USOO7470422B2

(12) United States Patent (10) Patent No.: US 7470,422 B2 Freund et al. (45) Date of Patent: *Dec. 30, 2008

(54) METHOD FOR THE PRODUCTION OF 6,150,418 A 11/2000 Hochrainer et al. PROPELLANT GAS-FREE AEROSOLS FROM 6,455,524 B1 9/2002 Bozung et al. AQUEOUSMEDICAMENT PREPARATIONS 6,491,897 B1 12/2002 Freund et al. 6,630,466 B2 10/2003 Bozung et al. 6,890,517 B2 5/2005 Drechsel et al. (75) Inventors: Bernhard Freund, Gau-Algesheim 2002fO193392 A1 12/2002 Schmeizer et al. (DE); Bernd Zierenberg, Bingen am 2004/OO19073 A1* 1/2004 Drechsel et al...... 514,291 Rhein (DE) 2004/O132761 A1 7/2004 Drechsel et al. (73) Assignee: Boehringer Ingelheim Pharma GmbH FOREIGN PATENT DOCUMENTS & Co. KG, Ingelheim (DE) DE 19625 O27 A1 1, 1997 DE 1962O 509 A1 11, 1997 (*) Notice: Subject to any disclaimer, the term of this EP O310910 A1 4f1989 patent is extended or adjusted under 35 EP O37O 632 B1 5, 1990 U.S.C. 154(b) by 0 days. EP O 489,217 A1 6, 1992 JP 4-275235 A 9, 1992 This patent is Subject to a terminal dis JP 5-58888 A 3, 1993 claimer. JP 8-508280 A 9, 1996 JP 10-130 148 5, 1998 (21) Appl. No.: 11/506,128 JP 11-508547 7, 1999 JP 2001-5O1914. A 2, 2001 (22) Filed: Aug. 17, 2006 WO WO 91/14468 A1 10, 1991 WO WO94f13262 6, 1994 (65) Prior Publication Data WO WO97/O1329 A1 1, 1997 WO WO97, 12687 A1 4f1997 US 2007/0077207 A1 Apr. 5, 2007 WO WO99,07340 A1 1, 1999 WO WOOO, 23O37 A1 4/2000 Related U.S. Application Data OTHER PUBLICATIONS (63) Continuation of application No. 10/417.766, filed on U.S. Appl. No. 09/396,673. Fruend, Betal, pending. Apr. 17, 2003, now abandoned, which is a continuation U.S. Appl. No. 09/497,696, Lamche, H. etal, pending. of application No. 09/331,023, filed as application No. JP 08-508280 Abstract. PCT/EP97/07062 on Dec. 16, 1997, now abandoned. JP 05-058888 Patent Abstracts of Japan. JP 04-275235 Abstract. (30) Foreign Application Priority Data JP 10-130 148 Abstract. JP 2001-50 1914 Abstract. Dec. 20, 1996 (DE) ...... 19653 969 JP 11-508547 Abstract. The Merck Index, 12th Edition. #217 and #5089, 1996. (51) Int. Cl. Moren et al., “Aerosol dosage forms and formulations' Aerosols in A6 IK 9/12 (2006.01) Medicine, Principles, Diagnosis and Therapy, 2nd Edition, Chapter A6 IK 38/00 (2006.01) 13, Section 4, 1993. A6M I5/00 (2006.01) (52) U.S. Cl...... 424/45; 424/434; 424/43; * cited by examiner 514/826; 514/642; 128/200.14 Primary Examiner Mina Haghighatian (58) Field of Classification Search ...... 424/45, (74) Attorney, Agent, or Firm Michael P. Morris; 424/434, 43: 514/826,642; 128/200.14 Mary-Ellen M. Devlin; Timothy X. Witkowski See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention relates to pharmaceutical preparations U.S. PATENT DOCUMENTS in the form of aqueous solutions for the production of propel 5,497,944 A 3, 1996 Weston et al. lant-free aerosols. 5,964,416 A 10/1999 Jaeger et al. 5,976,573 A 11, 1999 Kim 18 Claims, No Drawings US 7,470,422 B2 1. 2 METHOD FOR THE PRODUCTION OF betamimetics, anticholinergics, antiallergics, antihistamines, PROPELLANT GAS-FREE AEROSOLS FROM and , as well as combinations of these active ingredi AQUEOUSMEDICAMENT PREPARATIONS entS. It was found, in a series of examinations, that the nebulizers RELATED APPLICATIONS described above can feature spraying anomalies when using aqueous pharmaceutical solutions (generally, double distilled This application is a continuation of U.S. Ser. No. 10/417. or demineralized (ion exchanged) water is used as a solvent). 766, filed Apr. 17, 2003, now abandoned, which was a con These spraying anomalies represent an alteration of the tinuation of U.S. Ser. No. 09/331,023, filed Sep. 15, 1999, spraying pattern of the aerosol, with the consequence that in now abandoned, which is a filing under 35 U.S.C. S 371 of 10 extreme cases an exact dose can no longer be guaranteed to PCT/EP97/07062, filed Dec. 16, 1997. the patient as a result of the altered mean droplet size distri bution (alteration to the lung accessible part of the aerosol). BACKGROUND AND SUMMARY OF THE These spraying anomalies especially occur when the nebu INVENTION lizers is used at intervals, for example, with breaks of approxi 15 mately 3 or more days between utilization. It is possible that The present invention relates to pharmaceutical prepara these spraying anomalies, which in extreme cases can lead to tions in the form of aqueous solutions for the