Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0007—Effervescent
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• the present invention relates to an effervescent preparation containing at least one basic medicinally active substance, characterized in that an alkalization of the urine and thus an increased accumulation of the basic medicinally active substance is avoided.
• Effervescent preparations as medicinal products have long been known and are used in the form of effervescent powder, tablets or granules. As a rule, there are solid preparations containing an acid / base pair that are in contact with. React water with CO 2 evolution (EP 0 474 040, EP 0 369 228, PC Schmidt, I. Christin, Die Pharmazie, 1990, 45, 89-110).
• the effervescent formulation leads to a faster disintegration of the dosage form and dissolution of the active ingredient and can therefore lead to a better and faster bioavailability of the drug than a classic tablet formulation.
• Effervescent preparations are, for example in the case of active substances with a long absorption time or with a tendency to irritate the gastric mucosa, a form of formulation which can alleviate the disadvantageous active substance properties mentioned. Effervescent preparations containing drugs are therefore becoming increasingly popular.
• the task was to find an effervescent formulation for basic active ingredients that avoids alkalinization of the urine and thus an accumulation of the basic active ingredient, thus ensuring optimal therapy and reducing the risk of side effects.
• the effervescent preparation according to the invention avoids alkalinization of the urine and thus an increased accumulation of the basic medicinally active substance, which goes far beyond the intrinsic accumulation behavior in non-brewing formulations.
• the present invention relates to an effervescent preparation containing an effervescent set, at least one basic medicinally active substance and, if appropriate, one or more further active compounds, characterized in that an increased accumulation of the basic medicinally active substance is avoided.
• Basic medicinally active substances within the scope of the invention have a protonatable basic primary, secondary or tertiary nitrogen such as, for example, pseudoephedrine, chlorophenamine, phenylephrine, diphenhydramine, clemastine, bromophenamine, hydroxyzine, tripelenamine, pyrilamine, mequitazine, promethazine, cyproheptadine, doxylamine, doxylamine, doxylamine, doxylamine , Epinephrine, phenamine, trimeprazine, cyclizine, medicine, hydroxzin and azatadine and their physiologically acceptable salts.
• a protonatable basic primary, secondary or tertiary nitrogen such as, for example, pseudoephedrine, chlorophenamine, phenylephrine, diphenhydramine, clemastine, bromophenamine, hydroxyzine, tripelenamine, pyrilamine, mequitazin
• Pseudoephedrine, chlorphenamine, phenylephrine and clemastine and their physiologically acceptable salts are preferred.
• Pseudoephedrine and its physiologically acceptable salts such as, for example, pseudoephedrine hydrochloride and pseudoephedrine sulfate are particularly preferred.
• the invention also includes mixtures of the substances mentioned.
• the basic medicinally active substance is used in therapeutically effective amounts.
• Pseudoephedrine hydrochloride or pseudoephedrine sulfate are preferred in a dosage of 10 to 100 mg, particularly preferably in a dosage of 20 to 70 mg.
• the effervescent preparation may contain one or more other active ingredients such as analgesics, antibiotics, antihistamines, antidepressants, antidiabetic agents, antihypertensives, anticoagulants, lipid-lowering agents, antineoplastic agents, antiviral substances, anti-inflammatory substances, antitussives, expectorants, anticonvulsants, anticonvulsants, anti- anticonvulsants, anti- anticonvulsants , Anti-asthmatics and antidiuretics called.
• Analgesics are preferred.
• the analgesics include, for example, acetylsalicylic acid, paracetamol, ibuprofen, naproxen, diclofenac, propiphenazone, metamizole and COX-2 inhibitors such as celecoxib and Rofecoxib.
• Representative antibiotics are, for example, beta-lactam antibiotics, chloramphenicol, neomycin, tetracyclines, cephalosporins, erythromycin, ciprofloxacin, moxifloxacin, norfloxacin and enrofloxacin.
• Representative antihistatic agents are, for example, fexofenadine, dimethindene, cromoglicic acid, cetirizine, loratadine, perilamine, chlorphenamine, tetrahydrozoline and anatzolin.
• Representative antidepressants are, for example, amitriptyline, fluoxetine, doxepin, maprotilin and imipramine.
• Representative antidiabetic agents are, for example, acarbose, chloropropamide, glibenclamide and tolbutamide.
• Representative antihypertensives are, for example, amlodipine, nifedipine, felodipine, enalapril, ramipril, Capt ⁇ prü, cilazapril, trandolapril, fosinopril, quinapril, moexipril, lisinopril and perindopril, losartan, candesartan, irbesartan, irbesartan, irbesartan.
