such selectivity. Bakuro 7en has been used to treat spasticity in patients with multiple sclerosis. With baclofen The effects of this drug may be due to its undesirable effects, including drowsiness, insomnia and dizziness. limited.

Cyclobenzaprine is structurally and pharmacologically closely related to tricyclic antidepressants. However, it has side effects common to drugs in that group.

In addition to the centrally acting muscle relaxants mentioned above, dantrolene also acts by direct action on skeletal muscles. It is a typical non-centrally acting laxative drug that exhibits this effect. Dantrolene is listed below. It has the chemical structure of

Dantrolene is released from the sarcoplasmic reticulum through a direct effect on the excitation-contraction coupling or from the sarcoplasmic reticulum. Weakens skeletal muscle contraction by reducing the amount of calcium released. da Although trolene produces some central nervous system depressant effects, it is similar to centrally acting muscle relaxants. does not selectively reduce polysynaptic reflexes. One dose of trolene sodium For oral administration in an amount of 25 to 100 rv during administration or statically in an amount up to 10 μ/kg total dose. Can be used for intravenous administration.

Preferred articulatory laxatives for use in the practice of this invention include diazepam, kalineprodol, , including chlorzoquizazone, methocarbamol and orphenadrine citrate. I'm here.

Regarding the dosage of the skeletal muscle relaxant in the compositions of the present invention, the particular dosage may vary depending on the patient's Although it varies depending on age and weight, severity of symptoms, incidence of side effects, etc., presently preferred skeletal muscle relaxants for use in the unit dose compositions of the invention for Typical effective doses of the drug are approximately 2-10 μg of diazepam, 100-600 μg Prodol, 100-1000 ■ chloroxazone, 200-1500 ■ tocarbamol and 25 to 100 μ of orphenadrine citrate.

For compounds not indicated as members of preferred categories, their references Typical or suggested unit dosage ranges are well known to those skilled in the art. No. 9 of each product The package inserts list the usage range determined by the manufacturer.

These dose ranges are general guidelines followed by those familiar with skeletal muscle relaxants. be· Skeletal muscle relaxants are centrally acting or act directly on skeletal muscle tissue It may be. Skeletal muscle relaxants are one of the five structural categories listed above. Get into it.

Several centrally acting skeletal muscle relaxants on the market currently include aspirin or acetate. Available in the United States as a combination with minophen. These currently available pairs A list of combined products is shown in Table 1 above. These products can help relieve pain and We seek to provide analgesic ingredients that help reduce both the anxiety and painful experience when It is something to do. Elenpas (El・1+bmss) is an American jar Naruban Ogu Hospital Pharmacy (Amerlcan Journal) ofHospltal Pharmaay), Vol. 37, 1980.10 Commenting on published studies of said combination products in Mon. 1313-1323 Negative There is. He said the combination product treats both spasticity and pain associated with musculoskeletal disorders. products that provide ingredients for AMA Drug Evaluations (AMA) provides favorable symptom relief. Drug Evaluatlons) s 5th edition, page 103 contains some Based on the results of the study, the combination of laxatives and analgesics was compared to the same dose of analgesics alone. However, it is claimed to have significant benefits for patients with acute musculoskeletal problems. It states that The said A.M.A. The same page gives examples of combinations of skeletal muscle relaxants and analgesics.

Surprisingly, the inventors have now found that substantially aspirin, acetamin 7 It has a chemical structure different from that of Enacetin and 7 Enacetin, and there are organisms that are significantly different from them. A novel non-steroidal anti-inflammatory drug with unique chemical properties has been developed to advantageously and, if necessary, together with xanthine or xanthine conductor in new compositions. It has been administered to mammals, especially humans, to reduce pain and is preferred. We have found that it is possible to reduce side effects.

Norgesic and Norgesic Forte both contain caffeine. Ru. For the treatment of muscle tension and pain associated with anxiety conditions and mental and physical disorders. Many widely used laxative drugs produce significant sedation. Living whether similar clinical benefits are a result of the sedative effect itself or whether the drug actually provides a sedative effect. It is an unresolved question whether this induces dynamic V activity. Therefore, articulation Adding xanthines or xanthine-visitors, e.g. caffeine, to laxative formulations It would be possible to achieve the dual ρ objective by xanthine or Sanchin Ko conductor itself is a skeletal muscle relaxing ingredient that stimulates the central nervous system to a certain extent. will increase the activity of non-steroidal anti-inflammatory drugs while compensating for the analgesic effect of .