production of a dysfunction of the nebulizers, are as a result of microscopic propellant-free aerosols for inhalation. deposits in the area of the jet opening. In the last 20 years, the use of dosage aerosols has become Surprisingly, it was discovered that these spraying anoma a strong part of the therapy of obstructive lung diseases, lies no longer occur when the aqueous pharmaceutical prepa especially asthma. Usually, fluorochlorohydrocarbons are rations which are to be sprayed contain a defined effective used as propellant gases. Following the recognition of the quantity of a complexing agent, especially of EDTA (ethyl oZone damaging potential of these propellant gases, attempts enediamine tetraacetic acid) or salts thereof. The aqueous to develop alternatives have increased. One alternative is the pharmaceutical preparations according to the invention con development of nebulizers, where aqueous solutions of phar 25 tain water as a solvent, but if necessary, ethanol can be added macologically active Substance are sprayed under high pres to increase the solubility up to 70% (by volume), preferably sure so that a mist of inhalable particles results. The advan between 30% and 60% (by volume). tage of these nebulizers is that they completely dispense with Other pharmacological adjuvants such as preservatives, the use of propellant gases. especially benzalkonium chloride, can be added. The pre Such nebulizers are, for example, described in PCT Patent 30 ferred quantity of preservative, especially benzalkonium Application WO 91/14468 (the Weston Nebulizer), herein chloride, is between 8 and 12 mg/100 ml solution. incorporated by reference. With the nebulizers described Suitable complexing agents are those which are pharma here, active ingredients solutions in defined Volumes are cologically acceptable, especially those which are already sprayed through Small jets under high pressure, so that inhal approved by medical regulating authorities. EDTA, nitrilot able aerosols with a mean particle size of between 3 and 10 35 riacetic acid, citric acid, and ascorbic acid and their salts are micrometers result. A further developed embodiment of the especially suitable. The disodium salt of ethylenediaminetet aforementioned nebulizer is described in PCT/EP96/04351 raacetic acid is especially preferred. (the Jaeger Nebulizer A). The nebulizer portrayed in FIG. 6 of The quantity of complexing agent is selected so that an PCT/EP96/04351 (the Jaeger Nebulizer B) carries the trade 40 effective quantity of complexing agent is added to prevent mark Respimat(R). further occurrence of spraying anomalies. Usually, pharmaceuticals intended for inhalation are dis The effective quantity of the complexing agent Na-EDTA Solved in an aqueous or ethanolic Solution, and according to is between 10 and 1000 mg/100 ml solution, especially the Solution characteristics of the active Substances, Solvent between 10 and 100 mg/100 ml solution. The preferred range mixtures of water and ethanol may also be suitable. 45 of the quantity of complexing agent is between 25 and 75 Other components of the solvent are, apart from water mg/100 ml solution, especially between 25 and 50 mg/100 ml and/or ethanol, optionally other cosolvents, and also the phar Solution. maceutical preparation may also additionally contain flavour The following named compounds can principally be used ings and other pharmacological additives. Examples of cosol as active ingredients, singly or in combination, in the aqueous vents are those which contain hydroxyl groups or other polar 50 pharmaceutical preparation according to the invention. In groups, for example, alcohols, especially isopropyl alcohol, individual cases, it may be required to add a higher quantity of glycols, especially propylene glycol, polyethylene glycol, ethanol or a solution mediator to improve solubility. polypropylene glycol, glycol ether, glycerol, polyoxyethyl Tiotropium bromide, 3-(hydroxydi-2-thienylacetyl)oxy ene alcohols, and polyoxyethylene fatty acid esters. Cosol 8,8-dimethyl-8-azoniabicyclo[3.2.1]oct-6-ene-bromide vents are suitable for increasing the solubility of adjuvant materials and, if necessary, active ingredients. 