SA01220503B1 - INHALABLE FORMULATION of a solution containing TIOTROPIUM salt - Google Patents

Abstract

Abstract: The present invention relates to a propellant-free inhalable formulation of tiotropium bromide or tiotropium bromide monohydrate dissolved in water or in a mixture of water and ethanol and propellant-free aerosols produced therefrom. .,

Description

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From a solution containing inhalable formulation Cu tiotropium containing tiotropium salt Background of the invention With a respirable composition free of propellant opal The invention relates to a tiotropium solute of a pharmaceutically acceptable salt of tiotropium propellant- free inhalable formulation in combination with one other active substance on ethanol in water or a mixture of water and ethanol for inhalation ALE and cinhalation aerosols by inhalation Jaa tof less preferred ° produced therefrom. The composition shall be according to propellant-free inhalable aerosols 3 gallons, in particular for administration of the active substance by inhalation; Specifically Lid for the invention COPD 5 asthma for the treatment of asthma alpha 7 beta 4 beta 0 alpha 1 (with the chemical composition ctiotropium known as tiotropium methyl-7-exa-a-SUA asl beta)-)-7-[(hydroxydi-7-thienyl acetylcholine) * 0 (10,28,4B,50,7B)-)-7-[(hydroxydi-2- ethylene) Noonan ]' '" Jia) LF LY] azonia A — gm cthienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0**]nonane 418/176 AL From patent application European invention No. tiotropium bromide Tiotropium has the following chemical structure: bromide salt of tiotropium, and the bromide salt of tiotropium has

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The compound has important pharmacological properties and is known as tiotropium bromide, and tiotropium and its salts are highly effective anticholinergics and can provide therapeutic benefit in the treatment of asthma or COPD (obstructive disease $l Chronic obstructive pulmonary disease - and the monohydrate of tiotropium bromide is valuable from a pharmacological point of view as well. The two compounds are Slade Baa according to the present invention. The present invention relates to compositions of a liquid active substance from these compounds It may be administered by inhalation; the liquid compositions Gy of the invention shall meet the quality standards of the Alle ER and it is recognized that to obtain an optimal distribution of the active substances in lung AS, a liquid composition without propellant gases administered using Particularly suitable are such inhalers which are capable of nebulising (converting into an aerosol) a small amount of a liquid composition in a dosage required for therapeutic purposes within a few seconds into a captive aerosol for therapeutic inhalation. and within the scope of the invention; vo Preferred atomizers are those Cua ¢ microlitres can be atomized less than 00 microlitres is preferred; and most preferably less than 10 microliters of the active substance solution preferably in one puff to form an aerosol having an average particle size of less than 100 microns preferably less than 10 microns until equal to the acceptable part For inhalation of the aerosol Guns aerosol quantity 28 Ladle AL" Y. A device of this type for the propellant-free administration of a measured amount of a respirable liquid pharmaceutical composition is described in detail for example in International Patent Application No. 91/1447 entitled Atomizing Device and Methods, as well as in the international patent publication No. (AY) YAY, see Figures QT I and the attached description. In a nebulizer of this type, a pharmaceutical solution is converted by a high pressure of no more than

¢ 00 bar to an aerosol directed into the lungs; is sprayed. Within the scope of the specifications of the present invention, reference is made to the total contents of the above-mentioned publications. In nebulizers of this type, the compositions of the solutions are stored in storage 268©7012. It is essential that the compositions of the active substances used are sufficiently stable upon storage and at the same time that they can be administered directly. if possible without additional processing; according to their medicinal purposes. In addition to that; It should not contain any constituents that might interact with the inhalation lea in such a way as to damage it or the pharmaceutical quality of the solution or the resulting aerosol. For atomizing the solution a special nozzle is used as described eg in ipp 0 95/079507 or ipp 0 44/17687. Laat is referenced here to these two publications. IPO 717489/18 describes compositions of solutions for the inhaler described above that contain an additive disodium salt of editic acid (edetate 800::00). and for aqueous vo compositions of solutions to be converted into respirable aerosols using the inhalation lea described above; Specifications prefer a minimum concentration of sodium edetate of 00 mg/100 fill to reduce the occurrence of irregularities in spraying. Among the examples described, there is a composition containing tiotropium bromide. In this composition, the active substance is dissolved in water. And the ratio of sodium edetate is 0 Y.001 mg/mL again. General description of the invention and amazingly; It has now been found that compositions of solutions of tiotropium salts in water or a water-ethanol mixture, Cua ethanol, have an additive ratio of sodium edetate significantly less than 0 © mg/100 mL; It showed a decrease in the ve reactivity of the drained composition compared with the composition containing tiotropium bromide

tiotropium bromide known from the previous technique. In addition; The spray quality is good (Ton) and the resulting aerosol has good fan properties to be given by inhalation. Another feature of the composition is that, thanks to the absence or low proportion of the additive sodium edetate in the composition of the active substance; The pH of the WS SPH solution can be reduced. Low pH levels are necessary for the long-term stability of the totropium salts in the composition. The lady objective of the present invention is therefore to provide an aqueous composition of an active substance that contains the tiotropium salt Pharmaceutically acceptable tiotropium meets the high standards required by Sail to obtain an optimal atomization of a solution using the inhalers mentioned earlier in this statement.0 Compositions of the active substance Gy of the invention should be of sufficiently high pharmaceutical quality; Pharmacologically stable with a storage time of some years; preferably at least one year; preferably two years.The goal of LAT is to supply propellant-free compositions of solutions containing tiotropium salts by nebulization under pressure using a nebulizer; a volume of 0 The composition dispensed by the resulting aerosol within a specified frequency range.The objective of the AT is to supply compositions of tiotropium containing solutions AR sale, other that may be administered by inhalation.ig of the invention;( Say Use any pharmaceutically acceptable salts of tiotropium for composition. When the term tiotropium salt is used within the scope of the present invention; - It should be taken as an indication for tiotropium «« < 0:00. According to the invention, the reference corresponds to ctiotropium, which is a free ammonium cation; Reference to tiotropium in the form of a salt (tiotropium salt) that contains an anion in the form of counter-ion. Preferably tiotropium salts that can be used within the scope of the present invention are compounds containing; ve plus tiotropium as the opposite ion (anion) on chloride

