Classifications

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Definitions

• compositions comprising meloxicam
• This invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising meloxicam or a pharmaceutically acceptable salt thereof and at least a second pharmaceutically active compound selected from the group consisting of vitamins, antiphlogistic agents and crude drugs.
• an oral pharmaceutical dosage form comprising such a composition.
• a further objective of this invention is related to the use of the composition and the oral pharmaceutical dosage form.
• this invention relates to the use of meloxicam and at least a second pharmaceutically active compound selected from the group consisting of vitamins, antiphlogistic agents and crude drugs for the manufacture of such an oral pharmaceutical dosage form.
• this inventions relates to a method of treating or alleviating of an inflammatory disease, symptoms of an inflammatory disease, headache, toothache, ache after tooth extraction, sore throat, otalgia, arthralgia, neuralgia, lumbago, myalgia, muscle stiffness of shoulder, pain of contusion, pain of fracture, pain of sprain, menstrual pain, traumatic pain, chill, exothermic reaction, fever and/or cold and various symptoms of cold such as fever, pyrexia, arthralgia, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose, sneezing, cough and phlegm.
• COX inhibitors which nonspecifically inhibit cyclooxygenase (COX), a rate-limiting enzyme for biosynthesis of prostaglandin (PG) from arachidonic acid. Inhibition of COX contributes to anti-inflammatory, analgesic and antipyretic effects by inhibiting production of PGE 2 , on the other hand, it also causes adverse drug reactions such as digestive disorders and renal disorders.
• COX includes two types of isoforms, i.e. COX-1 and COX-2.
• COX-1 is constitutively (a certain amount of protein is developed regardless of proliferation or environmental changes) developed in most of the organs such as stomach and kidneys.
• COX-2 is induced by various inflammatory mediators or endotoxin in local inflammatory areas.
• Meloxicam is a known selective COX-2 inhibitor.
• Oral administration of a selective COX-2 inhibitor still may, however, cause some side effects in the digestive system such as stomach indisposition and stomachache.
• oral pharmaceutical compositions with strengthened efficacy and superior safety by increasing anti-inflammatory, analgesic and antipyretic effects, while alleviating side effects such as gastrointestinal disorders are desired.
• a combination of an inhibitor of nitric oxide synthase for treatment of inflammation and inflammatory diseases and a COX-2 inhibitor for treatment of inflammation-related diseases is disclosed in the specification of International Publication WO 99/18960.
• a combination of a COX-2 inhibitor and a leukotriene B4 receptor antagonist as effective for treatment of inflammation and inflammation-related diseases is disclosed in the specification of International Publication WO 96/41645.
• a combination of a COX-2 inhibitor and a 5-lipoxygenase inhibitor as effective for treatment of inflammation and inflammation-related diseases is disclosed in the specification of International Publication W096/41626.
• a composition comprising a COX-2 inhibitor and a leukotriene A4 hydroxylase inhibitor for treatment of inflammation and inflammation-related diseases is disclosed in the specification of International Publication WO 96/41625.
• a pharmaceutical composition comprising a COX-2 inhibitor and opioid analgesics as a method to increase efficacy of meloxicam is disclosed in the specification of the international publication WO 99/13799.
• a pharmaceutical composition comprising morphine and meloxicam in the ratio of 1 :10 is disclosed therein. Such a composition is, however, unfavorable for safety reasons since opioid may cause undesirable side effects.
• the aim of the present invention is to further improve the safety profile of meloxicam with respect to possible side effects and to provide a pharmaceutical composition and an oral pharmaceutical dosage form comprising meloxicam and having improved anti-inflammatory, analgesic and antipyretic effects.
• the present invention aims to provide highly safe oral pharmaceutical compositions comprising meloxicam with more improved anti-inflammatory, analgesic and antipyretic effects.
• a further objective of this invention is to provide more effective pharmaceutical compositions for the treatment of a cold with improved efficacy and safety.
• a further aim of this invention is to provide a method of treating or alleviating inflammatory diseases, headache, toothache, ache after tooth extraction, sore throat, otalgia, arthralgia, neuralgia, lumbago, myalgia, muscle stiffness of shoulder, pain of contusion, pain of fracture, pain of sprain, menstrual pain, traumatic pain, chill, fever, and the like.
• a further aim of this invention is to provide a method of treating or alleviating of a cold, including various symptoms thereof, such as sore throat, fever, chills, headache, runny nose, stuffy nose, sneezing, cough, phlegm, joint pain, muscular pain and the like.
• This invention relates to new pharmaceutical compositions comprising meloxicam or a pharmaceutically acceptable salt thereof and and a second pharmaceutically active compound selected from the group consisting of vitamins, antiphlogistic agents and crude drugs.
• meloxicam or the salt thereof is present in an effective amount allowing itself to exert anti-inflammatory, analgesic and antipyretic effects.
• An advantage of the present invention is that the composition of the invention allows a reinforcement of the therapeutic effects such as analgesic, anti-inflammatory and antipyretic effects without the need to increase. the dose of meloxicam. It is possible to provide pharmaceutical compositions as oral pharmaceutical dosage forms with improved efficacy and safety. Possible side effects of common NSAIDs, as e.g. gastrointestinal disorders, are avoided or alleviated by using meloxicam.
• composition of the present invention is especially suitable for the treatment or alleviation of inflammatory disease and to alleviate its symptoms such as headache, toothache, menstrual pain, sore throat, joint pain, muscle pain, neuralgia, lumbago, stiff shoulder, tooth extraction pain, contusion pain, earache, fracture pain, sprain pain, traumatic pain, chill and/or fever.
• composition of the present invention is especially suitable for the treatment or alleviation of common cold and to alleviate its symptoms such as fever, sore throat, chills, headache, joint pain muscular pain and/or phlegm.
• the improved safety profile enables the use of such compositions in non-prescription drugs.
• Meloxicam is a known selective COX-2 inhibitor which belongs to the acid enolcarboxamide (oxicam) type of non-steroidal anti-inflammatory drugs (NSAIDs).
• NSAIDs non-steroidal anti-inflammatory drugs
• the compound (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H1 ,2-benzothiazine- 3-carboxamide 1 ,1 -dioxide) is described in EP 0 002 482 B1 and US 4,233,299.