55 AS betamimetics: The proportion of dissolved pharmaceutical in the finished pharmaceutical preparation is between 0.001% and 30%— preferably between 0.05% and 3%, especially 0.01% to 2% Bambuterol Bitolterol Carbuterol Formoterol (weight/volume). The maximum concentration of pharma 60 Clenbuterol Fenoterol Hexoprenaline Procaterol ceutical is dependent on the solubility in solvent and on the Ibuterol Pirbuterol Salmeterol Tulobuterol dosage required to achieve the desired therapeutical effect. Reproterol Salbutamol Sulfonterol Terbutaline All substances which are suitable for application by inha lation and which are soluble in the specified solvent can be 1-(2-Fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2- used as pharmaceuticals in the new preparations. Pharmaceu 65 methyl-2-butylaminoethanol, ticals for the treatment of diseases of the respiratory passages erythro-5'-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)- are of especial interest. Therefore, of especial interest are 2H-1,4-benzoxazin-3-(4H)-one, US 7,470,422 B2 3 4 1-(4-Amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-bu It is obvious that those pharmacologically acceptable salts tyl-amino)ethanol, and will be used which dissolve in the solvent according to the 1-(4-Ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2- invention if necessary. (tert.-butylamino)ethanol. In the following text, the advantage of the pharmaceutical As Anticholinergics: preparation according to the invention will be explained more Ipratropium bromide, Oxitropium bromide, Trospium clearly with Examples. chloride, and N-f-fluoroethylene nortropine benzylate As a pharmaceutical Solution, pratropium bromide solu methobromide tion (c=333 mg/100 ml) with a pH value of 3.4, and the As Steroids: preservative benzalkonium chloride (c=10 mg/100 ml) was . (or the 17,21-dipropionate), 10 used. The tested solutions either contained no EDTA or -21-isonicotinate, and EDTA in a concentration of c=0.1 mg, 1 mg, 50 mg and 75 As Antiallergics: mg/100 ml as a disodium salt. Disodium cromoglycate, Nedocromil, and Epinastine. Unused Respimat(R) nebulizers were used for the test (tech Examples of Steroids which can be Used as Active Ingre nical data: Volumes of the applied pharmaceutical preparation dients in the Pharmaceutical Preparations According to the 15 approximately 15 ul, pressure approximately 300 bar, 2 Invention: streams impacting from two jet openings of size 5x8Lm). The operation mode for the test is set so that the units are used 5 times, are left to stand for 3 days, and then are used again 5 times, this pattern being repeated. 15 units were examined in Seratrodast Mycophenolate mofetil each series of measurements, the results with regard to spray Pranlukast Zileutone anomalies are shown in Table 1. Budesonide Promedrol TABLE 1 Mometasome furoate Beclomethasone, Douglas comethasone enbutate 25 Concentration of Number of CiclometaSone EDTA in nebulizers with Duration of butyl Test No. mg/100 ml spray anomalies test in days Deflazacort CiclometaSone Alisactide 1 0 mg/100 ml 2 2O -butyrate propionate 2 0 mg/100 ml 5 9 -pivalate AlclometaSone-dipropionate 3 0.1 mg/100 ml 5 6 30 Lotrisone Canesten-HC 4 1 mg/100 ml 6 6 FluticaSone-propionate 5 50 mg/100 ml O 2OO -Aceponate -acetate 6 50 mg/100 ml O 2OO Mometasone-furoate 7 75 mg/100 ml O 2OO Hydrocortisone-aceponate MometaSone 8 75 mg/100 ml O 2OO -propionate Hydrocortisone 35 Formulation Examples (for Fenoterol and Ipatropium bro Dexamethasone Flucorolone acetonide mide) acetonide -acetate Deprodone Propionate Aristocort-diacetate 40 Diflupredinate Composition Dexamethasone isonicotinate Beclomethasone-Dipropionate Components in mg/100 ml capronate Formocortal Triamcinolone-Hexacetonide Cloprednol Fenoterol 833.3 mg Formebolone Benzalkonium chloride 10.0 mg EDTA: 50.0 mg Funisolide 45 Fuazacort HCl (1n) ad pH 3.2 Hydrocortisone-17-Butyrate Ipatropium bromide 333.3 mg Fuocortin Benzalkonium chloride 10.0 mg Betamethasone Dipropionate EDTA: 50.0 mg Betamethasone adamantoate HC1 (1N) ad pH 3.4 Fluodexane Budesonide Clobetasone 50 Demetex Trimacinolon Benetonide In analogy to the above Examples, the following solutions were produced. and 9-O-chloro-6-C.