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Home , Alloclamide, Ambroxol, Fenethazine, Guaiacolsulfonate, Iproheptine, Isoaminile

US 2004O259955A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0259955A1 Umehara et al. (43) Pub. Date: Dec. 23, 2004

(54) NEW PHARMACEUTICAL COMPOSITIONS (30) Foreign Application Priority Data CONTAINING AMBROXOLAND ISOPROPAMIDE ODIDE Nov. 8, 2002 (EP)...... O2O24 981 (75) Inventors: Norimitsu Umehara, Tokorozawa-shi Publication Classification (JP); Nobuo Miyadai, Narita (JP); Minoru Okada, Inzai (JP) (51) Int. Cl." ...... A61K 31/137 (52) U.S. Cl...... 514/649 Correspondence Address: BOEHRINGER INGELHEM CORPORATION (57) ABSTRACT 900 RIDGEBURY ROAD The present invention relates to novel pharmaceutical com P. O. BOX 368 positions comprising as pharmacologically active com RIDGEFIELD, CT 06877 (US) pounds a combination of an expectorant-effective amount of brom hexine or or a pharmacologically acceptable (73) Assignee: Boehringer Ingelheim International Salt thereof and a parasympatholytic ()-effec GmbH, Ingelheim (DE) tive amount of isopropamide iodide. Qualitative and quan Appl. No.: 10/691,101 titative formulae of this invention include pharmaceutically (21) acceptable carriers or excipients. The formulation further (22) Filed: Oct. 22, 2003 comprises Suitable pharmaceutically acceptable carriers or excipients. In addition, this invention is related to the usage Related U.S. Application Data of these compounds for treating the various Symptoms caused by the common cold. The composition of the present (60) Provisional application No. 60/498,406, filed on Aug. invention is especially effective in the treatment of Sputum 28, 2003. and/or runny nose caused by the common cold. US 2004/0259955 A1 Dec. 23, 2004

NEW PHARMACEUTICAL COMPOSITIONS 0010. Therefore, it is an objective of the present inven CONTAINING AMBROXOLAND SOPROPAMIDE tion to offer eXtremely effective pharmaceutical composi ODIDE tions that improve Sputum and/or runny nose. 0011) Another objective of the present invention is to RELATED APPLICATIONS offer a medicine for a cold using extremely effective phar 0001) The priority benefit of EP 02 024981.0 filed Nov. maceutical compositions that improve effectively sputum 8, 2002 and U.S. Provisional Application No. 60/498,406, and/or runny nose among the Symptoms of the common filed Aug. 28, 2003 are hereby claimed, both of which are cold. incorporated by reference herein. SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION 0012. The present invention relates to pharmaceutical 0002 The present invention relates to novel pharmaceu compositions comprising a combination of an expectorant tical compositions comprising as pharmacologically active effective amount of brom hexine or ambroXol or a pharma compounds a combination of an expectorant-effective ceutically acceptable Salt thereof and a parasympatholytic amount of brom hexine or ambroXol or a pharmacologically (anticholinergic) effective amount of isopropamide iodide. acceptable Salt thereof and a parasympatholytic (anticholin The pharmaceutical compositions further comprise pharma ergic)-effective amount of isopropamide iodide. ceutically acceptable carriers or excipients. 0003. The formulation further comprises suitable phar 0013 The invention further relates to methods of treating maceutically acceptable carriers or excipients. Additionally, various Symptoms caused by the common cold, in particular the present composition may contain other pharmaceutically Sputum and/or runny nose, comprising administering the active compounds. pharmaceutical compositions of the invention. 