ENHANCER FOR EATING ACTIVITY AND/OR GASTROINTESTINAL ACTIVITY

Abstract

An agent for secreting ghrelin, comprising ornithine or a salt thereof as an active ingredient, an agent for enhancing eating activity, comprising ornithine or a salt thereof as an active ingredient, and an agent for enhancing gastrointestinal activity, comprising ornithine or a salt thereof as an active ingredient.

Claims

1. A method for enhancing gastrointestinal activity, comprising the step of administering an effective amount of ornithine or a salt thereof.

2. A method for preventing or ameliorating a symptom caused by reduced gastrointestinal activity, comprising the step of administering an effective amount of ornithine or a salt thereof.

3. The method for prevention or amelioration according to claim 2, wherein the symptom caused by reduced gastrointestinal activity is at least one symptom selected from indigestion, constipation, cachexia, anorexia nervosa, functional dyspepsia, and wasting disease.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0014] FIG. 1 shows enhancement of the ghrelin signaling system by which ornithine elicits the eating activity or gastrointestinal activity enhancing effect according to the present invention. In the figure, white circle, black circle, and black square represent the time-dependent changes of blood growth hormone for saline-administered control group (n=5), ornithine hydrochloride-administered group (5 g/kg, n=5), and ghrelin antagonist D-Lys3-GHRP-6 (0.8 mg/kg, i.v., n=7) and ornithine hydrochloride-administered group (5 g/kg, n=7), respectively. The symbol # in the figure means a statistically significant difference (P<0.05) when comparing ornithine hydrochloride-administered group with saline-administered group, and the symbol * in the figure means a statistically significant difference (P<0.05) when comparing ghrelin antagonist D-Lys3-GHRP-6 and ornithine hydrochloride-administered group with ornithine hydrochloride-administered group. Statistical processing was performed by using ANOVA and Fisher's test.

[0015] FIG. 2 represents the effect of intraduodenal administration of ornithine hydrochloride on blood ghrelin concentration (mean±standard error; n=4), showing that blood ghrelin concentration tends to increase due to ornithine hydrochloride administration.

[0016] FIG. 3 shows the effect of ornithine on small intestinal transit (mean±standard error; n=4). The symbol ** in the figure means a statistically significant difference (P<0.01) when comparing ornithine hydrochloride-administered group (3 g/kg) with control group, and the symbol in the figure means a statistically significant difference (P<0.001) when comparing ornithine hydrochloride-administered group (5 g/kg) with control group. Statistical processing was performed by using ANOVA and Fisher's test.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Ornithine used in the present invention includes L-ornithine or D-ornithine, and preferably L-ornithine.

[0018] Ornithine used in the present invention may be obtained by any process. L-ornithine can be obtained, for example, by chemical synthesis method [Coll. Czechoslov. Chem. Commun., 24, 1993 (1959)], fermentation method (JP-A-1978-24096, JP-A-1986-119194), and the like. L-Ornithine and D-ornithine can also be purchased from Sigma-Aldrich, and the like.

[0019] Examples of the ornithine salt include an acid addition salt, a metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, and the like.

[0020] Examples of the acid addition salt include an inorganic acid salt, such as hydrochloride, sulfate, nitrate, or phosphate; and an organic acid salt, such as acetate, maleate, fumarate, citrate, malate, lactate, a-ketoglutarate, gluconate, or caprylate.

[0021] Examples of the metal salt include an alkali metal salt, such as a sodium salt or a potassium salt; an alkali-earth metal salt, such as a magnesium salt or a calcium salt; an aluminum salt; and a zinc salt, and the like.

[0022] Examples of the ammonium salt include an ammonium salt, a tetramethylammonium salt, and the like.

[0023] Examples of the organic amine addition salt include a morpholine salt, a piperidine salt, and the like.

[0024] Examples of the amino acid addition salt include salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid, and the like.

[0025] Among the above salts of ornithine, hydrochloride or aspartate may preferably be used. However, another salt, or two or more combinations of the above salts may be optionally used.

[0026] As the agent for enhancing eating activity and/or gastrointestinal activity of the present invention, ornithine or a salt thereof can be administered as such. However, it is normally preferred to provide the agent as various kinds of preparations.

[0027] The preparation may be produced by mixing the active ingredient with one or more pharmaceutically acceptable carriers, and by using any method well known in the technical field of pharmaceuticals. The preparation may further comprise other active ingredients for any other treatment.

[0028] The preparation can be produced by using an additive, such as an excipient, a binder, a disintegrant, a lubricant, a dispersant, a suspension, an emulsifier, a diluent, a buffer, an antioxidizing agent, or a bacteria inhibitor.

[0029] The dosage form may be an oral form, such as a tablet, a powder, a granule, a pill, a suspension, an emulsion, an infusion/decoction, a capsule, a syrup, a liquid, an elixir, an extract, a tincture, or a fluidextract; or a parenteral form, such as an injection, a drop, a cream, or a suppository. Preferred is an oral form.