-fluoro-11-3-17-O-dihydroxy-16-O-me thyl-3-oxo-1,4-androstadiene-17-f-carboxylic acid-me 55 thylester-17-propionate. Concentration Benzalkonium Other especially suitable active ingredients for the produc Active ingredient mg/100 ml chloride EDTA Solvent tion of aqueous pharmaceutical preparations for applications Berotec 104-1667 10 mg 50 mg Water by inhalation are: Atrovent 83-1333 10 mg 50 mg Water B-Sympatico-mimetics, e.g. Fenoterol, Salbutamol. Formot Berodual 60 (Atrovent) 41-667 10 mg 50 mg Water erol, or Terbutalin; (Berotec) 104-1667 10 mg 50 mg Water Anticholinergics, e.g. patropium, OXitropium, or Tiotro Salbutamol 104-1667 10 mg 50 mg Water pium; Combivent (Atrovent) 167-667 10 mg 50 mg Water Steroids, e.g., Beclomethasone dipropionate, Budesonide, or (Salbutamol) 833-1667 10 mg 50 mg Water Flunisolide; 65 Ba 679 Br 4-667 10 mg 50 mg Water Peptides, e.g., insulin; and (Tiotropium Pain killers, e.g., Fentanyl. US 7,470,422 B2 5 6 sisting of fenoterol, ipratropium bromide, Salbutamol, tiotro -continued pium bromide, and oxitropium bromide. 4. The method according to claim 3, wherein the pharma Concentration Benzalkonium Active ingredient mg/100 ml chloride EDTA Solvent ceutical Solution further comprises an adjuvant. 5. The method according to claim 4, wherein the adjuvant bromide) is a preservative. BEA 2108 Bir 17-833 10 mg 50 mg Water Oxivent 416-1667 10 mg 50 mg Water 6. The method according to claim 5, wherein the adjuvant is benzalkonium chloride. *In the form of the disodium salt 7. The method according to claim 1, wherein the method is 10 A concentration range from 10 mg to 20,000 mg/100 ml is accomplished using a Weston Nebulizer. conceivable for the active ingredients, depending on the dose 8. The method according to claim 1, wherein the method is per operation and their solubility. The specified doses are accomplished using a Jaeger Nebulizer A. calculated based on a therapeutically effective single dose of 9. The method according to claim 1, wherein the method is approximately 12 microliters per operation. The active ingre 15 accomplished using a Jaeger Nebulizer B. dient concentrations of the pharmaceutical preparations can 10. The method according to any one of claims 1 to 3 or 7 alter when the volume of the individual dose is altered. to 9, wherein the complexing agent is nitriloacetic acid, citric The concentration range for the complexing agents (for acid, ascorbic acid, or a salt thereof. example DiNa-EDTA) is between 10 and 1000 mg/100 ml 11. The method according to any one of claims 1 to 3 or 7 (dependent on the pH value of the solution). The preferred to 9, wherein the complexing agent is EDTA or a salt thereof. range is between 25 mg and 100 mg/100 ml. 12. The method according to claim 11, wherein the con The quantity of benzalkonium chloride should be in the centration of the complexing agent is between 25 and 75 range of 8 to 12 mg/100 ml. mg/100 ml solution. The solutions are set to a pH of 3.2 to 3.4 with 0.1 or 1N 13. The method according to any one of claims 1 to 3 or 7 HC1. All concentrations relate to 100 ml of finished active 25 to 9, wherein the pharmaceutical solution contains up to 70% ingredient solution. (by volume) ethanol. We claim: 14. The method according to any one of claims 1 to 3 or 7 1. A method of providing defined Volumes of an aqueous to 9, wherein the pharmaceutical solution contains the phar pharmaceutical Solution comprising a pharmacologically macologically active ingredient in a concentration of 0.001 to active ingredient and an effective quantity of a complexing 30 2 g/100 ml solution. agent for the prevention of spraying anomalies as a propel 15. The method according to claim 2, wherein the pharma lant-free aerosol for inhalation, the method comprising: cologically active ingredient is selected from the group con (a) pressurizing the pharmaceutical Solution; and sisting of fenoterol, ipratropium bromide, Salbutamol, tiotro (b) passing the pressurized pharmaceutical Solution pium bromide, and oxitropium bromide. through an atomizing means to provide defined Volumes 35 of the pharmaceutical Solution as a propellant-free aero 16. The method according to claim 1, wherein the pharma Sol. ceutical Solution further comprises an adjuvant. 2. The method according to claim 1, wherein the pharma 17. The method according to claim 16, wherein the adju cologically active ingredient is selected from the group con vant is a preservative. sisting of betamimetics, anticholinergics, antiallergenics, 40 18. The method according to claim 17, wherein the preser and antihistamines. vative is benzalkonium chloride. 3. The method according to claim 1, wherein the pharma cologically active ingredient is selected from the group con