US 20070224267A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0224267 A1 PSchorn et al. (43) Pub. Date: Sep. 27, 2007

(54) AMBROXOL FOR THE TREATMENT OF (30) Foreign Application Priority Data PAINFUL CONDITIONS IN THE MOUTH AND PHARYNGEAL CAVITY Feb. 27, 2002 (DE)...... DE 102 08 313 (76) Inventors: Uwe Pschorn, Mainz (DE): Publication Classification Jean-Michel Vix, Wiesbaden (DE); Anke Esperester, Mainz (DE) (51) Int. Cl. A6II 3/85 (2006.01) Correspondence Address: A6II 3 L/13 (2006.01) MICHAEL P. MORRIS A6II 3/19 (2006.01) BOEHRINGERINGELHEM CORPORATION A6II 3L/435 (2006.01) 900 RIDGEBURY ROAD A6IR 9/20 (2006.01) P. O. BOX 368 A6II 3/34 (2006.01) RIDGEFIELD, CT 06877-0368 (US) A6II 3 L/35 (2006.01) 21) Appl. No.: 11A51245 (21) Appl. No 9 (52) U.S. Cl...... 424/464; 514/277: 514/470; (22) Filed: May 21, 2007 514/557; 514/576; 514/638; 5147646 Related U.S. Application Data (63) Continuation of application No. 11/185.558, filed on (57) ABSTRACT Jul. 20, 2005, which is a continuation of application No. 10/376,349, filed on Feb. 27, 2003, now aban doned. The invention relates to the use of ambroxol and the phar macologically acceptable salts thereof for preparing a phar (60) Provisional application No. 60/386,164, filed on Jun. maceutical composition for the treatment of painful condi 5, 2002. tions in the oral and pharyngeal cavity.

-o- ambroXOl 20 mg -O- placebo

O 20 40 60 8O 100 120 140 160 18O time after first suckable tablet in min)

Patent Application Publication Sep. 27, 2007 Sheet 1 of 2 US 2007/0224267 A1

-o- ambrOXOl 20 mg -O- placebo

C CS CD S a n

1OO 120 140 160 180 time after first suckable tablet in min)

Figure 1 Patent Application Publication Sep. 27, 2007 Sheet 2 of 2 US 2007/0224267 A1

-A- ambroXol 20 mg A -O- ambroXol 30 mg V -O- placebo E R A G E

P

D

O 20 40 60 80 100 120 140 160 180 time after first suckable tablet in min)

Figure 2 US 2007/0224267 A1 Sep. 27, 2007

AMBROXOL FOR THE TREATMENT OF PAINFUL the tablet (base line) up to 3 hours after taking the first CONDITIONS IN THE MOUTH AND suckable tablet containing 20 mg or 30 mg of ambroxol PHARYNGEAL CAVITY hydrochloride and placebo.

