JP2006111558A - Tablet-like gastrointestinal mucoadhesive oral preparation having multilayer structure - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a gastrointestinal mucoadhesive preparation (GI-MAPS) of tablet type, efficiently absorbing a substance that deteriorates by digestive juice, or the like, and has low permeability of an absorption membrane of digestive tract. <P>SOLUTION: The gastrointestinal mucoadhesive nucleated tablet having an excellent absorption ratio is obtained by once preparing a tablet comprising a water-insoluble layer and a layer containing (a) an adhesive substance, (b) a solution and absorption ameliorant such as a surfactant, (c) a medicine, a health food or a nutritive substance and preferably further (d) a stabilizer and forming a surface layer by using an enteric coating substance. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention includes additives such as surfactants that promote dissolution and absorption and drugs or health foods or nutritional substances, and protects drugs / health foods / nutrients from digestive fluids as well as drugs / health foods / nutritions The present invention relates to a tablet-type small intestine mucosa-adhesive oral preparation having a multilayer structure for the purpose of high absorption of substances. More specifically, the present invention relates to proteins such as insulin, desmopressin, erythropoietin, interferon, insulin, parathyroid hormone, health foods and nutritional substances such as collagen, hyaluronic acid, agarisk, propolis, fucoidan, and lactotripeptide. As mentioned above, it is degraded by gastric acid, digestive fluid, etc., or the gastrointestinal absorption membrane permeability is low, so that high absorption of drugs, health foods and nutrients that are difficult to absorb from the gastrointestinal tract after oral intake Therefore, after oral intake, protect the drug / health food / nutrient from the digestive fluid in the digestive tract and form a locally high concentration gradient of drug / health food / nutrient between the absorbed cells and the system. To improve the absorption rate (bioavailability) and efficacy of drugs, health foods and nutrients Is needed, it relates intestinal mucoadhesive oral tablet formulation types.

  In order to increase the bioavailability of drugs that cannot be expected to be sufficiently effective by oral administration due to the low absorption rate (bioavailability) of ordinary administration methods, Takada first adheres to the gastrointestinal mucosa and is a difficult / low absorbable drug Gastrointestinal mucoadhesive patch system technology (registered trademark GI-MAPS) has been invented to enhance the oral absorbability of GI. Takada previously invented a composition aimed at improving the absorption of health foods and nutrients as a technique for improving the absorption of health foods and nutrients from the digestive tract. GI-MAPS, invented by Takada, is an oral patch with a complex structure, and compositions intended to improve absorption of health foods and nutrients are capsules, granules or powders. In the field of pharmaceuticals and health foods, the shape of tablets is generally the most widespread, and it has high market value as a shape that is easy for patients and consumers to accept. According to conventional tablet manufacturing techniques, methods such as enteric coating for drugs that are decomposed by gastric juice or addition of an absorption enhancer when absorption from the gastrointestinal tract is low are generally used. However, these techniques are not effective for substances that are degraded by digestive fluid and have low permeability to the gastrointestinal absorption membrane. In fact, only desmopressin tablets are available on the market for oral absorption, but the absorption rate is said to be about 0.05%. Compared to ordinary oral preparations, the absorption rate is extremely low, indicating the limitations of conventional techniques.

