WO1994016703A1 - Ciclobenzaprine-caffeine combination as a muscle relaxant - Google Patents
Ciclobenzaprine-caffeine combination as a muscle relaxant Download PDFInfo
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- WO1994016703A1 WO1994016703A1 PCT/US1994/000557 US9400557W WO9416703A1 WO 1994016703 A1 WO1994016703 A1 WO 1994016703A1 US 9400557 W US9400557 W US 9400557W WO 9416703 A1 WO9416703 A1 WO 9416703A1
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- pharmaceutically acceptable
- muscle
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- stimulant
- xanthine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
Definitions
- Cyclobenzaprine hydrochloride (3-5H-dibenzo[a,d]cyclo- hepten-5-ylidene)-N,N-dimethyl-l-propanamine hydrochloride) is a known muscle relaxant marketed under the trademark FLEXERILTM.
- the compound is formulated into a pharmaceutically acceptable formulation for oral administration as ten milligram tablets and may contain inactive ingredients such as hydroxypropyl cellulose, hydroxy- propyl methylcellulose, iron oxide, lactose, magnesium stearate, starch and titanium dioxide. Cyclobenzaprine hydrochloride is useful for relief of muscle spasm associated with acute musculoskelatal conditions. See U.S. Pat. No. 3,882,246.
- cyclobenzaprine hydrochloride is to relieve pain, tenderness, and limitation of motion and restriction in the activities of day to day living which are all symptoms associated with skeletal muscle spasm.
- the usual dose of cyclobenzaprine hydrochloride is 10 mg three times a day and the maximum dose generally should not exceed 60 mgs per day.
- Specific muscle relaxants which may be used in the present invention include alcuronium chloride, atracurium besylate, baclofen, carbolonium bromide, carisoprodol, chlorphenesin carbamate, chlorzoxazone, dantrolene sodium, decamethonium bromide or iodide, camdinium bromide, gallamine triethiodide, hexafluroenium bromide, mephenesin, meladrazine, metaxalone, methocarbamol, metocurine iodide, pancuronium bromide, pridinol mesylate, styramate, suxamethonium bromide and chloride, thiocolchicoside, tolperisone hydrochloride, tubocurarine chloride, vecuronium bromide the biologically active stereoisomers thereof.
- the tablets may be uncoated or coated with a suitable and conventional coating agent to delay disintegration or to provide a sustained delivery method.
- Agents such as glyceryl monostearate or glyceryl distearate alone or with a suitable wax are conventional coating agents.
- Hard gelatin capsules may also be formulated with the active ingredients of the present invention to produce a suitable pharmaceutically effective composition.
- Inert solid diluents such as lactose, pregelantinized starch, calcium carbonate, calcium phosphate starch, or kaolin may be utilized.
- Soft gelatin capsules may be prepared wherein the active ingredients are mixed with water or an oil medium such as arachis oil, peanut oil or the like.
- Aqueous suspensions may be prepared which contain the active ingredients.
- Suppositories for administration of the active ingredients may also be prepared if rectal administration of the drug is necessary. Excipients utilized when this route of administration is chosen are generally non-irritating.
- Caffeine as recited herein includes those pharmaceutically acceptable salts such as the citrate or hydrate such as the monohydrate.
- the invention may further include combinations of xanthines with cyclobenzaprine and its pharmaceutically acceptable salts wherein the xanthine has a similar stimulating effect as caffeine.
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Abstract
The claimed invention is a combination of the muscle relaxant cyclobenzaprine hydrochloride and the stimulant caffeine. The combination may further include an analgesic selected from an ibuprofen salt such as ibuprofen lysinate. The combination is useful for providing effective relief and treatment of muscle spasms of local origin while concurrently reducing or eliminating the associated side effects of drowsiness thereby enabling the patient to fully achieve the beneficial effects of the muscle relaxant.
Description
TITLE OF THE INVENTION
CYCLOBENZAPRINE-CAFFEINE COMBINAΗON AS A MUSCLE
RELAXANT
BACKGROUND OF THE INVENTION
This invention is related to compositions and methods for treating muscle spasm of local origin without interfering with muscle function. More particularly, this invention claims a combination of the muscle relaxant cyclobenzaprine hydrochloride and caffeine. The claimed combination is useful for treating muscle spasm while concurrently reducing the side effect symptoms of drowsiness which often occur after administration of cyclobenzaprine alone.
