Pharmaceutical Compositions for Use As Mast Cell Stabilizer Or an Antihistamine

Home , Mast cell stabilizer, Tramazoline

Europaisches Patentamt European Patent Office © Publication number: 0 571 670 A1 Office europeen des brevets

EUROPEAN PATENT APPLICATION

@ Date of publication of application: © Applicant: THE PROCTER & GAMBLE 01.12.93 Bulletin 93/48 COMPANY One Procter & Gamble Plaza © Designated Contracting States: Cincinnati Ohio 45202(US) AT BE CH DE DK ES FR GB GR IT LI LU NL PT SE @ Inventor: Bazin, Ann Louise 65 Holland Park London W11 3AH(GB) Inventor: Koochaki, Patricia Elaine 92141 Souffle Circle Cincinnati, Ohio 45242(US)

© Pharmaceutical compositions for the stabilization of mast cells or antihistamine activity comprising a bicyclic aromatic flavour compound as active ingredient or in combination with an auxiliary mast cell stabilizing ingredient.

Rank Xerox (UK) Business Services (3. 10/3.6/3.3. 1) 1 EP 0 571 670 A1 2

Field of the Invention binds strongly to the acid polysaccharide, leaving a weak negative charge, such that the histamine can This invention relates to pharmaceutical com- be easily displaced under the influence of appro- positions and to the use of bicyclic aromatic flavour priate metal cations. compounds in the manufacture thereof. In particular 5 Aromatic flavouring agents such as menthol, the invention relates to the use of a bicyclic ar- camphor and eucalyptol have been widely used in omatic flavour compound for the manufacture of a pharmaceutical decongestant compositions for the composition for use as a mast cell stabilizer or an treatment of the symptoms of coughs and colds. antihistamine. The invention further relates to the Menthol is the active component in peppermint oil use of a bicyclic flavour compound for the manu- io and it has been shown to offer significant symp- facture of a composition for treatment of seasonal tomatic improvement in patients with irritable bowel allergic rhinitis and a composition for the treatment syndrome (Proceedings of the BPS, 10-12 April, of perennial allergic rhinitis. A further aspect of the 1985, 293P). It is believed that menthol produces invention relates to a pharmaceutical composition inhibition of gastrointestinal smooth muscle by de- for use as a mast cell stabilizer or an antihistamine 75 creasing the influx of extra-cellular calcium through comprising a bicyclic aromatic flavour compound potential-dependent channels while having no ef- and sodium cromoglycate. The composition has fect on the intracellular mobilization of calcium. But improved efficacy for mast cell stabilization and there has been no indication in the art that any of antihistamine activity. the common flavouring compounds are useful per 20 se in stabilizing mast cells or regulating histamine Background of the Invention activity or that they are valuable for the treatment of allergic rhinitis and related diseases. Approximately 10 % of the population of the Sodium cromoglycate has been used as a pro- United Kingdom and the United States suffer from phylactic in the treatment of asthma and allergic seasonal allergic