• the invention may employ either meloxicam itself or a pharmaceutically acceptable salt thereof.
• the pharmaceutically acceptable salt of meloxicam includes sodium salt, potassium salt, ammonium salt, meglumine salt, tris salt, and salts of meloxicam with a basic amino acid as examples.
• Various salts of meloxicam are described in EP 0 002482 B1 , US 4,233,299 and WO 99/49867.
• the pharmaceutical composition comprises meloxicam or a pharmaceutically acceptable salt thereof and one or more vitamins.
• compositions of the present invention may also include other pharmacologically active substances such as an antacid, a sedative, a central nervous system stimulant, an antitussive agent and/or an expectorant.
• pharmacologically active substances such as an antacid, a sedative, a central nervous system stimulant, an antitussive agent and/or an expectorant.
• an antacid as a further ingredient an improvement of the bioavailability and/or a decrease of the possibility of side effects in the digestive system may be obtained.
• a central nervous system stimulant may reinforce therapeutic effects such as analgesic, anti-inflammatory and antipyresis without the necessity of increasing the dose of meloxicam.
• a reinforcement of analgesic By using a sedative as a further ingredient a reinforcement of analgesic, anti-inflammatory and antipyresis therapeutic effect is obtainable.
• an antitussive agent By using an antitussive agent as a further ingredient an additional alleviation of symptoms, like e.g. cough and sneezing, can be obtained.
• an expectorant By using an expectorant an additional alleviation of symptoms of common cold, like e;g. fever, sore throat, chill, headache, joint pain, muscular pain, and/or sputum, can be obtained.
• common cold like e;g. fever, sore throat, chill, headache, joint pain, muscular pain, and/or sputum.
• a pharmaceutical composition according to this invention may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more vitamins according to this invention and one or more, preferably one antacid.
• This composition may additionally comprise one or more, preferably one central nervous system stimulant, one or more, preferably one antitussive agent, one or more, preferably one expectorant and/or one or more, preferably one sedative.
• a further pharmaceutical composition according to this invention may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more vitamins according to this invention and one or more, preferably one central nervous system stimulant.
• This composition may additionally comprise one or more, preferably one antacid, one or more, preferably one antitussive agent, one or more, preferably one expectorant and/or one or more, preferably one sedative.
• compositions according to this invention may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more vitamins according to this invention and one or more, preferably one antitussive agent.
• This composition may additionally comprise one or more, preferably one central nervous system stimulant, one or more, preferably one antacid, one or more, preferably one expectorant and/or one or more, preferably one sedative.
• compositions according to this invention may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more vitamins according to this invention and one or more, preferably one expectorant.
• This composition may additionally comprise one or more, preferably one central nervous system stimulant, one or more, preferably one antacid, one or more, preferably one or two antitussive agents and/or one or more, preferably one sedative.
• compositions according to this invention may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more vitamins according to this invention and one or more, preferably one sedative.
• This composition may additionally comprise one or more, preferably one central nervous system stimulant, one or more, preferably one antacid, one or more, preferably one expectorant and/or one or more, preferably one or two antitussive agents.
• the pharmaceutical composition comprises meloxicam or a pharmaceutically acceptable salt thereof and one or more antiphlogistic drugs.
• compositions of the present invention may also include other pharmacologically active substances such as an antacid, a sedative, a central nervous system stimulant, an antitussive agent, an expectorant, a vitamin and/or an anti-H1-histamine.
• a pharmaceutical composition according to this invention may include other pharmacologically active substances such as an antacid, a sedative, a central nervous system stimulant and/or a vitamin.
• a pharmaceutical composition according to this invention may include other pharmacologically active substances such as an antacid, a central nervous system stimulant, an antitussive agent, an expectorant, a vitamin and/or an anti-H1-histamine.
• pharmacologically active substances such as an antacid, a central nervous system stimulant, an antitussive agent, an expectorant, a vitamin and/or an anti-H1-histamine.
• an antacid as a further ingredient an improvement of the bioavailability and/or a decrease of the possibility of side effects in the digestive system may be obtained.
• a central nervous system stimulant may reinforce therapeutic effects such as analgesic, anti-inflammatory and antipyresis without the necessity of increasing the dose of meloxicam.
• an antitussive agent as a further ingredient an additional alleviation of symptoms, like e.g. cough and sneezing, can be obtained.
• an expectorant By using an expectorant an additional alleviation of symptoms of common cold, like e.g. fever, sore throat, chill, headache, joint pain, muscular pain, and/or sputum, can be obtained.
• common cold like e.g. fever, sore throat, chill, headache, joint pain, muscular pain, and/or sputum.
• an anti-H1-histamine as a further ingredient an alleviation of symptoms of common cold such as fever, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose and/or sneezing is obtainable.
• the pharmaceutical composition comprises meloxicam or a pharmaceutically acceptable salt thereof and one or more crude drugs.
• compositions of the present invention may also include other pharmacologically active substances such as an antacid, a sedative, a central nervous system stimulant, an antitussive agent, an expectorant, a vitamin, an anti-H1-histamine and/or an antiphlogistic agent.
• pharmacologically active substances such as an antacid, a sedative, a central nervous system stimulant, an antitussive agent, an expectorant, a vitamin, an anti-H1-histamine and/or an antiphlogistic agent.
• a pharmaceutical composition according to this invention may include other pharmacologically active substances such as an antacid, a sedative, a central nervous system stimulant, a vitamin and/or an antiphlogistic agent.
• pharmacologically active substances such as an antacid, a sedative, a central nervous system stimulant, a vitamin and/or an antiphlogistic agent.
• a pharmaceutical composition according to this invention may include other pharmacologically active substances such as an antacid, a central nervous system stimulant, an antitussive agent, an expectorant, a vitamin, an anti-Hi -histamine and/or an antiphlogistic agent.
• pharmacologically active substances such as an antacid, a central nervous system stimulant, an antitussive agent, an expectorant, a vitamin, an anti-Hi -histamine and/or an antiphlogistic agent.
• an antacid as a further ingredient an improvement of the bioavailability and/or a decrease of the possibility of side effects in the digestive system may be obtained.