: + bromide cbromide iodide 00:16 methane sulfate : 016120690101002 para-toluenesulphonate para-toluenesulphonate and/or methyl sulfate -methylsulphate and within the scope of the present invention tiotropium bromide is preferred as the salt 0 Always refer to tiotropium bromide within the scope of the invention as a reference to all possible modified amorphous and crystalline forms of tiotropium bromide. These forms may for example contain molecules of a solvent in their crystal structure Crystalline structure Among all the modified crystalline forms of tiotropium bromide, those that also contain water (Gay (hydrates) of the invention are preferred. It is particularly preferred within the scope of the present invention to use tiotropium monohydrate. bromide monohydrate and preferably in compositions according to the present invention are combinations containing tiotropium salt and only one other active substance.In the compositions according to the invention tiotropium salts are dissolved in a solvent. The solvent may be exclusively water, or it may be a mixture of ele and ve ethanol. Ethanol may be added to the composition to increase the solubility of the additives or other active substances other than tiotropium salt, preferably tiotropium bromide. tiotropium bromide or tiotropium bromide monohydrate 1130M0000. dual does not specify the relative ethanol to water; It could be 90 in size» for example. preferably; The upper limit for ethanol should not exceed 7170 by volume; In particular, it is not more than »> 710 in size and the most preferred is not more than 770 in size. The remaining volumetric percentage is water. The preferred solvent is cle without the addition of -ethanol and the concentration of tiotropium salt depends on the percentage of tiotropium in the finished pharmaceutical preparation on the desired therapeutic effect. For most diseases that respond to tiotropium, the tiotropium concentration ranges from 0.0066 105 ve by weight; Preferably between 0.000 and 77 wt.

The pH of the composition according to the invention ranges between 0.0 and 4.9; It is preferable between 7,9 and © and the best between 7,7 and 0,¥, and it is especially preferred between 7,7 and JA, FY. pharmacologically Examples of preferred inorganic acids for this purpose include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and/or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid citric acid malic acid 1-tartaric acid 6:88 maleic acid succinic acid succinic acid cfumaric acid acetic acid formic acid and/or propionic acid etc. The preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use salt-forming acids in addition to acid addition salt with the active substance. or in vo in the case of combinations; With one or more active ingredients. It is organic acids; Ascorbic acid is preferable to fumaric acid and citric acid acid 016, especially citric acid, according to taste. Mixtures of the mentioned def acids may also be used, particularly in the case of acids that have other properties in addition to their acidic properties; For example, those that act as flavorings or antioxidants, such as citric acid or ascorbic acid. Hydrochloric acid deserves a special mention as an inorganic acid. And according to desire; Pharmacologically accepted bases can be used to accurately calibrate ye pH. Suitable bases include, for example, alkali metal hydroxides YYYo

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And the alkali ion is .alkali metal carbonates and 4,388 alkaline carbonates are alkali metal hydroxides. Bases of this type were used; 13) 5 sodium Preferred is sodium alkali ion Take care to ensure that the resulting salts; which are later present in the finished pharmaceutical composition; Pharmacologically compatible with the aforementioned acid, or (EDTA) editic acid of the invention; Gay «08::70?» does not need to be added. to the present composition in the form of edetate, one of the salts known therefrom; Sodium edetate A complexing agent Any complexing agent Stabilizer Stabilizer and/or its salts Editic acid Preferred HAT adectic acid and includes an embodiment the content is sodium edetate And in a preferred embodiment where sodium edetate is used ml. In this case; 001 mg/01 less than sodium edetate on a basis of sodium edetate x ml or some other range of 001/mg 01 there are 530 (preferable from © mg/100 ml to less From, more than zero to © mg/100 ml.

Yo to Oesodium edetate 01. The content of Sodium edetate AT and in embodiment ranges from 001 ml/mg YO preferably not more than 001 cde/mg

JIS In a preferred embodiment this additive Vo is also removed similarly as sodium edetate The notes regarding sodium edetate apply to other additives with similar complexing properties that can be used instead of edetate eg tertiary acetic acid (Fie sodium edetate) Sodium and its salts nitrilotriacetic acid Preferably complexing agents within the scope of the present invention mean molecules that are capable of entering into complex bonds. Preferably these compounds should have the effect of complexing cations and most preferably cations Metallic tiotropium in the composition Other active substances other than tiotropium salt are chosen Anti-allergic agents Specially recombinant cantihistamines from among antihistamines Steroids Ss leukotriene antagonists Cantiallergic agents Yo

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These active substances include: steroids: Alclomethasone Cloprednol Dipropionate-clomethasone Cloprednol Alclomethasone-dipropionate Fluocortin butyl alisactide Cortivazole Cortivazol Amcinonide Deflazacort Aminoglutethimide Deflazacort diacetate Aristocort Demetex diacetate Deprodone Beclomethasone Propionate Deprodone Propionate Clomethasone Beclomethasone Douglas Dexamethasone Dexamethasone-1-Isonicotensate with Clomethasone-710; 17-Dipropionate Dexamethasone-21 -isonicotinate “Beclomethasone-17,21-dipropionate” Dexamethasone Endrisone Budesonide Fluazacort Butixocort Fluclorolone acetonide Canesten-HC-110 Flunisolide Flunisolide Cyclometasone Fluquinolone Acetonide Fluocinolone acetonide Clobetasol Fluocinonide Clobetasone Fluocortin