Cyclobenzaprine hydrochloride (3-5H-dibenzo[a,d]cyclo- hepten-5-ylidene)-N,N-dimethyl-l-propanamine hydrochloride) is a known muscle relaxant marketed under the trademark FLEXERIL™. The compound is formulated into a pharmaceutically acceptable formulation for oral administration as ten milligram tablets and may contain inactive ingredients such as hydroxypropyl cellulose, hydroxy- propyl methylcellulose, iron oxide, lactose, magnesium stearate, starch and titanium dioxide. Cyclobenzaprine hydrochloride is useful for relief of muscle spasm associated with acute musculoskelatal conditions. See U.S. Pat. No. 3,882,246.
Caffeine (l,3,7-Trimethylpurine-2,6-(3H,lH)dione) is a known central nervous system stimulant. The drug's mode of action occurs on the higher centers and it produces wakefulness and enhanced mental activity. Caffeine is also known to facilitate the performance of muscular work. Caffeine is generally administered in dosages of 20-400 mgs and may be administered orally or parenterally. Most of the biological effects or actions of caffeine are probably mediated through antagonistic activity on adenosine receptors. Caffeine has also been used as an analgesic adjuvant to enhance the effect of an analgesic such as aspirin.
Combinations of a muscle relaxant, aspirin, and caffeine have been disclosed. NORGESIC™ and NORGESIC™FORTE are
currently marketed products which contain the muscle relaxant orphenadrine citrate in combination with aspirin and caffeine. Orphenadrine has the formula:
Combinations of muscle relaxants with nonsteroidal anti- inflammatory drugs have also been disclosed. See U.S. Pat. Nos. 4,780,463; 4,722,938; and 4,923,898. In addition, see U.S. Pat. No. 3,625,962.
Applicants invention, however, is directed to a combination of the muscle relaxant cyclobenzaprine and its pharmaceutically acceptable salts with caffeine, wherein the caffeine is used to countereffect the associated drowsiness side effects and to enhance analgesic properties of an additional ingredient such as (S)-ibuprofen or (S)-ibuprofen lysine wherein these compounds are substantially free of the (R)-ibuprofen stereoisomer if the non-steroidal antiinflammatory drugs are optionally added to the combination of cyclobenzaprine and caffeine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to a combination of the muscle relaxant cyclobenzaprine and its pharmaceutically acceptable salts and hydrates with the stimulant caffeine. The invention and claimed combination may be formulated in combination with typical pharmaceutically acceptable ingredients in order to prepare tablets, capsules, caplets and sustained release formulations. The claimed invention is useful in the treatment of skeletal muscle spasm including acute muscle spasm and the associated pain in a manner that provides a less sedating formulation by virtue of the additional element caffeine.
Studies have indicated that cyclobenzaprine acts within the central nervous system at the brain stem level. Cyclobenzaprine hydrochloride has the following formula:
The compound is known to reduce tonic somatic motor activity influencing the gamma and alpha motor systems. The pharmacological behavior of cyclobenzaprine parallels structurally related tricyclic antidepressants and sedation is one of the known side effects that occur after administration of this class of molecules. There is a need, therefore, to counteract the sedative effects of muscle relaxants such as cyclobenzaprine hydrochloride with a stimulant such as caffeine. The combination enables effective utilization of the muscle relaxant to relieve skeletal muscle spasm of local origin while concurrently enabling the patient in need of treatment thereof to stay awake. The combination therefore effectively enhances the utility of the muscle relaxant itself since the ultimate puipose of cyclobenzaprine hydrochloride is to relieve pain, tenderness, and limitation of motion and restriction in the activities of day to day living which are all symptoms associated with skeletal muscle spasm. The usual dose of cyclobenzaprine hydrochloride is 10 mg three times a day and the maximum dose generally should not exceed 60 mgs per day.