[0030] For example, when the dosage form suitable for oral administration is a tablet, a powder, or a granule, these can be prepared by adding a sugar (lactose, glucose, sucrose, mannitol, sorbitol, or the like); starch (potato, wheat, corn, or the like); an inorganic substance (calcium carbonate, calcium sulfate, sodium hydrogencarbonate, sodium chloride, or the like); an excipient, such as crystalline cellulose, or a plant powder (licorice powder, gentian powder, or the like); a disintegrant ,such as starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium hydrogencarbonate, or sodium alginate; a lubricant ,such as magnesium stearate, talc, hydrogenated vegetable oil, Macrogol, or silicone oil; a binder, such as polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carmellose, gelatin, or starch paste; a surfactant, such as fatty acid ester; a plasticizer, such as glycerin; and the like.

[0031] When the dosage form suitable for oral administration is a liquid preparation, such as a syrup, the preparation can be prepared by adding water, a sugar (sucrose, sorbitol, fructose, or the like), glycol (polyethylene glycol, propylene glycol, or the like), an oil (sesame oil, olive oil, soybean oil, or the like), an antiseptic (p-hydroxybenzoate, or the like), a paraoxybenzoic acid derivative (methyl paraoxybenzoate, or the like), a preservative (sodium benzoate, or the like), a flavor (strawberry flavor, peppermint, or the like), and the like.

[0032] When the dosage form suitable for parenteral administration is an injection, the preparation comprises a sterilized aqueous preparation which comprises ornithine or a salt thereof, and which is preferably isotonic to the recipient's blood. For example, a solution for injection can be prepared by using a carrier comprising a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution, or the like.

[0033] The preparation suitable for oral administration may also contain an additive generally used in foods and drinks, such as a sweetener, a color, a preservative, a thickening stabilizer, an antioxidant, a color former, a bleaching agent, an anti-fungal agent, a gum base, a bittering agent, an enzyme, a brightening agent, an acidulant, a flavor enhancer, an emulsifier, a toughening agent, a production agent, a flavor, or a spice extract.

[0034] It is desirable to administer the preparation by the route that is the most effective for eating activity and/or gastrointestinal activity. Examples of the administration route include oral administration; parenteral administration, such as intravenous, intraperitoneal, or subcutaneous administration; and the like. Preferred is oral administration.

[0035] The concentration of the ornithine or a salt thereof in the agent for enhancing eating activity and/or gastrointestinal activity of the present invention is appropriately determined according to the type of preparation, the effect expected from the preparation administration, and the like. For example, in the case of an oral form, the concentration of ornithine or a salt thereof is normally 0.1 to 100% by weight, preferably 0.5 to 80% by weight, particularly preferably 1 to 70% by weight.

[0036] The dose and the administration frequency of the agent for enhancing eating activity and/or gastrointestinal activity of the present invention depend on the dosage form, the age and the body weight of patients, and the nature or seriousness of the symptoms in need of treatment. Normally, the agent is given in a daily dose of 50 mg to 30 g, preferably 100 mg to 10 g, particularly preferably 200 mg to 3 g for adults in terms of an ornithine or a salt thereof, once to several times a day.

[0037] The agent for enhancing eating activity of the present invention can be used for an effect expected from enhancing eating activity.

[0038] The agent for enhancing gastrointestinal activity of the present invention can be used for an effect expected from enhancing gastrointestinal activity.

[0039] Further, the agent for eating activity of the present invention can be used for preventing or ameliorating a symptom caused by reduced eating activity. Examples of a symptom caused by reduced eating activity include impairment in eating caused by a symptom which is associated with impairment in eating, and which does not involve organic injury in the gastrointestinal tract (impairment in eating due to functional dyspepsia, impairment in eating due to age-related gastrointestinal malfunction, or the like) and the like. An individual presenting the symptom can be relieved from the symptom by administering the agent for enhancing eating activity of the present invention.

[0040] Further, the agent for enhancing gastrointestinal activity of the present invention can be used for preventing or ameliorating a symptom caused by reduced gastrointestinal activity. Examples of a symptom caused by reduced gastrointestinal activity include indigestion, constipation, cachexia, anorexia nervosa, functional dyspepsia, wasting disease, and the like. An individual presenting the symptom can be relieved from the symptom by administering the agent for enhancing gastrointestinal activity of the present invention.

[0041] Further, in the present invention, ornithine or a salt thereof can be used for the manufacture of the agent for enhancing eating activity and/or gastrointestinal activity.

[0042] Furthermore, the present invention includes a method for enhancing eating activity and/or gastrointestinal activity. The method of the present invention comprises the step of administering ornithine or a salt thereof to a subject in need of enhancing the eating activity and/or gastrointestinal activity in amounts sufficient for enhancing the eating activity and/or gastrointestinal activity of the subject.

[0043] The following describes test examples concerning the ghrelin secretion promoting effect that leads to the enhancement of eating activity and/or gastrointestinal activity by ornithine, as well as concerning the enhancement of gastrointestinal activity by ornithine.

Test Example 1

[0044] Changes in blood ghrelin concentration were examined according to the following testing method.

