Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-04-26
2002-08-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S489000, C424S490000, C424S491000, C424S494000, C424S497000, C424S484000, C424S486000, C424S488000
Reexamination Certificate
active
06428805
ABSTRACT:
This application is a 371 of PCT/JP 99/04560, filed Aug. 24, 1999, the entirety of which is hereby incorporated by reference.
1. Technical Field
The present invention relates to a powdery composition for nasal administration having an improved absorptivity of drugs through the nasal mucosa. More specifically, the present invention relates to a powdery composition for nasal administration that can be easily prepared using a drug and colloidal cellulose, and that can attain a high maximum blood concentration.
2. Background Art
In nonpeptidyl and nonproteinaceous drugs such as anti-inflammatory steroids, for example, there is a need for the development of drugs for nasal administration, because: (1) local nasal mucosa can be the target site of action; (2) an immediate action is desired; (3) some drugs are poorly absorbed through oral administration, and the like.
Many of peptidyl and proteinaceous drugs cannot be readily absorbed in the body because,for example, after oral administration they are decomposed by proteolytic enzymes in the gastrointestinal tract:and the like. In order to use such drugs for treatment of diseases, therefore, they have to be administered via injection in most cases. Injection, however, imposes a considerable burden on patients in terms of pain, the need for hospital visits, and the like. Accordingly, there is a need for the development of noninvasive administration methods such as drugs for nasal administration that can replace injections.
Nasal administration is a method of administration in which drugs are transferred via the nasal mucosa to the blood. Nasal administration is under intensive study as an administration method of the non-injection type, similar to percutaneous administration, ocular administration, rectal administration, pulmonary administration, and the like. Among the non-injection type methods of administration, nasal administration can be easily applied. In addition, since the nasal mucosa has a well-developed blood system as compared to the skin, the ocular mucosa, the rectal mucosa, and the like, nasal administration is considered to have excellent absorptivity of drugs among the non-injection type of methods. Accordingly, nasal administration has been put into practical use for some drugs as pharmaceutical formulations for nasal administration. Furthermore, immediate action equivalent to that of injection can be expected by nasal administration, since it offers the rapid migration of drugs into the blood compared to oral administration. However, the absorptivity of drugs via nasal mucosa depends on the physical properties such as lipophilicity and molecular weight etc. of drugs. Generally, it has been noted that highly water-soluble drugs, highly fat-soluble drugs, and peptidyl and proteinaceous drugs having high molecular weights have low absorptivity. Accordingly, various ideas have been proposed to enhance the absorptivity;of these drugs via nasal mucosa.
For example, Suzuki et al. (Japanese Examined Patent Publication (Kokoku) No. 60-34925) report a sustained-release formulation for the nasal cavity comprising a cellulose ester and a drug.
The sustained-release formulation for the nasal cavity of the above Patent Publication is intended to adhere to the nasal mucosa so as to gradually release the drug for an extended period of time, thereby enabling the absorption of the drug via the nasal mucosa and a sustained-release of the effective amount thereof. However, since the sustained-release formulation for the nasal cavity of the above Patent Publication focuses on the slow release of the drug, the formulation is considered not to have a sufficient function of promoting the absorption of the drug. Besides, the preferred embodiments of the drug are anti-inflammatory steroids, analgesic anti-inflammatory drugs, anti-histamine drugs, and drugs having anti-allergy actions, i.e., drugs for which the maintenance of the local concentration of the drug is important rather than the absorptivity into the systemic blood circulation.
Thus, the sustained-release formulations for the nasal cavity of the above Patent Publication are not expected to have high absorptivity via the nasal cavity for highly water-soluble drugs, highly fat-soluble drugs, and peptidyl and proteinaceous drugs having high molecular weights. Thus, there is a need for the development of compositions for administration to the nasal mucosa in which these drugs can be effectively used in terms of therapeutic effects and therapeutic efficiency.
Nolte et al. (Hormone Metabolic Research Vol. 22, 170-174, 1991) and Bruice et al. (Diabetic Medicine Vol. 8, 366-370, 1991) report on insulin formulations for nasal administration that contain an absorption-promoting agent such as sodium glycolate or sodium taurofusidate. However, due to a problem of irritation of the nasal mucosa, these absorption-promoting agents have not been put into practical use.
It has already been disclosed in the specifications of Japanese Examined Patent Publication (Kokoku) No. 62-42888 and W097/31626 that a combination of crystalline cellulose which is a component of colloidal cellulose, and a viscosity-increasing agent is effective for nasal administration.
Suzuki et al. (Japanese Examined Patent Publication (Kokoku) No. 62-42888) report on a powdery composition for nasal administration having an excellent absorptivity via the nasal mucosa, said composition comprising a polypeptide and a water-absorbing and low water-soluble base. They also report that such a composition permits the nasal absorption of polypeptides without using an absorption-promoting agent.
However, even for the compositions of the above Patent Publication, the nasal absorption ratio (area under the curve (AUC) of blood concentration along the time after nasal administration) of polypeptides never exceeds 10-20% that after injection administration. According to Example 4 of the above Patent Publication, for example, the maximum blood concentration after the administration of 10 units of insulin to rabbits is 200, &mgr;U/ml or lower, or about 20% that of the injection administration of the same unit, and the absorption ratio determined from AUC thereof is estimated to be 10% or lower.
The Patent Publication further describes the combined use of a water-absorbing and water-soluble base, and a water-absorbing and low water-soluble base at a ratio of 0.1-60% by weight, most preferably 1-50% by weight based on the weight of the water-absorbing and low water-soluble base. However, as the object and effects. of the combined use, it only states the effect of slow release (slow and sustained) compared to the use of the water-absorbing and low water-soluble base alone. Furthermore, the Patent Publication makes no mention of using nonpeptidyl and nonproteinaceous drugs instead of polypeptides.
The specification of W097/31626 describes that, by combining a plurality of water-absorbing and low water-soluble bases including crystalline cellulose and a plurality of water-absorbing and water-soluble bases, including hydroxypropyl cellulose, powdery compositions for nasal administration that exhibit an excellent maximum blood concentration can be provided for various drugs, i.e. peptidyl and proteinaceous drugs and nonpeptidyl and nonproteinaceous drugs.
However, in the above cases the combination of components is same as colloidal cellulose and the building components are identical, but the above components merely mixed as disclosed in the above two Patent Publications are different from a colloidal cellulose that is an essential component of the present invention, and therefore these Patent Publications make no mention of the present invention. For example, though one of the features of colloidal cellulose is that it can be well dispersed in an aqueous medium so as to form a stable suspension, it is well known to a person skilled in the art that the effect is different from and much superior to a simple mixture of crystalline cellulose and a viscosity-increasing agent as described in a pamphlet for Avicel manufactured by Asahi Chemical Industry Co
Dohi Masahiko
Fujii Takao
Uejima Yasuhide
Di Nola-Baron Liliana
Teijin Limited
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