Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/14—Antitussive agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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 antitussive agents, expectorants and anti-H1-histamines.
• 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 antitussive agents, expectorants and anti-H1-histamines for the manufacture of such an oral pharmaceutical dosage form.
• this invention relates to a method of treating or alleviating of an cold, including various symptoms thereof such as fever, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose, sputum and/or sneezing.
• Common cold is an ordinary disease: average morbidity rate of common cold per person is 5 to 6 times in a year.
• Rhinovirus, parainfluenza virus, or adenovirus induces upper respiratory infections after a temporary loss of autonomic adjustments due to causes such as exposure to cold.
• Medicines suppressing infection or proliferation of viruses, which causes cold, have not been found until today except those for some diseases such as influenza A.
• Symptomatic therapy has, therefore, been mainly used for the treatment of common cold, and the principal purpose of the therapy is to prevent loss of bodily strength.
• NSAIDs non-steroidal anti-inflammatory drugs
• Antitussive agents alleviate symptoms such as cough and sneezing.
• Expectorants alleviate symptoms such as sputum.
• Anti-H1-histamines alleviate symptoms such as runny nose, stuffy nose and sneezing.
• these medicines do not have sufficient effects in treating or alleviating symptoms of common cold in terms of balance between efficacy and safety.
• 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 PGE2, 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. And it has become evident that COX-2 is induced by various inflammatory mediators or endotoxin in local inflammatory areas.
• Meloxicam is a known selective COX-2 inhibitor.
• Oral pharmaceutical compositions for the treatment of common cold with strengthened expression of efficacy and superior safety by potentiating anti-inflammatory, analgesic, antipyretic, antitussive and/or expectorant effects, while alleviating side effects such as gastrointestinal disorders are desired.
• a pharmaceutical composition comprising selective COX-2 inhibiting NSAIDs and antiallergics or anti-H1-histamines, which are mequitazine, ketotifen, epinastine, chlorpheniramine and carbinoxamine, as effective for treatment of rhinitis is disclosed in the Publication of the Japanese Patent Application JP2001-247481 A.
• NSAIDs and antiallergics or anti-H1-histamines which are mequitazine, ketotifen, epinastine, chlorpheniramine and carbinoxamine
• the primary objective of this invention is to provide more effective pharmaceutical compositions for the treatment of a cold with improved efficacy and safety.
• a further objective of this invention is to provide more effective pharmaceutical compositions for alleviation of symptoms of a cold, including various symptoms thereof such as fever, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose, sputum and/or sneezing.
• the invention also aims to provide pharmaceutical compositions and oral pharmaceutical dosage forms comprising an antitussive agent with improved efficacy and safety.
• the invention also aims to provide pharmaceutical compositions and oral pharmaceutical dosage forms comprising an expectorant with improved efficacy and safety.
• the invention also aims to provide pharmaceutical compositions and oral pharmaceutical dosage forms comprising a specific anti-H1-histamine with improved efficacy and safety.
• a further aim of this invention is to provide a method of treating or alleviating of a cold, including various symptoms thereof such as fever, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose, sputum and/or sneezing.
• This invention relates to new pharmaceutical compositions comprising meloxicam or a pharmaceutically acceptable salt thereof and a second pharmaceutically active compound selected from the group consisting of antitussive agents, expectorants and anti-H1-histamines.
• meloxicam or the salt thereof is present in an effective amount allowing itself to exert anti-inflammatory, analgesic and antipyretic effects.
• composition of the invention allows a reinforcement of the therapeutic effects such as analgesic, anti-inflammatory, antipyretic, antitussive and/or expectorant 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.
• the composition of the present invention is especially suitable for the treatment or alleviation of a cold, including various symptoms thereof such as fever, sore throat, chills, headache, joint pain, muscular pain, runny nose, stuffy nose, sputum and/or sneezing.
• 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-thiazoIyl)-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 0 002 482 B1 , US 4,233,299 and WO 99/49867.
• the pharmaceutical composition comprises meloxicam or a pharmaceutically acceptable salt thereof and at least one antitussive agent.
