KR20170026241A - Complex preparation for oral use - Google Patents

Abstract

The present invention an oral complex formulation, comprising an immediate release compartment and a controlled-release compartment. The oral complex formulation provides as an active ingredient at a controlled-release rate by including: vitamin B12, vitamin B6, vitamin B9 and choline in the immediate release compartment; and vitamin D, vitamin E, vitamin C, silymarin, and biphenyl-dimethyl-dicarboxylate in the controlled release compartment.

Description

[0001] The present invention relates to a complex preparation for oral use,

The present invention relates to an oral combination preparation containing controlled release of vitamin B12, vitamin B6, vitamin B9, choline, vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate.

Liver disease is becoming an important cause of adult disease and death in Korea. The liver is an organ with a large buffer capacity. Since the liver is not aware of the symptoms at an early stage of the disease, the disease is often found in a state of advanced disease, and effective therapeutic agents and diagnostic methods are lacking. The causes of liver disease include alcohol, drugs, chemicals, hepatitis viruses, metabolic diseases such as obesity and insulin resistance, and autoimmune diseases. In addition, the liver is the center of the blood storage and circulation, blood volume control and detoxification in the human body. Recently, as the industrialization has increased opportunities for exposure to harmful substances, the liver has been suffering from continuous detoxification. Especially, And the liver damage caused by the causes of the immune system is caused by abnormalities, as well as other diseases are increasing the cause.

In most of the liver diseases, complications and liver cancer, which have a great influence on the prognosis of the disease, are mostly developed after hepatic fibrosis and cirrhosis, so they understand the progress of liver disease and inhibit its progress. It is necessary to develop a therapeutic agent.

Korean Patent Laid-Open No. 10-2014-0137288 discloses a composition for treating liver disease, and Korean Patent Publication No. 10-2014-0137289 discloses a composition for treating hepatopathy Compositions for treating diseases are disclosed. However, the development of a more economical, stable and effective therapeutic agent for liver diseases is required.

In view of this background, the inventors of the present invention developed a new composite composition containing nine active ingredients effective for improving liver function, and improved compliance and convenience for dosing for effective delivery of the composition and at the same time, , The therapeutic effect and the liver function improving effect, thereby completing the present invention.

Korean Patent Publication No. 10-2014-0137288 Korean Patent Publication No. 10-2014-0137289

It is an object of the present invention to provide a rapid release compartment containing vitamin B12, vitamin B6, vitamin B9, choline and pharmaceutically acceptable excipients and vitamin D, vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, controlled release And a controlled release compartment comprising a pharmaceutically acceptable excipient and a pharmaceutically acceptable additive.

It is also an object of the present invention to provide a fast-release compartment comprising vitamin B12, vitamin B6, vitamin B9, choline and a pharmaceutically acceptable additive; A controlled release first compartment comprising vitamin D, a controlled release base, and a pharmaceutically acceptable additive; And a controlled release second compartment comprising vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, a controlled release base, and a pharmaceutically acceptable additive.

In one aspect of the present invention, the present invention relates to a composition comprising a rapid-release compartment containing vitamin B12, vitamin B6, vitamin B9, choline and a pharmaceutically acceptable additive, and vitamin D, vitamin E, vitamin C, silymarin, A controlled release compartment comprising a biphenyl dimethicyldicarboxylate, a controlled release base, and a pharmaceutically acceptable additive.

The oral combination preparation of the present invention can effectively control the release of the components contained in each compartment, including two compartments, a quick-release compartment and a controlled-release compartment.

The immediate-release compartment of the oral combination preparation of the present invention includes vitamin B12, vitamin B6, vitamin B9 and choline as active ingredients.

In the present invention, 'vitamin B12' refers to an anti-anemic agent, also called cyanocobalamine.

In the present invention, 'vitamin B6' is a substance present in the form of pyridoxine, pyridoxal, pyridoxamine or phosphorylated form in food, and three kinds of the above-mentioned pyridoxine, pyridoxal and pyridoxamine It is known that it is able to convert in vivo, is a component of enzymes important for protein metabolism, and is involved in the hem synthesis process, which is a component of hemoglobin.

In the present invention, 'vitamin B9' refers to folic acid which is a water-soluble vitamin of the vitamin B group.

In the present invention, 'choline' is a type of vitamin B complex, and is a lipotropic factor. It is a component of complex lipids such as lecithin and plasmarogens, and is a component of acetylcholine, It is known.

In the present invention, the vitamin B12 may be substituted with a cobalamine derivative, the vitamin B6 may be substituted with pyridoxal or pyridoxamine, the vitamin B9 with a folate salt, choline with lecithin or methionine, It can be used as a reference.

In the present invention, the vitamin B12, vitamin B6, vitamin B9 and choline can also be used in free base form, derivatives thereof, or salts known in the art.

In the present invention, vitamin B12, vitamin B6, vitamin B9 and choline are commercially available, or synthesized by methods known in the art, used in nature or cultivated, But it is not limited to those obtained by treating by a method known in the art.

The vitamin B12, vitamin B6, vitamin B9 and choline have a common function as a group, and their typical functions are as follows: 1) Acceleration of the action of the liver regeneration gene, 2) The synthesis of proteins, fats and carbohydrates into polymers; (8) the synthesis of fatty acids; (b) the synthesis of proteins, fats and carbohydrates; Synthesis, 9) elimination of homocysteine which causes aggravation of hepatitis, cirrhosis or liver cancer in liver disease, and 10) detoxification by methylation of toxic substance.

For the purpose of the present invention, the above-mentioned vitamin B12, vitamin B6, vitamin B9 and choline are used for improving liver function.

The controlled-release compartment of the oral combination preparation of the present invention contains vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate as active ingredients.

