Title:  Nasally administrable compositions

United States Patent:  6,589,559

Issued:  July 8, 2003

Inventors:  Yanagawa; Akira (Yokohama, JP)

Assignee:  DOTT Research Laboratory (Yokohama, JP)

Appl. No.:  673466

Filed:  October 17, 2000

PCT Filed:  February 16, 2000

PCT NO:  PCT/JP00/00864

371 Date:  October 17, 2000

102(e) Date:  October 17, 2000

Abstract

A nasally administrable composition of a physiologically active substance, wherein an effective amount of said physiologically active substance is dispersed homogeneously in and adsorbed homogeneously onto a fine powdery form of a cereal, thereby enhancing the absorption of the physiologically active substance into a body via the nasal route. Examples of the cereal are rice, wheat, soybean, corn, foxtail, millet, buckwheat and the like, especially rice, and the physiologically active substance is a physiologically active peptide.

DISCLOSURE OF THE INVENTION

Accordingly, the object of the present invention is to provide a new nasally administrable composition that can nasally administer physiologically active substances with higher bioavailability though the mucous membrane of nasal cavity, and with the excellent pharmaceutical stability of the compositions.

One aspect of the present invention is to provide the nasally administrable composition containing a physiologically active substance and fine powdery form of cereal, wherein a physiologically effective amount of said physiologically active substance is dispersed homogeneously in and adsorbed homogeneously onto said fine powdery form of cereal.

The other aspect of the present invention is to provide fine powdery form of cereal as a carrier to be used for nasally administrable composition.

In still another aspect of the present invention, use of fine powdery form of cereal as a carrier for nasally administrable composition, is provided.

The nasally administrable composition of the present invention constitutes a characteristic future of using fine powdery form of cereal as a carrier to be used for nasally administrable composition, which has not yet been. Therefore, according to the present invention, when the physiologically active substance was administered nasally with fine powdery form of cereal as the carrier, the active substance contained in the composition may be extremely well absorbed into the body through the mucous membrane of the nasal cavity.

BEST MODES FOR CARRYING OUT THE INVENTION

The fine powdery form of cereal to be used in the present invention as a carrier may have a mean particle size from about 10 .mu.m to about 500 .mu.m, preferably from about 15 .mu.m to 300 .mu.m, since the physiologically active substance has to be atomized to the nasal cavity with the carrier.

The cereal to be used as a carrier of the present invention may be, for example, rice, wheat, soybean, corn, foxtail, millet, buckwheat and the like, which is eaten by the human beings as a staple principal food. Among them, the purified starch component of wheat or corn, that is corn starch, has been commonly used in the drugs as the excipients; however, the fine powdery form of these cereals intact has never been used as a carrier for the nasally administrable compositions up to present, and is first attempt by the present inventor.

The fine powdery form of the cereal, such as rice, may be prepared by pulverizing the polished rice by conventional technique, in order to obtain the purposed fine powdery form having a suitable mean particle size. The rice to be used for the present invention may include Japanese and foreign rice; however, Japanese rice is preferred. The examples of such Japanese rice are sold in Japanese brand name "Akita-komachi", "Sasa-nishiki", "Koshi-hikari", "Hitome-bore" and so on.

The fine powdery form of other cereal may also be foreign as well as Japanese cereal prepared by pulverizing in conventional technique, in order to obtain the fine powdery form having a suitable mean particle size.

The physiologically active substances to be contained in the nasally administrable composition of the present invention are not particularly limited as long as it is nasally administrable. The substances unlikely to be orally administered, especially, physiologically active peptides, can be used. The inventor of the present invention had found that the physiologically active peptides, such as glycoproteins, peptide hormones, physiologically active proteins and enzyme proteins show high absorption rate into the body.

Glycoproteins as the physiologically active substance include various interferons, such as .alpha.-interferon, .beta.-interferon, .gamma.-interferon and the like.

Peptide hormones include calcitonin, insulin, thyrotropin-releasing hormone (TRH) such as thyroliberin, luteinizing hormone-releasing hormone (LH-RH) such as buserelin and leuprolelin, LH-RH antagonists, somatostatin (growth hormone-releasing factor), adrenocorticotropic hormone (ACTH), adrenocorticotropic hormone-releasing hormone (CRH) such as corticoliberin, growth hormone-releasing hormone (GH-RH) such as somatorelin and the like.

Furthermore, they include gonadotropin (gonadotropic hormone), gonadotropin-releasing hormone (GnRH) such as gonadoliberin, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), growth hormone such as somatotropin, prolactin (mammotropic hormone), follicle-stimulating hormone (FSH), glucagon, vasopressin, parathormone (parathyroid hormone), angiotensin, gastrin, secretin, melanocyte-stimulating hormone, oxytocin, protirelin, corticotropin, thyrotropin (thyroid-stimulating hormone), opioid peptide such as .beta.-endorphin and enkephalin, G-CSF, erythropoietin, superoxide dismutase (SOD) and the like.

In addition, various types of interleukins, urokinase, lysozymes, and vaccines are also included.

Physiologically active peptides of the present invention are not limited to those mentioned above, and other peptides which can be combined with the specific carrier and administered nasally may also be used to make the compositions of the present invention.

Furthermore, the physiologically active substances unlikely to be administered orally can be used in the nasally administrable composition of the present invention. Such physiologically active substances may include various kinds of drugs on the market, or those under clinical development. Examples of such physiologically active substances include hypnotic and sedatives, anti-epileptics, minor tranquilizers, major tranquilizers, antidepressants, muscle relaxants, anti-allergic agents, antirheumatics, cardiotonics, antiarrthymics, antihypertensive diuretics, .alpha.-blocking agents, .beta.-blocking agents, calcium channel antagonists, angiotensin converting enzyme inhibitors (AEC), antihypertensives, vitamins, coronary vasodilators, cerebral circulation and metabolism ameliorators, anti-arteriosclerotcs, cardiovascular agents, bronchodilators, anti-ucceratives, antiemetics, antiobesity agents, platelet aggregation inhibitors, antidiabetics/symptomatic antidiabetics, DNA/RNA, and so on.

The amount of the above-mentioned physiologically active substances to be contained in the composition of the present invention is not specifically limited and may contain at least effective amounts of the active substances. Thus, it is preferred for the physiologically active substance mentioned above to be contained at a rate from 0.0001 to 30 weight %, preferably from 0.01 to 20 weight %, more preferably from 0.1 to 5.0 weight %, per 100% total weight of the composition.

Furthermore, the amount of the fine powdery form of the cereal as the carrier may be 70 to 99.995 weight %, preferably 80 to 99.99 weight %, and more preferably 95 to 99.9 weight %, per 100% total weight of the composition.

The composition of the present invention is prepared by admixing the physiologically active substance with the fine powdery form of the cereal as a specific carrier, thereby yielding a fine powder of a nasally administrable composition in which the physiologically active substance is dispersed homogeneously in and adsorbed homogeneously onto the carrier.

The composition thus prepared can be administered alone or with other pharmaceutically known ingredients added as desired.

In order to prevent the activity loss of the physiologically active substance prior to administration such as nasal administration, it may be filled in low-grease type capsules and packaged in an appropriate form, preferably in a closed form such as combined blister and aluminum packaging.

Claim 1 of 19 Claims

What is claimed is:

1. A nasally administrable composition, comprising an effective amount of a physiologically active substance dispersed homogeneously in and adsorbed homogeneously onto a fine powdery form of a cereal.

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