• compositions of the first embodiment may also include other pharmacologically active substances such as an antacid and/or a central nervous system stimulant.
• 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 pharmaceutical composition according to this first embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one antitussive agent and one or more, preferably one antacid.
• This composition may additionally comprise one or more, preferably one central nervous system stimulant.
• a further pharmaceutical composition according to this first embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one antitussive agent and one or more, preferably one central nervous system stimulant.
• This composition may additionally comprise one or more, preferably one antacid.
• the pharmaceutical composition comprises meloxicam or a pharmaceutically acceptable salt thereof and at least one expectorant.
• compositions of the second embodiment may also include other pharmacologically active substances such as an antacid, a central nervous system stimulant and/or an antitussive 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.
• a pharmaceutical composition according to this second embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one expectorant and one or more, preferably one antacid.
• This composition may additionally comprise one or more, preferably one central nervous system stimulant and/or one or more, preferably one antitussive agent.
• a further pharmaceutical composition according to this second embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one expectorant and one or more, preferably one central nervous system stimulant.
• This composition may additionally comprise one or more, preferably one antacid and/or one or more, preferably one antitussive agent.
• compositions according to this second embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one expectorant and one or more, preferably one antitussive agent.
• This composition may additionally comprise one or more, preferably one central nervous system stimulant and/or one or more, preferably one antacid.
• the pharmaceutical composition comprises meloxicam or a pharmaceutically acceptable salt thereof and at least one anti-H1-histamine.
• compositions of the third embodiment may also include other pharmacologically active substances such as an antacid, a central nervous system stimulant, an antitussive agent, an expectorant and/or a vitamin.
• 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 pharmaceutical composition according to this third embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine 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 or two antitussive agents, one or more, preferably one expectorant and/or one or more, preferably one vitamin.
• a further pharmaceutical composition according to this third embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine 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 or two antitussive agents, one or more, preferably one expectorant and/or one or more, preferably one vitamin.
• compositions according to this third embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine according to this invention and one or more, preferably one or two antitussive agents.
• 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 vitamin.
• compositions according to this third embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine 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 vitamin.
• compositions according to this third embodiment may comprise meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine according to this invention and one or more, preferably one vitamin.
• 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.
• compositions of the third embodiment with three or more active ingredients are preferred: a pharmaceutical composition comprising meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine according to this invention and one or more, preferably one or two antitussive agents; a pharmaceutical composition comprising meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine according to this invention and one or more, preferably one or two antitussive agents and one or more, preferably one central nervous system stimulant;
• composition comprising meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine according to this invention and one or more, preferably one or two antitussive agents and one or more, preferably one central nervous system stimulant and one or more, preferably one vitamin;
• composition comprising meloxicam or a pharmaceutically acceptable salt thereof and one or more, preferably one anti-H1 -histamine according to this invention and one or more, preferably one or two antitussive agents and one or more, preferably one central nervous system stimulant and one or more, preferably one expectorant.
• compositions according to this invention may comprise one or more antitussive agents as a second active ingredient in addition to meloxicam.