RELATED APPLICATION DESCRIPTION OF THE INVENTION 0001. This application claims priority benefit of U.S. 0009 Surprisingly, it has been found that, when admin provisional application Ser. No. 60/386,164, filed Jun. 5, istered locally in Suitable doses or concentrations, ambroXol 2002. has a very good pain-relieving effect in the oral and pha ryngeal cavity in addition to being very well tolerated. BACKGROUND TO THE INVENTION 0010) The invention therefore relates to the use of 0002 The invention relates to the use of ambroxol and ambroXol or one of the pharmacologically acceptable salts the pharmacologically acceptable salts thereof for preparing thereof for preparing a pharmaceutical composition for the a pharmaceutical composition for the treatment of painful treatment of pain in the oral and/or pharyngeal cavity, conditions in the oral and pharyngeal cavity. selected from among acute Sore throat, aphthae, gingivitis, parodontopathies, pressure points caused by prostheses, pain 0003 Painkillers for relieving pain in the oral and pha after oro-pharyngeal interventions, lesions on the mucous ryngeal cavity often have the drawback of side effects, e.g. membrane in the oral and pharyngeal cavity and herpes in the form of local irritations. simplex in the oral and pharyngeal cavity, particularly 0004 The active substance ambroxol (trans-4-(2-amino aphthae, gingivitis, parodontopathies, pressure points 3,5-dibromobenzylamino)-cyclohexanol) is a known expec caused by prostheses, pain after oro-pharyngeal interven torant and mucolytic. It is used in oral preparations such as tions, lesions on the mucous membrane in the oral and syrups, capsules, tablets, inhalable solutions, drops or Suck pharyngeal cavity and herpes simplex in the oral and pha able pastilles. ryngeal cavity, most particularly for the treatment of acute Sore throats. By acute Sore throats are meant severe Sore 0005 The aim of the present invention is to prepare a throats, for example inflamed throats with difficulty swal well-tolerated active substance for the treatment of pain in the oral and pharyngeal cavities. lowing or with burning in the throat. 0011. The invention further relates to a pharmaceutical SUMMARY OF THE INVENTION composition containing ambroxol or one of the pharmaco logically acceptable salts thereof and one or more active 0006 The invention relates to pharmaceutical composi Substances selected from among the , vitamins, tions comprising ambroXol, bromhexine or one of the phar corticoids, antiinflammatories, Virostatics, antibiotics, anti macologically acceptable salts thereof. The invention also mycotics and proteolytic enzymes. relates to pharmaceutical compositions comprising ambroXol or one of the pharmacologically acceptable salts 0012 Suitable antiseptics are for example cetylpyri thereof and one or more active Substances (e.g., antiseptics, dinium-Cl, -Cl, -digluconate, Vitamins, corticoids, antiphlogistics, antibiotics, antimy benzalkonium-Cl or ethacridine-lactate. cotics, and proteolytic enzymes, lysozyme hydrochloride, 0013 Suitable vitamins are for example dexpanthenol dipotassium glycyrrhizinate, ammonium glycyrrhizinate, (pantothenic acid) or ascorbic acid. , chlorpheniramine maleate, nos capine, dequalinium chloride, dextromethorphane, 0014 Suitable corticoids are for example triamcinolone phthalinate, potassium guaiacolsulphonate, d1-methylephe or prednisolone-acetate. drine hydrochloride, chlorhexidine hydrochloride, and 0015 Suitable antiinflammatories are for example ben potassium cresolsulphonate). The invention also relates to Zydamine-Cl or choline Salicylate. methods comprising administering a pharmaceutical com position of the invention for the treatment of painful con 0016 Suitable virostatics are for example acyclovir or ditions in the oral and pharyngeal cavity (e.g., acute Sore idoxuridine. throat, aphthae, gingivitis, parodontopathies, pressure points 0017 Suitable antibiotics are for example thyrotricin or caused by prostheses, pain after oro-pharyngeal interven bacitracin. tions, lesions on the mucous membrane in the oral and pharyngeal cavity and herpes simplex in the oral and pha 0018 Suitable antimycotics are for example amphoteri ryngeal cavity). Various formulations are provided in the cin B or nystatin. invention (e.g., Solid. Suckable or slowly dissolving formu 0019. An example of a suitable proteolytic enzyme is lation, semisolid formulation). lysozyme. BRIEF DESCRIPTION OF THE FIGURES 0020 Suitable ethereal oils are for example peppermint oil, thyme or Sage oils. 0007 FIG. 1 shows the course, over time, of the average 0021. The invention further relates to a pharmaceutical change in pain intensity (PID) for the period before taking composition containing ambroXol or one of the pharmaco the tablet (base line) up to 3 hours after taking the first logically acceptable salts thereof and one or more active suckable tablet containing 20 mg of ambroxol hydrochloride Substances, selected from the group consisting of lysozyme and placebo. hydrochloride, dipotassium glycyrrhizinate, ammonium gly 0008 FIG. 2 shows the course, over time, of the average cyrrhizinate, cetylpyridinium chloride, chlorpheniramine change in pain intensity (PID) for the period before taking maleate, noscapine, dequalinium chloride, dextromethor US 2007/0224267 A1 Sep. 27, 2007 phan, phenolphthalinate, potassium guaiacolsulphonate, dil 0033. The invention further relates to the use of a suck methylephedrine hydrochloride, chlorhexidine hydrochlo able tablet containing ambroXol based on Sugar as ride, and potassium cresolsulphonate. the matrix