• Representative anticoagulants are, for example, bishydroxycoumarin and warfarin.
• Representative lipid-lowering agents are, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, itavastatin, pitavastatin, rosuvastatin and cerivastatin.
• Representative antineoplastic agents are, for example, adriamycin, fluorouracil and methotrexate.
• a representative antiviral substance is, for example, acyclovir.
• Representative anti-inflammatory substances are, for example, cortisone, hydrocortisone, betamethasone, dexamethasone and prednisolone.
• Representative Arititussiva are for example codeine, dihydrocodeine, dextrometorphan and clobutinol.
• Representative expectorants are, for example, ambroxol, acetylcysteine, bromhexine and carbocistein.
• Representative muscle relaxants are, for example, diazepam, danbrölen, cyclobenzaprine and methocarbamol.
• Representative anticonvulsants are, for example, diphenylhydantoin and barbiturates.
• Representative antidiarrheals are, for example, loperamide and diphenoxylate.
• Representative antiasthmatics are, for example, theophylline, beclomethasone and epinephrine.
• Representative diuretics are, for example, chlorothalidone, indapamide, bendrofluethiazide, metolazone, cyclopenthiazide, polythiazide, mefruside, ximapid, chlorothiazide and hydrochlorothiazide.
• the examples given also mean the corresponding physiologically acceptable salts.
• the invention also includes mixtures of the active compounds mentioned.
• active ingredients which may be mentioned are, for example, acerylsalicylic acid, paracetamol, ibuprofen, diclofenac, metamizole and COX-2 inhibitors such as, for example, celecoxib and rofecoxib and their physiologically acceptable salts.
• Acetylsalicylic acid, ibuprofen, paracetamol, naproxen and their physiologically acceptable salts are particularly preferred.
• the invention also includes mixtures of the active ingredients mentioned.
• the active ingredient (s) which may be present are used in therapeutically effective amounts. Dosages of 0.5 to 5 mmol are preferred. Dosages of 0.8 to 3 mmol are particularly preferred. Preferred is acetylsalicylic acid in a dosage of 100 to 1000 mg, paracetamol in a dosage of 100 to 1000 mg, ibuprofen in a dosage 100 to 1000 mg, naproxen in a dosage 100 to 1000 mg or mixtures of these active ingredients in a total dosage of 100 to 1000 mg.
• acetylsalicylic acid in a dosage of 250 to 500 mg
• paracetamol in a dosage of 250 to 500 mg
• ibuprofen in a dosage of 100 to 300 mg
• naproxen in a dosage of 250 to 500 mg or mixtures of these active ingredients in a total dosage of 200 to 500 mg.
• An effervescent preparation is preferred, characterized in that an effervescent set, pseudo-ephedrine and one or more analgesics such as, for example, acetylsalicylic acid, paracetamol, naproxen and ibop calls and / or one or more antitussives such as, for example, dextomethorphan and / or one or more expectorants such as, for example Ambroxol and acetyl-oysteine are contained, whereby alkalinization of the urine and thus an increased accumulation of the basic active substance is avoided.
• antihistamines such as chlorpheniramine can be added.
• the ingredients can also be in the form of their physiologically acceptable salts.
• An effervescent preparation is particularly preferred, characterized in that an effervescent set, pseudoephedrine and one or more further active ingredients from the group consisting of acetylsalicylic acid, paracetamol and ibuprofen are contained, alkalinization of the urine and thus increased accumulation of the basic active substance being avoided and the Ingredients can also be in the form of their physiologically acceptable salts.
• the shower set reacts on contact with water or saliva with CO 2 evolution and consists of at least one basic and at least one acidic component.
• Carbonates may be mentioned as the basic component of the shower set.
• carbonates are understood to be carbonates, sesquicarbonates and hydrogen carbonates.
• Ammonium carbonate, ammonium bicarbonate and alkali and alkaline earth carbonates and bicarbonates such as, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, calcium magnesium carbonate, magnesium carbonate, magnesium bicarbonate and magnesium hydroxycarbonate are preferred.
• Sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, calcium hydrogen carbonate, magnesium carbonate, magnesium hydrogen carbonate and magnesium hydroxy carbonate are particularly preferred. It is also possible to use mixtures of the basic components mentioned.
• the basic component or components of the shower set are used in a total dosage of 1 to 20 mmol, preferably in a total dosage of 2 to 15 mmol, particularly preferably in a total dosage of 2 to 10 mmol.
• the acidic component can have more than one dissociation constant, that is to say can have more than one acid functional group.
• the acidic component can be an organic or inorganic acid in the form of its anhydride, its free acid or its acidic salt, in which, in the case of several acidic functional groups, some of the protons can be replaced by a cation or cations.