Okada Hiroaki, Nikkei Biobusiness, November 2003, pages 148-151. Isabel Gomez-Orellana and Duncan R. Paton, Advances in the oral delivery of proteins. Exptl. Opin. Ther. Patents, 9, 247-253, 1999. Rakhi B. Shah, Fakhrul Ahsan & Mansoor A. Khan, Oral delivery of proteins: Progress and prognostication. Crit. Rev. Ther. Drug Carrier Systems, 19, 135-169, 2002. J. Gordon Still, Development of oral insulin: Progress and current status. Diabetes Metab. Res. Rev., 18, suppl. 1, S29-S37, 2002. Y. H. Lee, B. A. Perry, J. P. Sutyak, W. Stern and P. J. Sinko, Regional differences in intestinal spreading and pH recovery and the impact on salmon calcitonin in dogs. Pharm. Res., 17, 284-290, 2000. PJ Sinko, YH Lee, V. Makhey, GD Leesman, JP Sutyak, H. Yu, B. Perry, CL Smith, P. Hu, EJ Wagner, LM Falzone, LT McWhorter, JP Gilligan and W. Stern, Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: in vitro permeability and in vivo oral absorption of salmon calcitonin (sCT). Pharm. Res., 16, 527-533, 1999. Kathryn Whitehead, Zancong Shen and Samir Mitragotri, Oral delivery of macromolecules using intestinal patches: Applications for insulin delivery.J. Control.Rel., Vol. 98, 37-45, 2004. Kanji Takada, PCT / JP99 / 06602, An Oral Formulation for Gastrointestinal Drug Delivery, WO00 / 32172. Koji Takada, small intestine target type oral DDS preparation, Japanese Patent Application No. 2004-091930. Takada Kanji, Oral preparation of erythrocyte growth factor erythropoietins and interferons using gastrointestinal mucoadhesive DDS, Japanese Patent Application No. 2004-091930. Koji Takada, a composition intended to improve absorption of health foods and nutritional substances, Japanese Patent Application No. 2004-114561. A biological adhesive / pharmaceutical composition for sustained release of an active ingredient, JP-A-7-173077. Gastrointestinal mucoadhesive matrix, formulation and coating agent, JP 2001-354550 A. Gastrointestinal mucoadhesive matrix, formulation and coating agent, JP 2001-354593. Bioadhesive tablet, Japanese Patent Application No. 10-113330.

The problem to be solved by the present invention is to make a tablet that efficiently absorbs a substance that is deteriorated by digestive juice and has low permeability to the digestive tract absorption membrane. As a new attempt, there are several prior art attempts to improve absorption by bioadhesion. Regarding bioadhesive tablets, JP-A Nos. 2001-354550 and 2001-354593 disclose tablets that maintain their action by adhering to the digestive tract mucosa and increasing the residence time in the digestive tract. In the tablet disclosed in the present invention, since the substance mainly adheres to the stomach, the substance with good permeability to the small intestinal mucosa and the substance that does not deteriorate due to digestive fluid, the absorption is improved by increasing the duration of absorption, Substances that deteriorate in digestive juice and substances that are essentially poorly absorbed are not effectively absorbed in the small intestine, which is the main absorption site, and it is difficult to improve the absorption. As for the bioadhesive multilayer tablet, Japanese Patent Application No. 10-113330 discloses a bioadhesive tablet that adheres to the sublingual, vagina, anus, nose, and rectum in a multilayer form. However, the gastrointestinal tract, stomach, small intestine, and large intestine are excluded as adhesion sites. The reason is that only the multilayer form disclosed in the invention does not adhere to the stomach, small intestine and large intestine when ingested. Therefore, these prior inventions cannot efficiently absorb poorly absorbed drugs or nutrients from the small intestine. Non-patent document 7 discloses a small intestine adhesive preparation having a multilayer structure for insulin, but the non-coated tablet is coated with a water-insoluble film except for the attached surface, and is not partially coated. Cannot be produced by conventional tablet production techniques. The known technologies listed here cannot produce tablets that solve this problem.

This time, as a result of repeated research to achieve the task, we have developed a coated tableted multi-layered structure with a gastrointestinal tract that has the shape of a tablet and the conventional tablet. A general technique for improving absorption efficiency by applying a manufacturing technique and adding a small amount of absorption accelerator could be invented. That is, a multilayer tablet is prepared by once preparing a tablet comprising a water-insoluble layer and an adhesive substance and a layer containing a pharmacologically active ingredient or health food or nutritional substance, and forming a surface layer using an enteric coating substance. It was devised to prepare gastrointestinal mucoadhesive nucleated tablets with structure. According to this technology, digestion fluid does not decompose, but small intestinal mucosa permeability is low. Usually, ingredients with pharmacological activity or health foods or nutritional substances that require adjuvants to promote absorption are also converted into ordinary tablets. In comparison, the absorption rate can be improved with a small amount of surfactant.