• a central nervous system stimulant may reinforce therapeutic effects such as analgesic, anti-inflammatory and antipyresis without the necessity of increasing the dose of meloxicam.
• an antitussive agent as a further ingredient an additional alleviation of symptoms, like e.g. cough and sneezing, can be obtained.
• an expectorant By using an expectorant an additional alleviation of symptoms of common cold, like e.g. fever, sore throat, chill, headache, joint pain, muscular pain, and/or sputum, can be obtained.
• common cold like e.g. fever, sore throat, chill, headache, joint pain, muscular pain, and/or sputum.
• a reinforcement of therapeutic effects such as analgesic, anti-inflammatory and antipyretic effects is obtainable.
• an anti-H1-histamine as a further ingredient an alleviation of symptoms of common cold such as fever, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose and/or sneezing is obtainable.
• compositions according to this invention may comprise one or more vitamins as a second or further active ingredient in addition to meloxicam.
• vitamin includes vitamins as such, vitamin-like substances and salts and derivatives of vitamins and of vitamin-like substances.
• compositions in the present invention may comprise one, two, three or more vitamins, which preferably are selected from the group consisting of vitamin B1 , vitamin B2, vitamin C and/or hesperidin, including salts, in particular pharmaceutically acceptable salts, and derivatives thereof.
• Vitamin B1 used in the present invention is preferably selected from the group consisting of thiamine, thiamine hydrochloride, thiamine nitrate, thiamine disulfide nitrate, thiamine disulfide, thiamine dicetylsulfate salt, dicethiamine hydrochloride, fursultiamine hydrochloride, fursultiamine, octotia ine, cycotiamine, bisibutiamine, bisbentiamine, prosultiamine, benfotiamine, cocarboxylase, dibenzoylthiamaine, etc.
• Vitamin B2 used in the present invention is preferably selected from the group consisting of riboflavin, riboflavin butyrate, riboflavin sodium phosphate, flavin adenine dinucleotide, etc.
• Vitamin C used in the present invention is preferably selected from the group consisting of ascorbic acid, sodium ascorbate, calcium ascorbate, etc.
• Hesperidin used in the present invention is preferably selected from the group consisting of hesperidin, alpha G hesperidin, etc.
• compositions according to this invention may comprise one or more antiphlogistic agents as a second or further active ingredient in addition to meloxicam.
• the one or more antiphlogistic agents used in the present invention is preferably selected from the group consisting of semi-alkaline proteinase, serrapeptase, bromelain and tranexamic acid.
• One of these antiphlogistic agents can be used in combination with meloxicam or a combination of two or more of these antiphlogistic agents can be used together with meloxicam.
• compositions according to this invention may comprise one or more crude drugs as a second active ingredient in addition to meloxicam.
• the one or more crude drug used in the present invention is preferably selected from the group consisting of earthworm (Lumbricus), cinnamon bark (Cinnamomi cortex), peony root (Paeoniae radix), moutan bark (Moutan cortex), Japanese valerian (Velerianae radix) , zanthoxylum fruit (Zanthoxylifi'uctus), ginger (Zing ⁇ beris rhizoma), citrus unshiu peel (Aurantii nobilis pericarpium), fennel (Foeniculi fructus), phellodendron bark (Phellodendri cortex), coptis rhizome (Coptidis rhizoma), zedoary (Zedoariae rhizoma), German chamomile (Chamomillaflos), gentian (Gentianae radix), oriental bezoar (Bezoar bovis), bear bile (Fel ursi), fourlea
• the one or more crude drugs are selected from the group consisting of earthworm, cinnamon bark, peony root, Japanese valerian, ginger, fennel, phellodendron bark, coptis rhizome, German chamomile, gentian, oriental bezoar, ginseng, scutellaria root, pueraria root, apricot kernel, jujube.
• crude drug can be in the form of a dried powder, an extract, a fluidextract, a tincture, an oil or other kind of preparations known to the one skilled in the art.
• the crude drug is a formulation according to the Kampo medicine.
• Kampo medicine formulations are described in 2004-5 Drug in Japan : OTC-Drugs (edited by Japan Pharmaceutical Information Center, issued by Yakuji Nippo, Ltd.).
• Preferred examples of Kampo medicine formulations are kakkon-to, keishi-to, kouso-san, saiko-keishi-to, sho-saiko-to, sho-seiryu-to, bakumondo-to, hange-koboku-to and mao-to.
• the preferred contents of the Kampo medicine formulations as mentioned above is given.
• Kakkon-to is an extract of the crude drugs pueraria root, glycyrrhiza, cinnamon bark, peony root, ginger, ephedra herb and jujube, preferably of the approximate ratios 8 : 2 : 3 : 3 : 1 : 4 : 4 by weight.
• Keishi-to is an extract of the crude drugs glycyrrhiza, " cinnamon bark, peony root, ginger and jujube, preferably of the approximate ratios 2 : 4 : 4 : 1 : 4 by weight.
• Kouso-san is an extract or a powder of the crude drugs glycyrrhiza, ginger, citrus unshiu peel, cyperus rhizome and perilla herb, preferably of the approximate ratios 1 : 1 : 3 : 4 : 2 by weight.
• Saiko-keishi-to is an extract of the crude drugs glycyrrhiza, cinnamon bark, peony root, ginger, ginseng, scutellaria root, bupleurum root, jujube and pinellia tuber, preferably of the approximate ratios 2 : 3 : 3 : 1 : 2 : 2 : 5 : 2 : 4 by weight.
• Sho-saiko-to is an extract of the crude drugs glycyrrhiza, ginger, ginseng, scutellaria root, bupleurum root, jujube and pinellia tuber, preferably of the approximate ratios 2 : 1 : 3 : 3 : 7 : 3 : 5 by weight.
• Sho-seiryu-to is an extract of the crude drugs glycyrrhiza, cinnamon bark, peony root, ginger, ephedra herb, schisandra fruit, asiasarum root and pinellia tuber, preferably of the approximate ratios 2 : 3 : 3 : 2 : 3 : 3 : 5 by weight.