rhinitis (hay fever). The symptoms 25 rhinitis since the early 1970's. The precise mecha- of hay fever are nasal, ocular and palatial irritation, nism by which the sodium cromoglycate works is sneezing and hypersecretion following exposure to still not clear but it has been suggested that it acts allergens. In Europe the main allergens are grass by preventing the release of histamines. GB-A- and tree pollens, hence allergic rhinitis commonly 1,144,906 discloses the preparation of sodium occurs during the spring and summer months. The 30 cromoglycate. symptoms of hay fever are believed to be due to Many clinical studies in humans conducted the stimulation of H-1 receptors by histamine, fol- during the last 20 to 25 years have consistently lowed by reflex activation of parasympathetic ner- demonstrated that sodium cromoglycate is both ves causing further increases in nasal secretion safe and effective in reducing the severity of symp- and obstruction. Histamine is released in the tis- 35 toms associated with seasonal allergic rhinitis. sues by the antigen-antibody reaction. Convention- RD-319097 discloses solutions of sodium al antihistamines are histamine H-1 receptor an- cromoglycate incorporating an aromatic flavouring tagonists. They diminish or abolish the main ac- agent. Flavouring agents can be selected from tions of histamine on the body. They effect this by menthol, eucalyptol, camphor and methyl salicate, a mechanism that involves the occupation of recep- 40 the concentration said to be typically from 0.001 % tor sites in the effector cells to the exclusion of to 0.5 %. The concentration of sodium histamine. They do not prevent the production or cromoglycate is in the range from 0.1 % to 10 %. release of histamine. Accordingly, it is an object of the invention to Most of the tissue histamine is present in mast provide pharmaceutical compositions having im- cells. When antigen comes into contact with the 45 proved effectiveness in the treatment of allergic tissues, some of the mast cells are disrupted and rhinitis and as mast cell stabilizers and antihis- subsequently histamine is released from them into tamines. the surrounding tissues. Other substances such as prostaglandins, leukotrienes and other inflammatory Summary of the Invention intermediaries are also released. These, in turn, 50 cause cascade mechanisms which lead to inflam- The present invention relates generally to phar- mation and symptoms of the allergic response. The maceutical compositions containing certain ar- nervous system is also stimulated by some of omatic flavour compounds and to use thereof in the these intermediaries to cause vasodilatation and treatment of a number of disease states involving oedema. Acid sulphate-containing polysaccharides 55 the antibody-antigen immune response system. Ac- are also present in the large granules of the mast cording to one aspect of the present invention cells. Histamine is stored in the granules as an there is provided the use of a bicyclic aromatic ionic complex with a basic protein, which itself flavour compound for the manufacture of a corn-