1 Fluocortolone capronate Lotrisone 8017011816 Mazipredone Fluodexan Medrysone Fluorometholone Meprednisone Fluticasone Methylprednisolone-Acip and nat Methylprednisolone-Aceponate Fluticasone- Mometasone propionate Mometasone furoate Mometasone furoate Formebolone Mycophenolate mofetil Formocortal Formocortal (Pranlukast) 0 Halcinonide: Halometasone Acetate-Paramethasone-acetate Halopredone-Prednicarbate Promedrol acetate Seratrodast Hydrocortisone Hydrocortisone «Tipredan Tabredan Taretoeb-11-Nosetrocorde» Tixocortol-pivalate «Hydrocortisone-17-Butyrate» Triamcinolone

Triamcinolone- Hydrocortisone-aceponate “Hexacetonide” Hydrocortisone-butyrate-propionate “Trilostan” Hydrocortisone-butyrate propionate Icomethasone Trimacinolone Aig “Benetonide senbutate “Ulobetasol-propion ate Alobetazole-propionate Ciclometasone Zileuton

1-1-iscordia-anth-fla-117-atep-11-warolz-afla--rolc-fla-4-17-telescope-atib-117-needatsordana- 4 11-mosca alpha-mqil-- ‎ methyl 9-alpha-chloro-6-alpha-fluoro-11-beta-17-alpha--dihydroxy-16- Jill propinoate -alpha-methyl-3-oxo-1,4-androstadiene-17- beta-carboxylate-17-propionate or ctiotropium bromide, especially combinations of tiotropium bromide ° “budesonide” and budesotide tiotropium bromide monohydrate Clie or beclomethasone dipropionate beclomechasone dipropionate “flunisolide” gia plus other (possible) drug-acceptable salts fluticasone or tiotropium bromide monohydrate A preferred combination includes tiotropium bromide 'budesonide' and tiotropium bromide monohydrate yi for example For example, an asteroid and preferably the concentration of the steroid beclomethasone propinoate AL (flunisolide) flunisolide (budesonide budesonide) in the compositions according to the invention from “fluticasone or fluticasone” dipropionate beclomethasone to 7.8 7 by weight; 1.1 wt.; - preferably to 75 wt.; and the best from 701 to eae to 7.9 by weight. And when using the installation with the 1.7 inhaler, and in particular, it is preferable from vo so that it dispenses an amount ranging from the above-mentioned steroid, it is preferable to adjust the concentration of the steroid for each spray. In particular, it is preferable to have concentrations of YOu up to 050 micrograms of steroids, where the effective dose is administered pharmacologically through one or two sprays. (Jl) fluoro-?-quinolyl) SEY;2(-1(-©(-)p(g)-1)-3-(7) confukast phenyl acid -(7-hydroxy-7-propyl)phenyl)thio)-methylcyclopropane- 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)- 3-(2-(2-hydroxy-2- acetic -1 oY )-¥ )=Y)-¥-(r))- 1 “propyl)phenyl)thio)-methylcyclopropane-acetic acid acid

JY) (ds (*))-(versus)-enel) din [YF] padi) bi ve

1-hydroxy-dimethyl ethyl)phyl)propyl)thio)methyl)cyclopropane-1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin)) -5-y!)-(E)-ethenyl)phenyl)-3-(2-(1- acetic J -Y] or hydroxy-1-methylethyl)phenyl)propyl)thio)methy acid!) -cyclopropane-acetic 1 [[7-(-th-butyl-7-thiazolyl)-*-benzofuranyl] oxymethyl]phenyl] Cm [2-[[2-(4-tert-butyl-2-thiazolyl) )-5-benzofuranylJoxymethyl[phenyl]acetic acid ° . Montelukast is preferred over pranlukast and/or zafirlukast. The leukotriene antagonist concentration ranges from +0.v to 01 wt.; preferably to 75 wt.; The best is from 1.1 to 7.5 by weight. The following are mentioned as examples of antihistamines and antiallergic agents: Antiallergic agents Ye. ¢ Azelastine “Astemizole” Bamipine (jel “Carbinoxamine hydrogen maleate) Carbinoxamine hydrogen maleate “Cetirizine” Cexchlorpheniramine “Chlorphenoxamine” Clemastine “Clemastine hydrogen fumarate” Clemastine hydrogen fumarate Desloratidine Y. Dimenhydrinate Dimetindene Disodium cromoglycate Diphenhydramine Yo Doxylamine

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Ebastine Emidastine Epinastine Fexofenadine ° Ketotifen Levocabastine Loratadine Meclozine Mequitazine Mizolastine (jw ¢ jie 1): Nedocromil Pheniramine and/or Promethazine Preferably Epinastine inedocromil disodium cromoglicate Ve disodium cromoglycate castemnizole ¢mequitazine carbinoxamine and/or clemastine and/or corresponding pharmaceutically acceptable salts Preferably in a recombinant composition the concentration of antiallergic and/or antihistamine agents ranges from 0.05 to 711 wt.; preferably to 101 wt.; best from 0.1 0 to 01 wt.; most preferable from 1.1 to OMY. All the mentioned AL will materials can also be used. The above are optionally in the form of pharmaceutically acceptable salts ea The preferred combination formulations are those in which tiotropium is present in dissolved Alla. The other active substance can be dissolved or suspended; This is generally determined vo by the other active substance and the solvent used in particular.

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It is preferable to form the additional active substance in the form of a suspension if it is vulnerable because it can be made baled with low pH levels. The feature is the dissolved form. The tiotropium pH range is more acidic and this is beneficial for the stability of tiotropium 0,9 and ©*,4; Ben 1 prefers tiotropium bromide the preferred acidity of tiotropium bromide

FY and 7.1 m f *,©; And the most preferred among especially ea" laa is preferred to be used in the form of steroids and in the case of steroids and this is especially true if the solvent used is water only fluticasone fluticasone can form the steroid cethanol and if ethanol is added ethanol without ethanol For example, constant cbudesonide Budesonide cad in solution has been found to be sufficiently non-10-ethanol and ele-ethanol at a pH of #0 if dissolved in a mixture of Ve With respect to the use of the compositions according to the invention in the inhaler described within the scope of the present invention; it is advantageous that all gradations of the composition are present in solution. Other Gy adjuvants and/or auxiliaries to the composition and other preferred co-solvents are those containing vo groups eg alcohols cpolar hydroxyl 7401 or other polar groups glycol dala splycols glycols “isopropylalcohol 005-especially isopropyl alcohol polypropylene glycol cpolyethyleneglycol polyethylene glycol cpropyleneglycol propylene polyoxy alcohols glycerol glycerol cglycolether polypropyleneglycol and polyoxyethylene alcohols esters Ethylene Y. -polyoxyethylene fatty acid esters means auxiliaries and additives; in this context; any drug-acceptable substance that is not an active substance; However, it can be formed with the active substance (substances) in the solvent, Ladle, and useful: the appropriate pharmacological method to improve the quality of the composition of the active substance. It is desirable that these substances do not have pharmacological effects, or that they do not have appreciable or at least undesirable pharmacological effects in ve.