• Bakumondo-to is an extract of the crude drugs glycyrrhiza, ginseng, rice, jujube, ophiopogon tuber and pinellia tuber, preferably of the approximate ratios 2 : 2 : 10 : ' 3 : 8 : 5 by weight.
• Hange-koboku-to is an extract of the crude drugs ginger, magnolia bark, perilla herb, pinellia tuber and poria sclerotium, preferably of the approximate ratios 1 : 3 :
• Mao-to is ah extract of the crude drugs glycyrrhiza, cinnamon bark, ephedra herb and apricot kernel, preferably of the approximate ratios 2 : 3 : 4 : 4 by weight.
• antacids are aminoacetic acid, synthetic aluminum silicate, hydrotalcite, magnesium oxide, dihydroxy aluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide -gel, aluminum hydroxide-sodium bicarbonate co-precipitate, magnesium carbonate, magnesium aluminometasilicate, magnesium hydroxide, sodium hydrogencarbonate and calcium hydrogenphosphate and the like.
• Suitable sedatives are allylisopropylacetylurea and bromvalerylurea and the like.
• Suitable central nervous system stimulants are caffeine (3,7-dihydro-1 ,3,7-trimethyl-1 H-purine-2,6-dione monohydrate), anhydrous caffeine (3,7-dihydro-1 ,3,7-thmethyl-1 H-purine-2,6-dione) and a salt complex of caffeine and sodium benzoate (caffeine and sodium benzoate) and the like. Also combinations of two or more central nervous system stimulants may be used.
• Suitable antitussive agents are tipepidine citrate, tipepidine hibenzate, dextromethorphan hydrobromide, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methyiephedrine hydrochloride, dimemorfan phosphate, ephedra herb, nandina fruit and the like. More preferably the one or more antitussive agents are selected from the group consisting of tipepidine citrate, dextromethorphan hydrobromide, dihydrocodeine phosphate, hoscapine hydrochloride, noscapine, and dl-methylephedrine hydrochloride. These antitussive agents can be used solely or mixed with more than two kinds.
• Suitable expectorants are potassium guaiacolsulfonate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, L-carbocisteine, ethyl L-cysteine hydrochloride, fudosteine, platycodon root, glycyrrhiza, cherry bark, polygala root, plantago seed, plantago herb, lycoris bulb, senega, fritillary bulb and the like. More preferably the one or more expectorants are selected from the group consisting of guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, L-carbocisteine and fudosteine.
• Examples of preferred anti-H1-histamines are diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, clemastine fumarate, triprolidine hydrochloride, promethazine hydrochloride, promethazine methylenedisalicylate, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, difeterol hydrochloride, difeterol phosphate, tripeiennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, mebhydroline napadisylate, mequitazine, ketotifen fumarate, epinastine hydrochloride, chlorpheniramine maleate, carbinoxamine maleate and the
• the pharmaceutical composition according to this invention further comprises at least one pharmaceutically acceptable carrier and/or excipient.
• suitable carriers and excipients are known to the one skilled in the art and are described for example in Japanese Pharmaceutical Excipients Directory 2000 (edited by Japan Pharmaceutical Excipients Council, issued by Yakuji Nippo, Ltd.).
• suitable carriers and/or excipients are lactose, sucrose, glucose, mannitol, xylitol, corn starch, potato starch, wheat starch, rice starch, tapioca starch, sodium carboxymethyl starch, microcrystalline cellulose, ethylcellulose, hydroxypropylmethylcellulose, low substituted hydroxypropylcellulose, hydroxypropylcellulose, croscarmellose sodium, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, polyvinylpyrrolidone, propyleneglycol, polyethyleneglycol, glycerol, vegetable oils, waxes, crospovidone, agar, light anhydrous silicic acid, magnesium stearate, talc, titanium oxide, acacia, sodium alginate, ethanol and purified water.
• this invention relates to a pharmaceutical dosage form which comprises a pharmaceutical composition according to this invention.
• the amount of meloxicam or of a salt thereof used for the oral pharmaceutical dosage form described in the invention is preferably in the range from 1 to 30 mg, more preferably in the range from 2.5 to 15 mg, and most preferably in the range from 5 to 10 mg. These amounts correspond to the preferred dosage ranges with respect to an adult and once daily given dose.
• the at least one second pharmaceutically active compound is selected from the group consisting of vitamins.
• the amount of the one or more vitamins in the oral pharmaceutical dosage form according to the present invention may be varied depending on the type of the vitamin. It preferably lies in the range from 0.1 to 2000 mg, and more preferably . in the range from 0.1 to 500 mg. These amounts correspond to the preferred dose given daily to an adult. In the following preferred amounts to be given daily to an adult (in the following called “daily combination dosage") of suitable vitamins comprised in a composition according to this invention are specified.
• the daily combination dosage of vitamin B1 for an adult is usually about 0.1 to 100 mg, preferably 0.5 to 50 mg, and more preferably 1 to 25 mg.
• the daily combination dosage of vitamin B2 for an adult is usually about 0.1 to 45 mg per day, preferably 1 to 30 mg, and more preferably 2 to 12 mg.
• the daily combination dosage of vitamin C for an adult is usually about 5 to 2000 mg per day, preferably 25 to 1000 mg, and more preferably 50 to 500 mg.
• the daily combination dosage of hesperidin for an adult is usually about 1 to 270 mg per day, preferably 9 to 180 mg, and more preferably 18 to 90 mg.
• the at least one second pharmaceutically active compound is selected from the group consisting of antiphlogistic agents.
• the amount of the one or more antiphlogistic agents in the oral pharmaceutical dosage form according to the present invention may be varied depending on the type of the antiphlogistic agent. It preferably lies in the range from 1 to 2000 mg, and more preferably in the range from 3 to 750 mg. These amounts correspond to the preferred dose given daily to an adult. In the following preferred amounts to be given daily to an adult (in the following called “daily combination dosage") of suitable antiphlogistic agents comprised in a composition according to this invention are specified.
• the daily combination dosage of semi-alkaline proteinase for an adult is usually between 2 and 60 mg (4000 and 120000 units), preferably between 4 and 45 mg (8000 and 90000 units), more preferably between 6 and 30 mg (12000 units and 60000 units).
