AU656775B2 - Novel taurine-based pharmaceutical composition for administration by inhalation - Google Patents

Abstract

Form of taurine administration giving rise to a novel therapeutic use. The pharmaceutical composition contains taurine or hypotaurine in combination with means for its administration by inhalation, especially in aerosol form, where the taurine concentration is between 5 g/1 and 50 g/1 of solvent. Application in the treatment of asthma and conditions affecting the respiratory tract.

Description

OPI DATE 02/11/92 AOJP DATE 10/12/92 APPLN. 1) i66139 92 6 PCT NUIMBER PCI/FR92/00282

DEMANDEDI

DE BREVETS (PCT) (51) Classification Internationale des brevets 5 (11) Num~ro de publication internationale: WO 92/171701 A61K 31/185, 9/72 Al (43) Date de publication internationale: 15 octobre 1992 (15.10.92) (21) Numniro de la demande internationale: PCT/FR92/00282 (81) Etats d~signis: AT (brevet europ~en), AU, BE (brevet europ~en), BR, CA, Cl- (brevet europ~en), DE (brevet euro- (22) Date de d~p6t international: 27 mars 1992 (27.03.92) p~en), DK (brevet europ~en), ES (brevet europ~en), FR (brevet europ~en), G'S (brevet europ~en), GR (brevet europ~en), IT (brevlet europ~en), JP, KR, LU (brevet Donn~es relatives i la prioriti: europ~en), MC (brevet europ~en), NL (brevet europ~en), 91/03693 27 mars 1991 (27.03.91) FR NO, RU, SE (brevet europ~en), US.

(71) Deposant (pour tous les Etats d~sign&~ sauf US): *A-Tf- Publi&e -VE-E-SFj-.[FR/FR]; 70, rue du Gouverneur-G~n&- Ai'ec rapport de rechierche internationale.

ral-Eb,(u&, F-92 130 Issy-les-Moulineaux (FR).

(72) Inventeur; et Invernteur/D~posant (US settlement) COVARRUBIAS, J& sus [MX/ITJ; Via G. Bechi, 3, I-Florence 667 (74)Mandataires: L'HELGOUALCH, Jean etc. Cabinet Sueur JiHelgoualch, 78, rue Carnot, F-95240 Cormeilles-en-Pearisis (FR).

(54) Title: NOVEL TAURINE-BASED PHARMACEUTICAL COMPOSITION FOR ADMINISTRATION BY INHALA-

TION

(54)Titre: NOUVELLE COMPOSITION PHARMACEUTIQUE A BASE DE TAURINE POUR L'ADMINISTRATION PAR INHALATION (57) Abstract Form of taurine administration giving rise to a novel therapeutic use. The pharmaceutical composition contains taurine or hypotaurine in combination with means for its administration by inhalation, especially in aerosol form, where the taurine concentration is between 5 g/l and 50 g/l of solvent. Application in the treatment of asthma and conditions affecting the respiratory tract.

(57) Abr~g6 L'invention concerne une forme d'administration de !a taurine procurant une nouvelle indication th~rapeutique. La composition pharmaceutique contient de la taurine ou de l'hypotaurine en combinaison avec, des moyens pour son administration par inhalation, en particulier sous forme d'a~rosol, Ia concentration de la taurine 6tant comprise entre 5 g/l et 50 g/l de solvant, Application pour le traitement de l'asthme et des affections des voies respiratoires.

Novel taurine-based pharmaceutical composition for administration by inhalation The present invention relates to a new form of administration of taurine and hypotaurin, providing a new therapeutic indication, and more particularly a new therapeutic application of taurine and hypotaurine by inhalation, namely by administration as aerosol, for the treatment of asthma and various respiratory failures, induced by atmospheric pollution, of certain hyper-reactive patients.

Taurine, or 2-aminoethanesulfonic acid, is an amino acid with a low toxicity, which properties have been described in a number of publications. Taurine is not often used as a drug, and its use in therapy has been described in the literature only in the treatment of heart failure.

Some taurine derivatives have also been described, as well as the pharmacological properties thereof, and, for example, European patent EP 307.788 relates to a taurine amide having mucolytic, hepatoprotective, detoxicant, and normolipemizing properties. Some other taurine amides, useful as leucotrienes antagonists, are described in Japanese patent application JP-A-03.068549.

