US 200600731 03A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0073103 A1 Guck et al. (43) Pub. Date: Apr. 6, 2006 (54) CONTROLLED DOSAGE AEROSOLS WITH (30) Foreign Application Priority Data LECT HINAS SURFACE-ACTIVE AGENT Dec. 24, 2002 (DE)..................................... 102 6O 8822 (76) Inventors: Franz Guck, Rheinfelden (DE): Gieselher Warnke, Herrischried (DE) Publication Classification Correspondence Address: (51) Int. Cl. D Peter Hochberg A6IL 9/04 (2006.01) 1940 East 6th Street A 6LX 3/573 (2006.01) 6th Floor (52) U.S. Cl. .............................................. 424/45: 514/179 Cleveland, OH 44114 (US) (21) Appl. No.: 10/540,648 (57) ABSTRACT (22) PCT Filed: Dec. 24, 2003 A controlled dosage aerosol containing at least one medici nal agent, pressure-liquefied isobutane as the propellant, and (86). PCT No.: PCT/EPO3/14901 lecithin as the Surfactant. US 2006/00731 03 A1 Apr. 6, 2006 CONTROLLED DOSAGE AEROSOLS WITH 0010 DE 1991 1 064 discloses controlled dosage aero LECT HINAS SURFACE-ACTIVE AGENT sols containing broncholytic and/or anti-inflammatory agents from the group of the glucocorticoids, with isobutane CROSS-REFERENCE TO RELATED as propellant and oleic acid or Span 85 as Surface-active APPLICATIONS Substances. These dosage aerosols, however, have the dis 0001. This application is a National Stage application of advantage of a dissatisfactory resuspensibility and of too International Application No. PCT/EP2003/014901, filed on quick a sedimentation of the active Substance in the propel Dec. 24, 2003, which claims priority of German application lant. number 102 60882.2, filed on Dec. 24, 2002. SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION 0011. An object of the present invention to provide a controlled dosage aerosol for medicinal agents, especially 0002) 1. Field of the Invention for anti-asthmatic medicinal agents from the group of the 0003. The subject matter of the present invention is glucocorticoids which does not have the disadvantages of controlled dosage aerosols which comprise at least one the controlled dosage aerosols known from DE 1991 1 064. medicinal agent as well as a mixture made of pressure liquefied isobutane as propellant and lecithin as Surface DETAILED DESCRIPTION OF THE active agent. INVENTION 0004 The present invention more particularly relates to 0012. It was surprisingly found that the adjuvant lecithin controlled dosage aerosols comprising at least one medicinal leads to a marked improvement of the resuspensibility of agent with anti-asthmatic action from the group of the medicinal agents, especially of glucocorticoids in isobutane. glucocorticoids as well as a mixture made of pressure 0013 Lecithins are glycerophospholipides that are made liquefied isobutane as propellant and lecithin. from fatty acids, glycerol, phosphoric acid and choline. 0005 2. Description of the Prior Art Naturally occurring lecithins are derivatives of 1,2-diacyl sn-glycerol-3-phosphoric acid. When extracting lecithin 0006 Aerosol pressurized gas packs, also called con from biological material one always obtains a mixture of trolled dosage aerosols or metered aerosols for short, which are produced and employed by using liquefied pressure lecithins that differ from each other by the different fatty acid gases or compressed gases as a propellant, have been known eSterS. for a long time. Generally, Such metered aerosols consist of 0014. According to the present invention, an advanta a pressure vessel. Such as of metal or glass, having a valve geous lecithin is soybean lecithin, which is already widely construction for withdrawing its content, and of the actual used in the pharmaceutics industry as an emulsifier. agent to be sprayed, which in most cases consists of an 0015. In a comparison of the sedimentation behaviour of active Substance solution as well as a propellant in the form Suspensions of medicinal agent in isobutane under addition of a gas or a gas mixture liquefied under pressure. The of soybean lecithin or various Surface-active agents com pressure-liquefied gas or pressure-liquefied gas mixtures monly employed in the production of anti-asthmatic metered should ideally be miscible with the active substance at any aerosols it was observed, as will be seen from the below ratio So that one single liquid phase is formed. As an example, that the medicinal agent Suspension with soybean alternative, the pressure-liquefied gas or gas mixture should lecithin took 10 times longer to sediment than a medicinal form a Suspension with the active Substance which can be agent Suspension with oleic acid, and 5 times longer than a shaken easily and above which a gas phase forms. Depend medicinal agent Suspension with Span 85. ing on the agent contained, these metered aerosols are used in the cosmetic and medical fields, or as a room spray, 0016. In further tests, with a ratio of medicinal agent to insecticidal spray, and the like. soybean lecithin of 1:2, 1:1 or 1:0.5, no differences were observed in the