MXPA04008220A

MXPA04008220A - Ambroxol for treating painful conditions in the mouth and pharyngeal cavity.

Info

Publication number: MXPA04008220A
Application number: MXPA04008220A
Authority: MX
Inventors: Pschorn Uwe
Original assignee: Boehringer Ingelheim Pharma
Priority date: 2002-02-27
Filing date: 2003-02-25
Publication date: 2004-11-26
Also published as: JP2005518435A; CA2477105A1; RU2311176C2; EP1480626A1; PL371584A1; RU2004129284A; AU2003210345A1; AU2003210345B2; MY144781A; ECSP045242A; PE20030830A1; AR038698A1; KR20040084944A; CN1638749A; UY27679A1; WO2003072094A1; ZA200405635B; BR0308038A; DE10208313A1; UA86741C2

Abstract

The invention relates to the use of ambroxol and the pharmacologically compatible salts thereof for producing a medicament used for treating painful conditions in the mouth and pharyngeal cavity.

Description

AMBROXOL FOR THE TREATMENT OF PAINFUL STATES IN THE BUCCAL AND PHARYNGAL CAVITY FIELD OF THE INVENTION The invention relates to the use of Ambroxol and its pharmacologically compatible salts for the preparation of a medicament for the treatment of painful conditions in the buccal and pharyngeal cavities. BACKGROUND OF THE INVENTION Analgesics for relieving pain in the oral and pharyngeal cavity often have the drawback of side effects, for example in the form of local irritations. The active substance Ambroxol (trans-4- (2-amino-3,5-di-bromobenzylamino) -cyclohexanol) is a known and known mucolytic. It is used in peroral forms such as juices, capsules, tablets, solutions for inhalation, drops or lozenges. It is the object of the present invention to provide a well-compatible active principle for the treatment of pains in the oral and pharyngeal cavities. Description of the invention Surprisingly, it was found that Ambroxol, in suitable doses or concentrations, has, in the case of local application, together with a very good compatibility, a very good calming effect in the oral and pharyngeal cavity. KEF: 157376 Therefore, the invention relates to the use of Ambroxol or one of its pharmacologically compatible salts for the preparation of a medicament for the treatment of pains in the oral and / or pharyngeal cavity, chosen from the group consisting of pains acute neck, canker sores, gingivitis, parodontopathies, areas of pressure of prosthesis, pain after oro-pharyngeal interventions, mucosal lesions in the oral cavity and pharyngeal and Herpes simplex in the oral cavity and pharyngeal, in particular thrush, gingivitis, parodontopathies, areas of prosthetic pressure, pain after oro-pharyngeal interventions, mucosal lesions in the oral and pharyngeal cavity and Herpes simplex in the oral and pharyngeal cavity, particularly preferred for the treatment of acute neck pain. Acute neck pains should be understood as intense neck pains, for example wounded neck with discomfort of swallowing or burning in the neck. Another object of the invention is a pharmaceutical composition containing Ambroxol or one of its pharmacologically compatible salts and one or several active ingredients chosen from the group consisting of antiseptics, vitamins, corticoids, antiphlogistics, viruses, antibiotics, antimycotics and proteolytic enzymes. Suitable antiseptics are, for example, cetylpyridinium-Cl, decalinium-Cl, chlorhexidine digluconate, benzalkonium-Cl or ethacridine lactate. Suitable vitamins are, for example, dexpanthenol (pantothenic