Title of Invention

"A PROPELLANT-FREE PHARMACEUTICAL PREPARATION"

Abstract

A propellant-free pharmaceutical preparation for the production of propellant-free inhalable aerosols which comprises a pharmacologically active substance selected from the group comprising betamimetics, anticholinergics and/or antiallergics dissolved in a solvent containing at least 70 % (v/v) ethanol whereby the active substance is not nitroglycerine or beclomethasone, 17, 21 dipropionate and optionally one or more pharmacologically harmless adjuvants, flavourings, a complex forming agent, wherein the proportion of dissolved pharmaceutical product in the pharmaceutical preparation is between 0.001 and 5.0 percent by weight.

Full Text

The present invention relates to a propellant-free pharmaceutical preparation. The present invention relates to pharmaceutical preparation in the form of stable ethanolic solutions of active substance for producing propellant gas-free aerosols. In the last 20 years, the use of metering aerosols has become an established component of the treatment of obstructive lung diseases, particularly asthma. Usually, fluorochlorohydrocarbons have been used as propellant gases. Since the ozone-damaging potential of these propellant gases was recognised, more and more efforts have been made to develop alternatives. One alternative is the development of nebulisers in which aqueous solutions of pharmacologically active substances are sprayed under high pressure so as to produce a mist of inhalable particles. The advantage of these nebulisers is that there is no need for any propellant gases whatever. Some nebulisers are described for example in PCT Patent Application WO 91/14468 (IN 177383), the contents of which are referred to hereinafter. In the nebulisers described therein, solutions of defined volumes containing active substances are sprayed, using high pressures through small nozzles so as to produce inhalable aerosols with a preferred particle size of between 1 and 10, preferably between 2 and 5 microns. EP 310910 discloses a nitroglycerin spray containing water, ethanol, a ph range of 2.4 - 8.7 and contained in a liquid pressurized container. This is an ethanolic solution which is not inhalable. US 5047230 discloses formulations with nitroglycerins as and free of propellant gas. This formulation is for a different use (antianginals). Hitherto, it has been assumed that, with conventional metering aerosols containing propellant gas, the optimum level of lung - bound particles is obtained in the aerosol. It has now been found, surprisingly, that by using ethanolic active substance solutions in combination with, for example, the above-mentioned nebulisers it is possible to generate a significantly better spectrum of inhalable particles than is usually the case with metering aerosols which contain propellant gas. Accordingly, in one aspect, we provide a pharmaceutical preparation for use in producing propellant gas-free aerosols which comprises a pharmacologically active substance in a solution containing at least 70% (v/v) ethanol. Suitable solvents for the pharmaceutical preparation within the scope of the present inventions are solutions containing at least 70% (v/v) of ethanol; solutions containing at least 85% (v/v) are preferred whilst solutions having an ethanol content of more than 95% (v/v) are particularly preferred. The concentration is given in percent by volume (v/v), the remainder being water. Most particularly preferred is ethanol which already contains small amounts of water, e.g. 96% ethanol, so that it is no longer hygroscopic and. evaporates azeotropically. Apart from water, the solvent may include other cosolvents and the pharmaceutical preparation may also contain flavourings and other pharmacological excipients. Examples of cosolvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols, especially isopropyl alcohol, glycols, particularly propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Cosolvents are suitable for increasing the solubility of the excipients and possibly the active substances. The proportion of dissolved pharmaceutical substance in the finished pharmaceutical preparation is between 0.001 and 5%, preferably between 0.05 and 3%, most particularly 0.01 to 2%, all percentages being by weight. The maximum concentration of pharmaceutical substance depends on the solubility in the solvent and on the dosage required to achieve the desired therapeutic effect. As pharmaceutically active agent in the new preparations it is possible to use any substances which are suitable for administration by inhalation and which are soluble in the solvent specified. These may include, in particular, betamimetics, anticholinergics, antiallergics, PAF-antagonists and particularly steroids and combinations of active substances thereof. The following are mentioned