• Antitussive agents used in this invention are not limited if the agents exhibit antitussive action.
• antitussive agents examples include alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, tipepidine citrate, tipepidine hibenzate, dibunate sodium, dextromethorphan hydrobromide, dextromethorphan phenolphthalein, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, c//-methylephedrine saccharinate, ephedrine hydrochloride, ephedrine sulfate, dimemorfan phosphate, eprazinone hydrobromide, clofedanol hydrochloride, benproperine phosphate, pholcodine, fominoben hydrochloride, ephedra herb (Ephedrae herba), nandina fruit (Nandinae
• Ephedra herb and nandina fruit can be used as a dried powder, a dried extract, a soft extract, a fluid extract, a tincture, oil, and the like, preferably, a dried extract, a soft extract and a fluid extract.
• the one or more antitussive agents are selected from the group consisting of tipepidine citrate, tipepidine hibenzate, dextromethorphan hydrobromide, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, dimemorfan phosphate, ephedra herb, and nandina fruit. More preferably the one or more antitussive agents are selected from the group consisting of tipepidine citrate, dextromethorphan hydrobromide, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, and dl-methylephedrine hydrochloride.
• compositions according to this invention may comprise one or more expectorants as a second or further active ingredient in addition to meloxicam.
• Expectorants used in this invention are not limited if the agents exhibit expectorant action. However, in terms of safety of the agents with minimum or no adverse event, expectorants used in the field of non-prescription drugs are preferred.
• expectorants examples include potassium guaiacolsulfonate, guaifenesin, potassium cresolsulfonate, bromhexine hydrochloride, ambroxol hydrochloride, L-carbocisteine, L-methylcysteine hydrochloride, ethyl L-cysteine hydrochloride, fudosteine, ipecac (Ipecacuanhae radix), lycoris bulb (Lycoridis bulbus), fritillaria bulb (Fritillariae bulbus), cherry bark (Pruni cortex), platycodon root (Platycodi radix), senega (Senegae radix), apricot kernel (Armeniacae semen), polygala root (Polygalae radix), glycyrrhiza (Glycyrrhizae radix), plantago seed (Plantaginis semen), plantago herb (Plantaginis herba),
• Lycoris bulb fritillaria bulb, cherry bark, platycodon root, senega, polygala root, glycyrrhiza, plantago seed and plantago herb
• a dried powder such as a dried powder, a dried extract, a soft extract, a fluid extract, a tincture, oil, and the like.
• the one or more expectorants are selected from the group consisting of potassium guaiacolsulfonate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, L-carbocisteine, ethyl L-cysteine hydrochloride, fudosteine, platycodon root and glycyrrhiza. More preferably the one or more expectorants are selected from the group consisting of guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, L-carbocisteine and fudosteine.
• compositions according to this invention may comprise one or more anti-H1 -histamines selected from the group as listed hereinbefore and hereinafter. These antihistamines can be used in one or mixed with more than two kinds.
• the anti-H1 -histamine is preferably selected from the group consisting of diphenhydramine, diphenylpyraline, clemastine, triprolidine, promethazine, alimemazine, isothipendyl, iproheptine, difeterol, tripelennamine, thonzylamine, fenethazine, methdilazine, mebhydroline, cyproheptadine, homochlorcyclizine, hydroxyzine, ebastine, cetirizine, emedastine, bepotastine, azelastine, oxatomide, fexofenadine, olopatadine, loratadine, acrivastine, brompheniramine and doxylamin, including pharmaceutically acceptable salts thereof.
• the invention may employ the anti-H1 -histamines in either a non-salt form or a pharmaceutically acceptable acid addition salt thereof.
• the pharmaceutically acceptable acid addition salts of those anti-H1 -histamines according to this invention include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, diphenhydramine citrate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, clemastine fumarate, triprolidine hydrochloride, promethazine hydrochloride, promethazine methylenedisalicylate, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, difeterol hydrochloride, difeterol phosphate, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, fenethazine tannat
• the one or more anti-H1 -histamines are selected from the group consisting of 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, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride and mebhydroline napadisylate.
• 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.
• 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-trimethyl-1 H-purine-2,6-dione) and a salt complex of caffeine and sodium benzoate (caffeine and sodium benzoate). Also combinations of two or more central nervous system stimulants may be used.
• vitamins examples include vitamin B-i, vitamin B 2 , vitamin C and hesperidin.
• 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