In addition to improved combination products, xanthine or xanthine derivatives, , it is particularly preferred by K to further add caffeine to the composition. Get results.

The xanthine derivative of the present invention is compound 2 of the following formula or a pharmaceutically acceptable version thereof. Contains penetrating salt.

In the above formula, R1-R5 each independently represent hydrogen, C4-C6 alkyl (straight chain or or branched), C4-C6 alkoxy, 01-C6 haloalkyl, CsNC6 loalkyl, hydroxy(C1-C6)alkyl, norodane, hydroxy(C 4-C4)-alkylamino(c,-c4)alkyl, C1-C4(dialkyl )amino(C1-C4)alkyl, C1-C4alkylcarbonyl(C4-C4 ) alkyl, C1-C6 alkyl ino, C1-C6 (dialkyl)amino, i represents ndryl, phenyl or allyl, R4 is hydrogen, C1-C6 alkyl/L/, hal:l (C4-c6) alkyl, C1-C6 alkylamino, c, ~c6 alkylthio, nitro, carboxy%C 1-C6 (dialkyl)amino, 03-C6 cycloalkyl, phenyl, naphthi R, Al(01-C4)alkyl or the following formula: (In the above formula, R5 is H4, C1- C6 alkyl, C1-C6 alkoxy, 01-C6 alkylthio, nitro or C1-C6 alkylamino, and n is 1, 2 or 3) It is a group that can be used.

Further description of xanthine and xanthine derivatives can be found in Applicants' pending publication. No. 4,552,899.

Caffeine, i.e. %3.7-sihydro1.3.7-drimethyl-IH-propylene Phosphorus-2,6-dione has the following formula.

As used herein, "caffeine" refers not only to caffeine as an anhydrous powder. and may increase analgesic or anti-inflammatory responses when used as described herein. Any non-toxic, pharmaceutically acceptable salt or derivative of caffeine that can be or any blended mixtures thereof are useful in the compositions of the present invention. For descriptions of salts, derivatives and mixtures of caffeine that can prove that ba, the me/l/ri”’f 7 f”yri x (Th@Merck Ind @x) h 9th edition, Merck & Co. .

Inc.), Rahvay% 2M-Chassis (1976 ), pp. 207-208.

Nevertheless, caffeine as an anhydrous powder is currently preferred, this If the specific amount of caffeine is given below, the amount is given as ■ on an anhydrous basis. Ru.

Selected N5AIDs and skeletal muscle relaxants can be combined with xanthine or When combined with xanthine derivatives, e.g. caffeine, unexpected effects such as I get a nice result: (1) Amount of selected N5AID required to obtain the same analgesic or anti-inflammatory effect (2) Large analgesic or anti-inflammatory effects across all doses; an inflammatory response is achieved, and (3) central nervous system stimulation is provided to the extent that bone Compensate for the possible sedative effects of muscle relaxants.

Furthermore, increasing the analgesia or increasing the anti-inflammatory response, i.e. Delivering the selected amount of N5AIDO necessary to induce a specific analgesic or anti-inflammatory response. Qualitatively reducing xanthine or xanthine derivatives, e.g. caffeine Capability is also a very important aspect of the invention. This discovery is important for the use of analgesic drugs in humans. It is therefore undesirable to use injections currently indicated as anti-inflammatory drugs. The incidence and/or severity of side effects will be reduced. Also, about N5AID Selected nine N5AID monomers can be used in caffeine formulations in 115 to 1/3 lower amounts. can achieve the same analgesic or anti-inflammatory effect as obtained by the use of . That is, the addition of xanthine or xanthine derivatives, e.g. caffeine, , in skeletal muscle relaxing formulations, up to about V3-415, the usual amount to achieve the same effect. Decrease the amount of selected nonsteroidal anti-inflammatory drugs used. However, this These proportions will depend on the individual response of the individual and the chosen dosage level of the active ingredient, etc. It can change accordingly. Alternatively, at a given dosage level, greater pain relief or an anti-inflammatory response can be achieved.