sedimentation time, so that a ratio of 0007. The propellants of controlled dosage aerosols have medicinal agent to soybean lecithin of 1:0.5 may advanta to satisfy special requirements. They must by no means react geously be chosen. with the components of the active agent solution. Also, the propellants must be non-irritating and non-toxic. Fluoro chlorinated hydrocarbons had proved particularly suitable. EXAMPLE However, because of their ozone-depleting effect it has been 0017 Comparison of the suspension behaviour of sus necessary to develop alternative propellants. pensions of medicinal agent in isobutane, using various 0008 However, the quality of these alternative agents Surface-active agents must be comparable to that of the fluorochlorinated hydro carbons; above all, they must be both non-injurious to health and ecologically compatible. Initially, partially halogenated Relative fluorochlorinated hydrocarbons were frequently propagated sedimentation as replacements but these still have an unacceptably high Glucocorticoid:oleic acid (100:1) 1 oZone-depleting ability. Glucocorticoid:Span 85 (1:1) 2 Glucocorticoid:soybean lecithin (1:2) 10 0009. DE 4132 176 discloses controlled dosage aerosols Glucocorticoid:soybean lecithin (1:1) 10 for administering isoprenalin derivatives, the so-called Glucocorticoid:soybean lecithin (1:0.5) 10 B-sympathomimetics, or the non-steroid anti-inflammatory agent DNCG wherein isobutane is employed as a propellant. US 2006/00731 03 A1 Apr. 6, 2006 0018. In further tests, the following formulations have 2. The controlled dosage aerosol according to claim 1, turned out to be especially advantageous: wherein said at least one medicinal agent is at least one glucocorticoid selected from the group consisting of corti Sol, prednisone, prednisolone, methylprednisolone, triamci Formulation 1: Glucocorticoid O.1% 0.2% nolone, prednylidene, fluocortolone, paramethasone, dex Lecithin O.05% 0.4% amethasone, betamethasone, flunisolide, fluticaSone, Isobutane 99.85% 99.4% Formulation 2: Glucocorticoid O.S96-1.0% beclomethasone, budesonide and anti-asthmatically active Lecithin O.25% 4.0% derivatives thereof. Isobutane 99.75% 95.0% 3. The controlled dosage aerosol according to claim 1, wherein said controlled dosage aerosol comprises glucocor 0.019 For the glucocorticoid beclomethasone diproprion ticoid in the amount of 0.1%-0.2%, lecithin in the amount of ate, the following formulation has been found useful: 0.05%-0.4% and isobutane in the amount of 99.85%-99.4%. 4. The controlled dosage aerosol according to claim 1, wherein said controlled dosage aerosol comprises glucocor Formulation 3: Becomethasone O.1%. 2.5% ticoid in the amount of 0.5%-1.0%, lecithin in the amount of Soybean lecithin O.05% 5.0% 0.25%-4.0% and isobutane in the amount of 99.75%-95.0%. Isobutane 99.85% 92.5% 5. The controlled dosage aerosol according to claim 1, wherein said lecithin is soybean lecithin. 0020 For budesonide the following formulation has been 6. The controlled dosage aerosol according to claim 1, found extremely useful: wherein said controlled dosage aerosol comprises beclom ethasone in the amount of 0.1%-2.5.0%, soybean lecithin in the amount of 0.05%-5.0% and isobutane in the amount of Formulation 4: Budesonide O.1%. 2.5% 99.85%-92.5%. Soybean lecithin O.05% 5.0% 7. The controlled dosage aerosol according to claim 1, Isobutane 99.85% 92.5% wherein said controlled dosage aerosol comprises budes onide in the amount of 0.1%-2.5.0%, soybean lecithin in the 0021 All quantities relate to percent by weight. amount of 0.05%-5.0% and isobutane in the amount of 0022. The inventive aerosols may be prepared by mixing 99.85%-92.5%. the various components under conditions in which the 8. The controlled dosage aerosol according to claim 5, propellant and the Surfactant are liquid and in which the wherein the ratio of glucocorticoid and Soybean lecithin is active agent is present in a Solid phase. 1:2. 0023 The suspension of medicinal agent is filled through 9. The controlled dosage aerosol according to claim 1 for the valve into the clinched tin under pressure, which tin at treating allergic diseases in humans and animals. the beginning of the filling process has room temperature. 10. The controlled dosage aerosol according to claim 1 for The suspension has a temperature of approx. -10 to +10°C. treating asthma or allergic rhinitis. Subsequently, the tin is filled up with the propellant, thereby cleaning the valve at the same time. 11. A process for the production of controlled dosage aerosols according to claim 1, comprising the steps of: 0024. The controlled dosage aerosols according to the present invention may be used in the treatment of humans mixing isobutane as a propellant in liquid form, lecithin as and animals, in particular in the treatment of allergic dis a Surface-active agent in liquid form, and at least one eases of the respiratory tract, Such as asthma or allergic medicinal agent as Solid Substance to form a liquid rhinitis (hay fever).