A pharmacologically active ingredient or health food or nutritional substance is mixed with an adhesive substance such as sodium alginate, propylene glycol ester alginate, sodium polyacrylate, methylcellulose, etc., and a tablet having a diameter of about 4 mm to 8 mm is formed using a tableting machine. . A water-insoluble substance such as chitin, chitosan, stearic acid, etc. is put in a mortar, and a core tablet containing health foods and nutritional substances is placed on the mortar, and tableting / molding is performed using a dry tableting machine. ˜11 mm tablets.
Or put water-insoluble substances such as chitin, chitosan, stearic acid into a mortar and make a depression in the center, then adhere to health foods and nutrients and sodium alginate, propylene glycol ester alginate, sodium polyacrylate, methylcellulose, etc. Nucleated tablets are made by putting an admixture with a substance into a dent and compressing at once.
For the third layer corresponding to the surface layer, an enteric coating agent used for pharmaceuticals can be used. For foodstuffs, use the above-mentioned nucleated tablets, such as small intestine-soluble aqueous shellac (Freund Sangyo) or yeast wrap (kirin beer), which is a coating agent obtained from yeast fraction, etc. It is formed by coating.
These production methods are merely one method for obtaining the tablet of the present invention, and are not limited to this method.

That is, according to the present invention, (a) an adhesive substance, (b) a dissolution / absorption improver such as a surfactant, and (c) a drug, health food or nutritional substance for obtaining high absorbency A gastrointestinal mucoadhesive nucleated tablet having a multilayer structure is provided.
The tablet of the present invention preferably further comprises (d) a stabilizer.

  Preferably, the surfactant is glycerin fatty acid ester, sucrose fatty acid ester, calcium stearoyl lactate, sorbitan fatty acid ester, propylene glycol fatty acid ester, polysorbate 80, monooleic acid, polyethylene glycol monooleate, polyethylene glycol monostearate, A chain fatty acid triglyceride, a medium chain fatty acid monoglyceride, a medium chain fatty acid diglyceride, a medium chain fatty acid mono-, di-glyceride, or lecithin. These surfactants are only examples, and the surfactants that can be used in the present invention are not limited to these.

  According to another aspect of the present invention, high absorptivity is obtained, including (a) an adhesive substance, (b) a dissolution / absorption improver such as a surfactant, and (c) a drug or health food or nutritional substance. A process for producing a nucleated tablet having a multi-layer structure for adhering to the digestive tract mucosa is provided.

  By using the tablet-type small intestine mucosa-adhesive preparation of the present invention, it is possible to develop it as an orally ingestible product that can efficiently use drugs, health foods, or nutrient substances with a formulation technology that is easy to manufacture industrially. become.

Hereinafter, embodiments of the present invention will be described in detail.
The small intestinal mucoadhesive preparation of the present invention comprises (a) an adhesive substance, (b) a dissolution / absorption improving agent such as a surfactant, and (c) a drug or health food or nutritional substance, and in some cases (d) It is characterized by containing a stabilizer and is taken orally. Hereinafter, each of these components will be described.

Adhesive substance The adhesive substance that gives the adsorbing mucosa of the present invention is a typical adhesive substance such as sodium alginate, propylene glycol alginate, sodium polyacrylate, methylcellulose, etc., but is limited to these adhesive substances. It is not done.
The adhesive substance may be added to a layer containing a drug or health food or nutritional substance, or may be added to a layer only for giving small intestine adhesion separately from the layer containing a drug or health food or nutritional substance.

  The surfactant that can be used in the present invention promotes the dissolution of a substance having low solubility in the digestive tract after oral intake and promotes the absorption of drugs / health foods and nutritional substances that have low absorption from the digestive tract. The type is not particularly limited as long as it exhibits a desired action, and preferably a glycerin fatty acid ester such as decaglycerin laurate L-7D, L- 10D (Ryoto polyglycerate), Decaglycerin myristic acid ester M-10D (Ryoto polyglyceryl ester), Decaglycerin stearate ester SWA-10D, SWA-15D, SWA-20D, S-24D, S-28D (Ryoto poly) Glycester), decaglycerin oleate O-15D, O-50D (ryoto polyglycerester), decagli Limbehenic acid ester B-70D, B-100D (Ryoto polyglycerester), Decaglycerin erucic acid ester ER-30D, ER-60D (Ryoto polyglyceride), Decaglycerin mixed fatty acid ester LOP-120DP (Ryoto polyglycerester) Polyglycerol stearate DS13W, DS3, HS11, HS9, TS4, TS2 (Ryoto polyglycerate), Polyglycerol laurate DL15 (Ryoto polyglycerol ester), Polyglycerol oleate DO13 (Ryoto polyglycerol ester), Stearoyl calcium lactate, sorbitan fatty acid ester, propylene glycol fatty acid ester, sucrose fatty acid ester Ryoto sugar ester S-1670, S-1570, S-1170, P-1570, P-1670, M-1695, O-1570, OWA-1570, L-1695, etc. (Mitsubishi Chemical Foods), DK ester F-160, F-140, F-110, etc. (Daiichi Kogyo Seiyaku), polysorbate 80, monooleic acid, Polyethylene glycol monooleate, polyethylene glycol monostearate, medium chain fatty acid triglyceride, medium chain fatty acid mono-, di-glyceride (Capmul MCM C10), medium chain fatty acid monoglyceride, medium chain fatty acid diglyceride, saturated fatty acid having 6-12 carbon atoms That is, caproic acid, caprylic acid, capric acid and lauric acid, lecithin and the like can be mentioned.

