The pharmaceutical composition of the present invention is a suspension. The suspension can be obtained by suspending a water-insoluble drug(active ingredient) in aqueous medium uniformly. The suspension can be administered in a specific dosage form. Not only a stability of pharmaceutical compositions during storage, but also a high retentivity of drug in the administration site such as nasal cavity can be obtainable by using suspending agents with thixotropic property.
Therefore, the aqueous suspension has been recognized as a useful dosage form and many suspension products have been available on the market.
It is potentially easy for microorganism such as bacteria to proliferate in the aqueous suspension due to its high moisture environment.
Therefore, preservatives are necessary to be added in such aqueous suspension for supplying the market. Generally, as such preservatives, benzalkonium chloride, benzethonium chloride, phenylethyl alcohol or paraoxybenzoic acid esters are used. However, these preservatives are undesirable for use because the damages on mucous membrane etc. as reported in not a few literatures.
For avoiding proliferation of microorganism without preservatives in aqueous formulation, several methods mentioned-below are actually used in general.
The first method is to prepare an aqueous formulation from sterilized ingredients under aseptic condition. The second method is to prepare an aqueous formulation from non-sterilized ingredients, and then, the obtained aqueous formulation is sterilized before or after filling in bottles. In the case of suspension, with respect to the first method, Karlsson et al. disclosed a steroid-containing composition sterilized by dry heat sterilization (WO99/25359). 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 sterilized ingredients including steroid, indicating that large and special manufacturing plant is necessary.
On the other hand, as the second method that is simpler than the first one from the viewpoint of equipments, some specific methods have been suggested as follows.
Firstly, filtration. However this method of sterilization is not applicable to suspension in general, because the suspension contains insoluble particles.
Secondly, radiation sterilization. For example, Illum et al. recommended a sterilization process for steroid-containing aqueous suspension by beta ray or gamma ray irradiation (Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174). However, it is known that many compounds including steroids and other possible ingredients are degraded by beta ray or gamma ray irradiation and then it is difficult to guarantee the security of the degradation products. Therefore, the sterilization methods recommended by Illum et al. are not unlikely applicable to pharmaceutical compositions in actuality.
Thirdly, autoclaving. The autoclaving is one of very common sterilization processes for sterilizing of pharmaceutical compositions. Since the autoclaving is done by heating at 121 degrees C., the method cannot be adopted for unstable drugs in the presence of water at such high temperature. But the third method, the autoclaving, is the most useful sterilizing method as long as the drug is stable enough not to be degraded under such high temperature.
However, there are still two problems to be solved as indicated below.
First, ciclesonide did not seem to be stable chemically at such high temperature, because ciclesonide has an acetal structure in its 16 and 17 positions.
Secondly, it is known that a drug content uniformity (The term “drug content uniformity” means that the drug concentrations sampled from any portions(ex. upper portion, middle portion or lower portion) of the suspension are almost same.) of aqueous suspension containing a water-insoluble drug tends to be depressed by autoclaving, even if the drug is chemically stable. Such a phenomenon, the depression of the content uniformity, is explained that some particles of water-insoluble drug that are once dissolved or partly dissolved to smaller particles under such high temperature appeared again as various size of particles during subsequent cooling, leading to wider range of particle size distribution in suspension.
O'Neill et al. suggested a method by adding saturated concentration of sodium chloride for avoiding depression of the content uniformity of water insoluble drug (U.S. Pat. No. 3,962,430). But, in case adding the saturated concentration of sodium chloride solution, osmotic pressure of the aqueous suspension becomes extremely high. Or the suspension becomes unstable, because the important factor to maintain the physical stability of suspension is matrix network resulted mainly from hydrogen bond that is easily destroyed by high ionic strength. The patent application by Nagano et al. (WO 01/28562) described the aqueous pharmaceutical composition having less than 290 mOsm osmotic pressure comprising ciclesonide and hydroxypropylmethylcellulose(“HPMC” hereinafter). In addition, the patent application by Nagano et al. (WO 01/28563) described the aqueous pharmaceutical composition comprising ciclesonide and HPMC.
However, Nagano et al. did not mention or suggest sterilizing the composition by autoclaving. Furthermore, Nagano et al. disclosed in these specifications that preservatives might be added to the pharmaceutical composition.
Therefore, there is no motivation concerning the composition without preservatives in both specifications.
The object of the present invention is to provide a ciclesonide-containing sterile aqueous suspension without preservatives.
Further, the other object of the present invention is to provide such a ciclesonide-containing sterile aqueous suspension that can maintain content uniformity of ciclesonide.
The above objects of the present invention have been achieved by discovering that ciclesonide content in the ciclesonide containing aqueous suspension is not depressed by autoclaving, namely, ciclesonide is not degraded by autoclaving in the aqueous suspension.
Further, the above objects of the present invention have been achieved by discovering that the uniformity of ciclesonide content can be maintained when hydroxypropylmethylcellulose is coexisted, even after sterilization by autoclaving.
USPTO Backgrounds
USPTO Backgrounds