1. Field of the Invention
The present invention relates to a novel intranasally applicable powdery pharmaceutical composition comprising a polypeptide having a physiological activity, a quaternary ammonium compound, and a lower alkyl ether of cellulose. More specifically, it relates to an intranasally applicable powdery pharmaceutical composition comprising a physiologically active polypeptide such as calcitonin and insulin, a quaternary ammonium compound such as benzalkonium chloride, and a lower alkyl ether of cellulose. This powdery composition has an excellent chemical stability and preservability of the polypeptides and, when this powdery composition is administered to the nasal cavity in the form of a spray, the polypeptides are effectively absorbed through the or nasal mucosa.
2. Description of the Related Art
Since peptide hormones such as insulin and calcitonin have a large molecular weight and are easily decomposed by proteinases such as pepsin, trypsin, and chymotrypsin, they are not easily absorbed by oral administration and, therefore, the intended pharmacological effects cannot be effectively exhibited. Accordingly, such peptide hormones are generally administered by injection. However, since the injectable administration is generally painful, various other administration methods have been proposed
For example, J. Pharm. Pharmacol., 33, 334 (1981) discloses rectal absorption of insulin and heparin in a suppository in which salicylic acid derivatives such as sodium salicylate, sodium 3-methoxysalicylate, and 5-methoxysalicylate are used as an absorption aid. Furthermore, other methods such as intratracheal administration methods (see Diabetes 20, 552, 1971) and eye instillation methods (see Tonyobyo Gakkai Shoshu, Japan, 237, 1974) are being studied. However, since these methods are disadvantageous in that high dosage amounts are required when compared with the injection, and that the absorption amounts are likely to vary, these methods are not practically acceptable.
On the other hand, as disclosed in, for example, Diabetes, 27, 296, 1978, as well as Japanese Unexamined Patent Publication (Kokai) Nos. 59-89619 and 59-130820, intranasally applicable liquid pharmaceutical preparations of insulin or calcitonin containing, as an absorption aid, certain surfactants, are proposed for administration to the nasal cavity. Furthermore, Japanese Unexamined Patent Publication (Kokai) No. 58-189118 discloses intranasally applicable liquid pharmaceutical preparations of insulin in which cyclodextrin is used.
However, for the intranasally applicable liquid pharmaceutical preparation of, for example, insulin or calcitonin, it is necessary to ensure that contamination of the liquid preparations caused by the invasion of, for example, microorganisms, is prevented. It is proposed in Japanese Unexamined Patent Publication (Kokai) No. 59-89619 that- benzalkonium chloride be included in the intranasally applicable liquid pharmaceutical preparations to prevent such contamination, and to enhance the preservability of medicines such as calcitonin.
Intranasally applicable powdery pharmaceutical preparations containing calcitonin, insulin, or the like, and lower alkyl ethers of cellulose are also known, as disclosed in Japanese Unexamined Patent Publication (Kokai) No. 59-163313. However, it is still necessary to improve the preservability of the medicines such as calcitonin and insulin and also to enhance the chemical stability of the medicines such as calcitonin and insulin even in these powdery preparations.