Vo surfactants (JB) the desired treatment context. Auxiliaries and additives include eg soya lecithin eg soy lecithin surfactants eg sorbitan esters oleic sorbitan esters oleic acid stabilizers and stabilizers polyvinylpyrrolidone ¢sorbitan trioleate and/or preservatives antioxidants other complexing agents ° for finished pharmaceutical formulation; shelf materials life works to extend the storage life of 85 and / or other additives known in the technology, including vitamins (flavourings) flavored on “sodium chloride” additives as well as pharmaceutically acceptable salts such as sodium chloride For example, suitable surfactants or suspension-stabilizing agents include all pharmaceutically acceptable lipophilic hydrocarbon materials that contain a special functional hydrophilic group and one or more hydrophilic functional group and esters. Csmg-fatty acids Csmpg-fatty alcohols Cs-o Fatty alcohols Esters cglycerides Glycerides clecithin Lecithin Cs-po-fatty acid esters Cs fatty acid Polyoxyethylenes Polymers oxyethylene cpropyleneglycol esters propylene glycol yo and/or carbohydrates sorbitan esters sorbitan esters cpolysorbates polysorbate compounds diglycol esters “Cypo-fatty acids Preferably fatty acids as carbohydrates and/or Triglycerides and/or propyleneglycol diesters are propylene, while Csop-fatty acids are preferred for fatty acids and sorbitans mono-, di- or binary; or Y. sorbethane trioleates (oleic acid oleic gals) and/or polymers thereof; Yay polymers may be used in particular. 65 Pharmacologically and toxicologically acceptable as suspension-stabilizing agents. block Retarded polymers based on the ratio 1:1 and the amount of surfactant can be up to the weight of the suspended fillers; preferably an amount ranging from 0.0001: to 0.1:0 in 0.75:0 Jenn. When it is particularly preferred an amount ranging from Ye 17 e

Preferred excipients include antioxidants such as ¢ascorbic acid (eg JB provided no buffer has been used to adjust pH; vitamin A | vitamin H ¢vitamin E) tocopherols And similar vitamins or provitamins found in the human body. Preservatives can be added to protect the composition from being contaminated with pathogenic bacteria, and the appropriate preservatives are those known from previous technology, in particular benzalkonium chloride or benzoic acid or benzoate compounds, Jie benzoates, sodium benzoate at the concentration known from the previous technique. sodium edetate plus the solvent which is water and/or water/ethanol and the tiotropium salt and in another preferred embodiment the -sodium edetate is omitted and these embodiments may optionally contain sodium chloride sodium chioride too. Vo and as the line mentioned several times; Tiotropium bromide is described in EP No. VITAL 418 and crystalline tiotropium bromide monohydrate can be obtained using a process which will be described in detail sol below. and to prepare a crystalline monohydrate according to the present invention; The Y. tiotropium bromide obtained by him should be dissolved in the manner described in EP No. YA 715 AT for example; first into the water; to heat up; Purified using activated charcoal, and after removing the activated charcoal, tiotropium bromide monohydrate crystallized slowly during slow cooling. The following procedure is preferred:

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suitability The solvent is mixed with Jeli-dad tiotropium bromide in a container obtained by the method described in European Patent No. ctiotropium bromide; For example. 18 VITAL ctiotropium bromide is used for each mole of tiotropium bromide per kg of water as A kg and the best is about 1 to 1.1 kg and preferably from 0.59 to 1.40 solvent. C (#0 °C) and the resulting mixture is heated with stirring; preferably to more than 10 C. The maximum selectable temperature (Celsius) is determined by the boiling point The solvent used. It is preferable that the mixture be heated to a range of: lignocellulose., or moistened with water; to this solution. It is preferable to add Gla and activated charcoal; g. and most preferably about 15 gm of TO coal. 11 to 100 grams, or better than 100 grams from the user, and according to desire, activated tiotropium bromide is suspended per mole of tiotropium bromide activated charcoal in water before adding it to the solution containing tiotropium bromide 001 grams, and the best is 001 To 001 gm preferably from Yeo to 71 Ve -tiotropium bromide is used to suspend ctiotropium bromide charcoal about 08 gm of water per mole of activated tiotropium bromide If activated charcoal is suspended in water beforehand Adding it to the solution containing ctiotropium bromide is recommended to rinse again with the same amount of water. After adding activated charcoal; Stirring continues at a constant temperature for y. min. and the mixture is filtered for 11 min.; And the best for a period of about 1 and 01 minutes; preferably between 10 to 0 to 506 g; 148 yield to remove the activated charcoal. Then the filter is rinsed with water. From 0 to 0 g is used, and the best is about 770 g of water for this Purpose » per mole 7701 to 000 preferably from the user. tiotropium bromide from tiotropium bromide