acid) or ascorbic acid. Suitable corticosteroids are, for example, triamcinolone or prednxsolone acetate. Suitable antiphlogistics are, for example, benzydamine-Cl or choline salicylate. Suitable virustatics are, for example, acyclovir or idoxuridine. Suitable antibiotics are, for example, thyrothricin or bacitracin. Suitable antifungals are, for example, amphotericin B or nystatin. A suitable proteolytic enzyme is, for example, lysozyme. Suitable essential oils are, for example, peppermint oil, thyme or sage. Another object of the invention is a pharmaceutical composition containing Ambroxol or one of its pharmacologically compatible salts and one or several active ingredients chosen from the group consisting of lysozyme hydrochloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, cetylpyridinium chloride, chlorpheniramine maleate, noscapine , decalinium chloride, dextromethorphan phenoltalinate, potassium guaiacolsulfonate, dl-methylephedrine hydrochloride, chlorhexidine hydrochloride, and potassium cresolsulfonate. Ambroxol is a metabolite of the secretolytic bromohexine. Both active principles represent a very well-compatible combination of active principles that positively influences the dual effect of Ambroxol. Also, an object of the invention is, therefore, a pharmaceutical composition consisting of pharmacologically compatible Ambroxol, bromohexine or s.us salts and pharmaceutical adjuvants, preferably with an Ambroxol: bromohexine ratio in a range of 4: 1 to 6: 1, particularly preferably 5: 1. Particularly preferred is a pharmaceutical composition in which the individual dose contains 15 to 50 mg of Ambroxol, preferably 20 mg of Ambroxol. Another object of the invention is a solid administration form, which can be sucked or slowly dissolved, of a pharmaceutical composition containing Ambroxol and one or several active ingredients chosen from the group consisting of antiseptics, vitamins, corticosteroids, antiphlogistics, antibiotics, antimycotics and proteolytic enzymes. Another object of the invention is the use of a pharmaceutical composition described above for the preparation of a medicament for the treatment of pains in the oral cavity and / or pharyngeal, chosen from the group consisting of acute neck pains, canker sores, gingivitis, parodontopathies , areas of prosthetic pressure, pain after oro-pharyngeal interventions, mucosal lesions in the oral and pharyngeal cavity and Herpes simplex in the oral and pharyngeal cavity, particularly preferred for the treatment of acute neck pain. Another object of the invention is the use of a pharmaceutical composition which is composed of Ambroxol hydrochloride, an aromatic substance, a lubricant, a matrix material, a sweetener and a polyethylene glycol for the preparation of a medicament for the treatment of pains in the oral and / or pharyngeal cavity, chosen from the group consisting of acute neck pains, canker sores, gingivitis, parodontopathies, prosthesis pressure zones, pain after oro-pharyngeal interventions, mucosal lesions in the oral and pharyngeal cavities and Herpes simplex in the oral and pharyngeal cavity, particularly preferred for the treatment of acute neck pain. Suitable aromatic substances are, for example, peppermint, eucalyptus or lemon, preferably peppermint aroma. Suitable matrix materials are, for example, calcium carbonate, calcium phosphate or sorbitol, preferably sorbitol.

