| Aqueous suspensions of ciclesonide for nebulisation -> Monitor Keywords |
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Aqueous suspensions of ciclesonide for nebulisationRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Cyclopentanohydrophenanthrene Ring System Doai, Hetero Ring Containing, -o-c-o- Is Part Of A Hetero Ring (e.g., Acetonide, Etc.)Aqueous suspensions of ciclesonide for nebulisation description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070117783, Aqueous suspensions of ciclesonide for nebulisation. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] This invention relates to a method for the preparation of sterile aqueous suspensions of ciclesonide by sterilization with moist heat. The invention further relates to pharmaceutical compositions in particular to aqueous suspensions of ciclesonide for administration by nebulization in the prophylaxis and/or treatment of respiratory diseases. BACKGROUND [0002] U.S. Pat. No. 5,482,934 discloses pregna-1,4-diene-3,20-dione-16-17-acetal-21 esters and their use in the treatment of inflammatory conditions. The compounds have the general structure: wherein R1 is 2-propyl, 1-butyl, 2-butyl, cyclohexyl or phenyl; and R2 is acetyl or isobutanoyl. Ciclesonide is the INN for a compound of formula I in which R1 is cyclohexyl and R2 is isobutanoyl with the chemical name [11.beta.,16.alpha.(R)]-16,17[(Cyclohexylmethylen)bis(oxy)]-11-hydroxy-21- -(2-methyl-1-oxopropoxy)pregna-1,4-dien-3,20-dion. [0003] This compound has undergone evaluation as an antiasthmatic and pharmacokinetic studies show that it will be useful in an inhaler formulation. Ciclesonide is only moderately absorbed after oral administration and has low systemic activity. Concentration of the drug in the lungs is high and metabolism by liver oxidases is very high, giving the drug a low plasma half-life. Systemic activity of ciclesonide is three times lower than that of budesonide, but anti-inflammatory activity is higher for the former. [0004] Suitable formulations for pressurized metered dose inhalers (MDIs) for inhalation for ciclesonide are for example disclosed in U.S. Pat. No. 6,264,923 and U.S. Pat. No. 6,120,752. [0005] Besides dry powder inhalers (DPIs) and pressurized metered dose inhalers (MDIs) nebulizers represent another class of devices allowing inhalative drug administration. Especially in case of children and elderly being not able to handle DPIs and MDIs correctly, nebulization is the preferred way of drug administration to the lungs. Thus it is desirable to provide ciclesonide in formulations suitable for administration by nebulization. Whereas in case of water-soluble drugs aqueous solutions are nebulized, this is not possible in case of water-insoluble drugs such as ciclesonide. Consequently these drug substances have to be applied in the form of suspensions. In order to allow deposition within the lungs the particle size of the aerosol droplets after nebulization needs to be in the range of approximately 1-7 .mu.m. If suspensions will be administered, the particle size of the suspended drug particles is critical, since only particles being smaller than the aerosol droplets themselves are nebulized. For example micronized drug substance with a mean particle size of 2-6 .mu.m is suitable for such suspensions. [0006] Another requirement for suspension for nebulization is that these suspensions have to be isoosmotic in order to avoid irritation of the tissue coming into contact with the formulation. [0007] In addition formulations for administration by nebulization have to be sterile. Whereas in case of solutions this can be achieved by sterilization of the final formulation by moist heat or by filtration through a bacteria retentive filter, achieving sterile suspensions with a defined particle size is more difficult. Sterilization by filtration is no option when micronized drug substance with a mean particle size of 2-6 .mu.m is used, since the particles are not able to pass the filter. [0008] Sterilization of the (powdered) drug substance by dry heat followed by preparation of the suspension under aseptic conditions represents another manufacturing method. This is only possible, if the drug substance is stable enough to withstand the high temperature during this sterilization process (according to European Pharmacopoeia 4.07, chapter 5.1.1. a temperature of 160.degree. C. for at least 2 h is required). WO99/25359 describes a process for the sterilization of a powdered form of a gluco corticosteroid. WO99/25359 discloses that the sterilization process of glucocorticosteroids by dry heat can be carried out at a significantly lower temperature than that considered necessary for the heat sterilization of other substances. The drug substance is exposed to 110-120.degree. C. for no longer than 10 h. WO99/25359 further discloses sterile pharmaceutical formulations comprising a glucocorticosteroid and one or more pharmaceutically acceptable additives, diluents or carriers. Examples of such additives include surfactants, pH regulating agents, chelating agents, agents rendering the suspension isoosmotic and thickening agents. These sterile formulations can be produced by mixing the sterilized glucocorticosteroid with any suitable additional ingredients, e.g. a surfactant, pH regulating or chelating agent, an agent rendering the suspension isoosmotic or a thickening agent. All components other than the glucocorticosteroid, can be produced by sterile filtration of their aqueous solutions. Examples 4 and 5 are related to sterile formulations comprising budesonide. [0009] WO00/25746 discloses a process for preparing a sterile micronised glucocorticosteroid (beclomethasone dipropionate) by gamma-irradiation. [0010] To provide the sterile aqueous suspension however it is needed that the suspension has to be prepared under aseptic condition throughout the manufacturing process with the sterilized ingredients including the steroid, indicating that a large and special manufacturing plant is necessary. [0011] Another method for providing sterile aqueous pharmaceutical compositions is sterilization of the suspension by radiation. Ilium et al (Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174) recommend a sterilization process for steroid-containing aqueous suspension by beta ray or gamma ray irradiation. [0012] Another very common sterilization process for sterilizing of pharmaceutical compositions is autoclaving (sterilization by moist heat). Since the autoclaving is done by heating usually at 121.degree. C., the method cannot be adopted for unstable