In the present invention, 'vitamin D' is a fat-soluble vitamin, and vitamin D2 (ergocalciferol) is synthesized from yeast and plant sterol ergosterol. Vitamin D3 (cholecalciferol) is synthesized from cholesterol precursor in skin cells, ≪ / RTI >

The vitamin D inhibits the progression of hepatocellular differentiation, proliferation and regeneration, 2) inhibits cholestasis by promoting bile acid transport protein synthesis, 3) inhibits the progression of nonalcoholic fatty liver disease, 4) prevents viral hepatitis, Prevention of liver cirrhosis, prevention of liver cancer, prevention of liver cirrhosis and inhibition of hepatic fibrosis synthesis, and 7) prolongation of lifespan of severe end stage patients such as cirrhosis patients, liver cancer patients and liver transplant recipients.

In the present invention, 'vitamin E' is a fat-soluble vitamin and is a tocol derivative. There are eight kinds of α-, β-, γ-, and δ-tocopherol and α-, β-, γ-, and δ-tocotrienols in nature.

In the present invention, 'vitamin C' includes all of the reduced type ascorbic acid and oxidized form dehydroascorbic acid which can be converted to each other, and is related to the formation of connective tissues and supporting tissues, It is known to be a substance.

The representative functions of vitamin E and C are ROS continuous oxidative stress relieving action, 1) prevention and treatment of fatty liver, 2) prevention and treatment of hepatitis, 3) prevention and treatment of cirrhosis and 4) It is known that it can help prevent and treat.

In the present invention, 'Silymarin' is a component extracted from Maria thistle with the scientific name of Carduus marianus Linne (Silybum mariannum), a medicinal plant belonging to the family Asteraceae, and is a flavonoid compound. The plant is native to southern Europe and North Africa, and later to the Americas, and is now grown for ornamental use and medicinal use. It is known that silymarin stabilizes the hepatocyte membrane, inhibits intracellular inflow of harmful substances, activates protein synthesis of hepatocytes, and promotes regeneration of hepatocytes. Especially, it has strong antioxidant activity, and decreases phospholipid synthesis, It is widely known for the treatment of various liver diseases caused by smoking, drinking, overwork and environmental pollution caused by various pollution, etc. It is known that it has the action of accelerating the recovery of blood LDL reduction, antiinflammatory, anticancer, acute viral hepatitis, chronic hepatitis and complication of liver cirrhosis Has been applied.

The main pharmacological effects of silymarin are as follows: 1) antioxidant effect, 2) glutathione increase action, 3) hepatic cell membrane stabilization 4) inhibition of toxic substance neutralization, detoxification, inflow, 5) promotion of protein synthesis, 6) inhibition of liver cirrhosis process, 7) inhibition of hepatic cell inflammation process, 8) ischemic state, radioactivity, iron accumulation 9) inhibition of TNF-alpha to prevent accumulation of lipid peroxides, and 10) use in the clinical treatment of acute viral, chronic hepatitis, alcoholic hepatitis, liver cirrhosis and fatty liver.

The silymarin of the present invention includes flavolignans in which the main component, Silybin, the isomer of Silibin, Silicristin, Silidianin and isosilybin, are mixed. can do.

Preferably, the silymarin of the present invention comprises from 65% to 80% of silymarin and other active ingredients (e.g., silibinins (sylibin: sylvin A + sylibin B), isocybinin, % By weight.

In the present invention, 'biphenyldimethyldicarboxylate' is also abbreviated as 'DDB', and is used as a therapeutic agent for hepatic diseases and as an liver protecting agent. Biphenyldimethyldicarboxylate has the function of clinically decreasing the activity of serum transaminase, in particular, serum glutamic pyruvic transaminase (SGPT), and it has a function of reducing carbon tetrachloride or thioacetamide thioacetamide toxicity, and increases the activity of cytochrome P450 2B1 mRNA and benzyloxyresorufin-O-dealkylase, while free radicals ) Is known to have the ability to remove. The representative pharmacological effects of the biphenyldimethyldicarboxylate are as follows: 1) antioxidant activity 2) improvement of fatty liver and chronic hepatitis 3) normalization of ALT elevation 4) increase of glutathione 5) Prevention, treatment, 6) liver protection from harmful substances, detoxification, 7) improvement of symptoms of liver poisoning, 8) inhibition of mutation of liver cancer prevention gene, 9) immunity enhancement, and 10) liver cell protection and promotion of liver regeneration.

In the present invention, the vitamin D is preferably replaced with cholecalcidiol, cholecalcitriol or ergocalciferol, silymarin with milk thisle extract, and biphenyldimethyldicarboxylate with omija extract And can be used interchangeably.

In the present invention, the vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate may be used in the free base form, derivatives thereof, or salts known in the art.

In the present invention, vitamin D, vitamin E, vitamin C, silymarin, and biphenyldimethyldicarboxylate are commercially available, synthesized by methods known in the art, used in nature or cultivated , Or a plant obtained from natural processes by a method known in the art can be used, but the present invention is not limited thereto.

The control release base contained in the controlled release part in the present invention is preferably a nutrient base or delayed release base.

The nutrient base may be selected from the group consisting of hydroxypropylmethylcellulose phthalate, Eudragit L (poly (methacrylic acid-methyl methacrylate) 1: 1 copolymer), Eudragit L100-55 (poly (methacrylic acid- ) 1: 1 copolymer), Eudragit S (poly (methacrylic acid-methyl methacrylate) 1: 2 copolymer), cellulose acetate phthalate, polyvinylacetate phthalate and shellac, The delayed-release base may be any one or more selected from cellulose derivatives, dimethylaminoethyl methacrylate copolymer, polyvinyl derivatives, polyethylene derivatives, carboxyvinyl polymers and gums.

In the present invention, the cellulose derivative may be any one or more selected from among hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and carboxymethylcellulose sodium.

Further, preferably, the dimethylaminoethyl methacrylate copolymer may be Eudragit E.

In addition, preferably, the polyvinyl derivative may be at least one selected from polyvinyl alcohol and polyvinyl pyrrolidone.

Further, preferably, the polyethylene derivative may be at least one selected from polyethylene glycol and polyethylene oxide.

Further, preferably, the carboxyvinyl polymer may be carbomer.

Preferably, the gums are at least one selected from guar gum, locust bean gum, carrageenan, gum arabic, gellan gum and xanthan gum.

