Source: {"pile_set_name": "USPTO Backgrounds"}

The subject compound and its synthesis method have been already disclosed (Non-patent Literature 1). Furthermore, its therapeutic or prophylactic activity against urinary frequency or urinary incontinence, antipruritic activity, analgesic activity, therapeutic or prophylactic activity against functional bowel disorder such as irritable bowel syndrome and antitussive activity have also been already disclosed (Patent Literature 1 to 5, an antitussive activity was disclosed after the priority date of the present application).
There is a concern that the storage stability may be decreased when the subject compound disclosed in the above-mentioned literature is formulated into an injection solution, liquid formulation or the like using it as a pharmaceutical active substance, since the subject compound in a state of solutions is likely to be affected by light, heat and oxygen. Although a common method for increasing solubility rate includes a method wherein the compound is lyophilized to be an amorphous powder, there is also a concern that the storage stability may be decreased since the hygroscopicity and the specific surface area increase compared to those powders having a high crystallinity.
For these reasons, considering an easy handling of such pharmaceuticals that have a high storage stability of the subject compound or convenience for patients, oral solid preparations are desirable for the known medical uses.
However, there is a concern that sufficient oral absorption may not be obtained when oral solid preparations are made using the subject compound as a pharmaceutical active substance, since the solubility rate of the subject compound in water is low.
Therefore, it has been considered that some sort of means for increasing the solubility rate of the subject compound concurrently with ensuring the storage stability is required.
When crystalline powders having a low solubility rate in water are used as a pharmaceutical active substance, methods in which the pharmaceutical active substance is ground into a fine powder may be used so that the solubility rate of the pharmaceutical active substance increases, which results in the increased oral absorption, and thus the increased bioavailability. However, there is a high possibility that, when the crystalline powders are finely ground according to such methods, crystalline powders may lose their crystalline structure and become amorphous, which results in the decreased storage stability. Thus, selection of the fine grinding process is relevant.
As a fine grinding process, those wherein tumbler mills such as a ball mill, fluid energy mills such as a jet mill, impact mills such as a hammer mill and a pin mill are used are known. However, properties of the powders obtained after grinding vary depending on a combination of the physicochemical properties of the compounds and the selected grinding process.
Although Patent Literatures or Non-patent Literatures listed below disclose the subject compound and its use, they are completely silent about the methodology for providing an appropriate crystalline finely-ground particles of the subject compound. Therefore, these literatures do not suggest at all that the subject compound may become a more useful pharmaceutical active substance when the subject compound is grounded by a specific grinding process so as to obtain crystalline finely-ground particles having a high solubility rate and thus a remarkably high bioavailability at the same time as having an ensured storage stability.    Patent Literature 1: WO 2004/033457    Patent Literature 2: WO 2005/094826    Patent Literature 3: WO 2006/049248    Patent Literature 4: WO 2007/055184    Patent Literature 5: WO 2007/072749    Non-patent Literature 1: Simon C. et. al., Tetrahedron, 50, 9757, 1994.