The amount of xanthine or xanthine derivative in the analgesic composition increases the lack of pain sensation. Pour in enough quantity to make a meal. In the case of caffeine, a typical unit dosage composition for Generally, it contains about 60 to about 200 μg (preferably about 65 to about 150 μg) of caffeine. I'm reading. This dose level of caffeine is generally sufficient to increase the lack of pain sensation. It is.

Certain N5AIDs are particularly long-acting and are administered less frequently than the usual 4 to 6 hourly intervals. For example, diflunisal and naproxen typically Typically, it is administered only twice per day, and piroxicam is administered only once per day.

When using such long-acting drugs, add additional doses in extended-release formulations. May include laxatives and/or additional analgesia-increasing amounts of caffeine. Chopsticks are preferred.

Typical therapeutically active ingredients of the invention for use in the pharmaceutical compositions and methods of the invention , along with its usual adult dosage, are shown in Table 4 below. The third row in the table is a cafe. Indicates that in is an optional third component in the compositions of the present invention. This first The non-steroidal anti-inflammatory drugs in combination with caffeine in Table 4 are As previously demonstrated, it produces surprisingly increased analgesic and anti-inflammatory responses in mammals. bring about Again, U.S. Pat. Nos. 4,420,483 and 4,464,376 and No. 4,479,956.

Tablets or capsules containing the amounts indicated in Table 4 are typical unit dosage forms. It shows. An asterisk (4) indicates that the amount near that mark is in extended release form, e.g. r　13　(19+13　(llfi"J is for the first 1301n9 for direct emission) This means that 130rn9 is in extended release form. It shows.

Skeletal muscle relaxant N5AID Optional caffeine diazepam Ibnolofen 2 ■ Zoo IV 65 or 130rv5M9 2009 65 or 13 0 ■ 10 ■ 400 ■ 65 or 130 ■ Diaze/mother naproxen ★ 21n9+ 2# 12519 651165#★51V+ 5W" 2501 9　130m Kano 1’30m9”10~+101R9500■　130Mochi 1-13 0■★★ Diazenoyamu fenoprofen 29 100 ■ 65 ~ or 130 Da 5# 200 W 65m or 130 ■lQmp 200W 65md (1307# Chlorzoxazone Ibunolo Fen 2501n9200 ■ 65 or 1301n930ω call 400 da 65 Or No. 100 Chlorzoxazone Naproxen 25011f+-250■'' 125■ 651 needle 65■"500) 500■ "250■ 130~+130~★5007M5001'l&"5001W 130111307Y” Table 4 (continued) Skeletal muscle relaxant N5AID optional caffeine chloroxazone Fenonorof en 250■ 100 1# 65 or 130 da 50019 2001n9 65 2: Taya 1301Q Chlorzoxazone Piroxicam 250!25019” 20!If 65 houses 65ri 250112501W” 20111 & 130111+1309★50 Ukano 500■★201”9 1 30 houses 130 da★ Karinprodol Ibnolofen 200 m9 200 ■ 65’tl Tama 130 ■ 400 19 400 1 9 65 or 1301v Kalingrodol Naproxen 20 Usano 200m9” 125 ■ 65m juice 65η★200m?+200m9 "250W 130711307W"400TfF40019"500■ No. 130) 130 ■ Kalingrodor Diflunisal 2001200m9”250 #6511651+I&”200i%200 W" 500 # 130! 130!★40 Seaweed sweat 400■" 500■ 130 Eave 130η” Table 4 (continued) Skeletal muscle relaxant N5AID Any caffeine Methocarbamol Ibuprofe hmm 400 # 20011’l & 65t 130mf? 800 m9 400 +1'+9 65t ball 30m? Methocarbamol Naf'loxene 400～→-4001+9" 125■ 65 needles 65■★40 Usui 400rn9 "250 ■ 130 stitches 13 o'clock" 800118001? l;”　5001n91 3011309” Methocarbamol Sulindac 400m? +400m9” 1501R96!W-1-651V”800Tv+ 800Tn? ”2001# 1301ff needle 130■★Citric acid orfenado Lin Ibuprofen 25 ■ 200 ■ 65 or: 130m250m9 4009 65 or 130m9 Orphenadrine Citrate Nazoloxene 2 5m? +-25m9” 125■ 65m leaf 6--25 needles 25da*250■ 1 30n needle 130■"501501W" 5001W 130M130119"ku Orphenadrine enoate Ketoprofen 25 ~ 25 ■ 65 (130 ■50m9 50 1n9 65 or 130V According to the practice of the present invention, N5AID/skeletal muscle relaxant compositions containing thin or xanthine derivatives appropriately selected with respect to the established route of administration and normal pharmaceutical practice; Mixed with suitable pharmaceutical diluents, carriers or other excipients (collectively referred to as “carrier” materials) When administered together, this can be achieved. Oral administration, e.g. in the form of tablets or capsules For the active drug ingredient, any orally inert pharmaceutically acceptable inert Carrier 5 For example, lactose, starch, sucrose, CeA/lose, stearin Magnesium acid, dicalcium phosphate, calcium sulfate and mannitol etc. can be matched. Additionally, if desired or necessary, suitable binders, lubricants, Agents, disintegrants and coloring agents can also be included in the mixture. as a suitable binder , dengun, gelatin, natural sugars, corn sweeteners, natural and synthetic ingredients. 9, for example, gum arabic, sodium alginate, caloxymethyl sesame Mention may be made of ululose, polyethylene glycols and waxes. of lubricant Among them, boric acid, sodium benzoate, and sodium acetate are recommended for use in these dosage forms. Examples include thorium and sodium chloride. Starch as a disintegrant methyl cellulose, agar, bentonite and guar gum, etc. Yes, but not limited to these. Sweeteners and flavors, if appropriate. Flavoring agents and preservatives may also be included.