0004 Another aspect of the present invention relates to DESCRIPTION OF THE INVENTION methods of using these compositions in the treatment of Symptoms of the common cold. 0014 Thus, it has surprisingly been found that a phar maceutical composition according to the present invention 0005. In particular, the inventive composition is useful in comprising as pharmacologically active compounds a com the treatment of expectoration and/or runny nose in the bination of an expectorant-effective amount of many Symptoms of the common cold. or ambroXol or a pharmacologically acceptable Salt thereof 0006 Common cold is a condition in which various and a parasympatholytic (anticholinergic)-effective amount reactions occur when Stimulated by microbes or chilliness to of isopropamide iodide, is Suitable for treating the Symptoms the respiratory organ (also known herein as respiratory of common cold. tract), and it is an acute inflammation in the respiratory 0015 The present invention relates to pharmaceutical organ, the airway from the mouth and nose through the compositions comprising as pharmacologically active com lungs. More precisely, it is called “common cold Syndrome' pounds a combination of an expectorant-effective amount of 0007 Nose inflammation caused by the common cold is brom hexine or ambroXol, preferably ambroXol, or a phar called acute rhinitis and brings about Symptoms Such as macologically acceptable Salt thereof and a parasym Sneezing and runny or Stuffy nose. In acute adenoiditis, patholytic (anticholinergic)-effective amount of isopropam which is an inflammation of the throat, congestion of the ide iodide. mucous membrane of the throat, Swelling, pain and other 0016 Ambroxol, to be used for pharmaceutical compo symptoms occur. When the affects the bottom of Sitions of the present invention, chemical name: trans-4-2- the respiratory organ, hoarse voice and Sometimes dyspnea amino-3,5-dibromobenzyl)aminocyclohexanol, is an occur. Once the infection reaches the bronchi, bronchioles, expectorant classified as a mucosal lubricant drug, which, by and lungs, onset of and Sputum begins. In addition to the increase in production of pulmonary Surfactant, has the the above-mentioned Symptoms in the respiratory organ, effect of lubricating the membrane of the airway. Ambroxol headache, fever, low back pain, wearineSS and anorexia of is a metabolite of brom hexine. the whole body appears. Furthermore, gastrointestinal Symptoms including abdominal pain and diarrhea Some 0017. In the present invention, preferably ambroxol times occur. hydrochloride is used. However, other acid addition salts including hydrobromate, oxalate, nitrate, Sulphonate, fuma 0008 Although coldness and allergic reaction are partly rate, maleate, Sulfate phosphate, and the like or freebase can attributed to the onset of the common cold, it is often caused also be used. by viral infection. The types of viruses that cause the common cold are thought to number more than 200. How 0018. In the present invention, bromhexine may be used ever, very few drugs are effective against the cold viruses at instead of part or all of the ambroxol. present. For this reason, Symptomatic treatment to control 0019 Bromhexine, to be used for pharmaceutical com Symptoms of common cold Such as runny nose, Stuffy nose, positions of the present invention, chemical name: 2-amino Sneezing, Sputum, throat pain, fever and muscle pain is the 3,5-dibromo-N-cyclohexyl-N-methylbenzylamine, is an main pharmaceutical therapy. expectorant classified as an airway Secretagogue, which has 0009. However, a drug effective for all symptoms has not the effect of increasing airway Secretion. been developed yet. Therefore, a combination drug manu 0020. In the present invention, preferably bromhexine factured for each Symptom is often used for treatment. hydrochloride is used. However, other acid addition salts US 2004/0259955 A1 Dec. 23, 2004 including hydrobromate, oxalate, nitrate, Sulphonate, fuma tartrate, tannate, diphe rate, maleate, Sulfate phosphate, and the like or freebase can nylpyraline teoclate, napadisylate, promethaz also be used. ine methylene two Salicylates, maleate, chlo rpheniramine maleate, difeterol phosphate, meduitazine, 0021. In the context of the present invention, brom hexine , cyproheptazine hydrochloride, iproheptine or its pharmacologically acceptable Salt may be blended hydrochloride, fumarate and