COMPOSITION COMPRISING LISURIDE COMPOUND FOR TREATING FRAGILE X SYNDROME OR RELATED DEVELOPMENTAL DISORDERS
20230024384 · 2023-01-26
Assignee
Inventors
Cpc classification
A61K31/48
HUMAN NECESSITIES
A61K31/475
HUMAN NECESSITIES
International classification
Abstract
The present invention relates to a composition for preventing, improving, or treating fragile X syndrome or related developmental disorders, comprising lisuride, a lisuride metabolite, or a pharmaceutically acceptable salt thereof.
Claims
1. A method for preventing or treating autism spectrum disorder, fragile X syndrome (FXS) or a fragile X syndrome-related developmental disorder, comprising administering a pharmaceutical composition comprising lisuride, a metabolite thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
2. The method according to claim 1, wherein the lisuride is represented by the following formula (1): ##STR00003##
3. The method according to claim 1, wherein the autism spectrum disorder is accompanied by one or more symptoms selected from hyperactivity or social deficit.
4. The method according to claim 1, wherein the fragile X syndrome is accompanied by one or more symptoms selected from the group consisting of repetitive behavior, hyperactivity, reduced learning ability, lack of social skills, impulsivity, and anxiety symptoms.
5. The method according to claim 1, wherein the fragile X syndrome-related developmental disorder includes one or more symptoms selected from the group consisting of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability, cognitive impairment, and impulse control disorder and anxiety disorder.
6. A health functional food composition for preventing or improving autism spectrum disorder, fragile X syndrome (FXS), or a fragile X syndrome-related developmental disorder, comprising lisuride, a metabolite thereof, or a pharmaceutically acceptable salt thereof.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0016]
[0017]
[0018]
[0019]
[0020]
[0021]
[0022]
DETAILED DESCRIPTION OF THE INVENTION
[0023] Hereinafter, the present invention will be described in more detail.
[0024] As described above, fragile X syndrome is characterized by cognitive deficits in learning and memory, lack of social skills, communication difficulties, and hyperactivity; and can be accompanied by autism and attention deficit hyperactivity disorder, which are also developmental disorders. Autism spectrum disorder is accompanied by symptoms such as hyperactivity, repetitive behaviors, or lack of social skills. However, drugs that can effectively and simultaneously treat one or more symptoms of autism spectrum disorder, fragile X syndrome, and any related developmental disorders, have not yet been reported.
[0025] Lisuride has therapeutic effects on direct or indirect symptoms of autism spectrum disorder, fragile X syndrome, or related developmental disorders (lack of sociability, prior wave suppression, etc.). A metabolite or a pharmaceutically acceptable salt thereof may be used as an active ingredient in a pharmaceutical composition for preventing and treating autism spectrum disorder, fragile X syndrome, and/or related developmental disorders.
[0026] Thus, the present invention provides a composition containing lisuride, a lisuride metabolite, or a pharmaceutically acceptable salt thereof as an active ingredient, for preventing, improving, or treating symptoms of autism spectrum disorder, fragile X syndrome (FXS), or related developmental disorders.
[0027] Lisuride, an active ingredient of the composition for treating autism spectrum disorder, fragile X syndrome, or related developmental disorders of the present invention, is a compound represented by the following chemical formula 1. The molecular formula is C.sub.20H.sub.26N.sub.4O and the molecular weight is 338.447 g/mol. The IUPAC name of lisuride is 1,1-Diethyl-3-(7-methyl-4,6,6a,7,8,9-hexahydro-indolo [4,3-fg]quinolin-9-yl)-urea:
##STR00002##
[0028] Lisuride of the present invention can include lisuride hydrate, lisuride derivatives, lisuride metabolites, etc. with the range of having the same efficacy as lisuride, and may also include solvates or stereoisomers thereof. The method for obtaining lisuride, lisuride hydrate, lisuride derivatives, lisuride metabolites, etc. is not particularly limited, and chemically synthesized or commercially available ones can be used using known methods.