• 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, camnellose 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 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 antitussive agents.
• the amount of the one or more antitussive agents in the oral pharmaceutical dosage form according to the present invention may be varied depending on the type of the antitussive agent. It preferably lies in the range from 1 to 12000 mg, and more preferably in the range from 2 to 10000 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 antitussive agents comprised in a composition according to this invention are specified.
• the daily combination dosage of alloclamide hydrochloride for an adult is usually between 2 and 150 mg, preferably between 5 and 100 mg, more preferably between 7.5 and 75 mg.
• Daily combination dosage of chloperastine hydrochloride for an adult is usually between 1 and 60 mg, preferably between 2 and 50 mg, more preferably between 4.8 and 48 mg.
• Daily combination dosage of pentoxyverine citrate for an adult is usually between 1 and 120 mg, preferably between 2 and 60 mg, more preferably between 4.8 and 48 mg.
• 120 mg preferably between 4 and 90 mg, more preferably between 6 and 60 mg.
• Daily combination dosage of tipepidine hibenzate for an adult is usually between 1 and 120 mg, preferably between 4 and 90 mg, more preferably between 7.5 and 75 mg.
• 180 mg preferably between 4 and 120 mg, more preferably between 9 and 90 mg.
• Daily combination dosage of dextromethorphan hydrobromide for an adult is usually between 1 and 120 mg, preferably between 2 and 96 mg, more preferably between 4.8 and 48 mg.
• Daily combination dosage of dextromethorphan phenolphthalein for an adult is usually between 1 and 120 mg, preferably between 2 and 96 mg, more preferably between 7.2 and 72 mg.
• Daily combination dosage of codeine phosphate for an adult is usually between 1 and 60 mg, preferably between 2 and 50 mg, more preferably between 4.8 and 48 mg.
• Daily combination dosage of dihydrocodeine phosphate for an adult is usually between 1 and 30 mg, preferably between 2 and 25 mg, more preferably between 2.4 and 24 mg.
• Daily combination dosage of noscapine hydrochloride and noscapine for an adult is usually between 1 and 120 mg, preferably between 2 and 96 mg, more preferably between 4.8 and 48 mg.
• Daily combination dosage of c /-methylephedrine hydrochloride and dl-methylephedrine saccharinate for an adult is usually between 1 and 150 mg, preferably between 3 and 75 mg, more preferably between 6 and 60 mg.
• Daily combination dosage of ephedrine hydrochloride and ephedrine sulfate for an adult is usually between 1 and 75 mg, preferably between 2 and 50 mg, more preferably between 3 and 37.5 mg.
• daily combination dosage of eprazinone hydrochloride for an adult is usually between 1 and 90 mg, preferably between 3 and 75 mg, more preferably between 6 and 60 mg.
• Daily combination dosage of clofedanol hydrochloride for an adult is usually between 1 and 150 mg, preferably between 5 and 100 mg, more preferably between 7.5 and 75 mg.
• Daily combination dosage of benproperine phosphate for an adult is usually between 2 and 160 mg, preferably between 4 and 120 mg, more preferably between 8 and 80 mg.
• Daily combination dosage of pholcodine for an adult is usually between 3 and 180 mg, preferably between 6 and 135 mg, more preferably between 9 and 90 mg.
• Daily combination dosage of fominoben hydrochloride for an adult is usually between 6 and 480 mg, preferably between 12 and 360 mg, more preferably between 24 and 240 mg.
• Daily combination dosage of ephedra herb for an adult is usually between 10 and 5000 mg, preferably between 20 and 4500 mg, more preferably between 40 and
• the at least one second pharmaceutically active compound is selected from the group consisting of expectorants.
• the amount of the one or more expectorants in the oral pharmaceutical dosage form according to the present invention may be varied depending on the type of the expectorant. It preferably lies in the range from 0.1 to
• a daily combination dosage of potassium guaiacolsulfonate for an adult is usually between 5 and 500 mg, preferably between 10 and 350 mg, more preferably between 25 and 250 mg.
• a daily combination dosage of guaifenesin, for an adult is usually between 5 and 900 mg, preferably between 10 and 500 mg, more preferably between 25 and 250 mg-
• a daily combination dosage of potassium cresolsulfonate, for an adult is usually between 5 and 540 mg, preferably between 10 and 360 mg, more preferably between 27 and 270 mg.
• a daily combination dosage of bromhexine hydrochloride for an adult is usually between 0.1 and 24 mg, preferably between 0.5 and 18 mg, more preferably between 1 and 12 mg.
• a daily combination dosage of ambroxol hydrochloride for an adult is usually between 1 and 90 mg, preferably between 2 and 60 mg, more preferably between 4 and 45 mg.
• a daily combination dosage of L-carbocisteine for an adult is usually between 25 and 1500 mg, preferably between 50 and 1050 mg, more preferably between 75 and 750 mg.