hydro with the isopropamide iodide in an amount of 1.2 to 32 mg chloride, and the like. They can be used either Singly or in as daily dosage for adults, 8 to 16 mg is more preferable, and two or more combinations. The amount of antihistamic 12 mg is most preferable. agent is commonly 1 to 300 mg as daily dosage for adults 0022. In the context of the present invention, ambroxol or and preferably, it is 1.5 to 150 mg. its pharmacologically acceptable Salt may be blended with 0031 Examples of an antitussive are hydro the isopropamide iodide in an amount of 5 to 90 mg as daily chloride, hydrochloric acid chloperastine, citrate, dosage for adults, 10 to 60 mg is more preferable, and 22.5 Sodium , hydrobromide, dex to 45 mg is most preferable. tromethorphan-phenol cover microcosmic Salt, tipepidine 0023) Isopropamide iodide, chemical name: 3-Carbam hibenzate, fendizoate, phosphate, dihy oyl-3,3-diphenylpropyl diisopropylmethylammonium drocodeine phosphate, citrate, iodide, to be used in the pharmaceutical compositions of the hydrochloride, noScapine, dl-methylephedrine hydrochlo present invention is an anticholinergic drug which blocks the ride, d1-methylephedrine Saccharin Salt, carbetapentane cit parasympathetic nerve and Suppresses the excessive Secre rate, dimenorfan phosphate, beinproperine phosphate, tion of membrane and moderates the runny nose. citrate, citrate, OXeladin tannate, eprazi none hydrochloride, hydrochloride, clo?edanol 0024. The preferred amount of isopropamide iodide is 1 hydrochloride, hydrochloride, 1-methylephedrine to 25 mg as daily dosage for adults, 2 to 10 mg is more hydrochloride, trimetoquinol hydrochloride, pseudoephe preferable, and 3 to 6 mg is most preferable. drine, hydrochloride, methoxyphe 0.025 In this present invention, the mixture ratio of namine hydrochloride, and the like. They can be used either isopropamide iodide to ambroXol, preferably in the form of Singly or in two or more combinations. The amount of the its pharmacologically acceptable Salt, e.g. ambroXol hydro antituSSive is commonly 2 to 900 mg as daily dosage for chloride, is commonly in the range of 0.01 to 5 weight part. adults and preferably, it is 12 to 90 mg. The range is preferably, 0.04 to 1 weight part and more 0032 Examples of stimulant drugs are d1-methylephe preferably, 0.1 to 0.3 weight part. drine hydrochloride, dl-methyledrine Saccharin Salt, caffeine 0026. The pharmaceutical compositions of the present and Sodium benzoate, caffeine, anhydrous caffeine, ephe invention can be administered orally in Single or multiple drine hydrochloride, , phenylpropanola doses. In addition, dosage of ambroXol or its pharmacologi mine hydrochloride, , l-methylephedrine cally acceptable Salt and isopropamide iodide can be hydrochloride, hydrochloride, d1-epi adjusted according to age, weight Symptom, and the like. nephrine hydrochloride, dl-isoproterenol hydrochloride, iso proterenol Sulfate, Sulfate, Sulfate, 0027. In addition, in the pharmaceutical compositions of Sulfate, trimetoquinol hydrochloride, hexoprena this invention, one or more Substance(s) selected from the line sulfate, clorprenaline hydrochloride, hydro group comprising as pharmacologically active Substance chloride, hydrochloride, hydrochlo antipyretic analgesics, , antituSSive, Stimulant ride, hydrobromide, fumarate, drug, Vitamins, crude drug, antacid, mucosa protective as hydrochloride, hydrochloride, hydro covering materials, antiphlogistic, quenching enzyme and chloric acid ethylcysteine, methyl hydrochloride, expectorant. and the like. They can be used either Singly or in two or more 0028. The amount of each of these pharmacologically combinations. The amount of the Stimulant is commonly 1 active Substances is decided according to a well-known to 900 mg as daily dosage for adults and preferably, it is 5 combination Standard in consideration of other kinds and to 600 mg. quantity of pharmacologically active Substances that are 0033 Examples of vitamins are vitamin B and the used together. derivative and