A number of studies have been performed for several years, on the effects of atmospheric pollution, namely by sulfur dioxide, nitrogen dioxide, carbon monoxide, organic fumes, ozone, etc, which are in part responsible for diseases such as chronic bronchitis, amphysema or asthma. More particularly, it has been noted that the development of such diseases is more important in industrialized countries suffering from a large atmospheric pollution, namely in urbanized areas where the pollution resulting from the exhaust gases of vehicles is combined with that of industrial plants. It has also been shown that an increase in the content of nitrogen dioxide in the air induces an increase in the number of persons suffering from asthma crisis in the population breathing such air.

Besides, it has been demonstrated that a long exposure to nitrogen dioxide induces an inflammation of the bronchioles, the alveolar ducts and the peribronchiolar alveoli of hamsters, as well as alteration and proliferation of epithelial cells.

This is probably due to the fact that nitrogen dioxide is an oxidizing agent, as are carbon dioxide and sulfur dioxide, which interacts with the cellular membrane according to a mechanism which, however, is not yet clearly explained.

It is known that the administration of certain compounds having an anti-oxidizing action or a free radicals scavengering action allows for some protection against such injury. For example, some favorable results have been observed during experimentations on laboratory models, with vitamin E (alpha-toccpherol), glutathione, dimethylsulfoxide or N-acetylcystein.

However, problems resulting from toxicity have not yet been resolved, and, more particularly, although vitamin E has a free radical scavengering action, it does not give any effective protection against oxidizing agents such as nitrogen dioxide or sulfur, and does not improve the epithelial barrier of bronchi.

Thus neither vitamin E, nor other free radicals scavengers such as DMSO, -can modify the hyper-reactivity of certain patients, and no satisfactory protection is obtained.

The use of cromoglycic salts, such as the disodium salt, has also been suggested in the treatment of asthma having an allergic origin. For example, the administration of sodium cromoglycate results in a stabilization of the bronchial epithelium, but it does not provide any protection against oxidizing pollutents and free radicals initiators.

A number of studies have been carried out to try to develop some compounds or compositions which are both free radicals scavengers and antioxidants, and which stabilize and protect the alveolar and bronchial epithelium, so as to provide a satisfactory protection of the respiratory ducts against the diseases induced by pollution.

Experimentations carried out by applicant have now revealed that the administration of taurine or hypotaurine by inhalation, namely under the form of aerosol, can be an excellent prevention treatment against diseases of respiratory ducts, more particularly a treatment of asthma, and also certain diseases induced by atmospheric pollution indicated above, such as chronic bronchitis and amphysema, whilst other forms of administration are not efficient.

Thus, one object of the present invention is a new application of taurine and hypotaurine as aerosol, for the treatment of diseases of respiratory ducts, more particularly for the prevention treatment of asthma and diseases induced by atmospheric pollution. Accordingly, the new pharmaceutical composition of the invention comprises taurine or hypotaurine in combination with means for the administration thereof by inhalation.

The clinical experimentations performed show that the administration of taurine by inhalation, under the form of aerosol, produces a significant decrease in the bronchospasms induced by the test of nebulization of distilled water, and more particularly provides a protective effect in the induced asthmatic reactions.

The results of such experimentations show that the new composition comprising taurine or hypotaurine according to the invention, when administered by aerosol, can be used in a new and unexpected indication, i. e. the basic and prevention treatment of diseases of respiratory ducts, more particularly asthma, with a satisfactory efficiency, without any adverse secondary effect.

Such results can be obtained according to the present invention by using taurine (2-amino-ethane sulfonic acid) as well as hypotaurine (2-amino-ethane sulfinic acid) by inhalation, preferably in aerosol, whilst no favorable result can be obtained in the case of administration under the form of drinkable solute or intravenous injection.

In accordance with the present invention, taurine or hypotaurine is dissolved in an appropriate solvent, and is preferably in the form of aerosol, in a convenient container, which allows to produce a nebulisate which is thrown into the respiratory ducts, i. e. the mouth and the trachea of the patient to be treated.

The solvent to be used for preparing the taurine solution according to the invention is selected from usual solvents which are pharmaceutically acceptable, but an aqueous solution is preferably used.

The taurine or hypotaurine concentration in the solution can be comprised between 5 g/l and 50 g/l of solution, and preferably between 15 g/l and 25 g/l.

The Thega propeller can be for example a freon as currently used in the technique of aerosols.

The doses of taurine administered by aerosol according to the invention are comprised between about 5 mg and 20 mg per day and per kg of weight, the unitary doses are of about 100- 500 mg, and the number of inhalations per day is between 3 and in the case of a patient of adult age.