Suitable sweeteners are, for example, saccharin, sodium saccharin, cyclamate, glycerin or sugar, preferably sodium saccharin. Lubricants for suitable tablets are, for example, polyethylene glycols, preferably Macrogol 6000. Suitable lubricants are, for example, talc or magnesium stearate, preferably talc. Another object of the invention is the use of a sucking tablet containing sugar-alcohol-based Ambroxol as a matrix material, characterized by a content in a pharmaceutically tolerable layered silicate and in a polyethylene glycol, optionally together with other adjuvants, substances flavors or aromatic pharmaceuticals for the preparation of a medicine for the treatment of pains in the oral and / or pharyngeal cavity, chosen from the group consisting of acute neck pains, canker sores, gingivitis, parodontopathies, pressure zones of prostheses, pains after oro-pharyngeal interventions, mucosal lesions in the oral and pharyngeal cavity and Herpes simplex in the oral and pharyngeal cavity, particularly preferred for the treatment of acute neck pain. Another object of the invention is the use of Ambroxol for the preparation of a medicament with an analgesic effect over a period of time of at least 3 hours, preferably over 3 hours, after an application. Likewise, the object of the invention is the use of a pharmaceutical composition containing Ambroxol for the preparation of a medicament with an analgesic effect over a period of time of at least 3 hours, preferably over 3 hours, after an app . A daily administration of 1 to 6 times, preferably 2 to 4 times, of the pharmaceutical composition according to the invention is preferred. Suitable acids for the formation of Ambroxol salts are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid and methanesulfonic acid, preferably hydrochloric acid. The effect of Ambroxol according to the invention will be explained by the following Examples of clinical studies investigating the activity of Ambroxol suction tablets of different intensity. These Examples serve only for the explanation of the invention and are not to be considered as limiting. Example 1 Investigation of the activity and compatibility of sucking tablets containing 20 mg of Ambroxol hydrochloride (trans-4- [(2-amino-3,5-dibromo-benzyl) amino] -cyclohexane hydrochloride, CAS Reg. No. 18683 -91-5) compared with placebo in the case of acute neck pain. A double-blind, multi-center, perspective, placebo-controlled, and randomized study was carried out over two days of treatment with aspirin tablets containing up to 6 mg of Ambroxol hydrochloride per day. Patients: 218 male / female patients were recruited (97 men, 121 women) with a mean age of 39.4 ± 15 years (range of variation: 17-81 years); of them, 215 patients were treated: 107 with 20 mg of Ambroxol and 108 with placebo. 26 patients discontinued therapy prematurely (13 in each treatment group). The population of "intention to be treated" (1AT) consisted of 208 patients (105 with treatment with Ambroxol and 103 with the corresponding application of placebo); 196 patients formed the Per-protocol (PP) population (97 with Verum or 99 with placebo). For the analysis for the safety of the drug, all treated patients were taken into account. Treatments: Double blind treatment with up to 6 tablets to suck each day that contained in each case 20 mg of Ambroxol or represented a placebo (compressed to suck without the active principle, but also with a pronounced mint flavor piperita comparable to Verum). End points: The time-weighted average pain reduction during the first 3 hours after the application of the first aspirin tablet, normalized to the degree of initial pain (SPIDnorm), in addition, the prosecution of the activity and compatibility on the part of the patients at the end of each day of treatment. Results: In both treatment groups, a reduction in pain intensity could be verified; the mean SPIDn0rm (± DT) after the first aspirin tablet amounted to 0.39 ± 0.27 for 20 mg of Ambroxol hydrochloride, and 0.28 ± 0.25 for placebo. The superiority of Ambroxol over placebo was demonstrated in a statistically significant treatment effect (p = 0.0029; ~ 95% confidence interval for the mean difference between the Ambroxol treatment groups minus placebo: 0.04 to 0.18). At the end of any one of the following days of ambulatory treatment with up to 6 tablets to suck, a greater number of statistically significant patients documented a greater degree of activity for active treatment with Ambroxol hydrochloride than for the placebo application. The compatibility of the test substance was shown to be as good as that of the placebo.