Salts thereof Such as Octotiamine, proSul 0029. Examples of antipyretic analgesics are ibuprofen, tiamine, furSultiamine, hydrochloric acid furSultiamine, bis acetaminophen, ethenZamide, aspirin, aluminum aspirin, bentiamine, benfotiamine, dicethiamine hydrochloride, isopropylantipyrine, Sasapyrine, Salicylamide, Sodium Sali cycotiamine, cocarboxylase, thiamin disulfide, thiamine cylate, lactyl phenetidine, and the like. They can be used hydrochloride, thiamin mononitrate, bisthiamine nitrate, either Singly or in two or more combinations. The amount of thiamine di-cetyl Sulfate Salt, bisibuthiamine, and the like, antipyretic analgesics is commonly 10 to 5000 mg as daily Vitamin B and the derivative and Salts thereof Such as dosage for adults and preferably, it is 225 to 3000 mg. riboflavin, riboflavin tetrabutyrate, riboflavin Sodium phos phate, flavin adenine dinucleotide Sodium, and the like, 0030 Examples of an antihistamine agent are vitamin C and the derivative and salts thereof Such as hydrochloride, hydrochlo ascorbic acid, Sodium ascorbate, calcium ascorbate, and the ride, diphenhydramine hydrochloride, difeterol hydrochlo like, hesperidin and the derivative and the Salt thereof, ride, hydrochloride, hydrochlo Vitamin F, vitamin A Such as acetate, retinol palmitate ride, hydrochloride, and the derivative and the salts thereof, vitamin E and the hydrochloride, hydrochloride, diphenhy derivative and Salts. Such as tocopherol, tocopherol Succi dramine Salicylate, carbinoxamine diphenyl disulphonate, nate, tocopherol calcium Succinate, tocopherol acetate, and US 2004/0259955 A1 Dec. 23, 2004

the like. They can be used either Singly or in two or more 0038 Pharmaceutical compositions of this invention are combinations. The amount of the vitamins is commonly 0.1 used as Solid, Semi-Solid and liquid preparations for oral to 2000 mg as defined daily dosage for adult and preferably, administration Such as tablets, granule, Subtle granules, it is 1 to 500 mg. powder, capsule, couplet, Soft capsule, pill, Suspension, emulsion, liquid, Syrup, dry syrup, and the like. Moreover, 0034) Examples of crude drug are crude drug powder these preparations may be manufactured after making them and/or the extract such as Ephedra Herb, Nandina Fruit, into micro particles Such as microcapsule, nanocapsule, Cherry Bark, Polygala Root, Glycyrrhiza, Platycodon Root, microSphere and nano sphere. Plantago Seed, Plantago Herb, Lycoris Radiata Herb, Senega, Fritillaria, Fennel, Philodendron Bark, Coptis Rhi 0039 These preparations can be manufactured according Zome, Zedoary, Chamomile, Cinnamon Bark, Gentian, Ori to methods known in the art. Preparation additive may be ental Bezoar, Bear Bile, Glehnia Root, Ginger, Atractylodes added to the pharmacologically active Substance, if neces Lancea Rhizome, Clove, Citrus Unshiu Peel, Atractylodes Sary. The manufacture method is not limited. Rhizome, Diryu (Earthworm), Panax Rhizome, Ginseng, Scutellaria Root, Pueraria Root, Apricot Kernel, Cyperus 0040. As an additive to the preparations of the pharma Rhizome, Nonglutinous Rice, Magnolia Bark, Schisandra ceutical compositions of this invention, the following can be Fruit, Bupleurum Root, Asiasarum Root, Peony Root, used including but not limited to: Stabilizer, Surfactant, Perilla Herb, Jujube, Ophiopogon Tuber, Pinellia tuber, plasticizer, lubricant, Solubilizer, reducing agent, buffer Poria Sclerotium, Kakkon-to, Keishi-to, Koso-San, Saiko agent, Sweetening agent, base, adsorbent, corrigent, binder, Keishi-to, Sho-Saiko-to, Sho-Seiryu-to, Bakumondo-to, Suspension, Suspending agent, antioxidant, polish, coating, Hange-koboku-to, Mao-to, Schizonepeta Spike, Forsythia wetting agent, wet modifier, filler, antifoaming agent, refrig Fruit, Polygala Root, Magnolia, Peach Kernel, Aconite erative agent, coloring matter, flavoring agent, perfume, Root, and the like. They can be used either Singly or in two Sugar coating agent, isotonizing agent, Softener, emulsifying or more combinations. The amount of the crude drug is agent, foaming agent, pH modifier, diluent, excipient, dis commonly 0.01 to 300 g in extract (converted into raw crude persing agent, disintegrator, fragrance, desiccant, antisep drug) and/or 0.0001 to 60 g in powder drug as daily dosage tics, preservative, Solubilizing agent, Solubilizer, Solvent, for adults and preferably, it is 0.05 to 30 g in extract Superplasticizer, antistatic agent, extender, moisturizing (converted into raw crude drug) and/or 0.002 to 6 g in agent, etc. powder. 