In the combination preparation for oral use of the present invention, the pharmaceutically acceptable additives may be at least one selected from diluents, binders, disintegrating agents and lubricants.

As the above-mentioned pharmaceutically acceptable additives, lactose, microcrystalline cellulose, calcium phosphate starch, glucose, mannitol, polyethylene glycol and the like can be used as a diluent to the extent that the effect of the present invention is not impaired. Starch, microcrystalline cellulose, mannitol, gum and gelatin. Examples of the disintegrant may include sodium starch glycolate, starch, pregelatinized starch, and the like. Examples of the disintegrant include starch, sodium starch glycolate, Starch and the like, and cellulose such as microcrystalline cellulose, crosslinked carboxymethyl cellulose, calcium salt of carboxymethyl cellulose or low-substituted hydroxypropyl cellulose, and alginic acid such as alginic acid, and crospovidone , And the like can be used. As the lubricant, for example, Air talc, stearic acid metal salts, lauryl sulfate, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl monostearate and polyethylene glycol 6000, etc., but can use, but is not limited thereto.

Preferably, the pharmaceutically acceptable additive may be lactose, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, silicon dioxide, or magnesium stearate.

In the combination preparation for oral use of the present invention, vitamin D is preferably vitamin D3. The vitamin D3 is preferably added to the oral combination preparation of the present invention preferably in an amount of 900 IU to 20,000 IU, 1000 IU to 20,000 IU, 1100 IU to 20,000 IU, 1500 IU to 20,000 IU, 1800 IU to 20,000 IU, 2000 IU to 20,000 IU, 5000 IU to 20,000 IU, or more preferably 10,000 IU to 20,000 IU, more preferably 1000 IU to 20,000 IU, 2000 IU to 20,000 IU, and 5,000 IU to 20,000 IU, particularly preferably 1000 IU to 10,000 IU, or 2000 IU to 10,000 IU, or 1000 IU, 2000 IU, 5000 IU, 10,000 IU, or 20,000 IU.

The oral combination preparation of the present invention, which contains vitamin D, specifically vitamin D3 in the above amounts, is extremely excellent in improving liver function such as effectively lowering ALT, AST, and BUN levels upon administration.

The quick-release compartment and the controlled release compartment of the present invention are physically separated from each other or partitioned so that components belonging to each compartment can obtain different release rates. The immediate-release compartment and the controlled-release compartment of the present invention can be implemented in a variety of formulations, for example, in the form of granules or pellets in which the particles are separated from one another.

The immediate-release compartment and the controlled-release compartment of the present invention may be in the form of granules or pellets, and may be tableted or tablet-filled. For example, the oral combination preparation of the present invention may be a single-dose, double-dose, multi-layered, coated tablet, or capsule.

The coating layer may include a coating layer composed of a coating agent, a coating aid, or a mixture thereof. The coating layer may be formed of, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, polyvinyl derivatives, waxes, Polyethylene glycol, talc, titanium oxide, and diethyl phthalate, but is not limited thereto.

The immediate-release compartment of the present invention is a rapid-release compartment of the present invention, which is produced by a conventional process for producing an oral solid such as mixing, coalescing, drying, granulating vitamin B12, vitamin B6, vitamin B9 and choline together with pharmaceutically acceptable additives , Granules or pellets. When direct tableting is possible, the composition may be obtained by mixing the active ingredient with a pharmaceutically acceptable additive, or the composition may be obtained by compression, granulation, sizing, and granulation to improve fluidity.

The controlled-release compartment of the present invention can be prepared by mixing, granulating or coating vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate with a controlled-release base and a pharmaceutically acceptable additive to form particles, granules or pellets Can be manufactured. When direct tableting is possible, the composition may be obtained by mixing the active ingredient with a pharmaceutically acceptable additive. Alternatively, the composition may be obtained by compression, granulation, sizing and granulation to improve fluidity.

The prepared immediate-release compartment and the controlled-release compartment may be prepared by post-mixing the pharmaceutically acceptable additives or by filling the composition into capsules to prepare the oral combination preparation, May optionally be mixed with a pharmaceutically acceptable additive, followed by tableting or filling into capsules to prepare a combined oral preparation.

The oral combination preparations of the present invention may be formulated as a single tablet in the form of a two-phase matrix in which two different immediate-release compartments and controlled-release compartments are separated by particles, granules or pellets, or a multi-layered tablet such as a two- A tablet, a tablet, a tablet, a tablet, a tablet, a tablet, a granule, or a pellet.

The oral combination preparation of the present invention comprises: 1) preparing quick-release granules by mixing vitamin B12, vitamin B6, vitamin B9, choline and a pharmaceutically acceptable additive; 2) preparing controlled release granules comprising vitamin D, vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, a controlled release base, and pharmaceutically acceptable additives; And 3) mixing the immediate-release granules and the controlled-release granules and tableting to prepare a single tablet.

Also, the combination preparation for oral administration of the present invention may be prepared by 1) preparing vitamin B12, vitamin B6, vitamin B9, choline, and pharmaceutically acceptable additives to produce a quick-release granule; 2) preparing controlled release granules comprising vitamin D, vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, a controlled release base, and pharmaceutically acceptable additives; And 3) injecting the quick-release granules and the controlled-release granules into a multi-layer tablet machine to produce multi-layer tablets.

The controlled release agent contained in the controlled-release granule may be a nutritive base or a delayed-release base.

The present invention provides a pharmaceutical composition for preventing or treating liver disease comprising the combination preparation for oral use of the present invention.

The composition of the present invention can be used to treat aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) (SOD activity), and thus can be effectively used as a therapeutic agent for liver diseases.

The term " liver disease " as used herein includes, but not limited to, non-alcoholic fatty liver disease, alcoholic fatty liver disease, hepatitis, liver cirrhosis, liver cancer and the like which can be treated by the oral combination preparation of the present invention. .