• a daily combination dosage of L-methylcysteine hydrochloride and ethyl L-cysteine hydrochloride for an adult is usually between 10 and 600 mg, preferably between
• a daily combination dosage of fudosteine for an adult is usually between 30 and
• a daily combination dosage of ipecac as ipecac substance for an adult is usually between 1 and 60 mg, preferably between 2 and 55 mg, more preferably between 5 and 50 mg.
• a daily combination dosage of lycoris bulb as lycoris bulb substance for an adult is usually between 4 and 1000 mg, preferably between 6 and 900 mg, more preferably between 8 and 800 mg.
• a daily combination dosage of fritillaria bulb as fritillaria bulb substance for an adult is usually between 5 and 4000 mg, preferably between 10 and 3000 mg, more preferably between 25 and 2500 mg.
• a daily combination dosage of cherry bark, platycodon root, senega or apricot kernel each in the form of a crude drug substance for an adult is usually between
• a daily combination dosage of polygala root, glycyrrhiza or plantago seed each in the form of a crude drug substance for an adult is usually between 10 and 6000 mg, preferably between 25 and 5500 mg, more preferably between 50 and 5000 mg.
• a daily combination dosage of plantago herb as plantago herb substance for an adult is usually between 10 and 12000 mg, preferably between 50 and 11000 mg, more preferably between 100 and 10000 mg.
• the at least one second pharmaceutically active compound is selected from the group consisting of anti-H1 -histamines.
• the amount of the one or more anti-H1 -histamines in the oral pharmaceutical dosage form according to the present invention may be varied depending on the type of the anti-H1 -histamine, it preferably lies in the range from 0.1 to 450 mg, and more preferably in the range from 0.1 to 150 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 anti-H1 -histamines comprised in an oral pharmaceutical dosage form according to this invention are specified.
• a daily combination dosage of diphenhydramine hydrochloride, diphenhydramine citrate, diphenhydramine salicylate and diphenhydramine tannate for an adult is usually between 5 and 450 mg, preferably between 10 and 150 mg, more preferably between 15 and 75 mg.
• a daily combination dosage of diphenylpyraline hydrochloride and diphenylpyraline teoclate for an adult is usually between 0.1 and 15 mg, preferably between 0.5 and
• a daily combination dosage of clemastine fumarate for an adult is usually between
• 0.1 and 4.5 mg preferably between 0.2 and 3 mg, more preferably between 0.3 and 1.5 mg.
• a daily combination dosage of triprolidine hydrochloride for an adult is usually between 0.1 and 9 mg, preferably between 0.3 and 6 mg, more preferably between 0.5 and 4 mg.
• a daily combination dosage of promethazine hydrochloride and promethazine methylenedisalicylate for an adult is usually between 1 and 75 mg, preferably between 3 and 60 mg, more preferably between 5 and 40 mg.
• a daily combination dosage of alimemazine tartrate for an adult is usually between 0.1 and 10 mg, preferably between 0.5 and 7.5 mg, more preferably between 1 and
• a daily combination dosage of isothipendyl hydrochloride for an adult is usually between 0.1 and 24 mg, preferably between 0.5 and 12 mg, more preferably between 1 and 7 mg.
• a daily combination dosage of iproheptine hydrochloride for an adult is usually between 10 and 225 mg, preferably between 20 and 200 mg, more preferably between 30 and 150 mg.
• a daily combination dosage of difeterol hydrochloride and difeterol phosphate for an adult is usually between 5 and 180 mg, preferably between 10 and 135 mg, more preferably between 18 and 90 mg.
• a daily combination dosage of tripelennamine hydrochloride for an adult is usually between 5 and 200 mg, preferably between 10 and 150 mg, more preferably between 20 and 100 mg.
• a daily combination dosage of thonzylamine hydrochloride for an adult is usually between 2 and 100 mg, preferably between 5 and 75 mg, more preferably between
• a daily combination dosage of fenethazine hydrochloride for an adult is usually between 2 and 180 mg, preferably between 5 and 90 mg, more preferably between 10 and 50 mg.
• a daily combination dosage of fenethazine tannate for an adult is usually between 5 and 270 mg, preferably between 15 and 200 mg, more preferably between 27 and
• a daily combination dosage of methdilazine hydrochloride for an adult is usually between 0.1 and 16 mg, preferably between 0.5 and 12 mg, more preferably between 1 and 8 mg.
• a daily combination dosage of mebhydroline napadisylate for an adult is usually between 10 and 300 mg, preferably between 20 and 225 mg, more preferably between 30 and 150 mg.
• a daily combination dosage of cyproheptadine hydrochloride for an adult is usually between 0.1 and 12 mg, preferably between 0.5 and 8 mg, more preferably, between 1 and 6 mg.