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position for the stabilization of mast cells. Accord- compositions. ing to a second aspect of the invention there is The preferred auxiliary mast cell stabilizer in- provided the use of a bicyclic aromatic flavour gredient in the compositions of the present inven- compound as essential active ingredient in the tion is sodium cromoglycate. The auxiliary mast manufacture of an antihistamine composition. Ac- 5 cell stabilizer ingredient is preferably incorporated cording to another aspect of the invention there is in the compositions of the invention at a level of provided the use of a bicyclic aromatic flavour from about 0.1 % to about 10 %, preferably from compound as essential ingredient in the manufac- about 0.05 % to about 5.0 % by weight of com- ture of a composition for treatment of seasonal position. allergic rhinitis. Additionally, the invention further io The compositions of the present invention are provides the use of a bicyclic aromatic flavour preferably provided in the form of an aqueous compound as essential ingredient in the manufac- solution containing a solubilizing agent in order to ture of a composition for treatment of perennial solubilize the bicyclic aromatic flavour agent. The allergic rhinitis. preferred solubilizer of the present invention is a 4- According to a further aspect of the invention 15 (1 ,1 ,3,3-tetramethylbutyl) phenol polymer with there is provided a pharmaceutical composition for formaldehyde and oxirane. This is sold under the use as a mast cell stabilizer or antihistamine com- trade mark Tyloxapol(RTM).The solubilizer is gen- prising a) from about 0.1 % to about 10 % by erally present at a level of from about 0.1 % to weight of the composition of sodium cromoglycate, about 2 %, preferably from about 0.5 % to about b) from about 0.005 % to about 0.2 % by weight of 20 1 .0 % by weight of the compositions. the composition of bicyclic aromatic flavour com- The compositions may additionally comprise pound, and c) an aqueous carrier. an antihistamine selected from diphenhydramine The pharmaceutical compositions of the inven- hydrochloride, chloropheniramine, tion are preferably provided in the form of an chloropheniramine maleate, doxylamine succinate, isotropic aqueous solution, especially preferred 25 bromopheniramine maleate, terfenadine, cetirizine, embodiments additionally comprising a solubilizing astamizole, loratidine, azelastine, acrivastine and agent for solubilizing the bicyclic aromatic flavour clemastine, preferably chloropheniramine. A topical compound. The composition can be provided in the steroidal agent can also be added to the composi- form of an aerosol spray. tion, such as hydrocortisone, predonisone, All levels and ratios herein are given by weight 30 predonisolone, triaminolone, triamcinolone ac- of total composition, unless otherwise specified. etonide, dexamethasone, bunedoside, flunisolide, betamethasone, beclomethasone dipropionate and Detailed Description of the Invention beclomethasone, preferably beclomethasone. These additional materials can be generally added In accordance with the present invention a 35 in a level from about 0.01 % to about 5 % by bicyclic aromatic flavour compound is used for the weight of total composition. manufacture of a composition for mast cell sta- The pharmaceutical compositions can be com- bilization and antihistamine activity. In its composi- plemented by various optional ingredients including tion aspect, the bicyclic aromatic flavour compound one or more sequestering agents, preservatives, can be used in combination with an auxiliary mast 40 solvents and cationic surfactants. cell stabilizer ingredient or it can be present as the Suitable sequestering agents for incorporation sole or primary active ingredient. Where the herein include polycarboxylates, amino polycarbox- bicyclic aromatic flavour compound is used as the ylates, polyphosphates, polyphosphonates and sole or primary active antihistamine ingredient, aminopolyphosphonates such as however, the compositions of the invention are 45 ethylenediaminetetra-acetic acid (EDTA), preferably essentially free of vasoconstrictor de- diethylenetriaminepenta-acetic acid, citric acid, glu- congestant active materials, such as ox- conic acid, pyrophosphoric acid, etc. as well as ymetazoline. their water-soluble salts, especially the alkali metal, The bicyclic aromatic flavour compound can be ammonium and alkanol ammonium salts. Seques- selected from eucalyptol and camphor. The highly 50 tering agents are generally employed in amounts in preferred aromatic flavour compound for use in the the range from about 0.001 % to about 0.2 %, present invention is camphor. The aromatic flavour preferably from about 0.01 % to about 0.1 % by compounds are preferably incorporated in the com- weight of the final pharmaceutical composition. positions of the invention at a level in the range of The pharmaceutical compositions can addition- from about 0.005 % to about 0.2 %, more prefer- 55 ally include preservatives. These can be water- ably from about 0.05 % to about 0.1 % by weight soluble or solubilizable preservatives such as of final composition. The aromatic flavour com- DMDM Hydantoin(RTM), Germall(RTM) 115, methyl, pound additionally acts as a flavouring agent in the ethyl, propyl, and butyl esters of hydrobenzoic