Other muscle relaxants employed herein may be selected from either of the polysynaptic depressant type or the non-polysynaptic depressant type. The polysynaptic depressant type of muscle relaxant or compounds with muscle relaxant activity include but .are not limited to carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, di.azep.am, metaxalone, bacolfen, quinine, methocarbanol and all the biologically active enantiomers, diastereomers or mixtures of stereoisomers thereof. Pharmaceutically acceptable salts of these active stereoisomers may
include citrates, hydrochlorides, sodium, sulfate and the like with the most preferred muscle relaxant being cyclobenzaprine hydrochloride. Of course, if a stereoisomerically pure active isomer of a muscle relaxant as disclosed herein is not readily available, it may readily be obtained by standard purification and resolution procedures using the racemic mixture as the starting material. The non-polysynaptic depressant type of muscle relaxant employed herein includes compounds that act as depressants of muscle-spindle activity and compounds that act on motor neurons.
Specific muscle relaxants which may be used in the present invention include alcuronium chloride, atracurium besylate, baclofen, carbolonium bromide, carisoprodol, chlorphenesin carbamate, chlorzoxazone, dantrolene sodium, decamethonium bromide or iodide, fazadinium bromide, gallamine triethiodide, hexafluroenium bromide, mephenesin, meladrazine, metaxalone, methocarbamol, metocurine iodide, pancuronium bromide, pridinol mesylate, styramate, suxamethonium bromide and chloride, thiocolchicoside, tolperisone hydrochloride, tubocurarine chloride, vecuronium bromide the biologically active stereoisomers thereof.
Caffeine (l,3,7-Trimethylpurine-2,6-(3H,lH)dione) is a known central nervous system stimulant. The drug's mode of action occurs on the higher centers and it produces wakefulness and enhanced mental activity. Caffeine is also known to facilitate the performance of muscular work. Caffeine is generally administered in dosages of 100- 300 mgs and may be administered orally or parenterally.
In addition to cyclobenzaprine and caffeine, additional active ingredients such as an NSAID may be added. For example, ibuprofen salts such as (S)-ibuprofen lysinate may optionally be added to provide effective and enhanced pain relief while simultaneously relieving inflammation, tenderness, and limitation of motion associated with skeletal muscle spasm. The claimed invention therefore includes a combination of cyclobenzaprine hydrochloride which is available in bulk or commercial quantities as sold under the trademark FLEXERIL™ and caffeine and an NSAID such as (S)-ibuprofen lysinate
preferably including (S)-lysine. Ibuprofen lysinate may be obtained by following the procedure described in U.S. Pat. 5,009,895.
A combination of cyclobenzaprine hydrochloride and caffeine contains between 1-10 mgs of cyclobenzaprine hydrochloride and between 30-100 mgs of caffeine per tablet and optionally contains between 50-500 mgs of (S)-ibuprofen (R) or (S) lysinate. These active ingredients are combined with pharmaceutically acceptable carriers to form tablets, capsules, caplets or sustained release formulations. A pharmaceutical composition containing cyclobenzaprine hydrochloride and caffeine and optionally (S)-ibuprofen-(S)-lysine .and additional inert ingredients is used in a method of treating muscle spasms and the associated pain in a patient in need of treatment thereof.
The claimed combination and pharmaceutical compositions thereof may be administered orally, patenterally, or rectally in formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral means intravenous or intramuscular. The claimed combination is not limited to humans but may also be administered to mammals such as mice, rats, horses, dogs, cows, pigs, cats etc. Preferably, the combination is administered to humans in a pharmaceutically effective form. The pharmaceutical composition of the invention may be delivered to a patient in need thereof by conventional or known delivery methods utilizing currently available drug delivery technology. Applicants invention therefore encompasses the claimed combination of active ingredients in combination with delivery agents or other suitable vehicles to achieve the desired biological or physiological effect.
Cyclobenzaprine hydrochloride is used at oral dosages of about 0.1 to 1.0 mg/kg of body weight per day. Adult humans may receive about 20 mgs to 60 mgs per day. The relative ratios of cyclobenzaprine hydrochloride to caffeine may vary depending upon the patient and the need. Comparable dosage forms and ratios are given regardless of the route of administration. The amount of active ingredients that are combined with the pharmaceutically acceptable carrier materials to produce a single dosage may vary depending upon
the target host and the particular mode of administration. For example, a formulation intended for oral administration in humans may contain from about 2.5 mg to 20 mg of cyclobenzaprine combined with 50 to 300 mgs of caffeine and optionally ibuprofen lysinate and further compounded with a known and appropriate carrier material which may vary from about 5 to 85% by weight of the total mass.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pharmaceutically elegant and/or palatable preparation that is concurrently pharmaceutically effective for the intended purpose and utility. Tablets containing the active combination of ingredients may also contain pharmaceutically acceptable excipients which are suitable for the manufacture and for the effective biological dispersion of the active ingredients. These excipients may include inert diluents such as pregelantinized starch, calcium sulfate, microcrystalline cellulose, lactose, fumed silica calcium phosphate. Granulating and disintegrating agents may also be added to the formulations and these may include hydroxypropyl cellulose, methyl cellulose, cellulose acetate phthalate, guar gum, ethyl cellulose, maize starch, or alginic acid. Binding agents such as starch, gelatin, or acacia and lubricating agents such as magnesium stearate, stearic acid or talc may also be added.