Conclusion: The application of suction tablets containing 20 mg of Ambroxol hydrochloride in patients with acute neck pain showed an effective pain relieving effect that is superior to the effect, already per se, of sucking a placebo. Figure 1 shows the time course of the mean variation of pain intensity (PID) for the time interval before ingestion (baseline) up to 3 hours after ingestion of the first tablet to suck with 20 mg of Ambroxol hydrochloride and placebo. E-example 2 Investigation of the activity and compatibility of sucking tablets containing 20 mg or 30 mg of Ambroxol hydrochloride (trans-4- [(2-amino-3,5-dibromo-benzyl) amino] -cyclohexane hydrochloride, CAS Reg. No. 18683-91-5) compared to placebo in the case of acute neck pain A double-blind, multi-center, perspective, placebo-controlled, and randomized two-day study was carried out. treatment with lozenges containing up to 6 mg of Ambroxol hydrochloride per day. Patients: 331 ambulatory patients with acute, uncomplicated neck pains, of at least moderately intense intensity, in whom no bacterial pharyngitis was present, were investigated. Treatments: Double blind treatment with up to 6 tablets to suck each day that contained in each case 20 mg or 30 mg of Ambroxol hydrochloride or represented a placebo (compressed to suck without the active principle, but also with a pronounced peppermint flavor) comparable to that of Verum). End points: The reduction of the pain weighted average in the time during the first 3 hours after the application of the first aspirin, normalized to the degree of pain of departure (SPIDn0rm) in addition, the inaccuracy of the activity and compatibility on the part of the patients at the end of each day of treatment. Results: All treatments led to a reduction in pain intensity; Mean SPIDnorm (± SD) after ingestion of the first aspirin tablet amounted to 0.53 ± 0.28 or 0.50 ± 0.30 for 20 mg or 30 mg of Ambroxol hydrochloride, as well as 0.38 ± 0.28 for placebo. The effect of the treatment was statistically significant. The superiority of the active treatments versus placebo could be demonstrated unequivocally (95% confidence interval (CI) for the mean differences between the treatment groups for sucking of Ambroxol 20 mg or 30 mg less placebo 0.08 to 0.23 or 0.05 to 0.20 At the end of any of the following days of ambulatory treatment with up to 6 tablets to suck, a greater number of statistically significant patients documented a greater degree of activity for the active treatments with Ambroxol hydrochloride than for the placebo application. The compatibility of the test substance was shown to be as good as that of the placebo Conclusion: The application of tablets with suction containing 20 mg or 30 mg of Ambroxol hydrochloride in patients with acute neck pain shows an effective pain relieving effect that is superior to the effect, already per se, of sucking a placebo. fications were tolerated equally well. Figure 2 shows the time course of the mean pain intensity variation (PID) for the time interval before ingestion (baseline) up to 3 hours after ingestion of the first 20 mg tablet. or 30 mg of Ambroxol hydrochloride and placebo. Ambroxol can be used alone or in combination with other pharmacologically active principles. As administration forms, all types of preparations which are suitable for local application can be used. To suck or dissolve slowly in the mouth are suitable, for example, tablets or candies based on sugary substances or sugary substitutes, or products as a pill with a base of gum arabic or gelatin. Semi-solid preparations for application to the mucosa of the mouth are, for example, gels, in particular gels based on cellulose or acrylate. Aqueous preparations are suitable as spraying solutions, mouthwashes and rinse solutions, advantageously with the addition of viscosity-increasing substances such as modified celluloses, acrylic acid derivatives or polyvinyl compounds. In addition, in particular the semi-solid and liquid forms may contain sweetening substances and wetting agents, for example glycols and sugar alcohols. All forms are usually flavored, for example by the addition of essential oils. The administration forms can be prepared according to known methods in pharmacy. The following pharmaceutical formulation examples illustrate the present invention, but without limiting it in its scope: Example 1) Tablets to suck per tablet Ambroxol Hydrochloride 20.0 mg Peppermint 16.0 mg Sorbitol 1373.5 mg Sodium Saccarin 0.5 mg Macrogol 6000 30 mg Talc 60 mg Example 2) Lozenges per tablet Ambroxol Hydrochloride 20. 0 mg Lysozyme Hydrochloride 5. 0 mg Dipotassium glycyrrhizinate 2. 5 mg Cetylpyridinium Chloride 1. 0 mg Chlorpheniramine Maleate 1. 0 mg Xylitol 920. 5 mg D-mannitol 9. 5 mg Polyvinylpyrrolidone 21. 0 mg Stearic acid 10. 0 mg Peppermint oil 6. 0 mg Light anhydrous silicic acid 1. 0 mg Talcum 1. 0 mg Magnesium stearate 1. 