The fatty liver refers to a phenomenon in which abnormally deposited fat cells appear in liver cells unlike the case of normal triglycerides. In normal liver, about 5% is composed of adipose tissue, and triglyceride, fatty acid, phospholipid, cholesterol and cholesterol ester are the major components of fat. However, once fatty liver occurs, most of the components are replaced by triglycerides. If the liver weight is 5% or more, it is diagnosed as fatty liver. Fatty liver is caused by fat metabolism disorder in hepatocytes or defects in the process of transporting excess fat, and it is mainly caused by fat metabolism disorder in the liver. Most of the fat accumulated in the liver is triglyceride, and fatty liver can be roughly divided into non-alcoholic fatty liver due to obesity, diabetes, hyperlipidemia, drug, and alcoholic fatty liver due to excessive drinking.

It is known that fatty liver is accompanied by a history of non-alcoholic fatty liver alcohol consumption, and it is known to be associated with metabolic diseases such as obesity, diabetes and hyperlipidemia. Non-alcoholic steatohepatitis or end-stage fibrosis liver disease include not only the accumulation of fat in the liver, but also non-alcoholic fatty liver disease.

In addition, the alcoholic fatty liver is caused by a high intake of alcohol, which promotes lipid synthesis in the liver and does not result in normal energy metabolism. Alcohol is not stored in the body and is completely eliminated by oxidation in the liver. Specifically, the alcohol in the liver is largely divided into the alcohol dehydrogenase (ADH) pathway, the microsomal ethanol oxidizing system (MEOS ) Pathway and the catalase pathway, which are then converted to acetaldehyde, which in turn is metabolized to the acetyl salt by dehydrogenase (ALDH). At this time, acetaldehyde is poisonous and can damage hepatocytes. Also, as a result of such alcohol metabolism, a large amount of fatty acid is produced, and liver fat accumulates. Especially, the toxic oxygen (ROS) rapidly increasing due to alcohol destroys the lipid metabolizing enzyme And lipid peroxidation accumulates. The fatty liver accumulated in the liver due to the above-mentioned causes is referred to as an alcoholic fatty liver.

In addition, cirrhosis refers to all forms of liver disease characterized by significant loss of hepatocytes, proliferation of fibrous tissue, and regenerative nodules. The main cause of cirrhosis is hepatitis virus, alcohol, and harmful oxygen (RO) due to metabolic syndrome. Therefore, the gene of the astrocytic cells having storage function is altered to produce type 1 collagen fiber Liver cirrhosis is caused by fibrosing of cirrhotic cells, and cirrhosis is induced by antiretroviral treatment, abstinence or nutritional supply and mass therapy.

The above-mentioned liver cancer refers to a disease caused by a patient suffering from chronic liver disease caused by a liver cirrhosis patient, alcohol or the like, and is diagnosed as a liver cancer if a typical hepatic mass is found or an AFP is increased in a blood test.

The cause of all liver diseases may vary from patient to patient, but chronic hepatitis (ROS) increases rapidly with hepatitis, liver cirrhosis, and liver cancer.

&Quot; Prevention " in the present invention refers to all actions that inhibit or delay the onset of liver disease by the administration of the oral combination preparation according to the present invention.

In the present invention, the treatment refers to all the actions of improving or alleviating symptoms of liver disease by administering the combination preparation for oral use according to the present invention.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, a pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is determined depending on the species and severity, age, sex, drug activity, Sensitivity, time of administration, route of administration and rate of excretion, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts.

For example, the effective dose of the composition of the present invention may be determined according to the pathological characteristics of the liver disease. In other words, liver disease is pathologically diagnosed as hepatitis in liver, but liver cancer and liver cancer are exacerbated in liver cancer, but hepatitis, liver cirrhosis, and hepatocellular carcinoma can be mixed from fatty liver in view of pathological histology. In addition, the first cause of liver disease is alcohol, toxic substance, metabolic syndrome, or hepatitis virus. However, ROS which is soaring due to these causes and cytokine- It can be fatty liver, hepatitis, liver cirrhosis or liver cancer as it destroys enzymes and destroys and destroys cells (Nature Reviews Gastroenterology & Hepatology 12, 387-400 2015). Therefore, the composition of the present invention may be administered once a day in the case of fatty liver, twice a day in the case of hepatitis, three times a day in the case of liver cirrhosis, liver cancer, and liver transplantation, But is not limited thereto.

For example, the composition of the present invention may be administered in an amount of 1,100 mg to 11,000 mg.

In addition, the composition of the present invention can be used alone or in combination with other medicines for the prevention or treatment of liver disease. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by a person skilled in the art.

The present invention provides a health functional food composition for improving liver function comprising the combination preparation for oral use of the present invention.

In the present invention, 'improvement' is meant to include treatment, alleviation and prevention of symptoms. In the present invention, it means that the liver function, liver condition, liver disease and liver disease are treated, alleviated or prevented.

The vitamin B12, vitamin B6, vitamin B9, vitamin D, vitamin E, vitamin C, silymarin and biphenyl dimethicyldicarboxylate in the food composition or health functional food composition comprising the combination preparation for oral administration of the present invention have an effect of improving liver function May be contained in an arbitrary amount (effective amount) depending on the application, formulation, and purpose of compounding.

The term " effective amount " as used herein refers to the amount of active ingredient capable of inducing liver function improving effect. Such effective amounts can be determined experimentally within the ordinary skill of those skilled in the art.

The food composition or health functional food composition of the present invention is a food prepared or processed in the form of tablets, capsules, powders, granules, liquids, or rings using raw materials or ingredients having useful functions in the human body Article 3 (1) of the Act on Functional Foods). The term "functional" as used herein refers to the structure and function of the human body, which has a beneficial effect on health uses such as controlling nutrients or physiological actions. In other words, it means that it can be useful for the health use of healthy people or half-health people.

The food composition or the health functional food composition may contain flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and aging agents (cheese, chocolate etc.), pectic acid and its salts, And salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, it may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination. In addition, the health functional food may be in the form of any one of meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, Lt; / RTI >

In addition, the above food composition or health functional food composition may further include a food additive, and the suitability of the additive as a 'food additive' is not limited to the General Rules for Food Additives approved by the Food and Drug Administration, It shall be determined according to the standards and standards for the item.