The tablets may be uncoated or coated with a suitable and conventional coating agent to delay disintegration or to provide a sustained delivery method. Agents such as glyceryl monostearate or glyceryl distearate alone or with a suitable wax are conventional coating agents.
Hard gelatin capsules may also be formulated with the active ingredients of the present invention to produce a suitable pharmaceutically effective composition. Inert solid diluents such as lactose, pregelantinized starch, calcium carbonate, calcium phosphate starch, or kaolin may be utilized. Soft gelatin capsules may be prepared wherein the active ingredients are mixed with water or an oil medium such as arachis oil, peanut oil or the like. Aqueous suspensions may be prepared which contain the active ingredients. Suitable excipients for these suspensions include sodium carboxymethylcellulose, methyl - cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, xanth.an gum, microcrystalline cellulose with sodium carboxymethylcellulose, gum tragacanth and gum acacia. Dispersing or wetting agents may be phosphatide such as lecithin or condensation products of an alkylene oxide with fatty acids such as polyoxyethlen stearate, sodium lauryl sulfate or condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol. The excipients may also include condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyoxyethylene sorbitan mono-oleate. Preservatives such as sodium benzoate, coloring agents, flavoring agents and sweeteners may also be added to the suspension.
Dispersible powders, oil-in-water emulsions, syrups and elixirs containing the active ingredients of the invention may also be prepared by conventional methods. Sterile injectable preparations containing the active ingredients of the invention may be utilized to affect the necessary therapeutic results. For parenteral administration, aqueous fluid dosage forms can be prepared in a variety of forms such as a combination of an aqueous suspension of cycloben∑izprine hydrochloride and an aqueous suspension of caffeine. Oil suspensions, freeze dried mixtures, or separate suspensions containing the two active ingredients may be combined to one central dispersion unit at the time of use.
Suppositories for administration of the active ingredients may also be prepared if rectal administration of the drug is necessary.
Excipients utilized when this route of administration is chosen are generally non-irritating.
Caffeine as recited herein includes those pharmaceutically acceptable salts such as the citrate or hydrate such as the monohydrate. The invention may further include combinations of xanthines with cyclobenzaprine and its pharmaceutically acceptable salts wherein the xanthine has a similar stimulating effect as caffeine.
Of course, the claimed combination of active ingredients may also be formulated in a pharmaceutically effective form for veterinary use and may be premixed in foods given to the animal in need of treatment thereof.
This invention is illustrated by the following examples which may readily be prepared to exemplify the various formulations which may be prepared for administration to patients or animals in need of treatment thereof. The examples are not to be construed as limiting the scope of the present invention and it is understood that the claimed combination of cyclobenzaprine and caffeine may be formulated with any known and effective pharmaceutical excipient or delivery agent in order to deliver the claimed combination to the patient or animal.
EXAMPLES
EXAMPLE 1 Per tablet, mg.
Cyclobenzaprine 2.5 mg
Caffeine 30.0 mg
Lactose 79.0 mg
Starch, corn 65.0 mg
Hydroxypropyl cellulose
(as 2% in ethanol) 8.0 mg
Add:
Starch, corn 55.0 mg
Guar gum 55.0 mg
Magnesium stearate 4.0 mg
The cyclobenzaprine, caffeine, lactose and corn starch are reduced to a fine powder by milling and remixing. The mixture is granulated with the hydroxyproply cellulose solution. The wetted mass is passed through a No. 10 stainless steel screen and dried in the dark at 110° F. The dried granules are passed through a No. 20 stainless steel screen, and the additional quantity of corn starch, guar gum and magnesium stearate added. The mixture is compressed using a 1/2" standard curvature punch into tablets and the tablet may be coated with a conventional protective film containing various types of cellulose polymers, dyes and opacifying agents.