As with surfactants, bile acids known to have an absorption promoting effect, chelators such as EDTA, organic acids, fatty acids (such as capric acid), and the like can also be used.
In the present invention, liquid, semi-solid or solid surfactants other than those described above can also be used. Specific examples of the surfactant that can be used in the present invention are listed below.

(A) Nonionic surfactant Alkyl glucoside, alkyl maltoside, alkylthioglucoside, lauryl macrogol glyceride, polyoxyethylene alkyl ether, polyoxyethylene alkylphenol, polyethylene glycol fatty acid ester, polyethylene glycol glycerol fatty acid ester, polyoxyethylene sorbitan Fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, polyglycerol fatty acid ester, polyoxyethylene glyceride, polyoxyethylene sterol, polyoxyethylene vegetable oil, polyoxyethylene hydrogenated vegetable oil, polyhydric alcohol and fatty acid, glyceride, vegetable oil, A reaction mixture of at least one member of the group consisting of hydrogenated vegetable oils and sterols, sucrose esters, Sugar ethers, sucrose glycerides, or mixtures thereof.

(B) Hydrophilic surfactant
PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG -20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG- 40 stearic acid ester, PEG-100 stearic acid ester, PEG-20 dilauric acid ester, PEG-25 glyceryl trioleic acid ester, PEG-32 dioleic acid ester, PEG-20 glyceryl lauric acid ester, PEG-30 glyceryl lauric acid ester PEG-20 glyceryl stearate, PEG-20 Lyseryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / caprylate glyceride, PEG-8 caprate / capri Rate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl ether, POE-23 Lauri Ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearic acid Esters, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenols, PEG 15-100 octylphenols, poloxamers, and mixtures thereof.

(C) Ionic surfactants: alkyl ammonium salts; bile salts; fusidic acid; fatty acid conjugates of amino acids, oligopeptides and polypeptides; glyceride esters of amino acids, oligopeptides and polypeptides; acyl lactylates; mono and diglyceride mono And diacetylated tartrate; succinylated monoglyceride; citrate mono- and diglyceride; alginate; propylene glycol alginate; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; lysophospholipid; camitin fatty acid ester salt; Sulfate salts; fatty acid salts; docusate sodium; and salts thereof.
Specific examples of the ionic surfactant include the following.

  Lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG phosphatidylethanolamine, PVP fatty acid Lactyl acid ester, stearoyl-2-lactylate, succinylated monoglyceride, mono / diglyceride mono / diacetyl tartaric acid ester, mono / diglyceride citrate ester, cholic acid ester, taurocholic acid ester, glycocholic acid ester, deoxycholic acid Ester, Taurodeoxycholic acid ester, Kenodeo Cycholic acid ester, glycodeoxycholic acid ester, glycochenodeoxycholic acid ester, taurochenodeoxycholic acid ester, ursodeoxycholic acid ester, lithocholic acid ester, tauroursodeoxycholic acid ester, glycoursodeoxycholic acid ester, corrisarcosine, N-methyl Taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinolate, linoleate, linoleate, stearate, lauryl sulfate, tetraacetyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and their Salts and mixtures thereof.