[0029] In the present invention, the term “pharmaceutically acceptable salt” or “salt thereof” may be an acid addition salt formed with a free acid. Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an aqueous solution of excess acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. In addition, equimolar amounts of the compound and acid or alcohol in water (e.g., glycol monomethyl ether) may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction. An inorganic acid or an organic acid may be used as the free acid. Non-limiting examples of the inorganic acid include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like, and these may be used alone or in a combination of two or more. The “pharmaceutically acceptable salt” or “salt thereof” may be an acid addition salt formed with a free acid. Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. In addition, equimolar amounts of the compound and acid or alcohol in water (e.g., glycol monomethyl ether) may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
[0030] The salts of lisuride may include all salts of acidic or basic groups that may be present in the compounds of lisuride unless otherwise indicated. For example, the salt of lisuride may include sodium, calcium, and potassium salts of a hydroxyl group, and other cosmetically acceptable salts of an amino group include hydrobromide, sulfuric acid, hydrogen sulfate, phosphate, and hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and it can be prepared through a salt preparation method known in the art.
[0031] In the present invention, “lisuride metabolite” or “metabolite thereof” refers to a product that is metabolized in the body of a subject to which lisuride has been administered.
[0032] In the present invention, “prevention” means any action that suppresses the onset or delays the onset by administration of the composition. In the present invention, “improvement” or “treatment” refers to any action in which the symptoms of the disease are improved or beneficially changed by the administration of the composition.
[0033] preferably includes any one or more symptoms selected from the group consisting of hyperactivity symptoms and social deficit symptoms, but is not limited thereto, and the symptoms reported as symptoms of autism spectrum disorder It can contain any.
[0034] In the present invention, “autism spectrum disorder” preferably includes any one or more symptoms selected from the group consisting of hyperactivity, repetitive behaviors, and social deficit symptoms, but is not limited thereto, and can contain any symptoms reported as symptoms of autism spectrum disorder.
[0035] In the present invention, “fragile X syndrome” preferably includes any one or more symptoms selected from the group consisting of repetitive behavior, hyperactivity, reduced learning ability, lack of sociability, impulsivity, and anxiety symptoms, but is not limited thereto, and may include any symptoms reported as symptoms of fragile X syndrome.
[0036] In the present invention, “fragile X syndrome-related developmental disorder” preferably includes any one or more developmental disorders selected from the group consisting of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability, cognitive impairment, impulse control disorder, and anxiety disorder, but not limited thereto, and may include anything that has been reported as a concomitant disorder or disease of fragile X syndrome.
[0037] In the present invention, the autism spectrum disorder may include autistic disorder, Rett's disorder, Asperger's syndrome, and Pervasive developmental disorder-not otherwise specified (PDD-NOS).
[0038] In the present invention, “fragile X syndrome-related developmental disorder” preferably includes any one or more symptoms selected from the group consisting of repetitive behavior, hyperactivity, reduced learning ability, lack of social skills, impulsivity, and anxiety symptoms, but not limited to, and may include any symptoms reported as symptoms of “disorders associated with fragility X”.
[0039] In the specific embodiment of the present invention, the present inventors confirmed the degree of social improvement according to the presence or absence of administration of lisuride in the fragile X syndrome animal model (Fmr1-deficient animal model) and autistic animal model (Cntnap2-deficient animal model), In an animal model deficient in Fmr1, sociability was decreased, but in mice treated with lisuride, sociability was improved. In addition, it was confirmed that the pre-pulse suppression was reduced in the Fmr1-deficient animal model, but recovered again by the lisuride treatment (
[0040] The composition of the present invention is used as a pharmaceutical preparation containing lisuride or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated and administered in various oral or parenteral dosage forms at the time of clinical administration but is not limited thereto.
[0041] The oral administration may include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like. rose, sucrose, mannitol, sorbitol, cellulose, and/or glycine), lubricants (e.g., silica, talc, stearic acid, and its magnesium or calcium salts and/or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, optionally starch, agar, alginic acid, or its sodium salt. It may contain disintegrants or effervescent mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.