0041 Examples of additives include but are not limited to: lactose, Sucrose, glucose, , Sorbitol, potato 0.035 Examples of antacid and mucosa protectives are Starch, corn Starch, wheat Starch, calcium carbonate, calcium aminoacetate, magnesium oxide, magnesium carbonate, Sulfate, Sodium hydrogencarbonate, Sodium chloride, micro magnesium Silicate, Synthetic aluminum Silicate, Synthetic crystalline cellulose, methyl cellulose, ethyl cellulose, hydrotalcite, dihydro aluminum-aminoacetate Salt, alumi hydroxypropyl methylcellulose, hydroxypropyl cellulose, num hydroxide gel, dried aluminum hydroxide gel, alumi carboxymethylcellulose, Sodium carboxymethylcellulose, num hydroxide-magnesium carbonate mixing dried gel, carboxymethylcellulose calcium, polyvinyl alcohol, magne aluminum hydroxide-Sodium bicarbonate co-precipitate, sium Stearate, talc, hydrogenated vegetable oil, macrogol, aluminum hydroxide-calcium carbonate-magnesium car Silicone oil, agar, calcium carbonate, Sodium hydrogencar bonate co-precipitate, magnesium hydroxide-potassium alu bonate, Sodium alginate, shellac, glycerin, aromatic essential minum Sulfate co-precipitate, magnesium aluminometasili oil, water-Soluble food dye, rake pigment, benzoic acid, cate and the like. They can be used either Singly or in two Sodium benzoate, para Oxybenzoic acid, ester, cationic Soap, or more combinations. The amount of antacid and mucosa dehydroacetic acid, boric acid, chlorobutanol, benzyl alco protective is commonly 10 to 8000 mg as daily dosage for hol, polySorbate 80, fatty acid ester of glycerin, white adults and preferably, it is 100 to 4000 mg. beeswax, medium-chain triglyceride, ascorbic acid, toco 0036) Examples of antiphlogistic and quenching enzymes pherol, Sodium thiosulfate, Sodium edetate, and the like. are bromelain, pronase, Serrapeptase, Semi-alkali proteinase, 0042. For example, when pharmaceutical compositions Streptokinase, Streptodornase, lysozyme chloride, tranex of this invention are manufactured as tablets, granule, fine amic acid, and the like. They can be used either Singly or in granule, powder, capsules, couplet, pill, or dry Syrup, in case two or more combinations. The amount of anti-inflamma granulated powders need to be adjusted, the pharmaceutical tory enzyme preparations is commonly 4 to 2000 mg as daily compositions are manufactured by generally used methods dosage for adults and preferably, it is 15 to 720 mg. including wet granulation methods Such as spray granula 0037 Expectorants, excluding ambroxol, include potas tion, agitate granulation, flow granulation, roll flow granu sium , , , foe lation, roll granulation and dry granulation Such as compac niculated ammonia Spirit, Sodium hydrogencarbonate, bro tion granulation. In addition, powders and granulated mhexine hydrochloride, fudosteine, carbocysteine, methyl powders which contain pharmacologically active Substance cysteine hydrochloride, , ethylcysteine hydro can be mixed and divided into Small Sachets. chloride, hydrochloride, aminophylline, theo phylline, diprophylline, proxyphylline, ammonium chloride, 0043. When manufactured as a capsule, the capsule can creSol potassium Sulphonate, 1-menthol, trimetoquinol be filled with powder medicine, granulated powders, Small hydrochloride, phenylpropanolamine hydrochloride, meth tablets, etc. by using a capsule-filling machine. Oxyphenamine hydrochloride, and the like. They can be used 0044) Tablets and couplets can be manufactured by mix either Singly or in two or more combinations. The amount of ing powder of the active constituent, powder agent, fine expectorant excluding ambroXol is commonly 1 to 3000 mg grain agent, granulated powder or pill and additive(s) of the as daily dosage for adults and preferably, it is 6 to 900 mg. preparation and put to compression molding. US 2004/0259955 A1 Dec. 23, 2004