3 5 EP 0 571 670 A1 6 acid, benzoic acid, Euxyl(RTM) K400, Bronopol(RTM) - The compositions of this invention can option- (2-bromo-2-nitropropane-1 ,3-diol), sodium benzo- ally contain one or more other known therapeutic ate, chlorhexadine, benzalkonium chlorides and 2- agents, particularly those commonly utilized in phenoxyethanol, parabens, benzyl alcohols, chlor- cough/cold preparations, such as pharmaceutically- butol, phenoxyethanol, Cetrimide, potassium sor- 5 acceptable decongestants, analgesics and expec- bate and thiomersal. A preferred preservative for torants. Suitable decongestants include, for exam- inclusion in the present invention is thiomersal. In ple, pseudoephedrine hydrochloride, general, amounts of from about 0.0005 % to about pseudoephedrine, phenylephedrine hydrochloride, 0.05 % are suitable herein with amounts of from phenylephrine, ephedrine hydrochloride, phenyl- about 0.001 % to about 0.01 % being preferred. io propanolamine, ephedrine sulphate, oxymetazoline, Additionally, solvents can be added to the xylometazoline, antazoline, naphazoline and compositions of the invention. Suitable solvents tramazoline; analgesics include acetaminophen and encompass lower alkyl alcohols, diols and polyols ibuprofen; while suitable expectorants include containing from one to six carbon atoms, preferably glyceryl guaiacolate, terpin hydrate and ammonium from two to four carbon atoms, for example, is chloride. ethanol, propylene glycol, isopropanol, butanol, In preferred embodiments of the invention the glycerol, etc. The solvent can be present in an compositions are preferably provided in the form of amount from about 0.1 % to about 50%, preferably a preferably pump-actuated aerosol spray. Spray from about 1 % to about 20 % by weight of the compositions herein preferably have a viscosity in composition. The balance of the composition is 20 the range from about 1 to about 100 cps, more water. preferably from about 1 to about 50 cps. Viscosity Cationic surfactants can be added to the com- is measured using a Brookfield RVT, Spindle RV1 positions for their germicidal activity. Suitable at 100 rpm and 25 °C. The spray pump for use in cationic surfactants are generally quaternary am- the adminstering of unit dosages of pharmaceutical monium compounds such as the alkylarylether 25 compositions of the present invention is preferably dimethylbenzylammonium chlorides, for example, of a finger actuated pump design. The composi- 2-[2-(p-octylcresoxy) ethoxy] ethyl dimethylben- tions are applied intra-nasally in a unit dosage zylammonium chloride. This is commercially avail- containing from about 0.01 mg to about 0.1 mg, able under the name methylbenzethonium chloride preferably from about 0.02 mg to about 0.06 mg of or Hyamine(RTM) 10X. The corresponding p-octyl- 30 camphor per unit dose and from about 1 mg to phenoxy derivative of this compound is commer- about 10 mg, preferably from 2 mg to 6 mg of cially available as benzethonium chloride, and is auxiliary mast cell stabilizer per unit dose. In the also suitable for the present purpose, as are the preferred spray pump device there are approxi- alkyldimethylbenzylammonium chlorides available mately 1 to 3 sprays per unit dose. under the name benzalkonium chloride. Other suit- 35 able cationic surfactants include alkyltrimethylam- Mast Cell Stabilization Test monium chlorides of which cetyltrimethylam- monium chloride is commercially available under Peritoneal rat mast cells are collected from 250 the trade name Cetab(RTM);alkyldime- to 300 g Wistar male rats by the following proce- thylethylammonium halides; alkylpyridinium chlo- 40 dure. Following sacrifice, each rat is injected into ride, for example, cetylpyridinium chloride; al- the peritoneal cavity with 10 ml of ice cold HEPES- kylimidazolinium chloride such as alkylhydrox- buffered salt solution (HBSS), pH 7.2, containing 5 yethylimidazolinum chloride; alkyldimethyldich- U/ml heparin. The HBSS contains 137 mM of KCI, lorobenzylammonium chlorides; acylcolaminofor- 10mM HEPES, 5mM D-glucose, 2.7 mM KCI, 0.4 mylinethyl pyridinium chlorides available under the 45 mM NaH2PO+, 0.5 mM MgCI2 and 1 % foetal calf name of Emulsept(RTM); and alkylarylmethyl- serum (FCS). The abdomen is massaged gently for pyridinium chlorides such as polyalkylnaphthalene 2 to 3 minutes and then an incision is made in the methylpyridinium chloride available under the trade abdomen, the buffer removed by a pipette, and the name Emcol(RTM). The term "alkyl" in the afore- peritoneal cavity lavaged twice with ice-cold HBSS. mentioned cationic surfactants refers to alkyl radi- 50 The extract is then centrifuged at 200 rpm for 10 cals containing from eight to eighteen carbon minutes at 20 °C to collect the peritoneal mast atoms, preferably from ten to sixteen carbon cells. These cells are then suspended again in atoms, and mixtures thereof, this being the range in HBSS. A count of cells present is made using an which quaternary ammonium compounds are con- aliquot of this suspension by staining with Kimura sidered to have good germicidal activity. These 55 metachromatic stain. Typically, about 1.2 to cationic surfactants can be present in a range from 1.7x10G mast cells are collected from each animal. about 0.001 % to about 0.1 % by weight of com- The rat mast cells are then activated using a position. Compound 48/80 in the presence of the test ar-