• acidic components are tartaric acid, succinic acid, malic acid, malonic acid, maleic acid, fumaric acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha-hydroxy acids, ascorbic acid, isoascorbic acid, glutaric acid, amino acids, phosphoric acid, diphosphoric acid, triphosphoric acid, pyrophosphoric acid, metaphosphoric acid , Polyphosphoric acids, sulfuric acid, disulfuric acid and their acidic salts such as potassium hydrogen tartrate or sodium hydrogenphosphate, and other physiologically acceptable acids. Ascorbic acid, isoascorbic acid, tartaric acid, phosphoric acid and their acid salts are particularly preferred. It is also possible to use mixtures of the acidic components mentioned.
• the acidic component or components of the shower set are used in a total dosage of 1 to 20 mmol, preferably in a total dosage of 2 to 15 mmol
• citric acid as an acid component is possible if the basic component of the shower set consists exclusively of alkaline earth carbonates and / or hydrogen carbonates such as calcium carbonate, calcium hydrogen carbonate, magnesium carbonate, magnesium hydrogen carbonate and magnesium hydroxy carbonate or mixtures thereof.
• An effervescent set containing citric acid as the acidic component and calcium carbonate as the basic component is preferred.
• the equivalent ratio between the equivalents of citric acid and the sum of the equivalents of alkaline earth carbonates and / or hydrogen carbonates is at most 2: 1, preferably at most 1: 1.
• citric acid and alkali carbonates and / or hydrogen carbonates are possible if the equivalent ratio between the equivalents of citric acid and the sum of the equivalents of alkali carbonates and / or hydrogen carbonates is at most 1: 3, preferably at most 1: 4, particularly preferably at most Is 1: 5.
• the acidic active ingredient (s) which may be present is an acid
• the acidic active ingredient (s) such as acetylsalicylic acid, paracetamol and ibuprofen
• a combination of at least one acidic component and at least one basic component is also preferred as a shower set, the ratio of equivalents between the sum of the equivalents of the acidic components and the sum of the equivalents of the basic components being 1: 1 to 3: 1, preferably 1: 1 to 2, 5: 1 and particularly preferably 1: 1 to 1.5: 1.
• an effervescent preparation characterized in that an effervescent set containing citric acid and calcium carbonate, pseudoephedrine and one or more further active ingredients from the group consisting of acetylsalicylic acid, paracetamol and ibuprofen are contained, with an alkalinization of the urine and thus an increased accumulation of the basic medicinally active substance is avoided and the ingredients can also be present in the form of their physiologically acceptable salts.
• Another object of the invention is a medicament containing the effervescent preparation according to the invention and at least one further auxiliary.
• auxiliaries include binders, lubricants, flavorings, wetting agents, sweeteners, anti-foaming agents, diluents, colorants and stabilizers.
• binders which may be mentioned are glycol, polyethylene glycol, dextrose, sucrose, sugar, starch, invert sugar, mannitol, cellulose, methyl cellulose and their derivatives.
• lubricants examples include magnesium stearate, stearic acid, talc, paraffin, hydrogenated castor oil, polyethylene glycol, fumaric acid, adipic acid, sodium benzoate, sodium stearyl fumarate and their salts.
• the sodium, potassium, ammonium, calcium and magnesium salts of fumaric acid and adipic acid are preferred.
• Flavorings include, for example, synthetic and natural flavorings that are suitable for food. For example, orange aroma, lime aroma, optarom orange, eucalyptus oil, peppermint oil, vanilla and lemon aroma are preferred. Orange aroma, lime aroma and optarom orange, for example, are particularly preferred.
• Dioctyl sodium sulfosuccinate and sodium lauryl sulfate may be mentioned as wetting agents.
• sweeteners are sodium saccharin, cyclamate, invert sugar and aspartame.
• Silicone oil may be mentioned as an anti-foaming agent, for example.
• Starch and cellulose may be mentioned as diluents.
• dyes examples include titanium dioxide, beetroot powder, beta-carotene and all dyes that are suitable for food.
• stabilizers examples include polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol and their derivatives.
• Physiologically acceptable salts in the context of the invention can be acid addition salts of the compounds with mineral acids, carboxylic acids or sulfonic acids.
• salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid are particularly preferred.
• salts with customary bases can also be mentioned as salts, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triemylamine, emyldiisopropylamine, procaine, Dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenami or methylpiperidine.
• alkali metal salts for example sodium or potassium salts
• alkaline earth metal salts for example calcium or magnesium salts
• ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triemylamine, emyldiisopropylamine, procaine, Dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenami or methylpiperidine
• Another object of the invention is the use of the effervescent preparation for the treatment of diseases.