The efficiency of the taurine or hypotaurine composition according to the present invention has been controlled by an experimentation conducted with 9 patients from 10 to 40 years old, suffering from chronic asthma, in the conditions indicated hereinafter.

Asthma crisis are induced by a test consisting in inhaling ultrasonic nebulized distilled water, and the spirometric values of the patients are measured before and immediately after inhalation of distilled water. The same test is repeated after a delay of at least 3 to 4 days, but about 30 minutes after inhalation of 250 mg of taurine by aerosol, according to the present invention, and the spirometric measures are again conducted; the results are statistically processed.

The results show that in the first test, without inhalation of taurine by aerosol, there is a significant decrease in the spirometric values of the patients, which corresponds to a bronchial instability which is a characteristic of asthma.

Thus, the FVC parameter is decreased from 3.32 to 2.64. In contrast, after inhalation of taurine, the same parameter is not significantly modified (3.47 before inhalation of distilled water, and 3.15 after inhalation).

The same experiment is performed with two groups of patients; the first group receives taurine by aerosol in accordance with the present invention (administered dose: 125 mg whilst the second group receives taurine under the form of dietary solution (administered dose: 500 mg).

The results obtained show that only the first group resist to test of inhalation of distilled water which induces the bronchospasm.

The above results demonstrate that the composition comprising taurine or hypotaurine according to the present invention, administered under the form of aerosol, allows an efficient action, as preventive treatment, against asthma crisis, and more generally against respiratory diseases induced by atmospheric pollution.

A comparative study is carried out under the same conditions, where the patients are treated by inhalation of taurine in one group, and by an aerosol of disodium cromoglycate, in the second group, according to the usual technique. It is noted that a better therapeutic efficacity results from the inhalation of taurine.

Claims (7)

1. New pharmaceutical composition for the treatment of asthma and diseases of respiratory ducts, which comprises taurine or hypotaurine in combination with a pharmaceutically acceptable solvent suitable for administration thereof by inhalating means. 0 )"LS~u 51 2/94SPECI.H,5 asthma and diseases of respiratory duct rized in that it comprises tauri aGFuri nne in combination with means

2. New composition according to claim 1, characterized in that it comprises means for the administration of taurine or hypotaurine as aerosol.

3. New composition according to any of the preceding claims, characterized in that it comprises taurine or hypotau- rine in solution in an appropriate solvent, in combination with $9s a~ propeller.

4. New composition according to claim 3, characterized in that the taurine concentration is comprised between 5 g/l and 50 g/1 of solvent. New composition according to any of claims 3 and 4, characterized in that it comprises an aqueous solution of taurine. of a pharmaceutical composition for oF n by inhala- tion for the t asthma and diseases of respiratory -7-

6. A method for the treatment of asthma and/or diseases of the respiratory tract comprising administering by inhalation a pharmaceutically effective amount of taurine or hypotaurine. DATED this 21st day of June 1994. LABORATOIRE NATIVELLE By their Patent Attorneys: CALLINAN LAWRIE 4 4 4 4 4 4** 0 4 4 S 54 4 LL- INTERNATIONAL SEARCH REPORT International application No. PCT/FR92/00282 A. CLASSIFICATION OF SUBJECT IMATTER Int. Cl. 5 A61K 31/185 A61K 9/72 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int. Cl. 5 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A STN International Information Services, Data Base: 1,6 Chemical Abstracts, Vol.115, No.9, access number 92274m, (Columbus, Ohio, US), JP, A, 03068549 (YAMANOUCHI PHARMACEUTICAL CO.,LTD) March 1991, see abstract (cited in the application) A EP, A, 0307788 (RICERCHE DI SCHIENA) 22 March 1989, 1,6 see claims 1,5-6; column 1, lines 43-46; column 2, lines 23-25 (cited in the application) Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: laterdocument publishedafterthe international filingdateorpriority A!date and not in conflict with the application but cited to understand document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance earlier document but published on orafter the international filing date document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other considered to Involve an inventive step when the document is means combined withone or more othersuch documents, such combination n .being obvious t9 a person skilled in the art document published prior to the international filing date but later than en o ou t ero se n te a the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 17 June 1992 (17.06.92) 10 July 1992 (10.07.92) Name and mailing address of the ISA/ Authorized officer European Patent'Office Facsimile No. Telephone No. Form PrrS A rn1f (secnad sheet (J'ilv 19921 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. FR 9200282 SA 58804 This annex lists the patent family members relating to the patent documents cited in the above-mentioned internatonal search report. The members are as contained in the European Patent Office EDP file on 29/06/92 The European Patent Office i in no way liable for these particulars which are merely given for the purpose of information. EP-A- 0307782 22-03-89 JP-A- 1199961 11-08-89 US-A- 4840964 20-06-89 SFor more detaits abut this annex ee Offidcal Journal of the Eurpean Patent Office, No. 12/82 RAPPORT T)E RECHERCHE INTERNATIONALE Domastic Internaionale No PCT/FR 92/00282 1. CLASSEMENT DE L'INvENTION (si plusisurs rymboles de classification son: applicables, leo Indiquef tous) I Selon Is classification intersatlonale des bres'ets (013I) oe i la fois selon to classification ailionale et It C11I A 61 K 31/185 A 61 K 9/72