• the daily combination dosage of serrapeptase for an adult is usually between 1 and 30 mg (2000 and 60000 units), preferably between 2 and 22.5 mg (4000 and
• the daily combination dosage of bromelain for an adult is usually between 10 and 320 mg (5000 and 160000 units), preferably between 20 and 240 mg (10000 and 120000 units), more preferably between 40 and 200 mg (20000 and 100000 units).
• the daily combination dosage of tranexamic acid for an adult is usually between 25 and 2000 mg, preferably between 50 and 1500 mg, more preferably between 75 and 750 mg.
• the at least one second pharmaceutically active compound is selected from the group consisting of crude drugs.
• the amount of the one or more crude drugs in the oral pharmaceutical dosage form according to the present invention may be varied depending on the . type of the crude drug. It preferably lies in the range from 0.001 to 20 g, and more preferably in the range from 0.002 to 10 g. These amounts correspond to the preferred dose given daily to an adult. In the following preferred amounts to be given daily to an adult (in the following called “daily combination dosage") of suitable crude drugs comprised in a composition according to this invention are specified.
• the daily combination dosage of earthworm and/or scutellaria root for an adult is usually in the range up to 6 g, preferably between 0.2 and 4.5 g, more preferably between 0.4 and 3 g as crude drug substance.
• the daily combination dosage of cinnamon bark for an adult is usually in the range up to 10 g, preferably between 0.1 and 7.5 g, more preferably between 0.2 and 5 g as crude drug substance.
• the daily combination dosage of peony root, atractylodes lancea rhizome and/or atractylodes rhizome for an adult is usually in the range up to 10 g, preferably between 0.2 and 7.5 g, more preferably between 0.4 and 5 g as crude drug substance.
• the daily combination dosage of moutan bark, Japanese valerian, panax rhizome and/or ginseng for ah adult is usually in the range up to 12 g, preferably between 0.2 and 9 g, more preferably between 0.4 and 6 g as crude drug substance.
• the daily combination dosage of zanthoxylum fruit and/or perilla herb for an adult is usually in the range up to 4 g, preferably between 0.1 and 3 g, more preferably between 0.2 and 2 g as crude drug substance.
• the daily combination dosage of ginger for an adult is usually in the range up to 6 g, preferably between 0.05 and 4.5 g, more preferably between 0.1 and 3 g as crude drug substance.
• the daily combination dosage of citrus unshiu peel for an adult is usually in the range up to 10 g, preferably between 0.15 and 7.5 g, more preferably between 0:3 and 5 g as crude drug substance.
• the daily combination dosage of German chamomile and/or rice for an adult is usually in the range up to 20 g, preferably between 1 and 15 g, more preferably between 2 and 10 g as crude drug substance.
• the daily combination dosage of apricot kernel for an adult is usually in the range up to 8 g, preferably between 0.3 and 6 g, more preferably between 0.6 and 4 g as crude drug substance.
• the daily combination dosage of poria sclerotium for an adult is usually in the range up to 10 g, preferably between 0.5 and 7.5 g, more preferably between 1 and 5 g as crude drug substance.
• the daily combination dosage of cyperus rhizome and/or jujube for an adult is usually in the range up to 8 g, preferably between 0.2 and 6 g, more preferably between 0.4 and 4 g as crude drug substance.
• the daily combination dosage of fennel, phellodendron bark, zedoary, magnolia bark, schisandra fruit and/or asiasarum root for an adult is usually in the range up to 6 g, preferably between 0.3 and 4.5 g, more preferably between 0.6 and 3 g as crude drug substance.
• the daily combination dosage of coptis rhizome for an adult is usually in the range up to 6 g, preferably between 0.15 and 4.5 g, more preferably between 0.3 and 3 g as crude drug substance.
• the daily combination dosage of gentian and/or bear bile for an adult is usually in the range up to 1 g, preferably between 0.05 and 0.75 g, more preferably between 0.1 and 0.5 g as crude drug substance.
• the daily combination dosage of oriental bezoar for an adult is usually in the range up to 0.04 g, preferably between 0.001 and 0.03 g, more preferably between 0.002 and 0.02 g as crude drug substance.
• the daily combination dosage of fourleaf ladybell root for an adult is usually in the range up to 10 g, preferably between 0.25 and 7.5 g, more preferably between 0.5 and 5 g as crude drug substance.
• the daily combination dosage of clove for an adult is usually in the range up to 4 g, preferably between 0.05 and 3 g, more preferably between 0.1 and 2 g as crude drug substance.
• the daily combination dosage of pueraria root and/or ophiopogon tuber for an adult is usually in the range up to 16 g, preferably between 0.8 and 12 g, more preferably between 1.6 and 8 g as crude drug substance.
• the daily combination dosage of bupleurum root for an adult is usually in the range up to 14 g, preferably between 0.5 and 10.5 g, more preferably between 1 and 7 g as crude drug substance.
• the daily combination dosage of pinellia tuber for an adult is usually in the range up to 10 g, preferably between 0.4 and 7.5 g, more, preferably between 0.8 and 5 g as crude drug substance.
• the preferred dosage ranges of the crude drugs according to the invention are specified above. These dosage ranges apply in case only one crude drug is combined with meloxicam as well as two or more crude drugs, e.g. as a Kampo medicine formulation, are combined with meloxicam. In the following preferred amounts to be given daily to an adult (in the following called “daily combination dosage”) of Kampo medicine formulations comprised in an oral pharmaceutical dosage form according to this invention are specified.
• the daily combination dosage of kakkon-to for an adult is usually in the range up to 25 g, preferably between 0.5 and 20 g, more preferably between 5 and 12.5 g as crude drug substance.
• the daily combination dosage of keishi-to for an adult is usually in the range up to 15 g, preferably between 0.3 and 12.5 g, more preferably between 3 and 7.5 g as crude drug substance.
• the daily combination dosage of kouso-san for an adult is usually in the range up to 11 g, preferably between 0.1 and 9 g, more preferably between 1.2 and 5.5 g as crude drug substance.
• the daily combination dosage of saiko-keishi-to, sho-saiko-to and sho-seiryu-to for an adult is usually in the range up to 24 g, preferably between 0.4 and 18 g, more preferably between 4.8 and 12 g as crude drug substance.