EXAMPLE 2 Per tablet, mg.
Cyclobenzaprine 5.0 mg
Caffeine 100.0 mg
Calcium phosphate, dibasic 100.0 mg
Lactose 90.0 mg
Ethyl cellulose (as 5% in ethanol) 4.0 mg
Add:
Starch, corn 25.0 mg
Magnesium stearate 4.0 mg
The cyclobenzaprine, caffeine, calcium phosphate and lactose are mixed to a fine powder, i.e., through 60 mesh. The powder is granulated with the ethyl cellulose solution and the moist mass passed through a No, 10 screen, dried at 110° F, and rescreened through a No. 20 stainless steel screen. The com starch and magnesium stearate are
added and the mixture compressed to tablets with an 1/2 " punch. These tablets may be coated with a protective film.
EXAMPLE 3 Per tablet, mg.
Cyclobenzaprine 10.0 mg
Caffeine 150.0 mg
Lactose 79.0 mg
Starch, corn 65.0 mg
Hydroxypropyl cellulose
(as 2% in ethanol) 8.0 mg
Add:
Starch, corn 55.0 mg
Guar gum 55.0 mg
Magnesium stearate 4.0 mg
The tablets are prepared as described in Example 1.
EXAMPLE 4 Per tablet, mg.
Cyclobenzaprine 8.0 mg
Caffeine 50.0 mg
Pregelantinized starch 210.0 mg
Hydroxypropyl cellulose 17.0 mg
Add:
Microcrystalline cellulose 88.0 mg
Magnesium stearate 8.0 mg
The tablets are prepared as described in Example 1.
EXAMPLE 5 Per tablet, mg.
Cyclobenzaprine 5.0 mg
Caffeine 100.0 mg
Calcium phosphate, dibasic 100.0 mg
Lactose 90.0 mg
Ethyl cellulose (as 5% in ethanol) 4.0 mg
Add:
Starch, com 25.0 mg
Magnesium stearate 4.0 mg
The tablets are prepared as described in Example 2.
The following examples represent examples of capsules that contain the active ingredients of the claimed invention.
EXAMPLE 6 Per capsule, mg.
Cyclobenzaprine 5.0 mg
Caffeine 150.0 mg
Lactose 415.0 mg
Magnesium stearate 2.0 mg
The mixed powder is then encapsulated.
EXAMPLE 7 Per capsule, mg.
Cyclobenzaprine 10.0 mg
Caffeine 100.0 mg
Lactose 250.0 mg
Magnesium stearate 1.0 mg
The powdered components are mixed and put into an opaque gelatin capsule.
The following represent an example of sterile aqueous suspensions of the therapeutic mixtures described and claimed in the instant application.
EXAMPLE 8 Per ml., mg.
Cyclobenzaprine 5.0 mg
Caffeine 75.0 mg
Polysorbate 80 0.05 mg
Sodium CMC 15.0 mg
Sodium chloride to render the solution isoosmotic
Benzyl alcohol 9.0 mg
Water for injection to make 1.0 ml
The polysorbate 80 is dispersed at 65°C in water containing the sodium chloride and benzyl alcohol. The resulting mixture is sterilized by autoclaving. After the vehicle has cooled to room temperature, sterilized cyclobenzaprine and caffeine are dispersed therein. The resulting suspension is subdivided into amber vials with protection from light during the subdivision.
The examples as recited above should be construed as non-limiting and additional dosages and dosage forms may be administered to a patient in need of treatment thereof depending upon their individual biochemistry and condition. In addition, other active ingredients including and preferably ibuprofen lysinate in 50-600 mg quantities per tablet or formulation or delivery mode may optionally be added to the examples listed above to form a combination which provides enhanced pain relief and enhanced inflammation relief as well as providing relief via the bis combination of caffeine and cyclobenzaprine. Under circumstances in which the tri-combination is
called for, the caffeine is utilized not only to counter the effects of drowsiness caused or induced by the muscle relaxant but also to enhance the analgesic effects of the ibuprofen lysinate.