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Preferably a YOY and then the filtrate is slowly cooled; preferably to a temperature of 1 minute; Preferably Ye to 10 per Ve to 1 The cooling process takes place at a cooling rate of 10 to 10 minutes; And the best from © to *um per 0 to 10 from ? to um per and the most preferred from um to #um per approximately 70 minutes. And as desired; cooling can follow 210 to 10 to 5 m with additional cooling to less than 17 m and better than 71 m of hours; Between filtering and then the resulting crystals are separated by filtration to remove the solvent.If it proves necessary to expose the resulting crystals to suction filtering as the acetone washing solvent, another washing step, it is recommended to use water or acetone - EO to 1.7 liters, preferably from 001 to 1. Washing solvent stiotropium bromide can be used. A liter of solvent per mole of tiotropium bromide is 1.79, and the best is about tiotropium. bromide monohydrate To wash tiotropium bromide monohydrate crystals The washing step can be repeated as required.The resulting product is dried in vacuum or using air

SE is heated circulating so as to obtain a water content of ve for one facet. The present invention further relates to compositions of solutions of the type Gay, tiotropium bromide described above using crystalline tiotropium monohydrate obtained by the procedure described above. monohydrate and preferably to use the pharmaceutical compositions containing the tiotropium salts of the invention in an inhaler of the type previously described in this statement to produce the Gi tiotropium of the invention. At this point the propellant-free Ty aerosols to which Gane is referred again specifically to the patent documents described in this release should be mentioned in this release. As described at the beginning; The developer embodiment of International Patent Proceedings No. 177897/97 and Figure + is described therein. You can usefully use ve love

Va aerosols capable of producing aerosols (Respimat®) This aerosol (Respimat® (registered trademark) as the active substance and due to tiotropium for inhalation according to the invention contains tiotropium salt

Yoh Its cylindrical shape and size suitable for use ranging from less than 4 to 10 cm, the tool can be carried anywhere by the patient. Layo sprays and 7 to; 0 cm, a specified volume of the pharmaceutical compound is expelled through small orifices at high pressures; For the production of respirable aerosols. The preferred atomiser basically consists of a Cua upper housing +4 pump housing a nozzle nozzle clocking clamp ¢spring housing spring housing for storage container Pv510:8"; It is characterized by: Ve - pump housing fixed in the upper housing part and bearing at one end a nozzle body with nozzle or nozzle system <nozzle arrangement - hollow piston with valve body - flange Reducing power take-off flange in which the hollow body is fixed and located in the upper housing part; Vo - locking clamping mechanism placed in the upper housing part; - housing for the spring in which the spring is located; Rotatably fixed to the upper housing part by means of a rotating bearing – the lower housing part snaps onto the spring housing in the axial direction. Y. The hollow piston corresponds to the valve body device described in International Patent Publication No. AVN YTAY and protrudes partly towards the pump housing cylinder and is arranged to be axially movable in the cylinder. Reference is made in particular to figures from ef) and specifically to figure oF and its accompanying parts of the description. At the moment the spring is released, it exerts the hollow piston with the valve body; At its high-pressure end, the Unk in ranges from * to To | Mpa megapascal (from about 0 to 1001 bar); 01 to To is preferred

megapascals (about 100 to 1,000 bar) on the fluid; It is the measured volume of a solution of the active substance. Volumes from 01 to 00 μl are particularly preferred; The best are volumes from 0 to 10 μl; While a volume of 10 μl per run is particularly preferred. ° It is preferable to install the valve body at the end of the hollow piston facing the body of the nozzle. It is preferable that the nozzle in the nozzle body be microstructured, ie; Manufactured by micro-engineering. Microstructured orifice bodies are described for example in International Patent Publication No. 94/077607 and in Bel Publication International No. .49/17687. Reference is made in this patent to the contents of these two publications” and specifically Figure 1 in International Patent Bulletin No. 077607/14 and the accompanying description. The body of the nozzle consists, for example, of two sheets of glass and/or silicon tightly fitted together and at least one of them has one or more microstructured channels connecting the inlet end 002216 With the Vo end of the outlet end P00221. The outlet end of the nozzle shall have at least one round or non-round hole of * to 01 µm in depth and 0 to 11 µm in width; The depth is preferably from £0.0 to 7.5 microns and the length from 1 to 4 microns. if there are several holes for the nozzle; Two holes are preferred; the Jao© directions of the nozzles in the nozzle body may be parallel to each other or they may be angled relative to each other in the direction of the nozzle opening. in the case of a nozzle body containing at least two orifice holes at the outlet end; The spray directions may be inclined relative to each other at an angle ranging from 0° to 100°; Preferably at an angle ranging from 01 to 1510 degrees; The best is from 0 to 1001 degrees. Preferably, the orifice openings should be arranged so that the separation distance is from 01 ve to You microns; the best is from 100 to 100 microns; And the best is also the elderly

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micron. Therefore, they converge at 50 microns. The most preferred is a separation distance of 71 to © spray directions in the area of the nozzle openings. 7010 Bn, preferably not more than 001 inhalable aerosol. Preferred particle sizes for aerosols © aerosol 0.1 micron; preferably from ? to 01.0 and the composition contains The clamping of mercury on a spring, preferably a cylindrical compression spring -mechanical energy that acts as a storage for kinetic energy cylindrical helical compression spring and the spring affects the power reducing flange as a spring member and its movement is determined by the location of the suspension member. The range of movement of the power reduction flange accurately by means of an upper rail - for example, a spiral sliding gear, cstepping-up gear, and it is preferable that the spring be tightened by means of a lifting gear. upper housing in relation to the spring housing in the lower housing portion.In this case, the upper housing portion and the power reducing flange contain a grooved tooth of single speed or multiple speeds.in the form of engaging locking surfaces. ring around the power reducing flange. It contains, for example, an annular configuration that is flexibly deformable towards the radius intrinsically. Metal or plastics The ring is arranged in a plane perpendicular to the axis of the atomizer. And after the spring is pulled; The striking surfaces of the striking member slide in the path of the force reduction flange and prevent the spring from being released. The locking member is engaged or coupled with the locking member. And to operate the actuating button, the actuating button is connected via the Y button. The camnular plane is preferred by the mercury clamping structure. The actuating button moves parallel to the annular plane towards the atomizer, thus deforming the deformable ring in the annular plane. The creation details are described