• the daily combination dosage of bakumondo-to for an adult is usually in the range up to 30 g, preferably between 0.6 and 18 g, more preferably between 6 and 15 g as crude drug substance.
• the daily combination dosage of hange-koboku-to for an adult is usually in the range up to 6 g, preferably between 0.3 and 12 g, more preferably between 3.2 and 8 g as crude drug substance.
• the daily combination dosage of mao-to for an adult is usually in the range up to 13 g, preferably between 0.2 and 10 g, more preferably between 2.6 and 6.5 g as crude drug substance.
• the oral pharmaceutical dosage form of the invention may be orally given in divided doses, as e.g. 2, 3 or 4 doses per day. However, the oral pharmaceutical dosage form is preferably given orally once a day. Dose adjustment of meloxicam and the crude drug may reflect age, body weight, and. manifesting symptoms.
• the oral pharmaceutical dosage form described in the present invention comprises tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, troches, effervescent tablets, drops, suspension, fast dissolving tablets, oral fast-dispersing tablets, etc..
• Any of these formulations may be prepared using regular methods, and, in addition to the aforementioned components, any additives in common use may be used upon preparation of these formulations, if necessary.
• preparations formed into microparticles such as microcapsules, nanocapsules, microspheres, nanospheres, may also be included in the aforementioned formulations.
• compositions of the oral pharmaceutical dosage form and the formulation of all ingredients are preferably chosen in view of the desired mechanical, chemical and biological stability, release rate, masking of the taste, visual appearance, etc..
• the pharmaceutically active substances i.e. meloxicam or a pharmaceutically salt thereof and the second pharmaceutically active agent
• the pharmaceutically active substances can be dispensed in separate granules, multi-layer granules, multi-layer tablets or dry coated tablets, tablets of separated granules, microcapsules, etc.
• Coating preparations such as sugarcoated tablets, film coating tablets, coating granule, can be used as well as chewable tablets, oral fast dispersing tablets, matrix tablets, matrix granules, effervescent tablets, dusting powder, solid solutions, etc. These methods can also be combined.
• the properties of the inventive oral pharmaceutical dosage form such as stability, release, continuance, disintegration, distinglation, dissolution, concealment of taste, improvement in usage etc. can be regulated by the addition of additives known in the art.
• the oral dosage form is a combination of a first dosage form comprising meloxicam or a pharmaceutically acceptable salt thereof and a second dosage form comprising the at least second pharmaceutically active compound.
• the first dosage form releases the active ingredients faster than the second dosage form.
• the first dosage form may further comprise the second pharmaceutically active compound and optionally further active ingredients.
• the second dosage form may comprise further active ingredients.
• the second dosage form does not comprise meloxicam.
• the dosage form is a two layer tablet wherein the first layer comprises meloxicam or a pharmaceutical acceptable salt thereof and optionally a second pharmaceutically active compound, as for example a vitamin, antiphlogistic agent or crude drug, and optionally further active ingredients and pharmaceutically acceptable carriers and/or excipients.
• the second layer comprises the second pharmaceutically active compound, as for example a vitamin, antiphlogistic agent or crude drug, and optionally further active ingredients and pharmaceutically acceptable carriers and/or excipients, whereby the second layer has slow release properties compared with the first layer.
• the dosage form is a capsule comprising two kinds of granules.
• the first kind of granules comprise meloxicam or a pharmaceutical acceptable salt thereof and optionally a second pharmaceutically active compound, as for example a vitamin, antiphlogistic agent or crude drug , and optionally further active ingredients and pharmaceutically acceptable carriers and/or excipients.
• the second kind of granules comprise the second pharmaceutically active compound, as for example a vitamin, antiphlogistic agent or crude drug, and optionally further active ingredients and pharmaceutically acceptable carriers and/or excipients, whereby the second kind of granules have slow release properties compared with the first kind of granules.
• formulations may be prepared using regular methods by adding generally available pharmaceutical additives such as excipients, binders, disintegrators, lubricants, coating agents, sugar coating agents, plasticizers, antifoaming agents, polish, foaming agents, antistatic agents, desiccant, surfactant, solubilizer, buffer agents, resolvents, solubilizing agents, solvents, diluents, stabilizers, emulsifying agents, suspension, suspending agents, dispersing agents, isotonizing agents, adsorbents, reducing agents, antioxidant, wetting agents, wet modifier, filler, extender, adhesives, viscous agent, softeners, pH modifiers, antiseptics, preservatives, sweetening agents, corrigent, refrigerative agents, flavoring agents, perfume, fragrance, and coloring matters to the pharmacologically active compounds.
• additives are described in Japanese Pharmaceutical Excipients Directory 2000 (edited by Japan Pharmaceutical Excipients Council, issued by Yakuji
• Suitable pharmaceutical additives, carriers and excipients are lactose, sucrose, glucose, mannitol, xylitol, corn starch, potato starch, wheat starch, rice starch, tapioca starch, sodium carboxymethyl starch, microcrystalline cellulose, ethylcellulose, hydroxypropylmethylcellulose, low substituted hydroxypropylcellulose, hydroxypropylcellulose, croscarmellose sodium, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, polyvinylpyrrolidone, propyleneglycol, polyethyleneglycol, glycerol, vegetable oils, waxes, crospovidone, agar, light anhydrous silicic acid, magnesium stearate, talc, titanium oxide, acacia, sodium alginate, ethanol, purified water and etc...
• preparations are preferably manufactured by adding pharmaceutical additives to the pharmacologically active compounds.
• compositions and dosage forms according to this invention are advantageously usefull as analgesics, antipyretics and/or antiinflammatory agents.
• the invention relates to the use of the pharmaceutical composition and of the oral pharmaceutical dosage form, both as described hereinbefore, for the treatment and alleviation of an inflammatory disease, symptoms of an inflammatory disease such as headache, toothache, ache after tooth extraction, menstrual pain, sore throat, joint pain, muscle pain, otalgia, arthralgia,. neuralgia, lumbago, myalgia, muscle stiffness of shoulder, pain of contusion, pain of fracture, pain of sprain, traumatic pain, earache, chill, exothermic reaction and/or cold and various symptoms of cold such as sore throat, chill, pyrexia, headache, arthralgia and muscle pain.