material, characterised in that it contains a pharmaceutically acceptable layered silicate and a polyeth 0022 Ambroxol is a metabolite of the secretolytic bro yleneglycol, optionally together with other pharmaceutical mhexine. The two active substances represent a very well excipients, taste or flavouring agents to prepare a pharma tolerated combination of active substances which positively ceutical composition for treating pain in the oral and/or influences the dual effect of ambroXol. pharyngeal cavity, selected from among acute Sore throat, 0023 The invention therefore also relates to a pharma aphthae, gingivitis, parodontopathies, pressure points ceutical composition consisting of ambroXol, bromhexine or caused by prostheses, pain after oro-pharyngeal interven the pharmacologically acceptable salts thereof and pharma tions, lesions on the mucous membrane in the oral and ceutical excipients, preferably with a ratio of ambroxol to pharyngeal cavity and herpes simplex in the oral and pha bromhexine in the range from 4:1 to 6:1, more preferably ryngeal cavity, most particularly for the treatment of acute 5:1. Sore throats. 0034. The invention further relates to the use of ambroxol 0024. A particularly preferred pharmaceutical composi for preparing a pharmaceutical composition with a pain tion is one wherein the single dose contains 15 to 50 mg of relieving effect lasting for a period of at least 3 hours, ambroxol, preferably 20 mg of ambroxol. preferably more than 3 hours, after administration. 0.025 The invention further relates to a solid, suckable or 0035. The invention also relates to the use of a pharma slowly dissolving form of a pharmaceutical composition ceutical composition containing ambroXol for preparing a containing ambroXol and one or more active substances pharmaceutical composition with a pain-relieving effect selected from among the antiseptics, vitamins, corticoids, lasting for a period of at least 3 hours, preferably more than antiinflammatories, antibiotics, antimycotics and proteolytic 3 hours, after administration. enzymes. 0036) The pharmaceutical composition according to the 0026. The invention further relates to the use of a phar invention is preferably administered 1 to 6 times, preferably maceutical composition as described above for preparing a 2 to 4 times a day. medicament for the treatment of pain in the oral and/or pharyngeal cavity, selected from among acute sore throat, 0037 Acids suitable for forming salts of ambroxol aphthae, gingivitis, parodontopathies, pressure points include for example , hydrobromic acid, caused by prostheses, pain after oro-pharyngeal interven Sulphuric acid, phosphoric acid, nitric acid, oxalic acid, tions, lesions on the mucous membrane in the oral and malonic acid, fumaric acid, maleic acid, tartaric acid, citric pharyngeal cavity and herpes simplex in the oral and pha acid, ascorbic acid and methanesulphonic acid, preferably ryngeal cavity, most preferably for treating acute Sore hydrochloric acid. throats. 0038. The activity of ambroxol according to the invention is intended to be illustrated by the following examples of 0027. The invention further relates to the use of a phar clinical trials which investigate the effectiveness of different maceutical composition consisting of ambroXol hydrochlo strengths of Suckable tablets containing ambroXol. These are ride, a flavouring, a lubricant, a matrix material, a Sweeten intended solely to illustrate the invention and are not to be ing agent and a polyethyleneglycol for preparing a regarded as limiting. pharmaceutical composition for the treatment of pain in the oral and/or pharyngeal cavity, selected from among acute Sore throat, aphthae, gingivitis, parodontopathies, pressure EXAMPLE 1. points caused by prostheses, pain after oro-pharyngeal inter Investigation of the Activity and Tolerance of ventions, lesions on the mucous membrane in the oral and Suckable Tablets Containing 20 mg of ambroxol pharyngeal cavity and herpes simplex in the oral and pha hydrochloride(trans-4-(2-amino-3,5-dibromobenzy ryngeal cavity, most preferably for treating acute Sore l)aminocyclohexano hydrochloride, CAS Reg. No. throats. 18683-91-5) Compared with a Placebo in Treating 0028 Suitable flavourings may be, for example, pepper Acute Sore Throats mint, eucalyptus or lemon, preferably peppermint flavour 0039. A multi-centred, prospective, placebo-controlled, ing. randomised double-blind trial was carried out over two 0029 Suitable matrix materials may be, for example, days treatment with up to 6 Suckable tablets containing calcium carbonate, calcium phosphate or , preferably ambroxol hydrochloride per day. sorbitol. 0040 Patients: 218 patients (97 men, 121 women) with an average age of 39.4+15 years (range from 17-81 years) 0030) Suitable sweetening agents may be, for example, were recruited; of these 215 patients were treated: 107 with saccharin, Saccharin Sodium, cyclamate, glycerol or Sugar, 20 mg of ambroxol and 108 with placebo. 26 patients preferably saccharin Sodium. stopped the treatment early (13 in each treatment group). 0.031) Suitable tablet lubricants may be, for example, The intent-to-treat (ITT) population consisted of 208 polyethyleneglycols, preferably Macrogol 6000. patients (105 treated with ambroxol and 103 given the placebo); 196 patients formed the per-protocol (PP) popu 0032 Suitable lubricants may be for example talcum or lation (97 with test substance and 99 with placebo). For the magnesium Stearate, preferably talc. drug safety analysis, all the patients treated were studied. US 2007/0224267 A1 Sep. 27, 2007