[0045] Testing Method

[0046] Male, 8 to 9-week Wistar rats were used.

[0047] Ornithine hydrochloride or saline as a control was administered to the duodenum, and blood growth hormone (GH) was measured over time. The results are presented in FIG. 1. The blood ghrelin concentration at 90 minutes after ornithine administration is shown in FIG. 2.

Results

[0048] As shown in FIG. 1, the ornithine hydrochloride-administered group had increased blood GH concentration levels compared to the control group. The GH concentration increasing effect of ornithine was inhibited by ghrelin antagonist D-Lys3-GHRP-6 (0.8 mg/kg, i.v.). The test was conducted under the condition where the antagonist alone does not show the effect. The result thus showed that the GH secretion promoting effect of ornithine is mediated by ghrelin secretion. Indeed, as shown in FIG. 2, the blood ghrelin concentration had the tendency to increase by ornithine administration. Taken together, the ghrelin secretion promoting effect of ornithine was confirmed.

[0049] Because it is known that ghrelin has the effect on enhancing eating activity (FASEB J. 2004, 18, 439-456), it is believed that ornithine or a salt thereof is useful as an agent for enhancing eating activity from the above-mentioned results.

Test Example 2

[0050] Gastrointestinal motility function was examined through small intestinal transit measurements according to the following testing method.

Testing Method

[0051] Male, 5 to 7-week ddY mice were used. The mice were fasted for 18 hours prior to the testing, and each animal (n=4) was orally administered with 0.3, 1, 3, or 5 g/kg (body weight) of ornithine hydrochloride, or saline as a control. After 30 minutes, the mice were orally administered with a dyed test meal (Evans Blue 5%, carboxymethyl cellulose 1%). The animals were killed by cervical dislocation after 5 minutes, and immediately cut open in the stomach to remove the whole small intestine. For evaluation of the gastrointestinal motility, the full length of the small intestine, and the length from the pylorus to the farthest point marked by the movement of Evans Blue were measured. Evans Blue mobility was calculated according to the following equation, and used as an index.

Mobility (%)=(the length from the pylorus to the farthest point marked by the movement of Evans Blue/the full length of small intestine)×100

Results

[0052] As shown in FIG. 3, the ornithine hydrochloride-administered group had a significantly increased level of small intestinal transit compared to the control group, demonstrating that the ornithine had the promoting effect of the gastrointestinal motility (P<0.01 for the ornithine hydrochloride administration of 3 g/kg (body weight), and P<0.001 for the ornithine hydrochloride administration of 5 g/kg (body weight)).

[0053] Examples of the present invention are described below.

Example 1

Production of Tablet Comprising Ornithine

[0054] Ornithine hydrochloride (136.2 kg; L-ornithine hydrochloride, Kyowa Hakko Bio), microcrystalline cellulose (36.0 kg; Avicel FD101, Asahi Kasei Chemicals Corporation), sucrose fatty acid ester (6.6 kg; DK ester F-20W, Dai-Ichi Kogyo Seiyaku Co., Ltd.), calcium phosphate (1.2 kg; tricalcium phosphate, Taihei Chemical Industrial Co., Ltd.), and β-cyclodextrin (20.0 kg; Cerdex B-100, Nihon Shokuhin Kako Co., Ltd.) were mixed by using a conical blender (CB-1200 blender; Nihon Kansouki Co., Ltd.). The resulting mixture was compression-molded under the compression molding pressure of 10 kN with a rotary compression molding machine (VIRGO524SS1AY; Kikusui Seisakusho) to produce tablets (diameter 8 mm; 250 mg).

Example 2

[0055] Production of Enteric Capsule Comprising Ornithine

[0056] The mixture (20 kg) prepared in Example 1, and silicon dioxide (0.2 kg) were mixed and stirred. The resulting mixture was charged into a capsule filling machine and filled in 20,000 gelatin hard capsules (size 2). Surface of the resulting hard capsules were then coated with zein solution using Hi-Coater HCT-48 (Freund) to produce 20,000 enteric capsules comprising ornithine hydrochloride.

Example 3

Production of Enteric Tablet Comprising Ornithine

[0057] Surface of the tablets prepared in Example 1 were coated with shellac solution using Hi-Coater HCT-48 (Freund) to produce enteric tablets.

Example 4

Production of Drink Comprising Ornithine

[0058] Ornithine hydrochloride (1.28 kg; L-ornithine hydrochloride, Kyowa Hakko Bio), erythritol (3 kg; Nikken Chemical Laboratory), citric acid (0.05 kg; Kyowa Hi Foods), artificial sweetener (3 g), and flavor (0.06 kg) were stirred and dissolved in 50 L of water at a liquid temperature of 70° C. After being adjusted to pH 3.3 with citric acid, the solution was sterilized with a plate sterilizer, and charged into a bottle, followed by sterilization with a pasteurizer, to produce a drink.

INDUSTRIAL APPLICABILITY

[0059] The present invention can provide an agent for enhancing eating activity and/or gastrointestinal activity which is safe and effective, and comprises ornithine or a salt thereof as an active ingredient.