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omatic and antihistamine compounds and 0.015 % camphor histamine-release measured as follows. 720 M.I al- 0.025 % menthol iquots containing 9 x 10* mast cells at 37 °C are 0.0075 % eucalyptol added to vials containing various combinations of 2 % sodium cromoglycate aromatic flavour compounds. The concentrations of 5 0.002 % thiomersal (preservative) tyloxapol, menthol, camphor, and eucalyptol are 0.05 % EDTA 0.7 %, 0.025 %, 0.015 %, and 0.0075 % respec- 0.7 % tyloxapol solubizer tively. The solutions are incubated for about 10 and water to 100 %. minutes before 200 M.I aliquots are added to tubes containing 25 u.l of Compound 48/80, 25 u.l of io Example 2 sodium cromoglycate and/or buffer, giving a concentration of Compound 48/80 and sodium A second composition is prepared with the cromoglycate in the tubes of 0.1 g/ml and 0.005 % following formula: respectively. The histamine release reactions in the 0.015 % camphor tubes is terminated after 10 minutes (37 °C) by 15 0.002 % thiomersal adding 750 M.I of ice-cold HBSS and centrifuging 0.06 % EDTA the resulting solution for 10 minutes at 2000 rpm at 0.8 % tyloxapol solubilizer 4°C. The histamine released by stimulus and the and water to 100 %. total cell histamine content are respectively deter- mined by assaying the supernatant liquid after 20 Example 3 acidification with 5 % trichloroacetic acid (TCA) and by disintegrating the cells in 5 % (TCA) fol- A third pharmaceutical composition is prepared lowed by analysis by automated spectrofluoreme- having the following ingredients: try. 0.018 % camphor 25 2.3 % sodium cromoglycate Results 0.003 % thiomersal 0.06 % EDTA i) Induced Histamine Release 0.7 % tyloxapol solubilizer and water to 1 00 % The results from pretreating the rat peritoneal 30 mast cells with various combinations of aromatic Example 4 compounds showed that at the concentrations used in the experiment, sodium cromoglycate, menthol, A fourth composition is prepared as follows: camphor and eucalyptol did not induce release of 0.008 % eucalyptol histamine, while tyloxapol did induce net histamine 35 0.002 % thiomersal release (5.18 ± 1.08 %). (The net histamine release 0.07 % EDTA induced by compound 48/80 at the concentration 0.7 % tyloxapol solubilizer used (0.1 u.g/ml) was about three times the net and water to 1 00 % histamine release induced by tyloxapol (15.07 ± 2.0 The pharmaceutical compositions of the above %)). 40 Examples demonstrate effective mast cell stabilization and antihistamine activity. ii) Histamine Release Inhibition Claims In the presence of 100 M.M of sodium cromoglycate, Compound 48/80-induced histamine 45 1. The use of a bicyclic aromatic flavour com- release was inhibited by 67 % and tyloxapol-in- pound for the manufacture of a composition for duced histamine release by 152 %. In a series of the stabilization of mast cells. five experiments, camphor at 0.015 % was found to inhibit histamine release by 45 % against Com- 2. The use of a bicyclic aromatic flavour compound 48/80 and tyloxapol-induced histamine re- 50 pound as essential active ingredient in the lease. Eucalyptol at 0.0075 % gave a 9 % (non- manufacture of an antihistamine composition. significant) inhibitory effect. Menthol at 0.025 % was not effective. 3. The use of a bicyclic aromatic flavour compound as essential active ingredient in the Example 1 55 manufacture of a composition for treatment of seasonal allergic rhinitis. Pharmaceutical compositions of the invention are prepared with the following formula:

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4. The use of a bicyclic aromatic flavour com- tetramethylbutyl) phenol polymer with formal- pound as essential active ingredient in the dehyde and oxirane. manufacture of a composition for treatment of perennial allergic rhinitis. 16. A pharmaceutical compostion according to any 5 of claims 10 to 15 in the form of an aerosol 5. The use according to any of claims 1 to 4 spray. wherein the composition comprises the bicyclic aromatic flavour compound as the sole or primary active ingredient. w 6. The use according to any of claims 1 to 5 wherein the composition is essentially free of vasoconstrictor decongestant active materials.

7. The use according to any of claims 1 to 6 15 wherein the composition is in the form of an aqueous solution comprising the bicyclic aromatic flavour compound and a solubilizer therefor. 20 8. The use according to any of claims 1 to 7 wherein the bicyclic aromatic flavour agent is selected from camphor, eucalyptol and mixtures thereof. 25 9. The use according to claim 8 wherein the aromatic flavour agent is camphor.

10. A pharmaceutical composition for use as a mast cell stabilizer or antihistamine comprising 30 a) from 0.1 % to 10 % by weight of the composition of sodium cromoglycate, b) from 0.005 % to 0.2 % by weight of the composition of bicyclic aromatic flavour compound, and 35 c) an aqueous carrier.

11. A pharmaceutical composition according to claim 10 wherein the bicyclic aromatic flavour compound is selected from camphor, eucalyp- 40 tol and mixtures thereof.

12. A pharmaceutical composition according to claim 11 wherein the bicyclic aromatic flavour compound is camphor. 45

13. A pharmaceutical composition according to claim 11 or 12 in the form of an isotropic aqueous solution. 50 14. A pharmaceutical composition according to any of claims 11 to 13 additionally comprising an agent for solubilizing the bicyclic aromatic flavour compound in the aqueous carrier.

15. A pharmaceutical composition according to claim 14 in which the agent for solubilizing the bicyclic aromatic compound is 4-(1, 1,3,3-

6 Patent PARTIAL EUROPEAN SEARCH REPORT Application rNumoer J) European Office which under Rule 45 of the European Patent Convention shall be considered, for the purposes of subsequent proceedings, as the European search report EP 9Z 3U 4/11

DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant iXAsairnAiwr* ur inn Category of relevant passages to claim APPLICATION qnt. CI. 5) vol. 1-2, [-16 X,Y rAKEDA KENKYUSHOHO, 40, nos. A 61 K 31/12b S. NAGASHIMA et al.: L981, pages 27-36; A 61 K 31/075 substances with 'Isolation of A 61 K 31/35 inti-histamine like activity from 'Shi n-i 1,11 * Page 35, table V: "Cineol, Camphor" *

3ATENT ABSTRACTS OF JAPAN, vol. 16, no. L-9 190 (C-937), 8th May 1992; & JP-A-4 026 519 (LOTTE CO., LTD) 29-01-1992 * Abstract *

'ATENT ABSTRACTS OF JAPAN , vol. 16, 10. L-9 L83 (C-936), 6th May 1992; & JP-A-4 D23 367 (LOTTE CO., LTD) 28-01-1992 * Abstract *

SEARCHED (Int. C1.5)

A 61 K

INCOMPLETE SEARCH The Search Division considers that the present European patent application does not comply wnn the provisions of the European Patent Convention to such an extent that it is not possible to carry out a meaningful search into the state of the art on the basis of some of the claims Claims searched completely : Claims searched incompletely : 1-16 Claims not searched : Reason for the limitation of the search: Due to the aspecificity of the expression "a bicyclic aromatic flavour" the search for the claims containing such expression cannot be complete.

Place of starch Date of completion of tne searcn Ejuunincr THE HAGUE 20-01-1993 GERLI P F M CATEGORY OF CITED DOCUMENTS I : theory or principle underlying tne invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons A : technological background O : non-written disclosure & : member of the same patent family, corresponding P : intermediate document document Page z

European Patent PARTIAL EUROPEAN SEARCH REPORT Application Number Office EP 92 30 4711

LLAasiri^Aiiui^ ur inr. DOCUMENTS CONSIDERED TO BE RELEVANT APPUCATION Out. CI. 5) Citation of document with indication, where appropriate, Relevant Category of relevant passages to claim [. ALLG. MED. , vol. 55, no. 9, 1979, -9 >ages 599-603, Hippokrates Verlag GmbH, Stuttgart, DE; A. BACKHAUS et al . : 'Schnupfenspray Larylin" ' Abstract; page 600, left-hand column, lines 33-40 *

)E-A-1 807 747 (E. DIJK) -9 * Page 3, lines 11-14 *

ILINICAL ALLERGY, vol. 10 (suppl), LO-16 L980, pages 481-489, Blackwell scientific Publications; R.E.C. \LT0UNYAN: "Review of clinical activity ind mode of action of sodium SEARCHED (Int. C1.5) :romoglycate" * Whole document *

JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL LO-16 HEALTH, vol. 18, 1986, pages 91-101, Hemisphere Publishing Corp.; L.G. :0CKERHAM et al . : "Di sodium :romoglycate, a mast-cell stabilizer, alters postradiation regional cerebral alood flow in primates" * Whole article *