specifically by way of example: Tiotropium bromide, 3-[(hydroxydi-2-thienylacetyl)oxy]-8,8-dimethyl-8-azoniabicyclo[3,2,1]oct-6-en-bromide As betamimetics: Bambuterol Bitolterol Carbuterol Formoterol Clenbuterol Fenoterol Hexoprenaline Procaterol Ibuterol Pirbuterol Salmeterol Tulobuterol Reproterol Salbutamol Sulfonterol Terbutaline 1- (2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2- methyl-2-butylamino]ethanol, erythro-51 -hydroxy-81 - (l-hydroxy-2-isopropylaminobutyl) - 2H-1,4-benzoxazin-3-(4H)-one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert. - butyl-amino)ethanol, 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol. As anticholinergics: Ipratropium bromide Oxitropium bromide Trospium chloride Benzilic acid-N-3-fluorethylnortropine ester methobromide As steroids: Budesonide Beclomethasone (or the 17,21-dipropionate) Dexamethasone-21-isonicotinate Flunisolide As antiallergics: Disodium cromoglycate Nedocromil Epinastin As PAF-antagonists: WEB 2086 (4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-l-yl]-6H-thieno-[3,2-f][1,2,4]-triazolo[4,3-a] [1,4]diazepine) WEB 2170 (6-(2-chlorophenyl)-8,9-dihydro-l-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta[4, 5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine) The pharmaceutical preparations according to the invention may contain other excipients such as soya lecithin or surface-active substances. Surprisingly, it has also been found that the addition of an organic or inorganic acid, preferably in conjunction with a complex forming agent, leads to an improvement in the stability (shelf life) of steroid-containing preparations. This has been found particularly useful for pharmaceutical preparations which contain as active substance Flunisolide or the hydrate or hemihydrate thereof or Budenoside and which contain ethanol as solvent. Examples of inorganic acids include, hydrochloric acid, sulphuric acid or phosphoric acid; examples of organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid etc. The amount of acid in the finished pharmaceutical preparation is in every case selected so that the pH of the solution is between 2.0 and 7.0, more particularly between 3.0 and 4.0. In a preferred embodiment the pharmaceutical preparation also contains a complex forming agent. Examples of complex forming agents include EDTA, citric acid, nitrilo triacetic acid and the salts thereof. The quantity of complex forming agent is between 0.1 and 3 mg/100 ml, preferably between 0.2 and 2 mg/100.ml, particularly between 0.9 and 1.1 mg/100 ml, based on the finished pharmaceutical preparation. The preferred complex forming agent is EDTA (ethylene diamine tetraacetic acid or a salt thereof, such as the disodium salt). A preferred pharmaceutical preparation according to the present invention contains 1.667% Flunisolide in the ethanol (96% v/v) as solvent, which contains 0.01% (v/v) of EDTA as complex forming agent and is adjusted by the addition of acid to a pH of between 3.0 and 4.0. Examples of steroids which may be used as active substance in the pharmaceutical preparation according to the invention are: Seratrodast Pranlukast Butixocort Deflazacort Fluticasone Mometasone furoate Beclomethasone, Ciclometasone Fluocortin butyl Deflazacort Ciclometasone Prednicarbate Mycophenolate mofetil Zileuton Budesonide Promedrol Tipredane Icomethasone enbutate Cloprednol Halometasone Alclometasone Alisactide Hydrocortisone butyrate Tixocortol pivalate Lotrisone Deprodone Methylprednisolone- Aceponate Mometasone Hydrocortisone aceponate Ulobetasol propionate Triamcinolone Meprednisone Dexamethasone Medrysone Fluocinolone acetonide Deprodone pr-opi o/v,*Ve • Fluocinonide Difluprednate Dexamethasonisonicotinate Fluocortoloncapronate Triamcinolon hexacetonide Formebolone Endrisone Alclometasone dipropionate Canesten-HC Fluticasone propionate Halopredone acetate Mometasone furoate Mometasone Aminoglutethimide Hydrocortisone Fluorometholone Betamethasone Fluclorolone acetonide Paramethasone acetate Aristocort diacetate Mazipredone Betamethasone valerate Beclomethasone dipropionate Formocortal Cloprednol Clobetason Flunisolide Halcinonide Fluazacort Clobetasol Hydrocortisone-17-butyrate Diflorasone Flucortin Amcinonide Betamethasone dipropionate Cortivazol Betamethasone adamantoate Fluodexan Triiostane Budesonide Clobetasone Demetex Trimacinolon Benetonid 9a-chloro-6a-fluoro-llp,17a-dihydroxy-16a-methyl-3-oxo-1, 4-androstadiene-17(3-carboxylic acid-methylester-17-propionate. In another aspect, we provide use of a pharmaceutical preparation comprising a pharmacologically active substance in a solution containing at least 70% ethanol by volume in the preparation of a propellant gas-free composition for administration by inhalation. In a further aspect, we provide a method for preparing a preparation of the invention which