[0042] The present pharmaceutical composition containing lisuride, a lisuride metabolite, or a pharmaceutically acceptable salt thereof as an active ingredient, can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. At this time, to formulate a dosage form for parenteral administration, a pharmaceutical composition containing lisuride or a pharmaceutically acceptable salt thereof as an active ingredient is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, and it can be manufactured as an ampoule or vial unit dosage form. The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances. It can be formulated according to the method of formulation or coating conventionally.
[0043] In the present composition, the dose of lisuride, a lisuride metabolite, or a salt thereof to the human body may vary depending on the patient's age, weight, sex, dosage form, health status, and disease level. Based on an adult patient weighing 60 kg, generally, 0.001 to 1,000 mg/day, preferably 0.01 to 500 mg/day, may be administered in divided doses once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist.
[0044] The composition of the present invention may contain the active ingredient in an amount of 0.1 to 90% by weight based on the total weight of the composition. However, the content is not necessarily limited thereto and may vary depending on the patient's condition, the type of disease, and the degree of progression.
[0045] In another aspect, the present invention provides a health functional food composition for preventing or improving symptoms of autism spectrum disorder, fragile X syndrome (FXS), or related disorders containing lisuride, a lisuride metabolite, or a salt thereof as an active ingredient. The detailed contents of lisuride are the same as described above.
[0046] In the present invention, the term “health functional food” refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful for the human body. Here, ‘functionality’ refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological effects on the structure and function of the human body. The health functional food of the present invention can be prepared by a method commonly used in the art, and during the manufacture, it can be prepared by adding raw materials and components commonly added in the art. In addition, the dosage form of the health functional food may be manufactured without limitation as long as it is a dosage form recognized as a health functional food. The health functional food composition of the present invention has the advantage that there are no side effects that may occur during long-term administration using food as raw material, unlike general drugs, and has excellent portability, thereby it can be taken as a supplement to enhance the effect of alleviating the symptoms of fragile X syndrome or its related developmental disorders.
[0047] In the present health functional food for the prevention or improvement of autism spectrum disorder, fragile X syndrome, or related developmental disorders, when lisuride is used as an additive to a health functional food, it is added as it is or mixed with other food or food ingredients. They can be used together and can be used appropriately according to a conventional method. The mixing amount of the active ingredient may be appropriately determined according to each purpose of use, such as prevention, health, or treatment.
[0048] The formulation of health functional food may be in the form of powder, granules, pills, tablets, and capsules, as well as in the form of general food or beverages.
[0049] The type of food is not particularly limited, and examples of food to which the substance can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, and dairy products including ice cream, various soups, beverages, teas, drinks, alcoholic beverages, vitamin complexes, etc., and may include all foods in a conventional sense.
[0050] The mixing amount of the active ingredient may be appropriately determined depending on the purpose of its use (for prevention or improvement). In general, the amount of the compound (active ingredient) in the health food may be added in an amount of 0.1 to 90% by weight based on the total weight of the food. However, in the case of long-term intake for health and hygiene or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
[0051] Beverages among functional foods according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like conventional beverages. The above-mentioned natural carbohydrates may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As for the sweetener, natural sweeteners such as taumatine and stevia extract, and synthetic sweeteners such as saccharin and aspartame may be used. The ratio of the natural carbohydrate may be about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 mL of the beverage according to the present invention.
[0052] In addition to the above, the health functional food for the prevention or improvement of fragile X syndrome or related developmental disorders according to the present invention may include various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid, and its salts, organic acids, and protective properties. It may contain colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, and carbonating agents used in carbonated beverages. In addition, the health functional food composition for preventing or improving fragile X syndrome or related developmental disorders of the present invention may contain fruit for the production of natural fruit juice, fruit juice beverage, and vegetable beverage. These components may be used independently or in combination. The ratio of these additives is not limited but is generally selected in the range of 0.01 to 0.1 parts by weight relative to 100 parts by weight of the functional food of the present invention.