(D) Hydrophobic surfactant Alcohol; Polyoxyethylene alkyl ether; Fatty acid; Bile salt; Glycerol fatty acid ester; Acetylated glycerol fatty acid ester; Lower alcohol fatty acid ester; Polyethylene glycol fatty acid ester; Polyethylene glycol glycerol fatty acid ester; Fatty acid ester; Polyoxyethylene glyceride; Lactate ester of mono / diglyceride; Propylene glycol diglyceride; Sorbitan fatty acid ester; Polyoxyethylene sorbitan fatty acid ester; Polyoxyethylene-polyoxypropylene block copolymer; Transesterified vegetable oil; Sterol; Sugar ester Sugar ether; sucrose glyceride; polyoxyethylene vegetable oil; polyoxyethylene hydrogenated vegetable oil; Triol and fatty acid, glycerides, the reaction mixture of at least one of the group consisting of vegetable oils, hydrogenated vegetable oils and sterols; and mixtures thereof.

Specific examples of the hydrophobic surfactant include the following.
Oleic acid; lauric acid; stearic acid; palmitic acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4 distearate PEG-6 dioleate; PEG-8 dioleate; PEG-8 dioleate; PEG 3-16 castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 corn oil; PEG 6-20 PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric / capric glyceride mono-, di-, tri- and tetra-esters of vegetable oil and sorbitol ; Pentaerythrityl di, tetrastearate, isostearate; oleate; caprylenate or caprine Polyglyceryl 2-4 oleic acid ester, stearic acid ester or isostearic acid ester; polyglyceryl 4-10 pentaoleic acid ester; polyglyceryl-3 dioleic acid ester; polyglyceryl-6 dioleic acid ester; polyglyceryl-10 trioleic acid ester; Polyglyceryl-3 distearate; C.sub.6 to C.22 fatty acid propylene glycol mono- or diester; C.sub.6 to C.sub.22 fatty acid monoglyceride; C.sub.6 to C.sub. .22 fatty acid acetylated monoglycerides; C.sub.6 to C.sub.22 fatty acid diglycerides; monoglyceride lactate; diglyceride lactate; cholesterol; phytosterol; PEG 5-20 soy sauce sterol; PEG-6 sorbitan tetra; Hexastearate PEG-6 sorbitan tetraoleate; sorbitan monolaurate; sorbitan monopalmitate; sorbitan mono, trioleate; sorbitan mono, tristearate; sorbitan monoisostearate; sorbitan sesqueoleate; Sorbitan sesquistearate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetyl ether; PEG-2 stearyl ether; sucrose distearate; sucrose dipalmitate; ethyl oleate; isopropyl myristate Isopropyl palmitate; ethyl linolenate; isopropyl linolenate; poloxamer; cholic acid; ursodeoxycholic acid; glycocholic acid; taurocholic acid; lysocholic acid; deoxy Cycholic acid; chenodeoxycholic acid; and mixtures thereof.

The following are mentioned as a further specific example of the absorption improving agent which can be used by this invention.
Water-immiscible triglyceride vegetable oils (safflower oil, sesame oil, corn oil, castor oil, coconut oil, cottonseed oil, soybean oil, olive oil, etc .; water-immiscible refined and synthetic and semi-synthetic oils (eg mineral oil), known as MIGLYOL.RTM Triglycerides (caprylic / capric triglycerides, caprylic / capric / linoleic triglycerides, long chain triglycerides such as triolein, other mixed chain triglycerides that are liquid at room temperature, monoglycerides, diglycerides, and mono, di, Fatty acids and esters; water-soluble alcohols, glycerin and propylene glycol; water-miscible polyethylene glycols that are liquid at room temperature, such as PEG-400.