AV/Y 0d mercury clamping assembly in ISPM No. The lower housing portion pivots onto the spring housing and covers the filler; Shaft transmission and fluid storage container. vo

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airbrush operation; The upper part of the housing rotates relative to the lower part; so that the die takes the lower part of the spring housing with it. Meanwhile the spring is compressed and deflected by the spiral sliding tooth; The swaddle combination is automatically engaged. It is preferable that the angle of rotation be degrees. At the same time as the spring is tensioned; VAY degrees; eg 7701 for an integer part of the power reducing component in the upper housing part moves forward a certain amount; The hollow piston 0 is drawn back into the cylinder in the pump housing; As a result; Some fluid is sucked in front of the nozzle. high pressure chamber From the storage vessel to the high pressure chamber, as desired; Several replaceable storage containers containing the fluid to be atomized can be inserted into the nebulizer one by one and used. The storage container contains an aqueous according to the invention aerosol preparation -0 from the actuating button and the atomization process is initiated by gently pressing the actuating button then the clamping structure opens the way for the reducing component. The deflector spring pushes the piston towards the cylinder in the pump housing. The fluid emerges from the nozzle of the atomizer in the form of a spray. Further details of the composition are described in the two international patent publications as per reference 97/705946 5 AY/VYTAY PCT No. 1 for reference. The components of the atomizer (nebulizer) shall be made of a suitable material for its work. It is preferable to make a housing, for example, for the plastics of the atomizer and other parts as well, if its function allows; of plastic materials and for medical uses; Acceptable injection molding materials are used. The injection molding method is physiological. - Figures 1a/1b; Similar to Figures 76a/7b of the International Patent Publication, the Respimat® nebuliser (registered trademark) AV/I YAY (patent no. Ta 5) can usefully inhale aerosol preparations ,

YY: Brief explanation of the drawings. Figure 1a: Shows a longitudinal section through the atomizer with the spring fa gaia. Figure 1b: Shows a longitudinal section through the atomizer with the spring free. Detailed description ° ° The upper housing part (0) contains the pump housing (07); on its end is attached the (OF) holder Jalal) of the atomizer nozzle. In the holder is the nozzle body (0£) and the filter (ee) and the hollow plunger (OV) protruding into the power reduction flange (07) of the clamping assembly is partially screwed into the cylinder of the pump housing. Die end of it holds the hollow plunger The valve body (0A) and the hollow piston is sealed by the gasket (99). Inside the upper housing part there are: - the stop diaphragm (14) on which the power reduction flange rests when the spring is relaxed. On the power reduction flange there is the diaphragm (TY) on which the power reducing flange rests when the spring is tensioned. After the spring is tensioned, the locking member (717) slides between the baffle (11) and the support (17) in the upper housing. Operation (V6) with lock member.The upper housing portion terminates in the mouthpiece (15) and is closed by a removable protective cap Vo (17).The spring housing (VV) is attached to the pressure spring. (VA) compression spring rotates on the upper housing by means of snap-fit lugs (19) and rolling bearings. The lower housing (701) pushes onto the Cane of the spring. Inside the spring housing is the ele The replaceable storage (VY) of the fluid (VY) to be atomized. The storage vessel Y. is closed by the (VY) stopper through which the hollow piston protrudes into the storage vessel and dips its tip into the fluid (active substance solution supplier). The VE spindle of the mechanical part is mounted on the outside of the spring housing. The (VO) drive pinion is located at the lead 5a shaft end of the Gaal top. There is a slider (V1) on the spindle

Yi

L885 aerosol The nebulizer described above is suitable for atomizing aerosol preparations suitable for inhalation. The aerosol of the invention is for forming an aerosol of the invention using the method described above (Gy sediments and if the composition is atomized it should correspond to the quantity sprayed; within 74951 at ((Respimat® (registered trademark)) the least; preferably at least 798 of all actuations (puffs) of the inhaler; an oe quantity of this quantity. Preferably given as 701/7 specified with no tolerance More than 775 and preferably of the formulation in the form of a specific amount pide 01 and 0 between 0 and 1" mg; the best between per puff. The percentage of the amount dispensed that is outside the tolerance limit should be no more than

TINY for the desired quantity that is less than 01.9 and preferably less than YO. However; The composition according to the invention may also be atomized using inhalation devices other than those described above. jet-stream inhalers; For example, flow-stream inhalers iad tiotropium bromide An example of the process for the synthesis of tiotropium bromide-1 monohydrate 1 To 75.7 kg of tiotropium bromide add 10.0 kg of tiotropium bromide in water suitable reaction vessel. The mixture was heated to a range of 40-88 °C and stirred at a temperature of 1 kg of activated charcoal; Humidifier using water; kg of water; This mixture was added to the bromide-containing solution and washed with 7,; kg of water. The tiotropium bromide mixture obtained by this method was stirred for at least 10 minutes at 0008 C, then filtered through a filter and the filter was washed with a Ve to an external temperature of Bane hot in a preheater kg of water. The contents of the device were cooled to a temperature ranging from 7-1709 C at a rate of 7 and completed a (10) + minutes. The device was further cooled using cold water to a range of -710 #C for each crystallization process by stirring for at least another hour. The crystals were separated using a vo dryer

Yo separated using 9 liters of water crystal slurry by sorbent filtration; And washing the cold crystal sludge (10-719 AD). The resulting crystals were dried at cold acetone and acetone (a VOY +) kg of monohydrate bromide 1,4 fnitrogen for two hours under 5 YO nitrogen current (ratio: 7 of theoretical yield) Tiotropium bromide monohydrate ?- Examples of compositions 0 For a pharmacist: 1 for a preparation 1 gm of 001 contains Example amount of tiotropium bromide | Amount of monohydrate of bromide Amount of chloride of edetate headquarters pH; Sodium benzalkonium adjusted using tiotropium tiotropium 100001100 bromide 1 (its concentration is HCI sodium benzalkonium bromide based on standard tiotropium) edetate chloride based on “monohydrate” tiotropium tiotropium ove eee Joa | 0 fee 0 re Je fae | 0 [seen ve jee oan | 0 Overflow or Jee foes fo een [oe ve Leer | Lamash |e [oo fe] ve Jee |e oes [0 [0 ore Jee [eee omen] [ov ove Jee Jae |e | | Li and one of the liquid materials is ethanol, and the remainder is water or a mixture of water / ethanol mentioned above in an amount known from the previous technology.