• a daily combination dosage of homochlorcyclizine hydrochloride for an adult is usually between 1 and 60 mg, preferably between 3 and 45 mg, more preferably between 6 and 30 mg.
• a daily combination dosage of hydroxyzine hydrochloride for an adult is usually between 1 and 60 mg, preferably between 3 and 45 mg, more preferably between 6 and 30 mg.
• a daily combination dosage of hydroxyzine pamoate for an adult is usually between
• a daily combination dosage of ebastine for an adult is usually between 0.1 and 10 mg, preferably between 0.5 and 7.5 mg, more preferably between 1 and 5 mg.
• a daily combination dosage of cetirizine hydrochloride for an adult is usually between 0.5 and 20 mg, preferably between 1 and 15 mg, more preferably between
• a daily combination dosage of emedastine difumarate for an adult is usually between 0.1 and 4 mg, preferably between 0.2 and 3 mg, more preferably between 0.4 and 2 mg.
• a daily combination dosage of bepotastine besilate for an adult is usually between
• a daily combination dosage of azelastine hydrochloride for an adult is usually between 0.1 and 4 mg, preferably between 0.2 and 3 mg, more preferably between
• a daily combination dosage of oxatomide for an adult is usually between 1 and 60 mg, preferably between 3 and 45 mg, more preferably between 6 and 30 mg.
• a daily combination dosage of fexofenadine hydrochloride for an adult is usually between 5 and 240 mg, preferably between 10- and 180 mg, more preferably between 20 and 120 mg.
• a daily combination dosage of olopatadine hydrochloride for an adult is usually between 0.5 and 20 mg, preferably between 1 and 15 mg, more preferably between
• a daily combination dosage of loratadine for an adult is usually between 0.5 and 20 mg, preferably between 1 and 15 mg, more preferably between 2 and 10 mg.
• a daily combination dosage of acrivastine for an adult is usually between 0.5 and 24 mg, preferably between 1 and 18 mg, more preferably between 2 and 12 mg.
• a daily combination dosage of brompheniramine maleate for an adult is usually between 1 and 32 mg, preferably between 2 and 28 mg, more preferably between 4 and 24 mg.
• a daily combination dosage of doxylamin succinate for an adult is usually between 5 and 150 mg, preferably between 10 and 100 mg, more preferably between 15 and 75 mg.
• 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 antitussive agent 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 or oral fast-dispersing tablets.
• 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, and liposomes 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 an antitussive agent or an expectorant or an anti-H1 -histamine, and optionally further active ingredients and pharmaceutically acceptable carriers and/or excipients.
• the second layer comprises the second pharmaceutically active compound, as for example an antitussive agent or an expectorant or an anti-H1 -histamine, 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 an antitussive agent or an expectorant or an anti-H1 -histamine, 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 an antitussive agent or an expectorant or an anti-H1 -histamine, 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.
• pharmaceutical additives such as excipients, binders, disintegrators, lubricants, coating agents, sugar coating agents, plasticizers
• 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, antitussives, expectorants and/or antihistaminics.
• 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 a cold, including various symptoms thereof such as fever, sore throat, chills, headache, joint pain, muscular pain, cough, runny nose, stuffy nose, sputum and/or sneezing.
• compositions and dosage forms of the invention are effective for the treatment and alleviation of a cold, including various symptoms thereof such as fever, sore throat, chills, headache, joint pain, muscular pain, cough, runny nose, stuffy nose, sputum and/or sneezing.
• this invention relates to the use of a pharmaceutical composition as described hereinbefore for the manufacture of a medicament for the treatment or alleviation of a cold, including various symptoms thereof such as fever, sore throat, chills, headache, joint pain, muscular pain, cough, runny nose, stuffy nose, sputum and/or sneezing.
• 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 antitussive agents, expectorants and anti-H1 -histamines 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 a cold, including various symptoms thereof such as fever, sore throat, chills, headache, joint pain, muscular pain, cough, runny nose, stuffy nose, sputum and/or sneezing, in a patient in need of such treatment, which comprises orally administering to the patient a pharmaceutical composition according to this invention.
• 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 an antitussive agent, an amount of 1 to 12000 mg, more preferably 2 to 10000 mg, of the antitussive agent; b) in case the second pharmaceutically active compound is an expectorant, an amount of 0.1 to 12000 mg, more preferably 1 to 10000 mg, of the expectorant; c) in case the second pharmaceutically active compound is an anti-H1 -histamine, an amount of of 0.1 to 450 mg, more preferably 0.1 to 150 mg, of the anti-H1 -histamine.
