LV13113B - Ambroxol for the treatment of inflammation in the pharynx - Google Patents

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

LV 13113

Ambroxol for the treatment of inflammation in the pharynx

The invention relates to the use of ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanole) and the pharmacologically acceptable salts thereof for preparing a pharmaceutical composition for the treatment of inflammation in the pharynx.

Background to the invention

Antiinflammatory aģents for relieving pain in the pharynx often have the dravvback of side effects, e.g. in the form of gastrointestinal disturbances, allergies and local irritations in the case of topical preparations. No anti-inflammatory effect in the pharynx is known using pharmaceutical compositions containing exclusively conventional local anaesthetics as active ingredients like lidocaine and benzocaine.

It has been preclinical and clinically documented that ambroxol has a clear local anaesthetic and pain relieving effect.

The in vitro effect of ambroxol on the release and synthesis of cytokines involved in infiammatory diseases of the bronchopulmonary tract is described in the prior art.

There are many cases where substances vvhich have shovvn a particular anti-inflammatory effect in vitro but did not show the effect in vivo.

Ambroxol was shown to decrease the secretion of interleukin-2 (IL-2) and interferon-γ (INF-γ) by bronchoalveolar lavage celis and peripheral blood mononuclear celis stimulated with phythemagglutine (Pfeifer S, Zissel G, Kienast K, Muller-Quernheim J. EurJ Med Res 1997;2:129-132). IL-2 and INF-γ play a role in the course of chronic inflammation in the bronchoalveolar region. In a further study, Ambroxol was found to inhibit the production of the cytokines IL-1 and tumor necrosis factor α (TNF-α) in human mononuclear celis stimulated with lipopolysaccharide (Bianchi M, Mantovani A, Erroi A, Dinarello CA, Ghezzi P. Aģents Actions 1990;31:275-27)]. IL-1 and TNF-a are inflammatory mediators associated with pulmonary damage and lung fibrosis.

The effects seen in the aforementioned studies were interpreted as an anti-inflammatory effect of Ambroxol. 2

Hovvever, these results are contradictory to the in vitro findings of other authors, who stated that Ambroxol appears to enhance inflammatory responses through shifting the local balance of antiinflammatory IL-10 and inflammatory IL-12 to IL-12 dominance (Aihara M, Dobashi K, Akiyama M, Naruse I, Nakazavva T, Mori M. 5 Respiration 2000;67:662-671).

There are other examples that demonstrate that an in vitro effect on cytokine regulation does not correlate with the effects seen in vivo. For instance NSAIDs such as ketoprofen, were found to inducē the release of inflammatory TNF in vitro, but othervvise demonstrated clinical efficacy as anti-inflammatory compounds (Ghezzi P, 10 Melillo G, Meazza C, Sacco S, Pellegrini L, Asti C, Porzio S, Marullo A, Sabbatini V, Caselli G, Bertini R.. J Pharmacol Exp Ther 1998;287:969-974. No definite correlation could also be made betvveen in vivo anti-inflammatory animal data and in vitro inhibition of lipoxygenase / cyclogenase of compounds such as isoflavanes (Montandon JB, Zijlstra FJ, VVilson JH, Grandjean EM, Cicurel L. Int J Tissue React 15 1989;11:107-112).

The aim of the present invention is to prepare a well-tolerated active substance for the treatment of inflammation in the pharynx.

Description of the invention 20

Surprisingly, it has been found that, when administered locally , ambroxol has an anti-inflammatory effect on the pharyngeal mucosa.

The invention therefore relates to the use of ambroxol or one of the 25 pharmacologically acceptable salts thereof for preparing a pharmaceutical composition for the local treatment of inflammation in the pharynx.

The invention further relates to the use of a pharmaceutical composition containing ambroxol for preparing a medicament for the local treatment of inflammation in the pharynx. 30 Preferably the invention relates to the use of a pharmaceutical composition , vvherein the single dose contains 15 to 50 mg of ambroxol, preferably in form of its hydrochloride salt, most preferably 20 mg of ambroxol hydrochloride. LV 13113

More preferably the invention relates to the use of a solid, suckable or slowly dissolving formulation of a pharmaceutical composition, preferably to the use of lozenges.

Particularly preferred is the use of a liquid formulation of a pharmaceutical 5 composition in the form of a spray or gargle.

Further particu!arly preferred is the use of a pharmaceutical composition consisting of ambroxol hydrochloride, a flavouring, a lubricant, a matrix material, a svveetening aģent and a polyethyleneglycol.