Examples of the above-mentioned 'food additives' include natural products such as ketones, chemical products such as glycine, potassium citrate, nicotinic acid, cinnamic acid, coloring matter, licorice extract, crystalline cellulose, guar gum, Sodium laurate, sodium glutamate preparation, noodles-added alkaline agent, preservative agent, tar pigment preparation and the like.

The food composition or health functional food composition of the present invention may contain additives for nutritional supplementation, additives for improving functionalities and formulating within the range not to impair the effect of the present invention.

The invention relates to a fast-release compartment comprising vitamin B12, vitamin B6, vitamin B9, choline and a pharmaceutically acceptable additive; A controlled release first compartment comprising vitamin D, a controlled release base, and a pharmaceutically acceptable additive; And a controlled release second compartment comprising vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, a controlled release base, and a pharmaceutically acceptable additive.

The above-mentioned vitamin B12, vitamin B6, vitamin B9, choline, vitamin D, vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, pharmaceutically acceptable additives and controlled release bases are as described above.

Preferably the controlled release base is a nutrient base or delayed release base.

More preferably, the controlled release bases contained in the controlled release first compartment and the controlled release second compartment contained in the controlled release first compartment are enteric bases.

More preferably, the controlled release bases contained in the controlled release first compartment are delayed release bases and the controlled release bases included in the controlled release second compartment are enteric bases.

The above-mentioned nutritive and delayed-release bases are as described above.

Preferably, the vitamin D3 is present in the oral combination preparation of the present invention, preferably in the range of 900 IU to 20,000 IU, 1000 IU to 20,000 IU, 1100 IU to 20,000 IU, 1500 IU to 20,000 IU, 1800 IU to 20,000 IU, 2000 IU to 20,000 IU IU, 5000 IU to 20,000 IU, or 10,000 IU to 20,000 IU, more preferably 1000 IU to 20,000 IU, 2000 IU to 20,000 IU, 5000 IU to 20,000 IU, particularly preferably 1000 IU to 10,000 IU, Or 2000 IU to 10,000 IU, or 1000 IU, 2000 IU, 5000 IU, 10,000 IU, or 20,000 IU.

The immediate-release compartment and the controlled-release compartment are as described above.

The quick-release compartment, controlled-release first compartment, and controlled-release second compartment of the present invention are physically separated from each other or partitioned so that components belonging to each compartment can obtain different release rates. The immediate-release compartment, controlled-release first compartment, and controlled-release second compartment of the present invention can be implemented in a variety of formulations, for example, in the form of granules or pellets in which the particles are separated from one another.

The immediate-release compartment, controlled-release first compartment, and controlled-release second compartment of the present invention may be in the form of granules or pellets, tableted in tablets, or filled into capsules to be formulated.

The oral combination preparations of the present invention may be formulated as a single tablet in the form of a three-phase matrix in which three different immediate-release compartments, controlled-release first compartment and controlled-release second compartment are separated by particles, granules or pellets, And may be formulated into a capsule of the type separated by a multi-layer tablet, an inner core tablet, or a particle, granule or pellet such as tablet, tablet, etc., but is not limited thereto.

For example, the oral combination preparation of the present invention may be prepared by: 1) preparing vitamin B12, vitamin B6, vitamin B9, choline and pharmaceutically acceptable additives to produce quick-release granules; 2) preparing a controlled release first granulate comprising vitamin D, a controlled release base and a pharmaceutically acceptable additive; 3) preparing a controlled release second granule comprising vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, a controlled release base, and a pharmaceutically acceptable additive; And 4) combining the immediate-release granules, the controlled-release first granules and the second granules and tableting to prepare a single tablet.

Also, the combination preparation for oral administration of the present invention may be prepared by 1) preparing vitamin B12, vitamin B6, vitamin B9, choline, and pharmaceutically acceptable additives to produce a quick-release granule; 2) preparing a controlled release first granulate comprising vitamin D, a controlled release base and a pharmaceutically acceptable additive; 3) preparing a controlled release second granule comprising vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, a controlled release base, and a pharmaceutically acceptable additive; And 4) putting the quick release granule, the controlled release first granule and the second granule into a multi-layer tablet press and pressing to prepare a multi-layered tablet.

The coating tablet of the present invention may comprise a coating layer composed of a coating agent, a coating aid or a mixture thereof.

The coating layer may be made of at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, polyvinyl derivatives, waxes, fatty acids, gelatin, polyethylene glycol, talc, titanium oxide and diethyl phthalate. It is not limited.

The present invention provides a pharmaceutical composition for the prevention or treatment of liver disease comprising the oral combination preparation of the present invention.

The present invention also provides a health functional food composition for improving liver function comprising the oral combination preparation.

The pharmaceutical composition for preventing or treating liver diseases and the health functional food for improving liver function are as described above.

The oral combination preparation of the present invention comprises vitamin B12, vitamin B6, vitamin B9 and choline in a rapid-release compartment and vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate in a controlled release compartment , The nine components are included in one unit dosage form to significantly improve compliance and convenience for dosing and at the same time provide different controlled release to ultimately achieve maximum absorption of each active ingredient to prevent, Thereby exhibiting an effect of maximizing the liver function improving effect.