Examples 9 through 17: budesonide Each of Examples (1) through (A) may additionally contain: Example A+: 1.7 g budesonide grade C Acidity: Adjust using 1101 until it becomes “0.” (Y,0 Ex. 1.7 iad g of budesonide cbudesonide pH: adjust with HCl until it is 0,4; ex: 01 corresponds to examples 14 to 4g using 0.7 g budesonide 'budesonide - Example 11: Corresponds to Examples 4a to 4c using 0,' 0 g budesonide 'budesonide YY JL Corresponds to Examples A to *c using 0.7 g of budesonide i Examples 4 to 11 The steroid is present in the formulation as a suspension. Sorbitan trioleate can be used as a surfactant Examples 1 “to 11 Vo corresponds to the vowel from 4 to 11. and benzalkonium chloride is replaced by sodium benzoate. Examples 11 to V4 correspond to examples 9 to VY But instead of hydrochloric acid, citric acid was used exclusively to adjust the pH. »| Examples 01 to 01 correspond to the ingredients and amounts in Examples 9 to .19, but instead of water; Use a mixture of water (7 + vol) and ethanol (7900 vol) Budesonide is present in the solution.

Other Examples Corresponding to Examples 9 through Yo described above; Use the same amount of flunisolide beclomethasone dipropionate or fluticasone instead of budesonide and in the case of fluticasone: fluticasone ° it is preferable to add lecithin instead of sorbitan dioleate trioleate in Ala suspension structure. Steroids are formed as a suspension if the solvent used is water itself. And in Ala using a mixture of water and ethanol the steroid may be in the solution. Article YY ye Epinastine: 7 gm pale Yo: EDTA tiotropium bromide monohydrate: 71 mg hydrochloric acid, its concentration is 1.1 N, to adjust the pH to Fe - Add water until the volume is 100 ml.

Claims (1)