  Commercially available products include corn oil, propylene glycol, CREMOPHOR RH-40 (polyoxy-40 hydrogenated castor oil), LABRAFIL M 2125 (linoleoyl polyoxy-6 glyceride) and 1944 (oleoyl polyoxy-6 glyceride), ethanol PEG 400, Polysorbate 80, glycerin, peppermint oil, soybean oil (long chain triglyceride), sesame oil (long chain triglyceride), propylene carbonate, and tocopheroyl TPGS, MIGLYOL 812 (caprylic acid / capric acid triglyceride), oleic acid, olive oil ( Long chain triglycerides), CAPMUL MCM (medium chain monoglycerides), CAPMUL PG-8 (propylene glycol caprylyl mono and diglycerides), CREMOPHOR EL (polyoxy 35 castor oil), LABRASOL (caprylocaproyl polyoxy-8 glycerides), triacetin ( Acetyl triglycerides ), MAISINE 35-1 (glyceryl monolinolenic acid), OLICINE (glyceryl monooleate / linoleic acid ester), PECEOL (glyceryl monooleate), TRANSCUTOL P (diethylene glycol monoethyl ether), PLUROL Oleique CC (polyglyceryl- 6 dioleic acid ester), LAUROGLYCOL 90 (propylene glycol monolauric acid ester), CAPRYOL 90 (propylene glycol monocaprylic acid), MYVACETS (acetylated monoglyceride), ARLACELS (sorbitan fatty acid ester), PLURONICS (propylene and ethylene oxide copolymer), BRIJ 30 (polyoxyethylene 4-lauryl ether), GELUCIRE 44/14 (lauroyl polyoxyl-32 glyceride), and GELUCIRE 33/01 (glycerol ester of fatty acid).

  Other specific examples of commercially available surfactants include benzethonium chloride (HYAMINE.RTM. 1622, Lonza, Inc., Fairlawn, NJ); DOCUSATE SODIUM (Mallinckrodt Spec. Chem., St. Louis, Mo.); Poly Oxyethylene sorbitan fatty acid ester (TWEEN.RTM., ICI Americas Inc., Wilmington, Del.); LIPOSORB.RTM. P-20 (Lipochem Inc., Patterson NJ); CAPMUL.RTM. POE-0 (Abitec Corp., Janesville, Wis.).

  Further examples of absorption enhancers that can be used in the present invention include fatty acids such as capric acid and its derivatives such as N- [8- (2-hydroxybenzoyl) amino] caprylic acid (SNAC) and Sodium N- [8- ( 2-hydroxybenzoyl) amino] decanate (SNAD), glycyrrhizin, glutyrrhetinic acid, amino acid enamine derivatives (such as ethyl acetoacetate of phenylglycine), sodium salicylate or its derivatives, mixed micelles (monoolein and sodium glycocholate or taurocholic acid) Sodium mixed micelles, etc.), N-acyl collagen peptide, sodium N-acylamino acid, life-extending skin saponin and the like.

(3) Nutrients and health foods Drugs, nutrients or health foods whose activity is reduced by digestive fluid include proteins, peptides, amino acids and their analogues and mixtures, nucleic acids, nucleobases and their analogues and mixtures thereof , Lipids and their analogs and mixtures thereof, polysaccharides and their analogs and mixtures thereof. For example, insulin, desmopressin, erythropoietin, interferon, insulin, ercitonin, parathyroid hormone, chlorella, propolis, collagens, lactotripeptide, hyaluronic acid, catechins, polyphenols, glucosamine, chondroitin sulfate, shark cartilage extract, carnitine, Nattokinase, Coenzyme Q10, Meshimakobu extract, Agaricus extract, Ganoderma extract, milk peptide, sardine peptide, casein decapeptide, fucoidan, tocotrienol, sesame peptide or a mixture thereof. The application of the present invention is not limited to these.
Although the content of the nutrient substance which is an active ingredient in the small intestine mucosa-adhesive preparation of the present invention is not particularly limited, it is generally about 0.1 to 70% by weight.

(4) Stabilizer When health food / nutrients are easily hydrolyzed by digestive enzymes, better absorbability of health food / nutrients can be obtained by adding a stabilizer. For example, edible proteins such as casein and lactoferrin, and proteolytic enzyme inhibitors derived from natural products such as soybean trypsin inhibitor are typical stabilizers, and have an inhibitory effect on the hydrolysis of digestive enzymes. It is not limited to these stabilizers.

  The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the examples.