Figure 1 is a graph of elution at pH 1.2 of the tablet according to Example 1,
Figure 2 is a dissolution graph at pH 6.8 of the tablet according to Example 1,
Figure 3 is a graph of elution at pH 1.2 of the tablet according to Example 5,
Figure 4 is a graph of elution at pH 1.2 of the tablet according to Example 9,
Figure 5 is a graph of elution at pH 6.8 of the tablet according to Example 9,
6 is a graph of elution at pH 1.2 of the tablet according to Example 13,
Figure 7 is a graph of elution at pH 1.2 of the tablet according to Example 17,
Figure 8 is a graph of elution at pH 6.8 of the tablet according to Example 17,
9 is a graph of elution at pH 1.2 of the tablet according to Example 21,
10 is a graph of elution at pH 6.8 of the tablet according to Example 21. Fig.
11 is a graph showing changes in body weight following administration of a single composition according to Example 25,
12 is a graph comparing liver weights according to administration of a single composition according to Example 25,
13 is a graph comparing the weights of kidneys according to administration of a single composition according to Example 25,
14 is a graph comparing heart weights according to administration of a single composition according to Example 25. Fig. (* And ** mean statistical significance with G2, representing P <0.05 and P <0.01, respectively).
15 is a graph comparing values of aspartate aminotransferase (AST) according to administration of a single composition according to Example 25,
16 is a graph comparing the values of alanine aminotransferase (ALT) according to administration of a single composition according to Example 25,
17 is a graph comparing hepatic antioxidative activity (SOD activity) upon administration of a single composition according to Example 25. Fig.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

Reference Example 1: Materials

Vitamin B12 in DSM (Switzerland) or LYCORED, vitamin B6 in DSM (Germany), vitamin B9 in DSM (Switzerland), hydrogen stearate choline in Balcehm (Italy) or Algry, vitamin D in DMS , Vitamin E in DSM (Switzerland), Vitamin C in DSM (UK), Milk Thistle extract in Monteloeder (Spain), Silymarin in Teva (Israel) or Monteloeder, Omiza X in Kosice Biphenyl Dimethyl Dicarboxylate was purchased from Zhejiang Hisoar and used in Joe Foodtek (Korea). The sterilized water for injection of 0.5% carboxymethylcellulose (CMC) was purchased from CMC Co., Ltd. and sterilized water for injection was purchased from Korea Pharmaceutical Industry Co., Ltd. Also, D-galactosamine was purchased from Sigma-Aldrich Ltd and used.

The vitamin D used in Examples 1 to 24 was 90,000 ~ 110,000 IU / g of vitamin D3, and vitamin D was used according to the content described in Example 25. Also, vitamin B12 (1% powder) is a product obtained by dissolving vitamin B12 with an excipient (calcium phosphate), which means that 1% by weight of vitamin B12 is included in the vitamin B12 (1% powder), and vitamin E mixed powder E 50%) means that 50% by weight of vitamin E is contained in the mixed powder.

Reference Example 2: Preparation of an animal model

Seven-week-old Sprague-Dawley rats (SD) were purchased from Orient Bio (Seongnam, Korea) and used for the experiment. (W235 * L380 * H175, 3 animals / breeding box) of the Gyeonggi Bio Center Animal Breeding Area No. 5 of the Gyeonggi Bio Center where the test was carried out for 7 days. The breeding box was changed at least once a week.

The conditioning and test conditions were maintained at a temperature of 23 ± 3 ° C, a relative humidity of 55 ± 15%, a ventilation frequency of 10 to 20 times / hour, a lighting time of 12 hours (8:00 am to 8:00 pm off) Respectively. Temperature and relative humidity were measured every hour using a computer system, and the number of times of ventilation and illumination were measured periodically.

The feed was fed free from feedstuffs (Teklad certified irradiated global 18% protein rodent diet; 2918C, ENVIGO, UK) supplied by Doosan Biotech Co., Ltd. in a feeder.

The water was sterilized with ultraviolet sterilizer and microfiltration device and placed in a polycarbonate water bottle for free ingestion. The water quality test was carried out by Gyeonggi Provincial Health and Environment Research Institute and it was confirmed that it conformed to the water quality standard of drinking water. Negative bottles were replaced at least once a week.

The ethical rules of experimental animals were approved by the Experimental Animal Care Committee of the Gyeonggi Bio Center (Serial No .: 2016-04-0010).

Reference Example 3: Statistical Analysis

Statistical analysis was performed using SPSS statistics 22 for medical science, and the results were analyzed using ONE-WAY ANOVA and Student's t-test. Normal group and single composition administration group were compared with excipient control group, and P <0.05 was considered statistically significant.

Example 1: Preparation of a single tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 1 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules.

2) Manufacture of enteric granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 1 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt, Germany) and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, an enteric coating solution prepared by dissolving hydroxypropylmethylcellulose phthalate and acetylate monoglyceride in a 1: 1 mixture of ethanol and acetone was sprayed onto the granules to prepare enteric granules.

3) After mixing, tableting and coating

The quick-release granules and the enteric granules prepared in the preceding steps 1) and 2) were mixed with a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the granules and magnesium stearate And finally mixed with a V-type mixer.

The final mixture was tableted to 1,060 mg per tablet using a rotary tablet machine (Sejong, Korea), and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a single tablet of 1,100 mg per tablet.

Example 2: Preparation of a single tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 1 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules.

2) Manufacture of enteric granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 1 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt, Germany), and an enteric coating solution in which Eudragit L100 and triethyl citrate were separately dissolved in a 1: 1 mixture of ethanol and acetone was sprayed on the granules Granules were prepared.

3) After mixing, tableting and coating

The quick-release granules and the enteric granules prepared in the above steps 1) and 2) were mixed with a V-type mixer (Erweka, Germany), mixed with croscarmellose sodium and silicon dioxide, and then magnesium stearate was added And finally mixed with a V-type mixer. The final mixture was tableted to 1,060 mg per tablet using a rotary tablet machine (Sejong, Korea), and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a single tablet of 1,100 mg per tablet.

Example 3: Preparation of a single tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 1 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules.

2) Manufacture of enteric granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 1 below. The above mixture was put into a fluidized bed granulator (Glatt, Germany) and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, an enteric coating solution prepared by dissolving Eudragit L30D and triethyl citrate in purified water was sprayed onto the granules to prepare enteric-coated granules.

3) After mixing, tableting and coating

The quick-release granules and enteric-coated granules prepared in the above steps 1) and 2) were mixed with a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed therein. Then, magnesium stearate And finally mixed with a V-type mixer. The final mixture was tableted to 1,060 mg per tablet using a rotary tablet machine (Sejong, Korea), and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a single tablet of 1,100 mg per tablet.

Example 4: Preparation of a single tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 1 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules.