• an inflammatory disease such as headache, toothache, ache after tooth extraction, menstrual pain, sore throat, joint pain, muscle pain, otalgia, arthralgia,. neuralgia, lumbago, myalgia, muscle stiffness of shoulder, pain of contusion, pain of fracture,
• this invention relates to the use of the pharmaceutical composition and of the oral pharmaceutical dosage form, both as described hereinbefore, for the treatment and alleviation of various symptoms of common cold, for example such as fever, sore throat, chills, headache, joint, pain muscular pain, runny nose, stuffy nose, sneezing, cough and phlegm.
• compositions and dosage forms of the invention are effective for the treatment and alleviation of an inflammatory disease, symptoms of an inflammatory disease, headache, toothache, ache after tooth extraction, sore throat, otalgia, arthralgia, neuralgia, lumbago, myalgia, muscle stiffness of shoulder, pain of contusion, pain of fracture, pain of sprain, menstrual pain, traumatic pain, chill, exothermic reaction and/or cold and various symptoms of cold such as sore throat, chill, pyrexia, headache, arthralgia and muscle pain.
• this invention relates to the use of meloxicam or a pharmaceutically acceptable salt thereof for the manufacture of an oral pharmaceutical dosage form according to this invention.
• the invention also relates to the use of a pharmaceutically active compound selected from the group consisting of vitamins, antiphlogistic agents and crude drugs for the manufacture of an oral pharmaceutical dosage form according to this invention.
• this- invention further relates to a method of treating or alleviating of an inflammatory disease, symptoms of an inflammatory disease, headache, toothache, ache after tooth extraction, sore throat, otalgia, arthralgia, neuralgia, lumbago, myalgia, muscle stiffness of shoulder, pain of contusion, pain of fracture, pain of sprain, menstrual pain, traumatic pain, chill, exothermic reaction, fever and/or cold and various symptoms of cold such as sore throat, chill, pyrexia, headache, arthralgia and muscle pain, in a patient in need of such treatment, which comprises orally administering to the patient a pharmaceutical composition according to this invention.
• this invention also relates to a method of treating or alleviating of various symptoms of common cold, for example such as fever, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose, sneezing, cough and phlegm in a patient in need of such treatment, which comprises orally administering to the patient a pharmaceutical composition according to this invention.
• various symptoms of common cold for example such as fever, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose, sneezing, cough and phlegm.
• the patient to be treated according to this invention is a mammal, preferably a human.
• the preferred daily ' dose orally administered to the patient according to this invention is in the range of 1 to 30 mg meloxicam, more preferably 2.5 to 15 mg meloxicam, and a) in case the second pharmaceutically active compound is one or more vitamins, an amount of 0.1 to 2000 mg, more preferably 0.1 to 500 mg, of the one or more vitamins; b) in case the second pharmaceutically active compound is one or more antiphlogistic agents, an amount of 1 to 2000 mg, more preferably 3 to 750 mg, of the one or more antiphlogistic agents; c) in case the second pharmaceutically active compound is one or more crude drugs, an amount of of 0.001 to 20 g, more preferably 0.002 to 10 g, of the one or more crude drugs.
• the amount of the dosage form to be taken by a patient per day i.e. the number of tablets, capsules, caplets, troches, etc., or the amount of granules, syrup, solution, suspension, etc., e.g. measured in grams or milliliters, is such that the above specified preferred daily dose is achieved.
• Meloxicam or a pharmaceutically acceptable salt thereof and the at least one pharmaceutically active compound are preferably combined in a single oral dosage form as described above. Both, meloxicam or a salt thereof and the at least one pharmaceutically active compound may also be simultaneously administered in two separate oral dosage forms, one containing meloxicam or a salt thereof and the other containing the second pharmaceutically active compoundvitamin.
• compositions and dosage forms of the present invention are explained by the following examples which however do not limit the scope of the present invention.
• the examples 1.1 to 1.6 illustrate the first embodiment of the present invention
• the examples 2.1 to 2.6 illustrate the second embodiment of the present invention
• the examples 3.1 to 3.6 illustrate the third embodiment of the present invention.
• Example 1.1 Tablet The following ingredients are homogeneously mixed. The resulted mixed particles are compressed with a mold to prepare 250 mg-tablets.
• Meloxicam 45 g Bisbentiamine 60 g Riboflavin 36 g Hesperidin 120 g Lactose 603 g Microcrystalline cellulose 606 g Light anhydrous silicic acid 15 g Magnesium stearate 9 g Talc 6 g
• the following ingredients are homogeneously mixed.
• the resulted mixed particles are divided into 750 mg per portion.
• layer A and layer B are prepared by a regular method to provide mixed particles, and the particles are compressed to form 320 mg of two layer tablet (layer A 100 mg, layer B 220 mg).
• Layer A Meloxicam 15 g Thiamine hydrochloride 20 g Riboflavin sodium phosphate 4 g Allylisopropylacetylurea 120 g Anhydrous caffeine 160 g Lactose 135 g Microcrystalline cellulose 134 g Light anhydrous silicic acid .
• the following ingredients are prepared as granules by a regular method to prepare mixed particles.
• the granules are packed in amounts of 1000 mg.per pack.
• the following ingredients are prepared by a regular method to provide mixed particles, and the particles are compressed to form 175 mg-tablets.
• the tablets are transferred into a coating pan, and are coated using the equal volume mixture of ethyl alcohol contained 5% weight/volume of hydroxypropylmethylcellulose and purified water to increase in weight/volume by 5 mg per one tablet.
• film-coating tablets are prepared.
• the following ingredients are prepared as granules by regular methods, and filled into capsules, whereby the amount per capsule is 150 mg.
• Meloxicam 60 g Thiamine nitrate 8 g Riboflavin 16 g Ascorbic acid 400 g Hesperidin 144 g Allylisopropylacetylurea 480 g Anhydrous caffeine 240 g Mannitol 296 g Microcrystalline cellulose 756 g
• the following ingredients of the layer A and the layer B are processed through a regular method to provide mixed particles, respectively, and the particles are compressed to form two layer tablets at 300 mg (layer A 100 mg, layer B 200 mg) each.