(Sample A) 10 parts of agaricus extract, 10 parts of silo page 720, 10 parts of DK ester F-140 (Daiichi Kogyo Seiyaku), 23 parts of sodium alginate and 2 parts of magnesium stearate are mixed and rotated. Using a tableting machine, the tablet is molded with a 5 mm diameter square corner punch to make a 45 mg core tablet. Next, granules for preparing a water-insoluble layer are prepared. That is, 85 parts of chitosan powder is granulated with a 5% aqueous solution containing 10 parts of corn starch using a fluidized bed granulator according to a conventional method. Thereafter, the size is adjusted with a 16-mesh sieve, and 5 parts of magnesium stearate is mixed to form water-insoluble layer granules. First, 120 mg of water-insoluble layer granules are filled using a dry tableting machine. Next, a core tablet is placed and tableted to form a tablet with an outer diameter of 8 mm. By coating the exposed surface of the dry coated tablet with yeast wrap solution or aqueous shellac solution, a tablet-type small intestinal mucoadhesive preparation is obtained.
(Sample B) 10 parts of silicopage 720, 10 parts of DK Ester F-140 (Daiichi Kogyo Seiyaku), 43 parts of sodium alginate and 2 parts of magnesium stearate are mixed with 10 parts of Agaricus extract Tablet using a tableting machine with a 6mm diameter flat corner punch to make a 75mg tablet

 (Sample C) 70 parts of Agaricus extract was mixed with 10 parts of silo page 720, 50 parts of DK ester F-140 (Daiichi Kogyo Seiyaku), 100 parts of sodium alginate and 10 parts of magnesium stearate, Using a tableting machine, the tablet is molded with a 5 mm diameter square corner punch to make a 50 mg core tablet. Using a dry tableting machine, 110 mg of chitosan crushed with a ball mill is filled. Then put the core lock. The surrounding area was filled with 50 mg of Hibiswako 103, and then tableted to form tablets with an outer diameter of 8 mm. By coating the exposed surface of the dry coated tablet with yeast wrap solution or aqueous shellac solution, a tablet type small intestinal mucoadhesive preparation is obtained.

Using samples A, B, and C obtained in Examples 1 and 2, an adhesion test to the gastrointestinal mucosa was performed. A rat with a body weight of about 400 g that has been fasted for 15 hours or more is subjected to laparotomy under ether anesthesia, and the jejunum portion is removed. The jejunum is cut vertically, and the small intestine scholar side is affixed to the aluminum fixation table using Aron Alpha for surgery. Attach the water-insoluble layer side of each of samples A and C to the tip of Digital Force Gauge FGN-2 (manufactured by Nidec Symposium) with Aron Alpha. Any surface of the sample B may be attached. The force gauge is lowered, and once the samples A, B, and C come into contact with the jejunal mucosa, they are stopped and contacted for 1 minute. Thereafter, the force gauge was raised, and the peeling pressure when the samples A, B, and C were detached from the jejunal mucosa was measured. As a result, the peeling pressure of sample A was 3.5 newtons, the peeling pressure of sample B was 2.1 newtons, and the peeling pressure of sample C was 5.1 newtons.

  Mix 70 parts of Agaricus extract with 10 parts of silo page 720, 50 parts of DK Ester F-140 (Daiichi Kogyo Seiyaku), 100 parts of sodium alginate and 10 parts of magnesium stearate. Used to form a tablet with a 5 mm diameter square corner punch to make a 50 mg core tablet. First, 110 mg of chitosan is charged using a dry tableting machine. Next, a core tablet is placed and tableted to form a tablet with an outer diameter of 8 mm. By coating the exposed surface of the dry coated tablet with yeast wrap solution or aqueous shellac solution, a tablet type small intestinal mucoadhesive preparation is obtained.

  Using a high-speed stirring granulator, 20 parts of powdered cellulose and 40 parts of corn starch are mixed, and 15 parts of beeswax dissolved by heating are further mixed. After sizing with 16 mesh, powdered cellulose and 5 parts of magnesium stearate are mixed to form water-insoluble layer granules. Add 1 part of ethanol to 70 parts of propolis extract and stir well. Add 30 parts of Ryoto Sugar Ester S-1670 (Mitsubishi Chemical Foods) and 30 parts of Silopage 760, mix well, and then remove ethanol while heating to about 40 ° C to obtain a solid for core tablets. . First, 200 mg of water-insoluble layer granules are filled using a dry tableting machine. Next, a solid material for a core tablet is placed and formed into a tablet with an outer diameter of 10 mm. By coating the exposed surface of the dry coated tablet with yeast wrap solution or aqueous shellac solution, a tablet type small intestinal mucoadhesive preparation is obtained.