0.045 Coated preparations including Sugarcoated tablets, EXAMPLE 2 couplets, film-coated tablets and coated granulated powder can be manufactured by methods known in the art Such as Powder Medicine pan coating, flow coating and rolling coating methods and 0051 A powder was manufactured by evenly mixing the combination of these. following ingredients. The mixed powder was molded to 0.046 Preparations such as syrup, elixir, limonade, have 600mg per Sachet. extract, drinkable preparation and Soft and hard capsule agents comprising liquid or Semi-Solid Substance are nor mally manufactured by mixing, dissolving and Suspending Ambroxol hydrochloride 45 g Isopropamide iodide 6 g each pharmaceutically active agent and part of a preparation Acetaminophen 900 g additive Such as a resolvent (e.g. distilled water), adding Corn starch 289 g preparation additive including remaining resolvent and Lactose 540 g adjusting the Volume of liquid. Acid or alkali can be used to Magnesium stearate 20 g adjust pH, as necessary. Furthermore, when a fat-Soluble ingredient is included, it may be Solubilized, emulsificated and Slurred by using a preparation additive Such as deter EXAMPLE 3 gent, Solublizing agent, emulsifier and Suspending agents. If necessary at preparation, Warming, cooling, nitrogen dis Syrup placement, filtering and Sterilization can be performed. 0052 A total of 240 ml syrup was manufactured by 0047 Moreover, functions can be added using prepara dissolving the following ingredients in distilled water. tion additive for: improvement in Stabilization, slow release, continuance, quickly distinglation, quickly dissolution and dissolution of medicinal properties, concealment of taste, Ambroxol hydrochloride 0.15g improvement in usage. Adding these functions can be done Isopropamide iodide 0.02 g by methods known in the art. For example, dispensing Acetaminophen 3.00 g phosphate 0.08 g pharmaceutically active Substance in a separate granule, dl-Methylephedrine hydrochloride 0.20 g making multi-layer granules, multi-layer tablets or dry Chlorpheniramine maleate 0.03 g coated , tablets by Separating granules, microcapsules, Absolute caffeine 0.25 g coating preparations Such as Sugarcoated tablets, film coat Trehalose 120.00 g ing tablets, coating granule, foaming pharmaceutical prepa Citric acid 0.10 g Sodium citrate 0.10 g ration, chewable preparation, dissolving preparation in the Caramel 0.10 g mouth, matrix preparation, together comminution, making Aroma chemical 0.50 g Solid Solution, adding Sweetening agent, refrigerant, antioxi dant or Stabilizing agent, adjust to certain pH, Viscosity, oSmotic pressure, Salt concentration. These methods can be EXAMPLE 4 combined. 0.048. The present invention is further described in the Sugarcoated Tablet following examples which are provided for illustrative pur 0053 Tablet powder was manufactured with the follow poses only and are not to be construed as limiting. Indeed, ing ingredients in the usual manner and molded to have 270 other variants of the invention will be readily apparent to one mg per tablet. of ordinary skill in the art. 0049 All publications and patents cited herein are incor porated by reference in their entireties. Ambroxol hydrochloride 90 g Isopropamide iodide 12 g Ibuprofen 900 g EXAMPLE 1. Dihydrocodeine phosphate 48g dl-Methylephedrine hydrochloride 120 g Tablet Chlorpheniramine maleate 15 g Anhydrous caffeine 150 g 0050 Tablets were manufactured by evenly mixing the Thiamine nitrate 48g Ascorbic acid 600 g following ingredients. The mixed powder was molded by Corn starch 1257g direct compression to have 120 mg per tablet. Lactose 936 g Crystallized cellulose 360 g Hydroxypropylcellulose 180 g Light anhydrous Silicic acid 90 g Ambroxol hydrochloride 135 g Talc 36 g Isopropamide iodide 18 g Magnesium stearate 18 g Lactose 459 g Crystalline cellulose 450 g Light anhydrous silicic acid 8g Talc 5 g 0054. This tablet was coated in the coating pan, using Magnesium stearate 5 g coating liquid (ethyl alcohol: distilled water=1:1) containing 5% by weight hydroxypropylcellulose until the weight per tablet increased by 10 mg. Then, solution containing 2% by US 2004/0259955 A1 Dec. 23, 2004