Of course, one additional feature of the compositions of the present invention is that they provide therapeutic treatment while minimizing undesirable side effects. Any one or more of them that optimize the therapeutic effect, i.e. lack of pain sensation and skeletal muscle relaxation, etc. Can be formulated into sustained release forms that provide a controlled rate of release of more than one ingredient. Ru. Suitable sustained release dosage forms are impregnated with the active ingredient, with varying disintegration rates or controlled Controlled release polymeric polymer layer containing an IJ Fuchs layer and made into a tablet shape tablets or such impregnated or encapsulated porous polymeric matrices. It contains capsules containing sugar.

Similarly, injectable dosage units may be used for intravenous, intramuscular, or subcutaneous administration. can be achieved, and for such parenteral administration, the required Suitable sterile aqueous, non-aqueous, or aqueous solutions containing suitable solutes to provide permeability Use suspensions or non-aqueous suspensions.

Pharmaceutical compositions of the invention may be formulated by other methods known for the administration of analgesics. It can also be administered separately. The composition can be suitable for rectal administration; For example, it can be applied as a suppository.

The composition may also be suitable for topical application, eg, the composition may be suitable for topical application. from the group consisting of solutions, creams, gels, ointments, powders and aerosols suitable for administration. It can be applied in a selected pharmaceutically acceptable topical excipient.

Representative suitable formulations consistent with the objectives, features and advantages of this invention include: A non-limiting example is provided below.

Chloroxazone-250■ Ibuprofen -400■ Sufficient lactose for milled active ingredients and selected capsule size Methocarbamol-400■ Fenoprofen-200■ Sufficient lacto- or Chloroxazone-250■ Ibuprofen-4001n9 Caffeine -130rv Sufficient lactose for milled active ingredients and selected capsule size Example 4 Methocarbamol-400■ Fenozoro 7en-2001n9 Caffeine -130■ Sufficient lactose for milled active ingredients and selected capsule size From the foregoing examples, other exemplary acceptable pharmaceutical compositions are provided. O that would be obvious to the contractor While the present invention has been described and illustrated with respect to certain preferred embodiments thereof, the spirit of the invention Numerous changes, transformations and substitutions can be made without departing from the This will be understood by those skilled in the art.