0041 Treatments: Double-blind treatment with up to 6 (SPID); moreover, the assessment of effectiveness and suckable tablets per day, which either contained 20 mg of tolerance by the patient at the end of each day of treatment. ambroxol or constituted a placebo (suckable tablet without the active substance, but with a marked flavour of pepper 0051 Results: All the treatments led to a reduction in the mint similar to the test Substance). intensity of pain; the average SPID, (SD) after the first 0.042 End points: The average pain reduction, weighted Suckable tablet was taken was 0.530.28 or 0.50-0.30 for 20 for time, during the first 3 hours after administration of the mg and 30 mg ambroXol hydrochloride, respectively, and first suckable tablet, standardised to the degree of initial pain 0.38+0.28 for placebo. The effect of the treatment was (SPID); moreover, the assessment of effectiveness and statistically significant. The Superiority of the active treat tolerance by the patient at the end of each day of treatment. ments over the placebo could be clearly demonstrated (95% 0.043 Results: In both treatment groups there was a confidence interval (CI) for the average differences between reduction in the intensity of pain; the average SPID, the groups treated with Suckable tablets containing 20 or 30 (+SD) after the first suckable tablet was 0.39+0.27 for 20 mg mg of ambroxol minus placebo: 0.08 to 0.23 or 0.05 to 0.20). ambroxol hydrochloride and 0.28+0.25 for placebo. At the end of each Successive day of ambulant treatment with up to 6 Suckable tablets per day a statistically signifi 0044) The superiority of the ambroxol over the placebo cantly larger number of patients reported a higher degree of was apparent from a statistically significant treatment effect (p=0.0029; 95% confidence interval for the average differ effectiveness for the active treatments with ambroxol hydro ence between the ambroXol treatment groups minus placebo: chloride than for the administration of the placebo. The test 0.04 to 0.18). At the end of each successive day of ambulant substance was found to be tolerated just as well as the treatment with up to 6 Suckable tablets a statistically sig placebo in all dosages. nificantly larger number of patients reported a higher degree of effectiveness for the active treatment with ambroXol 0052 Conclusion: The administration of suckable tablets hydrochloride than for the administration of the placebo. containing 20 or 30 mg of ambroxol hydrochloride to The test substance was found to be tolerated just as well as patients with acute sore throat has a markedly effective the placebo. pain-relieving effect which is superior to the inherently beneficial effect of sucking a placebo. Both doses were 0045 Conclusion: The administration of suckable tablets tolerated equally well. containing 20 mg of ambroxol hydrochloride to patients with acute sore throat has an effective pain-relieving effect 0053 FIG. 2 shows the course, over time, of the average which is superior to the inherently beneficial effect of change in pain intensity (PID) for the period before taking Sucking a placebo. the tablet (base line) up to 3 hours after taking the first 0046 FIG. 1 shows the course, over time, of the average suckable tablet containing 20 mg or 30 mg of ambroxol change in pain intensity (PID) for the period before taking hydrochloride and placebo. the tablet (base line) up to 3 hours after taking the first 0054 Ambroxol may be used on its own or combined suckable tablet containing 20 mg of ambroxol hydrochloride with other pharmacologically active substances. It may be and placebo. applied in any of the preparation forms which are Suitable for local use. Preparations Suitable for Sucking or dissolving EXAMPLE 2 slowly in the mouth include, for example, tablets or sweets Investigation of the Activity and Tolerance of based on Sugar or Sugar Substitutes or pastille-like products Suckable Tablets Containing 20 or 30 mg of with a gum arabic or gelatine base. ambroxol hydrochloride(trans-4-(2-amino-3,5-di 0055 Examples of semisolid preparations for application bromobenzyl)aminocyclohexano hydrochloride, to the oral mucosa include gels, for example, especially gels CAS Reg. No. 18683-91-5) Compared with a Pla based on cellulose or acrylate. cebo in Treating Acute Sore Throats 0056 Suitable solutions for spraying, gargling and rins 0047 A multi-centred, prospective, placebo-controlled, ing include aqueous preparations, advantageously with the randomised double-blind trial was carried out over three days treatment with up to 6 Suckable tablets containing addition of viscosity-increasing Substances such as modified ambroxol hydrochloride per day. celluloses, acrylic acid derivatives or polyvinyl compounds. 0.048 Patients: 331 ambulant patients with acute uncom 0057. In addition, the semisolid and liquid forms in plicated sore throats of at least moderate severity but with no particular may contain Sweetening agents and moisture bacterial pharyngitis were investigated. retainers such as glycols and Sugar alcohols, for example. 0049 Treatments: Double-blind treatment with up to 6 0058 All the forms are flavoured in the conventional Suckable tablets per day containing either 20 mg or 30 mg way, e.g. by the addition of ethereal oils. of ambroXol hydrochloride or constituting a placebo (Suck able tablet without the active substance, but again with a 0059. The preparations may be produced by methods marked flavour of peppermint similar to the test Substance). known in pharmacy. 0050 End points: The average pain reduction, weighted 0060. The following examples of pharmaceutical formu for time, during the first 3 hours after administration of the lations illustrate the present invention without restricting its first suckable tablet, standardised to the degree of initial pain Scope: US 2007/0224267 A1 Sep. 27, 2007

