Title:  Large intestinal delivery composite

United States Patent:  6,248,362

Assignee:  Meiji Seika Kaisha, Ltd. (Tokyo-to, JP)

Filed:  March 26, 1998

Foreign Application Priority Data:  Mar 26, 1997[JP] (9-073599)

A process for delivering the orally administered active ingredients which are safe even in their successive administrations for a long period to the large intestine without elution of the ingredients before reaching the large intestine is disclosed. The process according to the present invention comprises a step of administering orally to animals including human a composite comprising a core containing the active ingredients, an internal layer comprising chitosan with which the core is coated, and an external layer comprising a gastric acid resistant material with which the internal layer is coated, wherein all of the materials in the composite have the empirically established safety to humans. When a material having an iron cation scavenging ability, particularly phytin is used as the active ingredient, it is possible to treat colon cancer efficiently by the process according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Definition

The term "materials having the empirically established safety to humans" means herein, for example, a "food" or "food additive." The term "food" or "food additive" is exemplified by but not limited to the materials of which use is permitted by Japanese regulations relating to foods and food additives, for example, the Japanese Food Sanitation Law. The term "food" or "food additive" which is also intended to encompass foods and food additives which are recognized in other countries outside Japan, even if not recognized under the Japanese regulations.

Composite

Active ingredients and cores, and processes for preparing them

Active ingredients contained in the core of the composite according to the present invention include those which is preferably delivered directly to the large intestine. Such active ingredients may be either solid or liquid. These ingredients is preferably those of which safety to humans have been confirmed, particularly foods and food additives, but not limited thereto.

The ingredients which are desirably delivered directly to the large intestine include iron cation scavengers, particularly phytins for the therapy or prophylaxis of colon cancer. As described above, phytins is likely to inhibit the absorption of minerals in small intestine. According to the composite of the present invention, it is possible to deliver the phytins solely to the large intestine where the phytins are released but not released in small intestine. The composite according to the present invention comprising phytins as the active ingredients is useful for the prophylaxis of colon cancer. The prophylactics of colon cancer comprising phytins as the active ingredients are described in details below.

Further preferred active ingredients include Lactobacillus bifidus, anti-oxidants, and peptides. Further, two or more of them may be used in combination.

The core may comprise the active ingredients solely or the active ingredients together with other excipients. Such excipients are preferably the materials of which safety to humans has been confirmed, particularly foods and food additives. Such excipients include sugar, starch, cellulose and lactose. Specifically, when the active ingredients or active ingredient containing concentrates are liquid, cellulose or lactose is preferably used.

In addition, the core may comprises the other ingredients, which include an antioxidant such as vitamin C and vitamin E and a agent for inhibiting an activity of water such as starch and nistose. These ingredients are preferably the materials of which safety to humans has been confirmed, particularly foods and food additives.

The core is preferably in the form of granulates, and granulation may be carried out by a method conventionally used in the art. The size of the core may be appropriately determined, and preferably in the range of 1-10 nm.

The amounts of the active ingredients in the core, that is the amounts of the excipients and the other ingredients are not specifically limited, but the amounts are preferably 10% by weight or more, desirably in the range of 30-95% by weight when the active ingredients are phytins.

Internal layer and process for preparing it

The internal layer of the composite according to the present invention comprises chitosan. Chitosan is a deacetylation product of chitin with a concentrated alkali solution, .beta.-1,4-poly-D-glucosamine. The molecular weight of chitosan is not specifically limited, but is preferably in the range of about 10,000 to 1,000,000, more preferably in the range of about 100,000 to 500,000. Furthermore, the degree of deacetylation is preferably in the range of about 30 to 100%, more preferably in the range of about 65 to 95%,

The internal layer may comprise a chitosan film which is formed buy coating the surface of the core with a chitosan solution. Chitosan may be dissolved in a dilute acid solution (preferably organic acids such as acetic acid, citric acid, or malic acid) to form a 1--about 10% chitosan solution, which is sprayed on the surface of the core and dried to form a chitsosan film. This procedure may be carried out by a coating technique well-known in the art with a film coating machine or the like.