The invention further relates to the use of a suckable tablet containing ambroxol 10 based on sugar alcohols as the matrix material, vvherein it contains a pharmaceutically acceptable layered silicate and a polyethyleneglycol, optionally together with other pharmaceutical excipients, taste or flavouring aģents for preparing a medicament fortreating inflammation in the pharynx.

The invention further relates to the use of ambroxol for preparing a pharmaceutical 15 composition for the reduction of redness in the throat associated with pharyngitis.

The invention further relates to the use of a pharmaceutical composition for preparing a medicament for the reduction of redness in the throat associated with pharyngitis. 20 Acids suitable for forming salts of ambroxol include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid and methanesulphonic acid, preferably hydrochloric acid. 25 The activity of ambroxol according to the invention is intended to be illustrated by the follovving three examples of clinical trials vvhich investigate 1. the inflammatory effect of Ambroxol Lozenges by measurement of the redness symptom and 2. the efficacy and tolerability of Ambroxol Lozenges relative to placebo in relieving the symptoms of sore throat of at least moderately severe 30 intensity in patients suffering from oro-pharyngeal catarrh accompanied by pain.

The examples are intended solely to illustrate the invention and are not to be regarded as limiting. 4

The first study was a multi-centre, prospective, placebo-controlled, randomized, double-blind trial involving two days of treatment with up to six lozenges containing 20 mg ambroxol hydrochloride per day.

Besides the primary endpoint, pain, which was reduced statistically significantly, also 5 the assessment of the redness of the pharyngeal mucosa was assessed at baseline and at day tvvo. 109 patients were treated with Ambroxol and 109 patients with placebo.

At baseline there was no difference betvveen the active treatment group and placebo; at visit tvvo (after tvvo days of treatment), in contrast, there was less redness in the īo active treatment group compared to placebo (p-value: 0.026) for Ambroxol Lozernges vs. placebo.

Two other confirmatory clinical trials were performed to investigate the efficacy and tolerability of Ambroxol Lozenges at doses of 20 mg ambroxol hydrochloride relative 15 to placebo in the same indication as in the first trial. The design was similar for both trials: multi-centre, prospective, placebo-controlled, randomized, double-blind trials involving three days of treatment with up to six lozenges containing 20 mg ambroxol hydrochloride per day.

In one study 111 patients were treated with Ambroxol Lozenges 20 mg vvhilst 108 20 patients were treated with placebo. At visit one there was no difference betvveen the active treatment and placebo; at visit tvvo (i.e. after three days of treatment) in contrast, there vvas less redness in the active treatment group compared to placebo (p-value: 0.010).

In the other study 128 patients vvere treated vvith Ambroxol Lozenges (20 mg) vvhile 25 1 27 patients vvere treated vvith placebo. The results regarding redness vvere similar to that of the former trial. At visit tvvo there vvas less redness in the active treatment group compared to placebo (p-value: 0.009).

As a result of the three confirmatory clinical trials the efficacy of Ambroxol Lozenges (20 mg) has been documented regarding pain relief in sore throat and decrease of 30 redness of the pharyngeal mucosa. Pain and redness are tvvo major symptoms of inflammation. Although the relieve of pain could at least partly be regarded as the local anaesthetic effect of ambroxol, by the decrease of redness Ambroxol Lozenges vvere clearly proven to feature anti-inflammatory properties clinically, in sore throat. This had not been demonstrated for the substance ambroxol before. 5 LV 13113

Figurē 1 shows the percentage of patients in relation to the redness of the throat for ali three studies.

Ambroxol may be used on its own or combined with other pharmacologically active 5 substances. It may be applied in any of the preparation forms vvhich are suitable for local use. Preparations suitable for sucking or dissolving slowly in the mouth include, for example, tablets or sweets based on sugar or sugar substitutes or pastille-like Products with a gum arabic or gelatine base.

Suitable Solutions for spraying, gargling and rinsing include aqueous preparations, īo advantageously with the addition of viscosity-increasing substances such as modified celluloses, acrylic acid derivatives or polyvinyl compounds.

In addition, the liquid forms in particular may contain sweetening aģents and moisture retainers such as glycols and sugar alcohols, for example.

Ali the forms are flavoured in the conventional way, e.g. by the addition of ethereal 15 oils. 6

The preparations may be produced by methods knovvn in pharmacy.

