Hydrogel suspension and manufacturing process thereof

#The present invention relates to a hydrogel suspension which comprises a fine particle and high molecular weight hydroxypropylmethyl cellulose (hereinafter abbreviated to HPMC) or methylcellulose (hereinafter abbreviated to MC), which exhibits high transparency and stability; and a manufacturing process thereof. More specifically, the present invention relates to a hydrogel suspension which is obtainable by dissolving high molecular weight HPMC or MC powders in a suspension of a fine particle which may comprise an active ingredient of submicron-scale or nano-scale; or mixing the suspension of a fine particle together with a solution of high molecular weight HPMC or MC; and a manufacturing process thereof.

#In case that a medicament is soluble in water or a solvent which is possible to be administered with the medicament, the medicament can be dissolved in the appropriate solvent to prepare a solution thereof and administered in the desired site or through an appropriate path way to deliver the medicament to the site. On the contrary, in case that a medicament is poorly soluble in water or other appropriate solvent which is possible to be administered with the medicament, the solubility of the medicament for water or the appropriate solvent can be enhanced by, for example, milling the medicament to a fine particle state or making the crystalline state of the medicament a high energy state, and then a suspension or the other may be prepared with the resulting soluble medicament to be used for administration.

#In order that the efficacy of a medicament is effectively exerted, it is necessary that the medicament is exposed to the desired site at the desired concentration for the desired period. However, it is thought that the retentivity of said conventional solution or suspension is low at the desired site and hence it is difficult to keep the desired period and concentration at the site. Then, in order to enhance the local retentivity of the medicament or make it sustained-released, a different drug formulation such as gel formulation and ointment may be often used. Especially, ophthalmic formulations have been studied about a variety of drug formulations such as a gel formulation and an ointment formulation so that the medicament would not easily flow through wink or lacrimal fluid (JP-A-2003-95924, JP-A-6-116137 (1994), JP-A-2005-206598, JP-A-2001-518510, JP-B-6-67853 (1994), JP-2729859).

#FIG. 1 shows dissolution behaviors of the gel formulations and the film formulation compared with the comparative example.

#FIG. 2 shows the correlation between the loading time of a shear stress on the gel (0.2% HPMC) and the viscosity thereof (rotational speed of the rotational viscometer: 0.2-2.5 rpm).

#FIG. 3 shows the correlation between the loading time of a shear stress on the gel (0.5% HPMC) and the viscosity thereof (rotational speed of the rotational viscometer: 0.2-1.0 rpm).

#The ingredient in the present suspension of a fine particle can be an organic or inorganic material, preferably an organic material and more preferably a pharmaceutical compound. The examples of the ingredient include rebamipide [chemical name: 2-(4-chlorobenzoyl-amino)-3-[2(1H)-quinolon-4-yl]propionic acid] and a salt thereof. The salt of rebamipide described herein includes salts formed with a conventional base such as sodium hydroxide, potassium hydroxide, triethanolamine, trimethanol(tris[hydroxymethyl]aminomethane), meglumine, diethanolamine and the like, preferably a water-soluble salt such as the salt of sodium hydroxide. Rebamipide can be used as the above salt form or as a free acid, provided that it should be used with an equimolar or more of the above base when it is used as a free acid. The amount of the above-mentioned acid is preferably at least the amount required to neutralize the above base.

#A process for preparing a fine particle from the above compound may be carried out with any of breakdown process such as a ball mill, a bead mill, a jet mill, and a hammer mill; spray dry; and built-up process such as crystallization.

#The particle size of the fine particle which may be used in the invention is not more than 11═, preferably not more than 500 nm, and more preferably not more than 200 nm.