Claims
1. A pharmaceutical composition for inducing skeletal muscle relaxation comprising a pharmaceutically effective amount of:
(i) an amount effective in the treatment of muscle spasms of at least one of the muscle relaxants, or a therapeutically active stereoisomer thereof, substantially free of its other stereoisomer or its pharmaceutically acceptable salts and;
(ii) a xanthine stimulant or its pharmaceutically acceptable salts and optionally
(iii) a pharmaceutically effective amount of an NSAID.
2. The pharmaceutical composition according to Claim
1 wherein the muscle relaxant is cyclobenzaprine hydrochloride and the xanthine stimulant is caffeine or a pharmaceutically acceptable salt thereof and the optional NSAID is ibuprofen lysinate.
3. The pharmaceutical composition according to Claim
2 wherein cyclobenzaprine hydrochloride is administered in a daily dosage to an adult human of between 1 .and 60 mgs/day and caffeine is administered in a daily dosage to an adult human of between 5 and 300 mgs/day and optionally the ibuprofen lysine is administered in a dosage of 50-600 mgs/day
4. A pharmaceutical composition for inducing skeletal muscle relaxation comprising a pharmaceutically effective amount of:
(i) an amount effective in the treatment of muscle spasms of at least one of the muscle relaxants, or a therapeutically active stereoisomer thereof, substantially free of its other stereoisomer or its phaimaceutically acceptable salts and; (ii) a xanthine stimulant or its pharmaceutically acceptable salts; and
(iii) a pharmaceutically acceptable carrier.
5. The pharmaceutical composition according to Claim
4 wherein the muscle relaxant is cyclobenzaprine hydrochloride and the xanthine stimulant is caffeine or a pharmaceutically acceptable salt thereof.
6. The pharmaceutical composition according to Claim
5 wherein the composition is administered in the form of a tablet.
7. The pharmaceutical composition according to Claim 5 wherein the composition is administered in the form of a capsule.
8. The pharmaceutical composition according to Claim 5 wherein the composition is administered in the form of a suspension.
9. The pharmaceutical composition according to Claim 5 wherein the composition is administered in the form of a sustained release formulation.
10. A pharmaceutical composition comprising a pharmaceutically effective amount of:
(i) an amount effective in the treatment of muscle spasms of at least one of the muscle relaxants, or a therapeutically active stereoisomer thereof, substantially free of its other stereoisomer or its pharmaceutically acceptable salts;
(ii) a xanthine stimulant or its pharmaceutically acceptable salts and
(iii) a pharmaceutically effective amount of an NSAID selected from an ibuprofen salt and
(iv) a pharmaceutically acceptable carrier. lo ¬
11. A method of treating skeletal muscle spasms which comprises administration of a pharmaceutically effective amount of:
(i) an amount effective in the treatment of muscle spasms of at least one of the muscle relaxants, or a therapeutically active stereoisomer thereof, substantially free of its other stereoisomer or its pharmaceutically acceptable salts;
(ii) a xanthine stimulant or its pharmaceutically acceptable salts; and
(iii) a pharmaceutically acceptable carrier.
12. The method of treatment according to Claim 11 wherein the muscle relaxant is cyclobenzaprine hydrochloride; and the xanthine stimulant is caffeine or salts thereof.
13. A method of treating skeletal muscle spasms while concurrently relieving a side effect condition of drowsiness, which comprises administration of a pharmaceutically effective amount of:
(i) an amount effective in the treatment of muscle spasms of at least one of the muscle relaxants, or a therapeutically active stereoisomer thereof, substantially free of its other stereoisomer or its pharmaceutically acceptable salts;
(ii) a xanthine stimulant or its pharmaceutically acceptable salts; and
(iii) a pharmaceutically acceptable carrier.
14. The method of treatment according to Claim 13 wherein the muscle relaxant is cyclobenzaprine hydrochloride and the xanthine stimulant is caffeine.
15. A method of treating skeletal muscle spasms while concurrently treating pain and inflammation and the side effect of drowsiness, which comprises administering to a patient in need of treatment thereof a pharmaceutically effective amount of:
(i) .an amount effective in the treatment of muscle spasms of at least one of the muscle relaxants, or a therapeutically active stereoisomer thereof, substantially free of its other stereoisomer or its pharmaceutically acceptable salts;
(ii) a xanthine stimulant or its pharmaceutically acceptable salts;
(iii) an analgesic selected from an ibuprofen salt such as (S)-ibuprofen-(S)-lysine or (S)-ibuprofen-(R)- lysine and
(iv) a pharmaceutically acceptable carrier.