For example, effective dosages outside the preferred ranges described above for the active ingredients may be used in the treatment. changes in mammalian responsiveness, severity of symptoms, if any, at observed doses. Related undesirable effects and similar considerations may apply. Ru. Accordingly, such changes or differences as may be expected in the practice of the invention. The results obtained are as expected in accordance with the purpose and practice of the present invention. subordinate Therefore, it is intended that the present invention be limited only by the scope stated in the claims. This is for illustration purposes only.

international search report 1-111--rv1 sand Hp (-mockery ＼＄1lea+n-内-is, lmon0/1 ls85102335ANNEX To THE ZNTERNATIONAL 5EARCHREPORT 0NINTEFLNATIONAL AP? L.I. CATION No, PCT/υS 85102335 (SA 11597 )

Claims (58)

[Claims] 1. A pharmaceutical composition for use in treating skeletal muscle disorders in a mammal, the composition comprising: (i) an effective amount of a skeletal muscle relaxant, and (ii) an analgesically effective amount of a propionic acid derivative, an acetic acid derivative, a fenamic acid derivative; biphenylcarboxylic acid derivatives or oxicams or their pharmaceutically acceptable The composition comprises a non-steroidal anti-inflammatory drug, including a salt thereof. 2. The propionic acid derivatives include ibuprofen, naproxen, and benoxaprof. fen, flurbiprofen, fenoprofen, ibuprofen aluminum, Fenbufen, Ketoprofen, Pirprofen, Carprofen, Oxap Rosin, Pranoprofen, Miroprofen, Thioxaprofen, Suprofe aluminoprofen, tiaprofenic acid, fluprofen or bucuroxy 2. A composition according to claim 1, which comprises phosphoric acid. 3. The acetic acid derivatives include indomethacin, sulindac, tolmetin, and diclofena. fenclofenac, alclofenac, ibufenac, isoxepa flofenac, thiopinac, didomethacin, acemethacin, fenti as claimed in claim 1, comprising Azac, Clidanac or Oxepinac. Composition. 4. The fenamic acid derivatives include mefenamic acid, meclofenamic acid, and flufenamic acid. , niflumic acid or tolfenamic acid. thing. 5. the biphenylcarboxylic acid contains diflunisal or flufenisal; The composition according to claim 1, wherein the composition comprises: 6. the oxicam comprises piroxicam, sudoxicam or isoxicam; The composition according to claim 1, wherein the composition comprises: 7. the skeletal muscle relaxant contains glyceryl monoether or a derivative thereof , the composition according to claim 1. 8. The glyceryl monoether or its derivative is mephenesin, carbamine Acid mephenesin, mephenesic acid succinate, methocarbamol or carba 8. The composition of claim 7, comprising chlorphenesin minate. 9. The composition of claim 1, wherein the skeletal muscle relaxant comprises an oxazole. A product. 10. the oxazole comprises mefenoxalone or metaxalone; The composition according to claim 9. 11. Claim 1, wherein the skeletal muscle relaxant comprises a substituted alkanediol. Compositions as described in Section. 12. the substituted alkanediol comprises meprobamate or kalineprodol; 12. The composition of claim 11, comprising: 13. Claim 1, wherein the skeletal muscle relaxant comprises benzazole. Composition of. 14. the benzazole contains zoxazolamine or chlorzoxazone; 14. The composition according to claim 13. 15. Claim 1, wherein the skeletal muscle relaxant comprises a benzodiazepine. composition. 16. The benzodiazepine contains chlordiazepoxide hydrochloride or diazepam. 16. The composition of claim 15, comprising: 17. The skeletal muscle relaxants include analexin, baclofen, chlormezanone, and hydrochloric acid. Contains cyclobenzaprine, orphenadrine citrate or dantrolene The composition according to claim 1, wherein the composition comprises: 18. The nonsteroidal anti-inflammatory drug is 100 mg to 400 mg of ibuprofen. and the skeletal muscle relaxant contains 100 mg to 1000 mg of chlorzo 2. A composition according to claim 1, comprising a xazone. 19. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. and the skeletal muscle relaxant contains about 2 mg to 10 mg of diazepam. A composition according to claim 1, comprising: 20. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. and the skeletal muscle relaxant contains about 100 mg to 600 mg of carisol. A composition according to claim 1, comprising prodol. 21. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. and the skeletal muscle relaxant contains about 200 mg to 2000 mg of methane. 2. A composition according to claim 1, comprising carbamole. 22. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. and the skeletal muscle relaxant contains about 25 mg to 100 mg of citric acid. A composition according to claim 1, comprising orphenadrine. 23. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. and the skeletal muscle relaxant contains about 100 mg to 1000 mg of chloride. A composition according to claim 1, comprising zoxazone. 24. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. and the skeletal muscle relaxant contains about 2 mg to 10 mg diazepam. A composition according to claim 1, comprising: 25. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. and the skeletal muscle relaxant contains about 100 mg to 600 mg of kalymp. 2. A composition according to claim 1, comprising rhodole. 26. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. and wherein the skeletal muscle relaxant contains about 200 mg to 2000 mg of methcapsine. 2. A composition according to claim 1, comprising lubamol. 27. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. and the skeletal muscle relaxant contains about 25 to 100 mg of orf citrate. A composition according to claim 1, comprising enadrine. 28. Its use in mammals requiring treatment for skeletal muscle relaxation, analgesia, and anti-inflammation. 2. A method of applying a treatment as described above, comprising: administering an effective amount of the composition according to claim 1 to A method comprising administering to an animal. 29. Provides skeletal muscle relaxation and increases analgesic and anti-inflammatory responses in mammals A pharmaceutical composition for use in promoting (i) an effective amount of a skeletal muscle relaxant; (ii) analgesic and anti-inflammatory effective amounts of propionic acid derivatives, acetic acid derivatives, fena; Muic acid derivatives, biphenylcarboxylic acid derivatives or oxicams or their pharmaceuticals non-steroidal anti-inflammatory drugs containing acceptable salts, and (iii) an amount of xanthine or is a xanthine derivative represented by the following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, R1 to R3 each independently represent hydrogen, C1 to C6 alkyl, or C1 to C6 alkyl. Koxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxy (C 1-C6) alkyl, halogen, hydroxy(C1-C4)-alkylamino( C1-C4)alkyl, C1-C4(dialkyl)amino-(C1-C4)alkyl Kyl, C1-C4 alkylcarbonyl (C1-C4) alkyl, C1-C6 alkyl kylamino, C1-C6(dialkyl)amino, indolyl, phenyl or acylamino represents the lil; R4 is hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 Alkylamino, C1-C6 alkylthio, nitro, carboxy, C1-C6 ( dialkyl)amino, C3-C6 cycloalkyl, phenyl, naphthyl, al( C1-C4) Alkyl or the following formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the above formula, R5 is halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C 6 alkylthio. nitro or C1-C6 alkylamino, and n is 1 , 2 or 3)] or a pharmaceutically acceptable version thereof toxic salts The said composition containing. 30. In the formula, R1 is C1 alkyl and R2 is C1 alkyl. alkyl, R3 is C1 alkyl, and R4 is hydrogen. Claim 2, comprising a conductor, and wherein the xanthine derivative is caffeine. Composition according to item 9. 31. The xanthine derivative contains about 60 to about 200 mg of caffeine. , the composition according to claim 30. 32. The propionic acid derivatives include ibuprofen, naproxen, and thioxapro. Phen, flurbiprofen, fenoprofen, ibuprofen aluminum , fenbufen, ketoprofen, pirprofen, carprofen, oxa Prozin, Pranoprofen, Miroprofen, Thioxaprofen, Suprofen Alminoprofen, Tiaprofenic Acid, Fluprofen and Bucloqui 30. The composition of claim 29, comprising cinic acid. 33. The acetic acid derivatives include indomethacin, sulindac, tolmetin, and diclofe. Naku, fenclofenac, alclofenac, ibufenac, isoxe Pak, flofenac, thiopinac, didomethacin, acemethacin, phen Claim 29 comprising Thiazac, Clidanac and Oxepinac composition. 34. The fenamic acid derivatives include mefenamic acid, meclofenamic acid, and flufenam. of claim 29, comprising the acids niflumic acid and tolfenamic acid. Composition. 35. The biphenylcarboxylic acid includes diflunisal and flufenisal. 