5 mg Example 3) Tablets to suck by tablet Ambroxol Hydrochloride 20.0 mg Noscapine 5.0 mg Decalinium Chloride 0.125 mg Sucrose (purified) 908.675 mg 1-menthol 1.0 mg Peppermint oil 0.6 mg Lemon scent 3.6 mg Corn starch 30.0 mg Polyvinylpyrrolidone 21.0 mg Magnesium stearate 10.0 mg Use 4) Tablets to suck per tablet Ambroxol Hydrochloride 20.0 mg Dextromethorphan phenoltalinate 10.0 mg Potassium gualaceolsulfonate 23.3 mg Cetylpyridinium chloride 1.0 mg Sucrose (purified) 869.7 mg Peppermint aroma 16.0 mg Corn starch 30.0 mg Poly inylpyrrolidone 20.0 mg Magnesium stearate 10.0 mg Example 5) Lozenges per tablet Ambroxol Hydrochloride 20.0 mg Dimethyl-Ephedrine Hydrochloride 6.25 mg Chlorhexidine Hydrochloride 5.0 mg Lactose 905.25 mg Hydroxypropyl Cellulose 25.0 mg replaced with Gering Hydroxypropyl Cellulose 20.0 mg Peppermint Aroma 16.0 mg Magnesium Stearate 2.5 mg Example 6 ) Tablets to suck per tablet Ambroxol Hydrochloride 20.0 mg Ammonium glycyrrhizate 1.67 mg Cresol potassium sulfonate 30.0 mg Lactose 884.83 mg Hydroxypropyl cellulose 25.0 mg replaced with Gering Hydroxypropylcellulose 20.0 mg Peppermint aroma 16.0 mg Magnesium stearate 2.5 mg It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Use of Ambroxol or one of its pharmacologically compatible salts for the preparation of a medicament for the treatment of painful conditions in the buccal and pharyngeal cavities, chosen of the group consisting of acute neck pains, canker sores, gingivitis, parodontopathies, pressure zones of prosthesis, pain after oro-pharyngeal interventions, mucosal lesions in the oral and pharyngeal cavity and Herpes simplex in the oral and pharyngeal cavity.
2. Pharmaceutical composition characterized in that it contains Ambroxol or one of its pharmacologically compatible salts and one or several active ingredients chosen from the group consisting of antiseptics, vitamins, corticoids, antiphlogistics, antibiotics, antimycotics and proteolytic enzymes.
3. Pharmaceutical composition characterized in that it contains Ambroxol or one of its pharmacologically compatible salts and one or several active ingredients chosen from the group consisting of lysozyme hydrochloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, cetylpyridinium chloride, chlorpheniramine maleate, noscapine, decalinium chloride , dextromethorphan phenoltalinate, potassium guaiacolsulfonate, dl-methylephedrine hydrochloride, chlorhexidine hydrochloride and potassium cresolsuifonate.
4. Pharmaceutical composition characterized in that it is composed of Ambroxol, bromohexine or its pharmacologically compatible salts and pharmaceutical adjuvants.
5. Pharmaceutical composition according to one of claims 2 to 5, characterized in that the individual dose 0 contains 15 to 50 mg of Ambroxol.
6. A solid form of administration, characterized in that it can be sucked or slowly dissolved from a pharmaceutical composition according to one of claims 2 to 4.
Semi-solid administration form of a pharmaceutical composition according to one of the claims 2 to 5, characterized in that it is in the form of a gel.
8. Use of a pharmaceutical composition according to one of claims 2 to 5 for the preparation of G a medicament for the treatment of pains in the oral and pharyngeal cavity, chosen from the group consisting of acute neck pains, canker sores, gingivitis, parodontopatías, areas of pressure of prosthesis, pain after oro-pharyngeal interventions, lesions of the mucosa in the oral cavity and 5 pharyngeal and Herpes simplex in the oral and pharyngeal cavity.
9. Use of a pharmaceutical composition consisting of Ambroxol hydrochloride, an aromatic substance, a lubricant, a matrix material, a sweetener and a polyethylene glycol for the preparation of a medicament for the treatment of pains in the oral and / or pharyngeal cavities, chosen from the group consisting of acute neck pains, canker sores, gingivitis, parodontopathies, prosthetic pressure zones, pain after oro-pharyngeal interventions, mucosal lesions in the oral and pharyngeal cavity and Herpes simplex in the oral and pharyngeal cavity .
10. Use of a suction tablet containing sugar-alcohol based Ambroxol as a matrix material, characterized by a content in a pharmaceutically tolerable layered silicate and in a polyethylene glycol, optionally together with other adjuvants, pharmaceutical flavoring or aromatic substances for the treatment of pains in the oral and / or pharyngeal cavity, chosen from the group consisting of acute neck pains, canker sores, gingivitis, parodontopathies, prosthetic pressure zones, pain after oro-pharyngeal interventions, mucosal lesions in the oral and pharyngeal cavity and Herpes simplex in the oral and pharyngeal cavity.
11. Use of Ambroxol according to claim 1, for the preparation of a medicament with an analgesic effect over a period of time of at least 3 hours after an application.
12. Use of a pharmaceutical composition according to one of claims 2 to 5, for the preparation of a medicament with an analgesic effect over a period of time of at least 3 hours after an application.