comprises bringing into admixture a pharmacologically active substance and ethanol of at least 70% v/v. Both the active substance and the ethanol will be of acceptable grades of purity for administration to subjects by inhalation. Table 1 shows a deposition study which was carried out on the one hand with a standard commercial metering aerosol Inhacort® (Flunisolide, dichloromethane, trichlorofluoromethane, cryofluoran, sorbitane triolate) = MDI and on the other hand with the pharmaceutical preparation according to the invention containing Flunisolide in 96% (v/v) ethanol, which was carried out with a nebuliser as in the above-mentioned PCT Application WO 91/14468 (BINEB®; technical data: volume of drug preparation administered 15 /il, pressure approx. 300 bar, 2 jets squeezed out of two nozzle openings measuring 5x8 /*m) . (Table Removed) The Table clearly shows the advantage of the pharmaceutical preparation according to the invention which was administered with the nebuliser described. Examples: Flunisolide hemihydrate-6a-fluoro-113,16a, 17a, 21-tetrahydropregna-l,4-diene-3,20-16 acetonide hemihydrate has a molecular weight of 442.5. When used in BINEB, 250 /ig of Flunisolide are dissolved, per dose, in 15 ^il of solution so as to give a concentration of 1.667% (g/100 ml) . 96% ethanol is used as solvent. In addition, the finished pharmaceutical preparation contains 1 mg/100 ml of disodium-EDTA. The pH of the pharmaceutical preparation is adjusted to pH 4 using 0.1 N HC1. Analogously to the above experiment, formulations were prepared containing Budesonide as active substance. The following mixtures of pharmaceutical preparations were made up, containing Flunisolide-hemihydrate as active substance. (Table Removed) The content of Flunisolide-hemihydrate was 1,666.7 mg/100 ml. The pH of the solution was adjusted using IN HC1 and was determined using a pH meter, pH 1162-Radiometer Copenhagen. The samples were transferred into 5 ml glass ampoules and stored at 80"C away from light. The combination AC showed the lowest amount of decomposition product after 30 days' storage. Further examples of formulations which additionally contain disodium EDTA as complex forming agent are shown in Table III. (Table Removed) The adjuvant menthol was added in order to mask the bitter flavour of the steroid if necessary. The formulations described above were packaged in 5 ml glass ampoules and stored at 80°C. The preferred preparation, on account of the small amount of decomposition product, is preparation III. Table IV shows some examples of formulations for. Budenoside. (Table Removed) After 3 months' storage at 80°C in sealed glass ampoules the amount of decomposition product was determined by HPLC. Formulations IV and V showed the smallest amount of decomposition product. We Claim: 1. A propellant-free pharmaceutical preparation for the production of propellant-free inhalable aerosols which comprises a pharmacologically active substance selected from the group comprising betamimetics, anticholinergics and/or antiallergics dissolved in a solvent containing at least 70 % (v/v) ethanol whereby the active substance is not nitroglycerine or beclomethasone, 17, 21 dipropionate and optionally one or more pharmacologically harmless adjuvants, flavourings, a complex forming agent, wherein the proportion of dissolved pharmaceutical product in the pharmaceutical preparation is between 0.001 and 5.0 percent by weight. 2. A pharmaceutical preparation as claimed in claim 1, wherein the solvent contains at least 85 % (v/v) ethanol. 3. A pharmaceutical preparation as claimed in any of claim 1 to 2, wherein the solvent contains at least 95 % (v/v) ethanol. 4. A pharmaceutical preparation as claimed in claims 1 to 3 wherein the active substance is Tiotropium or an acid addition salt thereof. 5. A pharmaceutical preparation as claimed in claims 1 to 3 wherein the active substance is 3-[hydroxydi-2-thienylacetyoxy]-8,8-dimethyl-8-azoniabicyclo[3,2,l]oct-6-ene or an acid addition salt thereof.

Documents:

121-DEL-2000-Abstract-(13-08-2008).pdf

121-DEL-2000-Abstract-(21-11-2008).pdf

121-DEL-2000-Abstract.pdf

121-DEL-2000-Claims-(13-08-2008).pdf

121-DEL-2000-Claims-(21-11-2008).pdf

121-del-2000-claims.pdf

121-del-2000-complete specification (granted).pdf

121-DEL-2000-Correspondence-Others-(13-08-2008).pdf

121-del-2000-correspondence-others.pdf

121-del-2000-correspondence-po.pdf

121-del-2000-description (complete)-13-08-2008.pdf

121-del-2000-description (complete).pdf

121-DEL-2000-Form-1-(13-08-2008).pdf

121-del-2000-form-1.pdf

121-del-2000-form-13-(13-08-2008).pdf

121-del-2000-form-18.pdf

121-DEL-2000-Form-2-(13-08-2008).pdf

121-del-2000-form-2.pdf

121-del-2000-form-3.pdf

121-del-2000-form-5.pdf

121-DEL-2000-GPA-(13-08-2008).pdf

121-del-2000-gpa.pdf

121-DEL-2000-Petition-137-(13-08-2008).pdf