2) Manufacture of enteric granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 1 below. The above mixture was put into a fluidized bed granulator (Glatt, Germany) and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, an enteric coating solution in which acrylate was dissolved in purified water was sprayed on the granules to prepare enteric-coated granules.

3) After mixing, tableting and coating

The quick-release granules and enteric-coated granules prepared in the above steps 1) and 2) were mixed with a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed therein. Then, magnesium stearate And finally mixed with a V-type mixer. The final mixture was tableted to 1,060 mg per tablet using a rotary tablet machine (Sejong, Korea), and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a single tablet of 1,100 mg per tablet.

1) Eudragit L100-55: poly (methacrylic acid-methyl methacrylate) 1: 1 copolymer

2) Eudragit L30D: 30% dispersion of poly (methacrylic acid-methyl methacrylate) 1: 1 copolymer

3) Acrylic Iz: a mixture of poly (methacrylic acid-methyl methacrylate) 1: 1 copolymer

Example 5: Preparation of a single tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 2 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules.

2) Preparation of delayed-release granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 2 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a delayed-release granule was prepared by spraying a coating solution prepared by dissolving hydroxypropyl methylcellulose and polyethylene glycol 6000 in a 1: 1 mixture of ethanol and water.

3) After mixing, tableting and coating

The quick-release granules and the delayed-release granules prepared in the above steps 1) and 2) were mixed with a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed therein. Magnesium was added and finally mixed with a V-type mixer. The final mixture was tableted to 1,060 mg per tablet using a rotary tablet machine (Sejong, Korea), and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a single tablet of 1,100 mg per tablet.

Example 6: Preparation of a single tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 2 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules.

2) Preparation of delayed-release granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 2 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a coating solution prepared by dissolving polyvinyl alcohol and polyethylene glycol 6000 in purified water was sprayed onto the granules to prepare delayed-release granules.

3) After mixing, tableting and coating

The quick-release granules and the delayed-release granules prepared in the above steps 1) and 2) were mixed with a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed therein. Magnesium was added and finally mixed with a V-type mixer. The final mixture was compressed to 1,060 mg per tablet using a rotary tablet machine (Sejong, Korea), and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare tablets having 1,100 mg per tablet.

Example 7: Preparation of a single tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 2 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules.

2) Preparation of delayed-release granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 2 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a coating solution prepared by dissolving methyl cellulose and triethyl citrate in ethanol was sprayed onto the granules to prepare delayed-release granules.

3) After mixing, tableting and coating

The quick-release granules and the delayed-release granules prepared in the above steps 1) and 2) were mixed with a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed therein. Magnesium was added and finally mixed with a V-type mixer. The final mixture was tableted to 1,060 mg per tablet using a rotary tablet machine (Sejong, Korea), and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a single tablet of 1,100 mg per tablet.

Example 8: Preparation of a single tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 2 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules.

2) Preparation of delayed-release granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 2 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a coating solution prepared by dissolving Eudragit E and triethyl citrate in a 1: 1 mixture of ethanol and acetone was sprayed onto the granules to coat the granules to prepare delayed-release granules.

3) After mixing, tableting and coating

The quick-release granules and the delayed-release granules prepared in the above steps 1) and 2) were mixed, and sodium starch glycolate and silicon dioxide were mixed with the mixture. Then, magnesium stearate was added thereto and mixed with a V- type mixer (Erweka, Germany). The final mixture was compressed to 1,060 mg per tablet using a rotary tablet machine (Sejong, Korea), and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare tablets having 1,100 mg per tablet.

4) Eudragit E: 1: 2: 1 copolymer of poly (butaned methacrylate- (2-dimethylaminoethyl) methacrylate-methyl methacrylate)

Example 9: Preparation of a two-layer tablet

1) Preparation of quick-release granules

As shown in Table 3, vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The quick-release granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed with a V-type mixer.

2) Manufacture of enteric granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 3 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. An enteric coating solution prepared by dissolving hydroxypropylmethylcellulose phthalate and acetylate monoglyceride in a 1: 1 mixture of ethanol and acetone was sprayed onto the granules to coat the granules to prepare enteric-coated granules. The enteric granules were put into a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate, followed by final mixing with a V-type mixer.

3) Double layer tableting

In this process, the tablet was tableted using a multi-layer tablet press (Piccola, UK). Namely, the enteric granule composition was placed in a first powder feeder, and the quick-release granule composition was placed in a second powder feeder to be tableted at a rate of 1,160 mg per tablet in order to minimize the intermixing between the layers, followed by a high-coater (Sejong, Korea) To form a film coating layer to prepare a two-layer tablet having a tablet of 1,200 mg per tablet.

Example 10: Preparation of a two-layer tablet

1) Preparation of quick-release granules

As shown in Table 3, vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The quick-release granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed with a V-type mixer.

2) Manufacture of enteric granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 3 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. An enteric coating solution prepared by dissolving Eudragit L100-55 and triethyl citrate in a 1: 1 mixture of ethanol and acetone was sprayed onto the granules to coat the granules, thereby preparing enteric granules. The enteric granule composition was placed in a V-type mixer, and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

3) Double layer tableting

In this process, the tablet was tableted using a multi-layer tablet press (Piccola, UK). Namely, the enteric granule composition was placed in a first powder feeder, and the quick-release granule composition was placed in a second powder feeder to be tableted at a rate of 1,160 mg per tablet in order to minimize the intermixing between the layers, followed by a high-coater (Sejong, Korea) To form a film coating layer, thereby preparing a two-layer tablet having a weight of 1,200 mg per tablet.

Example 11: Preparation of a two-layer tablet

1) Preparation of quick-release granules

As shown in Table 3, vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The quick-release granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed with a V-type mixer.

2) Manufacture of enteric granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 3 below. The above mixture was put into a fluidized bed granulator (Glatt, Germany) and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, an enteric coating solution prepared by dissolving Eudragit L30D and triethyl citrate in purified water was sprayed onto the granules to coat the granules to produce enteric granules. The enteric granules were put into a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate, followed by final mixing with a V-type mixer.