YA Protection Elements Liquid, propellant-free pharmaceutical JA £ - tiotropium salt as one of the materials (AIL" ad) with a concentration based on 0 tiotropium ranging from 0.0008 to 75 (OIL A" ad sale - 1 other choice of antiallergic substances Cantiallergics Antihistamines 7 Steroids and/or leukotriene antagonists A: ele - 9 or a mixture of water/ethanol as a solvent in which tiotropium salt 01 is dissolved on “JY! 11 - an acid to make a pH of 17oC between 0.0 and 4.5; sole - 1" drug-acceptable preservative; VY - a drug-acceptable complexing agent and/or stabilizer and/or Vt-24 co-solvent and/or adjuvants Adjuvants and Vo additives are acceptable as other drugs in addition to the preservative. tiotropium of claim 1; It is distinguished in that tiotropium salt Gy is a pharmaceutical preparation 7-1 sulfonate ¢iodide iodide chloride cbromide is a salt selected from bromide Y p-toluenesulphonate and toluene sulfonate cmethansulfonate methane v —Y 1 Pharmaceutical preparation Gy of claim 1; it is distinguished in that the active substance is Y tiotropium bromide 1 ;- Gay pharmaceutical preparation for protection element 1; is distinguished in that the active substance is a monomer Ya tiotropium bromide monohydrate Ya tiotropium bromide monohydrate Y 1 +- Pharmaceutical preparation Gy for one of the protective elements from 1 to 1 is distinguished in that the solvent is a water-ethanol mixture so that it does not exceed The proportion of ethanol is preferably 740 by volume; It is preferable that it not exceed 7700 in size, and it is preferable that it not exceed ‎IY. ¢ by size. 1b Pharmaceutical preparation according to claim 1 to is distinguished in that it does not contain Y complexing agent 1 “- Pharmaceutical preparation Gy of claim 1 to 7 ; It is distinguished in that it does not contain Y. stabilizer \ 8- A pharmaceutical preparation, Ga, for one of the elements: protection from 1 to A. It is distinguished in that the Y-edic acid salt is present in an amount greater than zero to not more than Yo mg/100 v mL; Preferably from 0 to less than 10 mg/100 ml. 0-1 Pharmaceutical preparation Ga for claimant 4 is distinguished in that the 1-edetic acid salt Y is sodium edetate. 11-1 Pharmaceutical preparation Ga for one of the claims From 1 to “Yo” it is distinguished in that the degree of acidity ranges between 7 and m, preferably between Y, v and 9 y, and the most diluted between 1, Y Y and *, Y -1 -1 Pharmaceutical preparation Gi, for one of the claims 1 to VY is distinguished in that the concentration of Y tiotropium ranges from 000056 to 78 by weight; Preferably not more than 7Y r by weight. 1-"1 pharmaceutical preparation Gy for one of the protection elements from 1 to OY is distinguished in that the preparation Y contains benzalkonium chloride as a preservative 1 VE Pharmaceutical preparation Gy for one of the agents from 1 to 1 and from 4 to OT characterized in Y that cosolvents and/or adjuvants and additives v 5 Pharmacologically accepted It is used in addition to the -preservative -1#9 1 Gig for SPF 40; it is distinguished in that the product contains an anti-oxidant Y as an adjuvant. Ae - 1 is a pharmacist according to one of the claims from 1 to Yo It is distinguished in that it does not use cosolvents and/or adjuvants and pharmaceutically acceptable v additives Regardless of the .preservative 1-1 Pharmaceutical Ga, for one of the alice of the above protection; It is distinguished in that the concentration of tiotropium Y ranges between vee) and p7 by weight 0 and preferably from 0.000 to 0/7 v by weight ¢ and aphth 1 | (from 2 FHK” to 0 and 7 wt. and most preferably from \ Sate ¢ to 70:1 wt. —VA 0 ly pharmaceutical of one of the above claims; It is distinguished in that all solvents are dissolved in the solvent ingredients ingredients Y 1 L - A pharmaceutical preparation according to one of the protection elements cdg is distinguished in that the additional substance (AIL) asl) Y active substance 800100021 is present in the form of a suspension v in the solvent -0 1 pharmaceutical preparation Gy of one of the foregoing claims; It is distinguished in that the additional “AIL” “ill Y” additional active substance is a steroid ug yw steroid of p10; It is distinguished in that the concentration of the steroid Ga, pharmaceutical preparation -71 1 to 77.8 wt. 1.1 ranges from 4.00 to 76 wt; Preferably from 1 1 7 - Pharmaceutical preparation Ga, for one of protection element 01 or 1; distinguished in that the steroid Y 10 is ALD cbudesonide beclomethasone propionate and < beclomethasone dipropionate fluticasone and / Or flunisolide 01 79- A dua preparation according to one of the protection elements from 1 to V4 is distinguished in that the additional AIL dll Y additional active substance is an anti-allergic and antiallergic substance and/or an antihistamine 1;*- Pharmaceutical preparation Gy of protective agent YY is distinguished in that the concentration of antiallergic substance Y and/or antihistamine ranges from 00069 r to 70 by weight; preferably not more than 10 by weight; the best is from 1.1 to 0 by weight; Preferably in a 0.1 to 1/1 wt. -Yo \ Pharmaceutical preparation Ga of one of claimants A or P is distinguished in that the substance YY cepinastine additional active substance epinastine A" asl Y "disodium cromoglycate disodium cromoglycate cnedocromil nedocromil v carbinoxamine cr benoxamine ¢mequitazine castemizole ¢ and/or Pharmaceutically acceptable salt opposite thereof. clemastine and/or clemastine ° distinguished in that substance VE to 1 of one of the protective elements of a pharmaceutical preparation Gy-71-1 is an additional active substance leukotriene Additional effective 0 .leukotriene antagonist 7 is distinguished in that the concentration of the anti-YT antigen of the protective element Gy 1-77 pharmaceutical preparation by weight; preferably to 01 to 0.06 ranges from leukotriene antagonist leukotriene Y to 77.5 by weight. 0.1 by weight and better than 0 r It is distinguished in that YY YT of one of the two protective elements Gy Pharmaceutical preparation —YA 01 is monteloxet leukotriene antagonist Y-1-acid czafirlukast zafirlukast ¢pranlukast _pranlukast ¢montelukast 7 YT fluoro-?-quinolinyl)(EY A) 00@) thio)methylcyclopropane-(J—8) 7-hydroxy-7-propyl) 1-(((R)-(3-(2-(6,7-difluoro-2-qu inolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy) - Lacytec | 1 -Y )=¥)-v-(R))- 1 “2-propyl)phenyl)thio)methylcyclopropane-acetic acid L-chlorothieto[© 1-b]pyridinyl (*)- (vs.)-ethynyl)phenyl)-?-(?-JET CY) \ ethyl)phenyl)propyl)thio)methyl)cyclo-acetic propane lithium-1-iscorde-1(q 1-((((( R)-3-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-1) chydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic acid 11 [7-[[71-(;-th-butyl-7-thiazolyl)-k-benzofuranyl]oxymethyl]phenyl] Acetic 1" F -[2-[[2-(4-tertbutyl-2-thiazolyl)-5-benzofuranylJoxymethyl]phenyl]acetic acid \Y 1 4 7- Pharmaceutical preparation Gs of protective ingredient 1 contains reduced water For the Y surfactant, tiotropium bromide is 1.700 by weight; v another BL" ad substance to choose from of gall anti-allergic cantiallergics antihistamines cantihistamines steroids and/or leukotriene antagonists ° benzalkonium chloride I forgot 7 /1.01 by weight; sodium edetate at a ratio of 70.05 by weight” so that 5 wa 7 degrees din gan prepared at 5.0 using hydrochloric acid A: or citric acid Citric acid -*0 1 Pharmaceutical preparation Giy for one of claims 1 to 9 to be used as a Pharmaceutical Composition Y for administration by inhalation .inhalation nebulizing to 9? For aerosolization 1 of a Gig protectant use of a pharmaceutical grade 1-1 or 11 YEETA/IPG Ga inhaler into a Y-inhalation device as described in Figures A and 1B in International Patent Publication No. 1 A l 11 i ¢ nebulising 33 A 79 to 1 use of a pharmaceutical preparation according to one of the Claims of 77-1 that works by spraying specified amounts of the pharmaceutical composition from an inhaler into a Y-containing inhalation nozzle through a bar nozzle Bar 001 to 001 by applying pressures ranging from 01 ¥ at least one having a depth of ? to a nozzle opening on a nozzle opening of ¢ microns to form an inhalable aerosol V0 and a width ranging from 1 microns to microns ° .inhalable aerosol for inhalation 1 yi one on a nozzle opening 4a gb is distinguished in that an opening FY of protection Gly Use at least 1 YY It shall be at least two orifices inclined relative to each other in the Y direction. 100° to 100° The nozzle opening at an angle of 1 is distinguished in The specified amounts range from FF or YY for a Gig protectant; GE use ©5© 1 to £ cm Y cm, width ranging from Vo to q, length ranging from inhaler Y, which is distinguished in that the mounting quantity is FO to YY for one of the protection elements from Gg use of YT discharged during at least 7997 of all operations of the formulation Y Ye device ranging from * to 10 mg with a tolerance range of inhaler inhaler is distinguished in that the amount of composition FV to 91 for one of the elements Protection from Gi use -77 1 drained through at least 7997 of all operations of the formulation Y JY eddy device with a range of 'pale' 01 and © 1 inhaler inhaler is distinguished in that it obtains Amount FY YT of one of two protections GE Use —FA 1 inhaler drained in at least 79,448 of all Y inhaler runs