  Using a high-speed stirring granulator, 20 parts of powdered cellulose and 40 parts of corn starch are mixed, and 15 parts of beeswax dissolved by heating are further mixed. After sizing with 16 mesh, powdered cellulose and 5 parts of magnesium stearate are mixed to form water-insoluble layer granules. Add 1 part of ethanol to 70 parts of propolis extract and stir well. Add 30 parts of Ryoto Sugar Ester S-1670 (Mitsubishi Chemical Foods) and 30 parts of Silopage 760, mix well, and then remove ethanol while heating to about 40 ° C to obtain a solid for core tablets. . First, 200 mg of chitosan is charged using a dry tableting machine. Next, a solid material for a core tablet is placed and formed into a tablet with an outer diameter of 10 mm. By coating the exposed surface of the dry coated tablet with yeast wrap solution or aqueous shellac solution, a tablet type small intestinal mucoadhesive preparation is obtained.

  Mix 30 parts of catechin, 30 parts of Ryoto decaglycerin laurate L-7D (Mitsubishi Chemical Foods), 56 parts of sodium alginate and 4 parts of magnesium stearate, and use a rotary tableting machine to make a 5 mm diameter flat corner Tableting is done with a square punch to make a 45 mg core tablet. Add 5 parts of magnesium stearate to 95 parts of chitosan and mix well. First, 115 mg of the chitosan layer is filled using a dry tableting machine. Next, a core tablet is placed and tableted to form a tablet with an outer diameter of 8 mm. By coating the exposed surface of the dry coated tablet with yeast wrap solution or aqueous shellac solution, a tablet type small intestinal mucoadhesive preparation is obtained.

  Mix well 30 parts of carnitine, 30 parts of Ryoto decaglycerin oleate O-15D, 56 parts of sodium alginate and 4 parts of magnesium stearate. Using a rotary tableting machine, the tablet is molded with a punch with a diameter of 7 mm in plane corners to give a 120 mg core tablet. First, 200 mg of a chitin layer is filled using a dry tableting machine. Next, a core tablet is placed and tableted to form a tablet with an outer diameter of 10 mm. By coating the exposed surface of the dry coated tablet with yeast wrap solution or aqueous shellac solution, a tablet type small intestinal mucoadhesive preparation is obtained.

  Many health food and nutritional products are on the market, but most do not have a guarantee for their absorption after ingestion. Takada previously invented GI-MAPS, LFNPS, LFMPS, etc. as a DDS technology to improve absorption of health foods and nutrients from the digestive tract. In order to enhance the practical use, a tablet type small intestine mucosa-adhesive preparation was invented. By using this DDS technology, the absorption improver and the drug / health food / nutrient are separated and delivered to the absorption cells without dilution to form a high concentration gradient to absorb the drug / health food / nutrient It has become possible to develop products with improved characteristics.

Claims (9)

Contains a drug or health food or nutritional substance whose activity is reduced by the action of digestive juice or requires an auxiliary agent for absorption from the small intestine, and (a) an adhesive substance and (b) a component that enhances absorption from the small intestine A nucleated tablet having a small intestine mucosa adhesive property having a multilayer structure comprising a layer forming a bioadhesive surface and a water-insoluble layer surrounding the bioadhesive surface. The tablet according to claim 1, further comprising (c) a stabilizer. The tablet according to claim 1 or 2, wherein the adhesive substance is alginic acid and its salts, propylene glycol alginate, polyacrylic acid and its salts, and methylcellulose. The tablet according to claim 1 or 2, wherein the component that enhances absorption from the small intestine is a surfactant. Surfactant is glycerin fatty acid ester, sucrose fatty acid ester, stearoyl calcium lactate, sorbitan fatty acid ester, propylene glycol fatty acid ester, polysorbate 80, monooleic acid, polyethylene glycol monooleate, polyethylene glycol monostearate, medium chain fatty acid triglyceride The tablet according to claim 1, which is medium chain fatty acid monoglyceride, medium chain fatty acid diglyceride, medium chain fatty acid mono-, di-glyceride or lecithin. The tablet according to claim 1 or 2, wherein the coating agent is hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, yeast wrap, shellac. The tablet according to claim 1 or 2, wherein the stabilizer is a protein or a protease inhibitor. The tablet according to claim 1, 2, or 7, wherein the protein is collagen, casein, lactoferrin, albumin, or egg white. The tablet according to claim 1, 2, or 7, wherein the protease inhibitor is soybean trypsin inhibitor, aprotinin.