[0053] Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these examples.
EXAMPLES
Example 1: Confirmation of the Social Improvement Effect and the Pre-Pulse Suppression Improvement Effect of Lisuride in the Fragile X Syndrome Animal Model
[0054] Preparation of Laboratory Animals and Drugs
[0055] Purchased a 5-week-old Fmr1 knockout mouse (Jackson Laboratory, USA) weighing about 22 g to 24 g, and acclimatized to an environment with a temperature of 23±2° C. and humidity of 55±10% and a light-dark cycle of 12 hours while allowing them to freely consume water and feed (Experimental Animal Center, Konkuk University). As experimental animals, wild-type (WT) with normal FMRP expression and male KO mice lacking FMRP (fragile X mental retardation protein) expression (fragile X syndrome; FXS) were used. Dosing and experiments were performed according to the age of the week. Dosing was performed at the same time. Behavioral experiments were conducted 30 minutes after administration. It was divided into groups administered with 1 mg/kg each of lisuride (Sigma Aldrich) in FMRP expression-deficient knock-out (Knock-Out) mice, wild-type (Wild Type) mice, and 0.25 (v/v) % DMSO in FMRP expression-deficient knock-out mice (6 mice per group). For the drug administration group, lisuride was dissolved in 0.25 (v/v) % DMSO and then administered intraperitoneally at a dose of 50 ug/kg. Meanwhile, 0.25 (v/v) % DMSO was intraperitoneally administered to the control group.
[0056] Confirmation of Social Improvement Effect of Lisuride in Fragile X Syndrome Animal Model 1
[0057] To confirm the therapeutic effect of lisuride on social deficits, one of the phenotypes of fragile X syndrome and related developmental disorders, a three-chamber test was performed in the Fmr1-deficient animal model. If the animal model spent more time with a novel mouse rather than a familiar mouse, it is judged to be social. The test animal was exposed to the stimulus mouse for 10 minutes, and to a new stimulus mouse (novel) for another 10 minutes. In this case, the old mouse is called familiar and the new mouse is called a novel mouse. The time the test mouse explored each stimulus mouse was measured and expressed as %. As a result of the experiment, it was confirmed that the wild type spent more time with the novel mouse than the familiar mouse, indicating normal sociability. On the other hand, the mice deficient in Fmr1 spent more time with the familiar mouse than the novel mouse, indicating impaired sociability. When Fmr1-deficient mice were treated with lisuride, more time was spent with the novel mouse than with the familiar mouse, indicating that sociability was improved through the treatment with lisuride (
[0058] Confirmation of Social Improvement Effect of Lisuride in Fragile X Syndrome Animal Model 2
[0059] To confirm the therapeutic effect of lisuride on social deficits, one of the phenotypes of developmental disorders, a home-cage test was performed using an Fmr1-deficient animal model. A home-cage test evaluates sociability in the breeding cage removing the possible confounders of stress due to abrupt changes in the environment. After raising the group of animals to be tested together, a wire cage was placed inside the home cage and allowed the animals to acclimatize for 30 minutes. A stimulus mouse was placed in a wire cage and the duration of sniffing by the subject mice to the wire cage was measured for 15 minutes. Lisuride was administered once daily for 5 days. The sniffing time was reduced in Fmr1-deficient mice, but it was confirmed that the sniffing time increased again when lisuride was administered, suggesting that sociability was improved by lisuride treatment (
[0060] Confirmation of Improvement Effect of Pre-Pulse Suppression of Lisuride in Fragile X Syndrome Animal Model
[0061] The startle response was confirmed using an Fmr1-deficient animal model. Mice were divided into groups, and 0.9% physiological saline (saline solution) or lisuride was intraperitoneally administered to wild-type or knock-out mice. Thereafter, sensorimotor gating was evaluated through a pre-wave suppression test (converted using Equation 1 below). As a result of the experiment, it was confirmed that the pre-pulse suppression was reduced in Fmr1-deficient mice, but the pre-pulse suppression was restored when lisuride was treated (