• Layer A Meloxicam 15 g Tranexamic acid 280 g Anhydrous caffeine 160 g Lactose 95 g Microcrystalline cellulose 230 g Sodium lauryl sulfate 6 g Light anhydrous silicic acid 6 g Talc 4 g Magnesium stearate 4 g
• Layer B Tranexamic acid 560 g Anhydrous caffeine 320 g Lactose 84 g Fumaric acid 100 g Succinic acid 100 g Hydroxypropylmethylcellulose 2208 100 g Hydrogenated oil 160 g Stearic acid 80 g Glycerol esters of fatty acids 80 g Magnesium stearate 16 g
• the following ingredients of the layer A and the layer B are processed through a regular method to provide mixed particles, respectively, and the particles are compressed to form two layer tablets at 310 mg (layer A 110 mg, layer B 200 mg) each.
• Layer A Meloxicam 45 g Semi-alkaline proteinase 60.
• the following ingredients are prepared as granules through a regular method to prepare mixed particles, and packed to give an amount of 1300 mg per one pack of granules.
• Meloxicam 37.5 g Bromelain 500.0 g Clemastine fumarate 6.7 g Dihydrocodeine phosphate 40.0 g dl-Methylephedrine hydrochloride 100.0 g Bromhexine hydrochloride 20.0 g Anhydrous caffeine 250.0 g
• Fast release granules Meloxicam 60.0 g Triprolidine hydrochloride 9.6 g Tipepidine hibenzate 160.0 g dl-Methylephedrine hydrochloride 160.0 g Anhydrous caffeine 240.0 g Microcrystalline cellulose 810.4 g Delayed release granules: Serrapeptase 40.0 g Microcrystalline cellulose 160.0 g Hydroxypropylmethylcellulose phthalate (coating layer) 36.0 g Glycerol esters of fatty acids (coating layer) 3.2 g Talc (coating layer) 0.8 g Slow release granules: Triprolidine hydrochloride 19.2 g Tipepidine.
• Fast release granules Meloxicam 60.0 g Isothipendyl hydrochloride 24.0 g Guaifenesin 666.4 g dl-Methylephedrine hydrochloride . 160.0 g Anhydrous caffeine 200.0 g Microcrystalline cellulose 729.6 g Delayed release granules: Semi-alkaline proteinase 80.0 g Microcrystalline cellulose 120.0 g Methacrylic acid copolymer LD (coating layer) 28.8 g Macrogol 6000 (coating layer) 3.2 g Talc (coating layer) 8.0 g Slow release granules: Isothipendyl hydrochloride 32.0 g Guaifenesin 1333.6 g dl-Methylephedrine hydrochloride 320.0 g Anhydrous caffeine 400.0 g Fumaric acid 400.0 g Microcrystalline cellulose 762.4 g Methacrylic acid copolymer S (coating layer
• the following ingredients are prepared as granules through a regular method to prepare mixed particles, and packed to give an amount of 1500 mg per one pack of granules.
• the following ingredients are prepared as granules through a regular method to prepare mixed particles, and packed to give an amount of 1400 mg per one pack of granules.
• Peony root extract 200 extract of 2 kg Peony root
• Glycyrrhiza extract 400 extract of 2 kg Glycyrrhiza
• Calcium carboxymethylcellulose 240 g Mannitol 1400 g Corn starch 220 g Light anhydrous silicic acid 42 g Aspartame 10 g Acesulfame potassium 10 g Fragrant materials 3 g
• the following ingredients are prepared as granules through a regular method to prepare mixed particles, and packed to give an amount of 1500 mg per one pack of granules.
• the following ingredients of the layer A and the layer B are processed through a regular method to provide mixed particles, respectively, and the particles are compressed to form two layer tablets at 400 mg (layer A 200 mg, layer B 200 mg) each.
• Layer A Meloxicam 15 g Japanese valerian extract 320 g (extract of 1.2 kg Japanese valerian) Allylisopropylacetylurea 120 g Anhydrous caffeine 120 g Lactose 161 g Microcrystalline cellulose 440 g Sodium lauryl sulfate 6 g Light anhydrous silicic acid 6 g Talc 8 g Magnesium stearate 4 g
• Layer B Allylisopropylacetylurea 240 g Anhydrous caffeine 240 g Lactose 68 g Fumaric acid 120 g Hydroxypropylmethylcellulose 2208 180 g Hydrogenated oil 120 g Stearic acid 120 g Glycerol, esters of fatty acids 120 g Magnesium stearate
• the following ingredients of the layer A and the layer B are processed through a regular method to provide mixed particles, respectively, and the particles are compressed to form two layer tablet at 270 mg (layer A 130mg, layer B 140mg) each.
• Layer A Meloxicam ' 15 g Ginseng extract 200 g (extract of 2.9 kg Ginseng) Gentian extract 40 g (extract of 0.4 kg Gentian) Isothipendyl hydrochloride 5 g Ambroxol hydrochloride 30 g Dihydrocodeine phosphate 16 g dl-Methylephedrine hydrochloride 40 g Anhydrous caffeine 50 g Lactose .
• Example 3.6 Capsules The following ingredients are prepared as fast release granules and slow release granules through regular methods, and capsule-filled to give an amount of 300 mg
• Fast release granules Meloxicam 60 g Powdered oriental bezoar 24 g Epinastine hydrochloride 80 g Ambroxol hydrochloride 120 g Dihydrocodeine phosphate 64 g f/ " -MethyIephedrine hydrochloride 160 g Noscapine 128 g Anhydrous caffeine 200 g Lysozyme hydrochloride 240 g Bisibutiamine 96 g Riboflavin 48 g Corn starch 160 g Hydroxypropylcellulose 40 g Microcrystalline cellulose 500 g Slow release granules: Ambroxol hydrochloride 240 g Dihydrocodeine phosphate 128 g dl-Methylephedrine hydrochloride 320 g Noscapine 256 g Anhydrous caffeine 400 g Fumaric acid 336 g Corn starch

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• 2005
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