The following examples of pharmaceutical formulatīons illustrate the present 5 invention vvithout restricting its scope:

Example 1)

Suckable pastille per pastille 10 ambroxol hydrochloride 20.0 mg peppermint flavouring 16.0 mg sorbitol 1373.5 mg saccharin sodium 0.5 mg Macrogol 6000 30 mg 15 talc 60 mg Example 2) Suckable pastille per tablet 20 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 25 Xylitol 920.5 mg D-Mannitol 9.5 mg Polyvinylpyrrolidone 21.0 mg Stearic acid 10.0 mg Peppermint oil 6.0 mg 30 light anhydrous silicic acid 1.0 mg talc 1.0 mg magnesium stearate 1.5 mg 7 7 LV 13113

Example 3)

Sprav or qarqle q/100q Ambroxol hydrochloride 1.0 9 Sorbitol 30.0 g Glycerol 10.0 g Ethanol 5.0 g l-Menthol 0.01 g Peppermint oii 0.06 g Saccharine 0,03 g VVater 53.9 g 8 LV 13113

Patent Claims 1. Use of ambroxol or one of the pharmacologically acceptable salts thereof for 5 preparing a pharmaceutical composition for the local treatment of inflammation in the pharynx. 2. Use of a pharmaceutical composition containing ambroxol for preparing a medicament for the local treatment of inflammation in the pharynx. 10 3. Use of a pharmaceutical composition according to claim 2, characterised in that the single dose contains 15 to 50 mg of ambroxol. 4. Use of a solid, suckable or slowly dissolving formulation of a pharmaceutical 15 composition according to one of claims 2 or 3. 5. Use of a liquid formulation of a pharmaceutical composition according to one of claims 2 or 3 in the form of a spray or gargle . 20 6. Use of a pharmaceutical composition consisting of ambroxol hydrochloride, a flavouring, a lubricant, a matrix material, a sweetening aģent and a polyethyleneglycol according to one of claims 2 to 4. 7. Use of a suckable tablet containing ambroxol based on sugar alcohols as the 25 matrix material, characterised in that it contains a pharmaceutically acceptable layered silicate and a polyethyleneglycol, optionally together with other pharmaceutical excipients, taste or flavouring aģents for preparing a medicament for treating inflammation in the pharynx. 30 8. Use of ambroxol for preparing a pharmaceutical composition for the reduction of redness in the throat associated with pharyngitis. 9 9. Use of a pharmaceutical composition according to one of claims 2 to 7 for preparing a medicament for the reduction of redness in the throat associated with pharyngitis. 10 LV 13113

Abstract

The invention relates to the use of ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanole) and the pharmacologically acceptable salts 5 thereof for preparing a pharmaceutical composition for the treatment of inflammation in the pharynx. 11LV 13113

Figurē 1. Redness of the Pharyngeal Mucosa. Post Treatment.

Percentage of Patients (%) 00 - Day 3 Day 3 Day 2 p = 0.010 p = 0.009 p = 0.026 90 -

Not or At least Not or At least Not or At least Cate9ory slightly slightlv slightlv markedly red markedly red markedly red red red red * Ambroxol 20 mg ū Placebo

Claims (9)

Use of ambroxol or one of its pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for the topical treatment of inflammation in the throat. 5 Use of a pharmaceutical composition comprising ambroxol for the manufacture of a medicament for topical treatment of inflammation in the throat. Use of a pharmaceutical composition according to claim 2, characterized in that the single dose contains 15-50 mg of ambroxol. Use of a pharmaceutical composition according to any one of claims 2 or 3 in a solid, suction or slow-soluble form. Use of a liquid form of a pharmaceutical composition according to one of claims 2 or 3 in solution or aerosol form. Use of a pharmaceutical composition comprising ambroxol hydrochloride, a flavoring agent, a lubricant, a base material, a sweetener and a polyethylene glycol according to one of claims 2 to 2. 7. Ambroxol-containing suction tablets, wherein the use of sugar alcohols as a base material is characterized in that it comprises a pharmaceutically acceptable layered silicate and polyethylene glycol, optionally together with other pharmaceutical excipients, flavoring agents, for the preparation of a medicament for treating inflammation in the throat. Use of ambroxol for the preparation of a pharmaceutical composition for reducing pharyngitis associated redness in the throat. 30 Use of a pharmaceutical composition according to one of claims 2 to 7 for the preparation of a medicament for reducing pharyngitis-related redness in the throat.