Pre-pulse suppression (%)=100−[(startle response to pre-stimulus+stimulus)/(start-up response to stimulus)]*100 [Equation 1]
Example 2: Confirmation of the Effect of Improving Sociability and Improvement of Pre-Pulse Suppression of Lisuride in an Autism Animal Model
[0062] Preparation of Laboratory Animals and Drugs
[0063] Purchased a 5-week-old Cntnap2 knockout mouse (Jackson Laboratory, USA) weighing about 22 g to 24 g and acclimatize to an environment with a temperature of 23±2° C., humidity of 55±10%, and a light-dark cycle of 12 hours while allowing them to freely consume water and feed. After breeding (Konkuk University Laboratory Animal Center), they were used for experiments. Wild-type (WT) mice showing normal expression of Cntnap2 and KO mice lacking Cntnap2 expression were used. The dosing and testing were performed according to the age of the week. Dosing was performed at the same time. Behavioral experiments were conducted 30 minutes after administration. It was divided into groups administered with 1 mg/kg each of lisuride (Sigma Aldrich) or 0.25 (v/v) % DMSO in Cntnap2 expression-deficient knock-out mice or wild-type mice. For the drug administration group, lisuride was dissolved in 0.25% DMSO and then administered intraperitoneally at a dose of 50 ug/kg. Meanwhile, 0.25 (v/v) % DMSO was intraperitoneally administered to the control group.
[0064] Confirmation of Social Improvement Effect of Lisuride in Autism Animal Model (Cntnap2-Deficient Animal Model)
[0065] To confirm the therapeutic effect of Iisuride on the lack of sociability, one of the phenotypes of developmental disorders, a three-chamber test was performed using an animal model lacking Cntnap2. Experimental results were expressed as a social interaction index by measuring the time the test mouse approaches or sniffs each stimulus mouse. The higher the social interaction index means more time spent or sniffing in the novel over the familiar mouse.
[0066] Cntnap2 deficient mice spent more time or sniffed more with the familiar mice than novel mice. The KO group's social interaction index was decreased compared to wild-type mice. On the other hand, when Cntnap2-deficient mice were treated with lisuride, they spent more time and sniffed more with the novel mouse than the familiar mouse (
Example 3: Confirmation of the Improvement Effect of Pre-Pulse Suppression and Hyperactivity Improvement of Lisuride in an Animal Model Treated with Apomorphine or MK-801
[0067] Confirmation of Improvement Effect of Pre-Wave Suppression of Lisuride
[0068] Startle response was confirmed in an animal model treated with apomorphine or MK-801 in wild-type mice. Mice were divided into groups, and 0.9 (w/v) % of physiological saline (saline solution) or lisuride was administered intraperitoneally to each group. Thereafter, sensorimotor gating was evaluated through a pre-wave suppression test (converted using Equation 1 above). As a result of the experiment, it was confirmed that, when wild-type mice were treated with apomorphine or MK-801, the pre-pulse suppression was reduced, but when lisuride was treated after apomorphine or MK-801, it was confirmed that the pre-pulse suppression was restored (
[0069] Confirmation of Effect of Lisuride in Improving Hyperactivity
[0070] To confirm the hyperactivity improvement effect of lisuride, an open-field test was performed using an animal model in which MK-801 was administered to wild-type mice, and the results are shown in
[0071] Hereinafter, an example of the preparation of a pharmaceutical or food containing lisuride as an active ingredient according to the present invention will be described, not intended to limit the invention but merely to describe it in detail. Using the active ingredient, the pharmaceutical or food composition of Preparation Example 1 or 2 was prepared according to a conventional method according to the following compositional components and composition ratios.
[Preparation Example 1] Preparation of Pharmaceutical Composition
[0072] <1-1> Preparation of Powder
[0073] Lisuride 20 mg
[0074] Lactose hydrate 100 mg
[0075] Talc 10 mg
[0076] The above ingredients were mixed and filled in an airtight bag to prepare a powder.