0061 Formulation 1) 0065 Formulation 5)

Suckable pastille per tablet Suckable pastille per pastille Ambroxol hydrochloride 20.0 mg dl-Methylephedrine Hydrochloride 6.25 mg ambroxol hydrochloride 20.0 mg Chlorhexidine Hydrochloride 5.0 mg Lactose 905.25 mg peppermint flavouring 16.0 mg Low-substituted Hydroxypropylcellulose 25.0 mg sorbitol 1373.5 mg Hydroxypropylcellulose 20.0 mg Peppermint flavour 16.0 mg Saccharin Sodium 0.5 mg Magnesium Stearate 2.5 mg Macrogol 6000 30 mg talc 60 mg 0.066 Formulation 6)

0062) Formulation 2) Suckable pastille per tablet Ambroxol hydrochloride 20.0 mg Ammonium glycyrrhizate 1.67 mg Suckable pastille per tablet Potassium Cresolsulphonate 30.0 mg Ambroxol hydrochloride 20.0 mg Lactose 884.83 mg Lysozyme hydrochloride 5.0 mg Low-substituted Hydroxypropylcellulose 25.0 mg Dipotassium glycyrrhizinate 2.5 mg Hydroxypropylcellulose 20.0 mg Cetylpyridinium Chloride 1.0 mg Peppermint flavour 16.0 mg Chlorpheniramine Maleate 1.0 mg Magnesium Stearate 2.5 mg Xylitol 920.5 mg D- 9.5 mg Polyvinylpyrrollidone 21.0 mg Stearic acid 10.0 mg 0067. The present invention is not to be limited in scope Peppermint oil 6.0 mg by the specific embodiments described herein, which are light anhydrous silicic acid 1.0 mg intended as single illustrations of individual aspects of the talc 1.0 mg invention, and functionally equivalent methods and compo magnesium Stearate 1.5 mg nents are within the scope of the invention. 0068 Indeed, various modifications of the invention, in addition to those shown and described herein will become 0063 Formulation 3) apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifica tions are intended to fall within the scope of the appended claims. Suckable pastille per tablet Ambroxol hydrochloride 20.0 mg 0069 Various patent applications and publications are NoScapine 5.0 mg cited herein, the disclosures of which are incorporated by Dequalinium Chloride 0.125 mg reference in their entireties. Sucrose (purified) 908.675 mg I-Menthol 1.0 mg Peppermint oil 0.6 mg Lemon flavour 3.6 mg 1-12. (canceled) Corn starch 30.0 mg 13. A method for the treatment of pain in the oral and/or Polyvinylpyrrollidone 21.0 mg pharyngeal cavity comprising administering ambroXol or Magnesium Stearate 10.0 mg one of the pharmacologically acceptable salts thereof, wherein the pain in the oral and/or pharyngeal cavity is selected from the group consisting of acute sore throat, 0064. Formulation 4) aphthae, gingivitis, parodontopathies, pressure points caused by prostheses, pain after oro-pharyngeal interven tions, lesions on the mucous membrane in the oral and pharyngeal cavity, and herpes simplex in the oral and Suckable pastille per tablet pharyngeal cavity. Ambroxol hydrochloride 20.0 mg 14. A pharmaceutical composition consisting of ambroXol Dextromethorphan phenolphthalinate 10.0 mg Potassium guaiacolsulphonate 23.3 mg or one of the pharmacologically acceptable salts thereof and Cetylpyridinium Chloride 1.0 mg one or more active Substances selected from the group Sucrose (purified) 869.7 mg consisting of corticoids, antibiotics, and