• use of the effervescent preparation for the treatment of flu-like infections, bacterial infections, fever, runny nose, cough, colds or allergies is preferred.
• the invention further relates to a method for producing the effervescent preparation according to the invention, characterized in that the components of the effervescent preparation are formulated in a pharmaceutical form which is common in the field of pharmaceutical preparations. Powders, granules, pearls, pellets or tablets are preferred. Powders, granules and tablets are particularly preferred. Known suitable methods are used to produce pharmaceuticals according to the invention.
• the present invention also encompasses all combinations of the preferred ranges.
• the basic medicinally active substance is administered in the same therapeutically effective amount in each of the following three preparations: preparation A as an effervescent preparation to be examined, preparation B as a non-effervescent preparation and preparation C as a standard Effervescent preparation, where preparation B contains no effervescent components and preparation C contains a usual effervescent set consisting exclusively of 600 mg sodium bicarbonate and 1000 mg citric acid.
• preparation A as an effervescent preparation to be examined
• preparation B as a non-effervescent preparation
• preparation C as a standard Effervescent preparation
• preparation B contains no effervescent components
• preparation C contains a usual effervescent set consisting exclusively of 600 mg sodium bicarbonate and 1000 mg citric acid.
• the three preparations are administered simultaneously on 5 consecutive days, the number of doses per day depending on the basic active pharmaceutical substance used and the dosage of this substance corresponding to a customary use.
• the plasma level B reflects the intrinsic accumulation behavior of the basic medicinally active substance.
• An increased accumulation of the basic medicinally active substance occurs when the difference between the plasma level A and the plasma level B in an accumulation ratio of more than 1: 2, preferably more than 1: 3, particularly preferably more than 1: 4 to the difference stands between the plasma level C and the plasma level B.
• the accumulation ratio is equal to the difference between plasma level A and plasma level B divided by the difference between plasma level C and plasma level B.
• An effervescent preparation containing an effervescent set, at least one basic medicinally active substance and optionally one or more further active ingredients is preferred, characterized in that the accumulation ratio is less than 1: 2, preferably less than 1: 3, particularly preferably less than 1: 4.
• Preparation 1 contained 60 mg pseudoephedrine HC1, 500 mg acetaminophen and 1 tablet Alka-Seltzer ® Cold & Cough ANC 6 (containing 600 mg citric acid and 1000 mg sodium hydrogen carbonate), preparation 2 contained 20 ml Sudafed ® Children's Nasal Decongestant Liquid Medication (corresponds to 60 mg Pseudoephedrine HC1). In 17 consecutive individual doses, both preparations were dissolved in 120 ml of water every 6 hours and 32 test subjects were administered within 2 minutes, so that 4 doses were administered on the first to fourth day and 1 dose on the fifth day.
• the plasma level of pseudoephedrine was measured 12 hours after the last dose and was on average 236.9 ng / ml in the group of test persons who received preparation 1 and in the group of test persons who received preparation 2, an average of 120.23 ng / ml.
• the plasma levels show an increased accumulation of pseudoephedrine.

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Citations (5)

• 2003
  • 2003-12-19 DE DE10359790A patent/DE10359790A1/de not_active Withdrawn
• 2004
  • 2004-12-07 WO PCT/EP2004/013886 patent/WO2005063199A1/de active Application Filing
  • 2004-12-07 BR BRPI0417796-7A patent/BRPI0417796A/pt not_active IP Right Cessation
  • 2004-12-07 CN CNA2004800373887A patent/CN1893920A/zh active Pending
  • 2004-12-07 KR KR1020067011963A patent/KR20060109492A/ko not_active Application Discontinuation
  • 2004-12-07 JP JP2006544276A patent/JP2007515418A/ja not_active Withdrawn
  • 2004-12-07 EP EP04803578A patent/EP1696874A1/de not_active Withdrawn
  • 2004-12-07 AU AU2004308590A patent/AU2004308590A1/en not_active Abandoned
  • 2004-12-07 CA CA002550342A patent/CA2550342A1/en not_active Abandoned
  • 2004-12-07 MX MXPA06006658A patent/MXPA06006658A/es active IP Right Grant
  • 2004-12-17 AR ARP040104747A patent/AR046955A1/es not_active Application Discontinuation
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  • 2006-06-16 EC EC2006006649A patent/ECSP066649A/es unknown
  • 2006-06-26 MA MA29140A patent/MA28276A1/fr unknown
  • 2006-07-18 NO NO20063327A patent/NO20063327L/no not_active Application Discontinuation

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