drugs in the presence of water at such high temperature. In case of sterilization of the final suspension formulation by moist heat there is a considerable risk of an increase of the particle size during the sterilization process. Furthermore ciclesonide does not seem to be stable chemically at such high temperature, because ciclesonide has an acetal structure in its 16 and 17 positions. [0013] WO 04/004739 is related to a ciclesonide-containing sterile aqueous suspension sterilized by autoclaving, wherein the concentration of ciclesonide after autoclaving is 95% or more comparing to that before autoclaving. It is further disclosed that it has been found that the uniformity of ciclesonide content can be maintained when hydroxypropylmethylcellulose is present in the suspension, even after sterilization by autoclaving. [0014] Commercially available suspension formulations for glucocorticosteroids for nebulization are e.g. available under the tradenames Pulmicort.TM. and Flixotide.TM.. Pulmicort.TM. nebules contain budesonide as drug substance. Besides the drug substance the suspension is composed of sodium chloride (agent to adjust osmolality) polysorbate 80 (suspending agent), sodium EDTA (chelating agent) citric acid/sodium citrate (buffering agent) and water. Flixotide.TM. nebules contain fluticasone propionate. Besides the drug substance the suspension is composed of sodium chloride (agent to adjust osmolality), polysorbate 20 and sorbitan monolaurate (suspending agents), monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous (buffering agent) and water. This formulation and its preparation are also disclosed in WO95/31964. On page 4 it is stated that bulk suspensions are sterilized by means of thermal sterilisation using steam. [0015] It is an object of the present invention to provide an aqueous suspension containing ciclesonide, in particular a sterile aqueous suspension, which is suitable for inhalative administration. [0016] When autoclaving aqueous suspensions of ciclesonide for nebulization containing excipients usually present in formulations for nebulisation (such as sodium chloride as agent to adjust osmolality), clogging of ciclesonide particles is observed during sterilization process, making the suspension no longer suitable for inhalative application. DESCRIPTION OF THE INVENTION [0017] Surprisingly it has been found now that sterile aqueous suspensions of ciclesonide comprising agents for adjusting osmolality can be prepared by autoclaving aqueous suspension of ciclesonide when using non-ionic agents for adjusting the osmolality as excipients in the suspension. No clogging of ciclesonide particles and no significant increase of the particle size of ciclesonide during the sterilization process is observed. [0018] Subject of the present invention is therefore a method for preparing a sterile aqueous suspension of ciclesonide suitable for nebulization comprising the steps of: [0019] (a) providing an aqueous suspension of ciclesonide, containing at least one non-ionic agent for adjusting the osmolality and optionally further pharmaceutically acceptable excipients and [0020] (b) autoclaving the aqueous suspension provided in (a). [0021] Ciclesonide is the INN for an active compound having the chemical name [11.beta.,16.alpha.-(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hy- droxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione. Ciclesonide and its preparation are described in U.S. Pat. No. 5,482,934. According to the invention, the name ciclesonide also includes solvates of ciclesonide, physiologically functional derivatives of ciclesonide or solvates thereof. Physiologically functional derivatives of ciclesonide, which can be mentioned in connection with the present invention, are preferably chemical derivatives of ciclesonide, which have a similar physiological function as ciclesonide or an active metabolite of ciclesonide, for example the 21-hydroxy derivative of ciclesonide (hereinafter also referred to as desisobutyryl-ciclesonide=des-CIC). The 21-hydroxy compound has the chemical name 16.alpha.,17-(22R,S)-cyclohexylmethylenedioxy-11.beta.,21-dihydroxy-pregn- a-1,4-diene-3,20-dione. This compound and its preparation are disclosed in WO 94/22899. According to the invention, the name "ciclesonide" is understood as meaning not only the pure R epimer of the compound [11.beta.,16.alpha.]16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy-21-(- 2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione but also R/S epimer mixtures in any desired mixing ratio (that is the compounds [11.beta.,16.alpha.(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy-- 21-(2-methyl-1-oxopropoxy) pregna-1,4diene3,20-dione and [11.beta.,16.alpha.(S)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy-- 21-(2-methyl1-oxopropoxy)pregna-1,4-diene-3,20-dione), those being preferred which essentially consist of R epimers. According to the invention, essentially consisting of R epimers means that the proportion of S epimers in the mixture is less than or equal to 5%, preferably less than or equal to 1%. [0022] The mean particle size of ciclesonide present in the aqueous suspension is preferably within a range, which allows effective administration of ciclesonide by nebulisalion. Preferably the mean particle size of ciclesonide (as determined by laser diffraction) is less than 12 .mu.m, preferably from 0.1 to 8 .mu.m, preferably 1 to 6 .mu.m, particularly preferably 2 to 4 .mu.m Ciclesonide with such particle size can be obtained by micronization of ciclesonide particles with greater particle size obtained in the manufacturing process of ciclesonide (e.g. as described in WO98/009982) or directly by crystallization processes leading to the desired mean particle size. [0023] The amount of ciclesonide, or a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the subject under treatment, and the particular disorder or disease being treated. It will further depend on the efficiency of the nebulizer used and the deposition of the aerosol droplets in the lung. Suitable concentrations of ciclesonide within the suspension for nebulization can be in the range of 0.005% to 0.5% (w/v) (i.e. 0.05 mg/ml to 5 mg/ml). Continue reading about Aqueous suspensions of ciclesonide for nebulisation... Full patent description for Aqueous suspensions of ciclesonide for nebulisation Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Aqueous suspensions of ciclesonide for nebulisation patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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