16. Tte method of treatment according to Claim 15 wherein the muscle relaxant is cyclobenzaprine hydrochloride and the xanthine stimulant is caffeine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU59950/94A AU5995094A (en) | 1993-01-29 | 1994-01-18 | Ciclobenzaprine-caffeine combination as a muscle relaxant |
| KR1019950704285A KR100307815B1 (en) | 1993-04-06 | 1994-04-05 | Acetic acid production method |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1101393A | 1993-01-29 | 1993-01-29 | |
| US011,013 | 1993-01-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994016703A1 true WO1994016703A1 (en) | 1994-08-04 |
Family
ID=21748480
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1994/000557 WO1994016703A1 (en) | 1993-01-29 | 1994-01-18 | Ciclobenzaprine-caffeine combination as a muscle relaxant |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU5995094A (en) |
| WO (1) | WO1994016703A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995007079A1 (en) * | 1993-09-07 | 1995-03-16 | The Procter & Gamble Company | Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agents and caffeine |
| EP1992333A1 (en) | 2007-05-08 | 2008-11-19 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Flurbiprofen and muscle relaxant combinations |
| WO2012137054A1 (en) | 2011-04-06 | 2012-10-11 | Campiglio Consulting Srl | Pharmaceutical composition containing cyclobenzaprine suitable to intranasal administration |
| US20150093436A1 (en) * | 2003-11-14 | 2015-04-02 | Aptalis Pharmatech, Inc. | Modified release dosage forms of skeletal muscle relaxants |
| US9498440B2 (en) | 2009-05-22 | 2016-11-22 | Inventia Healthcare Private Limited | Extended release pharmaceutical compositions |
| RU2680244C1 (en) * | 2017-12-28 | 2019-02-19 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Combination of flupirtine and cyclobenzaprine for treatment of pain syndromes |
| WO2019099995A1 (en) * | 2017-11-17 | 2019-05-23 | Neurana Pharmaceuticals, Inc. | Methods of administering tolperisone |
-
1994
- 1994-01-18 WO PCT/US1994/000557 patent/WO1994016703A1/en active Application Filing
- 1994-01-18 AU AU59950/94A patent/AU5995094A/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| CHEMICAL ABSTRACTS, Volume 105, Number 22, issued 01 December 1986, SUNSHINE et al., "Analgesic, Antiinflammatory and Skeletal Muscle Relaxant Compositions", page 392, No. 197174a. * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995007079A1 (en) * | 1993-09-07 | 1995-03-16 | The Procter & Gamble Company | Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agents and caffeine |
| US20150093436A1 (en) * | 2003-11-14 | 2015-04-02 | Aptalis Pharmatech, Inc. | Modified release dosage forms of skeletal muscle relaxants |
| US20150196505A1 (en) * | 2003-11-14 | 2015-07-16 | Aptalis Pharmatech, Inc. | Modified release dosage forms of skeletal muscle relaxants |
| US9375410B2 (en) * | 2003-11-14 | 2016-06-28 | Adare Pharmaceuticals, Inc. | Modified release dosage forms of skeletal muscle relaxants |
| US9399025B2 (en) * | 2003-11-14 | 2016-07-26 | Adare Pharmaceuticals, Inc. | Modified release dosage forms of skeletal muscle relaxants |
| EP1992333A1 (en) | 2007-05-08 | 2008-11-19 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Flurbiprofen and muscle relaxant combinations |
| US9498440B2 (en) | 2009-05-22 | 2016-11-22 | Inventia Healthcare Private Limited | Extended release pharmaceutical compositions |
| WO2012137054A1 (en) | 2011-04-06 | 2012-10-11 | Campiglio Consulting Srl | Pharmaceutical composition containing cyclobenzaprine suitable to intranasal administration |
| WO2019099995A1 (en) * | 2017-11-17 | 2019-05-23 | Neurana Pharmaceuticals, Inc. | Methods of administering tolperisone |
| CN111886007A (en) * | 2017-11-17 | 2020-11-03 | 纽兰娜制药股份有限公司 | Methods of administering tolperisone |
| RU2680244C1 (en) * | 2017-12-28 | 2019-02-19 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Combination of flupirtine and cyclobenzaprine for treatment of pain syndromes |
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| AU5995094A (en) | 1994-08-15 |
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