antimycotics. Peppermint flavour 16.0 mg 15. A pharmaceutical composition consisting of ambroXol Corn starch 30.0 mg Polyvinylpyrrollidone 20.0 mg or one of the pharmacologically acceptable salts thereof and Magnesium Stearate 10.0 mg one or more active Substances selected from the group consisting of dipotassium glycyrrhizinate, ammonium gly cyrrhizinate, cetylpyridinium chloride, dequalinium chlo US 2007/0224267 A1 Sep. 27, 2007 ride, dextromethorphane, phenolphthalinate, potassium aphthae, gingivitis, parodontopathies, pressure points guaiacolsulphonate, chlorhexidine hydrochloride, and caused by prostheses, pain after oro-pharyngeal interven potassium cresolsulphonate. tions, lesions on the mucous membrane in the oral and 16. A pharmaceutical composition consisting of pharyngeal cavity, and herpes simplex in the oral and ambroXol, brom hexine or the pharmacologically acceptable pharyngeal cavity. salts thereof and pharmaceutical excipients thereof. 21. A method for treating pain in the oral and/or pharyn 17. The pharmaceutical composition according to one of geal cavity comprising administering a Suckable tablet con claims 14 to 16 which is solid, suckable or slowly dissolving taining ambroXol based on Sugar alcohols as the matrix in the oral and/or pharyngeal cavity. material, a pharmaceutically acceptable layered silicate, and 18. The pharmaceutical composition according to one of a polyethyleneglycol, optionally together with other phar claims 14 to 16 in the form of a gel. maceutical excipients, wherein the pain in the oral and/or 19. A method for treating pain in the oral and/or pharyn pharyngeal cavity is selected from the group consisting of geal cavity comprising administering a pharmaceutical com acute Sore throat, aphthae, gingivitis, parodontopathies, position according to one of claims 14 to 16, wherein the pressure points caused by prostheses, pain after oro-pharyn pain in the oral and/or pharyngeal cavity is selected from the geal interventions, lesions on the mucous membrane in the group consisting of acute sore throat, aphthae, gingivitis, oral and pharyngeal cavity and herpes simplex in the oral parodontopathies, pressure points caused by prostheses, pain and pharyngeal cavity. after oro-pharyngeal interventions, lesions on the mucous 22. The method according to claim 13 wherein a pain membrane in the oral and pharyngeal cavity, and herpes relieving effect lasts for a period of at least 3 hours after simplex in the oral and pharyngeal cavity. administration of ambroXol or one of the pharmacologically 20. A method for the treatment of pain in the oral and/or acceptable salts thereof. pharyngeal cavity comprising administering a pharmaceuti 23. The method according to claim 19, wherein a pain cal composition consisting of ambroXol hydrochloride, a relieving effect lasts for a period of at least 3 hours after flavouring, a lubricant, a matrix material, a Sweetening agent administration of the pharmaceutical composition. and a polyethyleneglycol, wherein the pain in the oral and/or pharyngeal cavity is selected from among acute sore throat, k k k k k