weight titanium oxide, 3% by weight calcium carbonate, 1% weight by gum Arabic powder and 60% by weight sucrose was used to coat the tablets until the weight per tablet Ambroxol hydrochloride 45 g increased by 180 mg. Afterwards, Solution containing Isopropamide iodide 6 g sucrose of 60% by weight was used for coating until the Acetaminophen 900 g weight of one tablet increased by 10 mg. Dihydrocodeine phosphate 24g dl-Methylephedrine hydrochloride 60 g EXAMPLE 5 Pseudoephedrine hydrochloride 60 g Epinastine hydrochloride 10 g Serrapeptase 15 g Granule Agent Anhydrous caffeine 75 g Benfotiamine 24g 0.055 Granules were manufactured using the following Riboflavin 12 g ingredients in the usual manner and were packed in a Lactose 464 g cartridge to have 1300 mg for use as a granule agent. Microcrystalline cellulose 430 g Magnesium stearate 20 g Talc 15 g

Ambroxol hydrochloride 90 g Isopropamide iodide 12 g Ibuprofen 900 g Dihydrocodeine phosphate 48 g Methylephedrine hydrochloride 120 g What is claimed is: Chlorpheniramine maleate 15 g Anhydrous caffeine 150 g 1. A pharmaceutical composition comprising as pharma Thiamine nitrate 48 g cologically active compounds a combination of brom hexine Ascorbic acid 600 g Corn starch 293 g or ambroXol or a pharmacologically acceptable Salt thereof D-mannitol 5240 g and isopropamide iodide. Tartaric acid 200 g Aspartame 40 g 2. The pharmaceutical composition according to claim 1 Acesulfame potassium 40 g comprising as pharmacologically active compounds a com Perfume 4g bination of ambroXol or a pharmacologically acceptable Salt thereof and isopropamide iodide. 3. The pharmaceutical composition according to claim 2 EXAMPLE 6 comprising ambroXol hydrochloride. Tablet 4. The pharmaceutical composition according to claim 1 wherein the composition comprises 5 to 90 mg ambroxol 0056 Tablets were manufactured by evenly mixing the hydrochloride or a pharmacologically acceptable Salt thereof following ingredients. The mixed powder was molded by as daily dosage for adults. direct compression to have 300 mg per tablet. 5. The pharmaceutical composition according to claim 1 wherein the composition comprises 1 to 25 mg isopropam ide iodide as daily dosage for adults. Ambroxol hydrochloride 45 g 6. The pharmaceutical composition according to claim 1 Isopropamide iodide 6 g Ibuprofen 450 g wherein the mixture ratio of isopropamide iodide to Dihydrocodeine phosphate 24g ambroxol is in the range of 0.01 to 5 weight part. 6 g Pseudoephedrine hydrochloride 60 g 7. The pharmaceutical composition according to claim 1 Theophylline 150 g comprising one or more pharmacologically active com Lysozyme chloride 90 g pounds Selected from the group consisting of antipyretics, Anhydrous caffeine 75 g Fursultiamine 24g analgesics, , antituSSives, Stimulant drugs, Riboflavin 12 g Vitamins, crude drugs, antacids and mucosa protectives, Lactose 443 g antiphlogistics, quenching enzymes and expectorants. Crystalline cellulose 390 g Magnesium stearate 15 g 8. The pharmaceutical composition according to claim 1 Talc 10 g which is a Solid, Semi-Solid or liquid formulation. 9. A method for treating the common cold comprising administering the pharmaceutical composition according to EXAMPLE 7 claim 1. 10. A method for treating Sputum and/or runny nose Tablet comprising administering the pharmaceutical composition 0057 Tablets were manufactured by evenly mixing the according to claim 1. following ingredients. The mixed powder was molded by direct compression to have 240 mg per tablet.