In recent years, care for dementia including a senile dementia, an Alzheimer-type dementia or the like has become a social problem, and many therapeutic drugs are being developed. Of these, donepezil, which is available as a hydrochloride in a tablet or a granule form, is seen as being highly useful as a therapeutic drug for mild and moderate Alzheimer's dementia because of its acetylcholinesterase inhibiting action. Recently, a tablet which disintegrates in the mouth have been marketed for patients who have trouble swallowing, and transdermal administration by an ointment preparation has been proposed for cases in which oral administration is difficult (For examples, see Patent Document 1: Japanese Patent Application Laid-Open No. H11-315016).
Such development of the pharmaceutical composition suitable for the conditions and symptoms of the patient is extremely important from the standpoint of compliance or quality of life. In this sense, a sustained-release preparation is useful for the anti-dementia drug because the sustained-release characteristics of the drug allows the number of drug administrations to be reduced while providing the same or better therapeutic effects, potentially improving compliance.
In general, the sustained-release preparation containing the drug which is physiologically active can be classified into two type preparations, (1) a matrix type preparation, in which the drug and a sustained-release base are distributed uniformly in the preparation, and (2) a sustained-release coated type preparation, in which release is controlled by coating a surface of a core particle or a core tablet containing a physiologically active drug with a sustained-release coating.
Matrix type sustained-release preparations have a matrix in which the drug and the sustained-release base are present uniformly. The matrix is generally used as is as a tablet or a granule, and may be given a light-shielding coating or the like. Sustained-release coated preparations include those in which a coating which comprises the sustained-release base is applied to a core of the granule, the tablet or the like containing a drug, or those in which a layer containing the drug is applied on a core particle consisting of crystalline cellulose or sucrose which are so-called nonpareil, followed by another sustained-release coating. The sustained-release characteristics are also controlled in some cases by means of multiple layers of coating containing the drug or coating containing the sustained-release base.
However, because these sustained-release preparations now comprise the sustained-release base and other additives which were not included in conventional, fast-dissolving tablet and the like, care must be taken that the stability of the drug is not affected. In particular, many anti-dementia drugs are basic drugs containing an amino group, and in general, a highly reactive functional group such as the amino group which is nucleophilic has a property of easily producing degradation products, when reacting with carbonyl carbon, peroxide, oxygen or the like.
Since the degradation products of the drug or additives can affect the stability or efficacy of the pharmaceutical products, means of preventing generation of such degradation products or severely inhibiting the produced amounts are being studied in the field of preparation development. Regarding a method for stabilizing the anti-dementia drug, a composition containing an organic acid has been disclosed for stabilizing donepezil against light (For examples, see Patent Document 2: Japanese Patent Application Laid-Open No. H11-106353). It was reported that the light-stabilizing effect was evaluated as the effect of adding an organic acid to donepezil in an aqueous ethanol solution, and a residual ratio of donepezil was higher in a solution to which tosylic acid, mesylic acid, citric acid or the like had been added than in a solution with no added organic acids.