11. DOMAINES SURK LESQUELS LA REO{ERQCME A PORTE Documentation minimale consliabel Systime de classification Symboles de clssilfication A 61 K Documsentation consulikn autre que Ix documentat~on minimale dons la mesone o6 di tels documents font partle des inmaines sur lesquels is reclserclse pon# Ml. DOCUMEN4TS CONSIDESES COMM PERTINENTS' 0 Identification des documents tks, avoc indication, ai akessaire'iZ No. des nevendicatlons A STN International. Information Services, Base de 1,6 Donnees: Chemical Abstracts, vol. 115, no. 9, numdro d'accbs 92274m, (Columbus, Ohio, US), &t JP,A,03068549 (YAMANOUCHI PHARMACEUTICAL CO., LTD) 25 mars 1991, voir l'abrdgd (citde dans la demande) A EP,A,0307788 (RICERCHE DI SCHIENA) 1,6 22 mars 1989, voir les revendications 1,5-6; colonne 1, lignes 43-46; colonne 2, lignes 23-25 (citde dans la demande) Catonies sp~cales ds documents citk=1 -r document alirieur pubi& posthrlurssoent A Is date de 440ts lnternaulonal ou i Is date de prinniti cc n'appsstenen,.nt pas W' document d~klaissant rk4at ginkai do tecnique, in I ritat do Is technique perinent, soils citt pout aotaprendre cotsldd commo partlcallkwo'en at iment is priucipe ou Is thiorit copstibuant Is but di riovention IV document iatirlmr, mtals pablik A La date do 446~t Laterna. -A document paicullinment pertinent; inveatIon rei'endi- tinsel Cu -s nei daie fudj e o pit re cos14krik comm. souselle ou comme document poumat Jlaer an Acute ur Mae Nta Icatido ismiiqsint orns actlsith ioaieor~ pricilt ou clt6 pour ddtarnasixI data it pobliloa Wan Y' document parteildrwement portisent; rinvenion tres- autis itation ou pour aMk rlson tp&cae (tel'..qu'lalqde) iiat pat petre assiddi aomme impliquans uone 101 documents.t rMkreat A urse ivuigulon oalse, A mu usage, A activitt Inventive lorsque It document sot associlki A U ou a* erposition on tons eas Mayans pinoleurs ares documents dt ime uilre cate cumbi- P- incessat publik event 4 W do is 4pt lIneraziol wailt iauan~ km~t kvidesto pour the persons. do mitler. p oreet A Is data do psios'fi revendlqud W' doermset qul fit partle del Is ins famlile i irevets IV. CERTEIiCAMlON Date Ak Latielis It rocitsrthe lariasle a 40 ofaclvowt ackevit Data d'apddltln in pristns mp~ort is recherdei imeruatIoae

17-06-1992 OFFICE 1EUIOI'EEN DES BREVETS a lu'~urs PCTIISA/210 t~ k~Ilei (Jiniw lUSt ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMANDE INTERNATIONALE NO. FR 9200282 SA 58804 La privenit amex indique ls maubrcs de la famifle de brevets riatih; mii dociaments brevets cites dama e rapport de recberche internatonaic visi ci-dessus. Lesdits; mmbres soot coutenus: au fichier informatique de l'Office europ~m des brevets i In date du 29/06/92 Les renseignements fournis soot dons i titre indicatif et n'engagczfl paslIs responsabiliti de l'Ofice europien des brevets. Documnent brevet citi T Date de Membre(s) de I& Date de au rapport de recbercbe publication famifle de brevet(s) publfication EP-A- 0307788 22-03-89 JP-A- 1199961 11-08-89 US-A- 4840964 20-06-89 Pour tout reiseignement canceruant cette annexe vofr Journal Offiid de l'Oflice europixm des. brevets, No.12/82