30. The composition of claim 29, wherein: 36. The oxicams include piroxicam, sudoxicam and isoxicam. The composition according to claim 29, wherein the composition is 37. The skeletal muscle relaxant contains glyceryl monoether or a derivative thereof. 30. The composition of claim 29. 38. The glyceryl monoether or its derivative is mephenesin, carbamicin, etc. mephenesin phosphate, mephenesic acid succinate, methocarbamol and 38. The composition of claim 37, comprising chlorphenesin bamate. 39. 29. The skeletal muscle relaxant comprises oxazole. Composition of. 40. the oxazole includes mefenoxalone and metaxalone; A composition according to claim 39. 41. Claim 2, wherein the skeletal muscle relaxant comprises a substituted alkanediol. Composition according to item 9. 42. The substituted alkanediol includes meprobamate and carisoprodol. 42. The composition of claim 41, comprising: 43. Claim 29, wherein the skeletal muscle relaxant comprises benzazole. composition. 44. the benzazole contains zoxazolamine or chlorzoxazone; 44. The composition of claim 43. 45. Claim 29, wherein the skeletal muscle relaxant comprises a benzodiazepine. Compositions as described. 46. the benzodiazepines include chlordiazepoxide and diazepam; 46. The composition of claim 45. 47. The skeletal muscle relaxants include analexin, baclofen, chlormezanone, and hydrochloric acid. Contains cyclobenzaprine, orphenadrine citrate and dantrolene. 30. The composition of claim 29. 48. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. The skeletal muscle relaxant contains about 100 mg to 1000 mg of chlorzoxine. and said xanthine or xanthine derivative is about 60 m 30. The composition of claim 29, comprising between g and 200 mg of caffeine. 49. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. and the skeletal muscle relaxant contains about 2 mg to 10 mg of diazepam. and the xanthine or xanthine derivative is about 60 mg to 200 mg. 30. The composition of claim 29, comprising caffeine. 50. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. The skeletal muscle relaxant contains about 100 mg to 600 mg of kalimprodone. and about 60 mg of said xanthine or xanthine derivative. 30. The composition of claim 29, comprising ~200 mg of caffeine. 51. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. The skeletal muscle relaxant contains about 200 mg to 1500 mg of methocarba. and the xanthine or xanthine derivative contains about 60 m 30. The composition of claim 29, comprising between g and 200 mg of caffeine. 52. The nonsteroidal anti-inflammatory drug is about 100 mg to 400 mg of ibuprofe. The skeletal muscle relaxant contains about 25 mg to 100 mg of orofol citrate. henadorine, and the xanthine or xanthine derivative contains about 6 The composition according to claim 29, comprising 0 mg to 200 mg of caffeine. thing. 53. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. wherein the skeletal muscle relaxant contains about 100 mg to 1000 mg of chlorzoxa. and about 60 mg of said xanthine or xanthine derivative. 30. The composition of claim 29, comprising ~200 mg of caffeine. 54. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. and the skeletal muscle relaxant contains about 2 mg to 10 mg of diazepam. and the xanthine or xanthine derivative is about 60 mg to 200 mg. 30. The composition of claim 29, comprising caffeine. 55. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. wherein the skeletal muscle relaxant contains about 100 mg to 600 mg of karinprodone. and the xanthine or xanthine derivative is about 60 mg to 30. The composition of claim 29, comprising 200 mg of caffeine. 56. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. wherein the skeletal muscle relaxant contains about 200 mg to 1500 mg of methocarbamo. and about 60 mg of said xanthine or xanthine derivative. 30. The composition of claim 29, comprising ~200 mg of caffeine. 57. The non-steroidal anti-inflammatory drug is about 125 mg to 500 mg of naproxen. and the skeletal muscle relaxant contains about 25 mg to 100 mg of orphene citrate. and the xanthine or xanthine derivative contains about 60 29. The composition of claim 29, comprising mg to 200 mg of caffeine. . 58. Its use in mammals requiring treatment for skeletal muscle relaxation, analgesia, and anti-inflammation. 29. A method of performing such a treatment, comprising: administering an effective amount of the composition according to claim 29 beforehand; 2. A method comprising administering to an animal.