• 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 compound.
• 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 1.2 Powder The following ingredients were homogeneously mixed. The resulted mixed particles were divided into portions of 500 mg to prepare powder compositions.
• the following ingredients of the layer A and the layer B were processed through a regular method to provide mixed particles, respectively, and the particles were compressed to form two-layer tablets at 220 mg (layer A 100mg, layer B 120mg) each.
• the following ingredients were prepared as granules through a regular method to prepare mixed particles, and packed to give an amount of 1500 mg per one pack for granules.
• Example 1.5 Capsules The following ingredients were prepared as fast release granules and slow release granules through regular methods, and capsule-filled to give an amount of 225 mg (fast release granules: 75 mg, slow release granules: 150 mg) per one capsules.
• the following ingredients were prepared as fast release granules and slow release granules through regular methods, and capsule-filled to give an amount of 225 mg (fast release granules: 75 mg, slow release granules: 150 mg) per one capsules.
• the following ingredients were homogeneously mixed.
• the resulted mixed particles were divided into portions of 750 mg to prepare powder compositions.
• the following ingredients of the layer A and the layer B were processed through a regular method to provide mixed particles, respectively, and the particles were compressed to form two-layer tablets at 220 mg (layer A 100mg, layer B 120mg) each.
• the following ingredients were prepared as granules through a regular method to prepare mixed particles, and packed to give an amount of 1200 mg per one pack for granules.
• the following ingredients were prepared as fast release granules and slow release granules through regular methods, and capsule-filled to give an amount of 225 mg (fast release granules: 75 mg, slow release granules: 150 mg) per one capsules.
• Example 2.6 Capsules The following ingredients were prepared as fast release granules and slow release granules through regular methods, and capsule-filled to give an amount of 350 mg (fast release granules: 115 mg, slow release granules: 235 mg) per one capsules.
• 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 45 g Diphenhydramine hydrochloride 150 g Ambroxol hydrochloride 90 g Dihydrocodeine phosphate 48 g dl-Methylephedrine hydrochloride 120 g Anhydrous caffeine 300 g Lactose 435 g Microcrystalline cellulose 558 g Sodium lauryl sulfate 18 g Light anhydrous silicic acid 18 g Talc 9 g Magnesium stearate 9 g Layer B: Diphenhydramine hydrochloride 300 g Ambroxol hydrochloride 180 g Dihydrocodeine phosphate 96 g dl-methylephedrine hydrochloride 240 g Anhydrous caffeine 600 g Lactose 168 g Fumaric acid 300 g Succinic acid 60 g Hydroxypropylmethylcellulose 2208 540 g Hydrogenated oil 360 g Stearic acid 360 g Glycerol esters of fatty acids 360 g Magnesium
• 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 200 mg (layer A 80 mg, layer B 120 mg) each.
• the following ingredients are prepared as granules through a regular method to prepare mixed particles, and packed to give an amount of 1000 mg per one pack of granules.
• the following ingredients are prepared as fast release granules and slow release granules through regular methods, and capsule-filled to give an amount of 270 mg (fast release granules: 90 mg, slow release granules: 180 mg) per one capsule.
• 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 Slow release granules: Triprolidine hydrochloride 19.2 g Tipepidine hibenzate 320.0 g dl-Methylephedrine hydrochloride 320.0 g .
• 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
• 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 Succinic acid 80.0 g Microcrystalline cellulose 682.4 g Methacrylic acid copolymer S (coating layer) 360.0 g Glycerol esters of fatty acids (coating layer) 104.0 g Talc (coating layer) 48.0 g
• Example 3.6 Tablet The following ingredients are homogeneously mixed. The resulted mixed particles are compressed with a mold to prepare tablets at 250 mg each. Meloxicam 15 g Ebastine 1 ° Noscapine 40 Anhydrous caffeine 100 g Ascorbic acid 200 g

Landscapes

• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Pulmonology (AREA)
• Rheumatology (AREA)
• Pain & Pain Management (AREA)
• Physical Education & Sports Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (1)

Applications Claiming Priority (6)

Publications (1)

Family

ID=34970781

Family Applications (1)

Country Status (2)

Cited By (11)

Families Citing this family (6)

Citations (3)

Family Cites Families (2)

• 2005
  • 2005-03-26 WO PCT/EP2005/003231 patent/WO2005094832A1/en not_active Ceased
  • 2005-03-26 JP JP2007505475A patent/JP2007530620A/ja active Pending

Patent Citations (3)

Also Published As

Similar Documents

Legal Events