According to the preferred embodiment of the present invention, the chitosan solution described above may comprise the other ingredients such as a water proofing agent in order to increase the water resistance of the internal layer. There can be added water proofing agents such as glycerol, propylene glycol, or sugar esters which are known as a plasticizer. According to another preferred embodiment of the present invention, there can be also added food fibers such as wheat bran and corn fiber as a water resistant ingredient in an amount of 20-200% by weight to chitosan.

The thickness of the internal layer may be appropriately determined, and it is preferably in the range of 1--about 1,000 .mu.m, more preferably 100-300 .mu.m.

External layer and process for preparing it

The composite according to the present invention comprises an external layer comprising a gastric acid resistance material on the internal layer. The gastric acid resistant material may be any material in the art provided it is a film material which can protect the content from the environments in the stomach. In other words, a film forming material which has proteolysis in the small intestine and acid resistance in the stomach. It is preferably a material of which safety to humans has been confirmed, particularly foods and food additives. Specifically, it is preferably an antioxidant or a material used as a coating material for foods such as a enteric coating.

The preferred examples of such gastric acid resistant materials include prolamine proteins, such as wheat gliadin and zein, and oils and fats, among which, zein is employed most preferably from the viewpoint of film strength and availability. Zein is known a water-insoluable protein which is present primarily in the endosperm of corn, rich in proline and glutamic acid but free of tryptophan and lysine.

The external layer may be formed by coating the surface of the internal layer with a solution of the gastric acid resistant material and drying the solution to form a film. By way of example, when zein is employed as the gastric acid resistant material, zein may be dissolved in ethanol to form a 1-15% solution, which is treated in the same manner as in the case of the internal layer.

Furthermore, there can be added a water proofing agent as a film forming aid in order to increase the water resistance of the external layer.

The thickness of the external layer may be appropriately determined, and it is preferably in the range of 5-about 300 .mu.m, more preferably 10-about 50 .mu.m.

The composite according to the present invention is primarily in the form of granule, but the form is not limited thereto unless the effect according to the present invention is excessively decreased. It is also possible if necessary, to use a combination of coloring, dragee forming treatment, and/or the use of the composite as a constituent of an other composite.

Process for delivering the active ingredients to the large intestine/prophylaxis of colon cancer

The composite according to the present invention can deliver selectively the active ingredients to the large intestine solely. Thus, according to the present invention, there is provided a process for delivering the active ingredients to the large intestine solely.

Furthermore, when an iron cation scavenger, particularly phytins is used as an active ingredient, the composite according to the present invention is useful for a prophylactic of colon cancer. Thus, according to the present invention, there is provided a prophylactic for colon cancer. Also, from the other viewpoint, there is provided a process for preventing colon cancer, which comprises a step of administering the prophylactic orally.

The term phytins herein means phytic acid and salt thereof, and phytic acid having a structure in which inositol is linked to phosphoric acid is a chelating agent as strong as EDTA. The phosphate group is linked to inositol in an amount of 4-6 residues, and the chelating ability increases along with the increase of the residues. In particular, the phytin acid includes inositol 6-phosphate and a metal salt thereof, inositol 5-phosphate and a metal salt thereof, inositol 4-phosphate and a metal salt thereof, and a concentrate these compounds in a concentration of 10% by weight or more. For instance, phytin (calcium-magnesium salt of inositol 6-phosphate) and phytic acid correspond to this category. In this connection, when the number of the phosphate residues is 3 or less or the concentrate contains the compound only in a concentration of less than 10% by weight, satisfactory effects of the phytic acids may not be expected due to the low chelating ability, but the use of these phytic acids is also included in the present invention.

A proposed daily dosage of the composite according to the present invention for preventing colon cancer is 1 to 1000 mg in terms of phytins.

Furthermore, the phytins are known useful for the therapy of colon cancer as well as the prophylaxis and therapy of prostatic cancer, breast cancer and liver cancer. Thus, according to the present invention, there are provided a therapeutic agent of colon cancer as well as prophylactic and therapeutic agents of prostatic cancer, breast cancer and liver cancer. In addition, according to the present invention, there are provided a process for treating colon cancer as well as the processes for preventing and treating prostatic cancer, breast cancer and liver cancer.

Claim 1 of 24 Claims

What is claimed is:

1. A composite for delivering an active ingredient to the large intestine, said composite comprising

a core comprising the active ingredient,

an internal layer which is coated on said core comprising chitosan, and

an external layer coated on said internal layer comprising zein.

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