[0077] <1-2> Preparation of Tablets
[0078] Lisuride 10 mg
[0079] Corn Starch 100 mg
[0080] Lactose hydrate 100 mg
[0081] Magnesium stearate 2 mg
[0082] After mixing the above ingredients, tablets were prepared by tableting according to a conventional manufacturing method of tablets.
[0083] <1-3> Preparation of Capsules
[0084] Lisuride 10 mg
[0085] Microcrystalline Cellulose 3 mg
[0086] Lactose hydrate 14.8 mg
[0087] Magnesium stearate 0.2 mg
[0088] After mixing the above ingredients, the capsules were prepared by filling in gelatin capsules according to a conventional manufacturing method of capsules.
[0089] <1-4> Preparation of Injection
[0090] Lisuride 10 mg
[0091] Mannitol 180 mg
[0092] Sterile distilled water for injection 2974 mg
[0093] Sodium monohydrogen phosphate 26 mg
[0094] After mixing the above ingredients, the content of the above components per 1 ampoule (2 mL) was prepared according to a conventional method for preparing injections.
[0095] <1-5> Preparation of Liquid Preparation
[0096] Lisuride 10 mg
[0097] Isomerized sugar 10 mg
[0098] Mannitol 5 mg
[0099] Purified water appropriate amount
[0100] Lemon flavor appropriate amount
[0101] The above ingredients were dissolved by adding each ingredient to purified water according to a conventional manufacturing method. After adding an appropriate amount of lemon flavor, purified water was added to adjust the total volume to 100 mL, sterilized, and filled in a brown bottle to prepare a solution.
[Production Example 2] Preparation of Health Functional Food
[0102] <2-1> Manufacturing of Health Supplements
[0103] Lisuride 10 mg
[0104] Vitamin A acetate 70 μg
[0105] Vitamin E 1.0 mg
[0106] Vitamin B.sub.1 0.13 mg
[0107] Vitamin B.sub.2 0.15 mg
[0108] Vitamin B.sub.6 0.5 mg
[0109] Vitamin B.sub.12 0.2 μg
[0110] Vitamin C 10 mg
[0111] Biotin 10 μg
[0112] Nicotinamide 1.7 mg
[0113] Folic acid 50 μg
[0114] Calcium pantothenate 0.5 mg
[0115] Mineral mixture appropriate amount
[0116] Ferrous sulfate 1.75 mg
[0117] Zinc oxide 0.82 mg
[0118] Magnesium carbonate 25.3 mg
[0119] Potassium monophosphate 15 mg
[0120] Dibasic calcium phosphate 55 mg
[0121] Potassium citrate 30 mg
[0122] Calcium carbonate 100 mg
[0123] Magnesium chloride 24.8 mg
[0124] The composition ratio of the vitamin and mineral mixture is relatively suitable for health food in a preferred embodiment, but the mixing ratio may be arbitrarily modified to prepare granules and can be used for preparing health food compositions according to a conventional method.
[0125] <2-2> Manufacturing of Health Drinks
[0126] Lisuride 10 mg
[0127] Vitamin C 15 g
[0128] Vitamin E (powder) 100 g
[0129] Iron lactate 19.75 g
[0130] Zinc oxide 3.5 g
[0131] Nicotinic acid amide 3.5 g
[0132] Vitamin A 0.2 g
[0133] Vitamin B1 0.25 g
[0134] Vitamin B2 0.3 g
[0135] Purified water appropriate amount
[0136] After mixing the above ingredients according to a conventional health drink manufacturing method, stirring and heating at 85° C. for about 1 hour, the resulting solution was filtered and obtained in a sterilized 2 L container, sealed, sterilized, refrigerated, and then used in the manufacture of health beverage compositions.
[0137] Although the composition ratio is prepared by mixing ingredients suitable for relatively favorite beverages in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and national preferences such as demand class, demanding country, and use.
[0138] The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be modified into other specific forms without changing the technical spirit or essential features of the present invention. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.