3) Double layer tableting

In this process, the tablet was tableted using a multi-layer tablet press (Piccola, UK). Namely, the enteric granule composition was placed in a first powder feeder, and the quick-release granule composition was placed in a second powder feeder to be tableted at a rate of 1,160 mg per tablet in order to minimize the intermixing between the layers, followed by a high-coater (Sejong, Korea) To form a film coating layer, thereby preparing a two-layer tablet having a weight of 1,200 mg per tablet.

Example 12: Preparation of a two-layer tablet

1) Preparation of quick-release granules

As shown in Table 3, vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The quick-release granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed with a V-type mixer.

2) Manufacture of enteric granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 3 below. The above mixture was put into a fluidized bed granulator (Glatt, Germany) and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, an enteric coating solution in which acrylate was dissolved in purified water was sprayed on the granules to coat the granules to produce enteric granules. The prepared enteric-coated granules were put into a V-shaped mixer, and then sodium starch glycolate and silicon dioxide were mixed with the granules. Then, magnesium stearate was added thereto and the mixture was finally mixed with a V-type mixer.

3) Double layer tableting

In this process, the tablet was tableted using a multi-layer tablet press (Piccola, UK). Namely, the enteric granule composition was placed in a first powder feeder, and the quick-release granule composition was placed in a second powder feeder to be tableted at a rate of 1,160 mg per tablet in order to minimize the intermixing between the layers, followed by a high-coater (Sejong, Korea) To form a film coating layer, thereby preparing a two-layer tablet having a weight of 1,200 mg per tablet.

Example  13: Manufacture of two-layer tablet

1) Preparation of quick-release granules

As shown in Table 4, vitamin B12, vitamin B6, vitamin B9 and hydrogen stearate choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The quick-release granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed with a V-type mixer.

2) Preparation of delayed-release granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 4 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a delayed-release granule was prepared by spraying a coating solution prepared by dissolving hydroxypropylmethylcellulose and polyethylene glycol 6000 in a 1: 1 mixture of ethanol and water, and coating the granules. The prepared delayed-release granules were put in a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate and finally mixed in a V-type mixer.

3) Double layer tableting

In this process, the tablet was tableted using a multi-layer tablet press (Piccola, UK). That is, the delayed-release granule composition was placed in a first powder feeder, and the quick-release granule composition was placed in a second powder feeder to be tableted at a rate of 1,160 mg per tablet, ) To form a film coating layer, thereby preparing a two-layer tablet having a particle size of 1,200 mg per tablet.

Example  14: Preparation of two-layer tablets

1) Preparation of quick-release granules

As shown in Table 4, vitamin B12, vitamin B6, vitamin B9 and hydrogen stearate choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The quick-release granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed with a V-type mixer.

2) Preparation of delayed-release granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 4 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a coating solution prepared by dissolving polyvinyl alcohol and polyethylene glycol 6000 in purified water was sprayed on the granules to coat the granules to prepare delayed-release granules. The prepared delayed-release granules were put in a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate and finally mixed in a V-type mixer.

3) Double layer tableting

In this process, the tablet was tableted using a multi-layer tablet press (Piccola, UK). That is, the delayed-release granule composition was placed in a first powder feeder, and the quick-release granule composition was placed in a second powder feeder to be tableted at a rate of 1,160 mg per tablet, ) To form a film coating layer, thereby preparing a two-layer tablet having a particle size of 1,200 mg per tablet.

Example  15: Preparation of two-layer tablets

1) Preparation of quick-release granules

As shown in Table 4, vitamin B12, vitamin B6, vitamin B9 and hydrogen stearate choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The quick-release granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed with a V-type mixer.

2) Preparation of delayed-release granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 4 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a delayed-release granule was prepared by spraying a coating solution prepared by dissolving methylcellulose and triethyl citrate in ethanol, and coating the granules. The prepared final delayed-release granules were put in a V-shaped mixer, and sodium starch glycolate and silicon dioxide were mixed with the granules. Then, magnesium stearate was added thereto, followed by final mixing with a V-type mixer.

3) Double layer tableting

In this process, the tablet was tableted using a multi-layer tablet press (Piccola, UK). That is, the delayed-release granule composition was placed in a first powder feeder, and the quick-release granule composition was placed in a second powder feeder to be tableted at a rate of 1,160 mg per tablet, ) To form a film coating layer, thereby preparing a two-layer tablet having a particle size of 1,200 mg per tablet.

Example  16: Preparation of two-layer tablet

1) Preparation of quick-release granules

As shown in Table 4, vitamin B12, vitamin B6, vitamin B9 and hydrogen stearate choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Preparation of delayed-release granules

Vitamin D, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 4 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a coating solution prepared by dissolving Eudragit E and triethyl citrate in a 1: 1 mixture of ethanol and acetone was sprayed onto the granules to coat the granules to prepare delayed-release granules. The prepared delayed-release granules were put in a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate and finally mixed in a V-type mixer.

3) Double layer tableting

In this process, the tablet was tableted using a multi-layer tablet press (Piccola, UK). That is, the delayed-release granule composition was placed in a first powder feeder, and the quick-release granule composition was placed in a second powder feeder to be tableted at a rate of 1,160 mg per tablet, ) To form a film coating layer, thereby preparing a two-layer tablet having a particle size of 1,200 mg per tablet.

.

.

Example 17: Preparation of three-layer tablet

1) Preparation of quick-release granules

As shown in Table 5, vitamin B12, vitamin B6, vitamin B9 and hydrogen stearate choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Manufacture of first enteric granule

Vitamin D was mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 5 below. The mixture was prepared by dispersing hydroxypropyl cellulose and hydroxypropylmethylcellulose phthalate in a 1: 1 mixture of water and ethanol to prepare granules in a high-speed mixer. After the association, the mixture was granulated using a 25-well, dried at 60 ° C using a dryer (Jayutec, Korea), and dried at 25 ° C to form first enteric granules. The prepared primary enteric granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed in a V-type mixer.

3) Manufacture of second enteric granule

Vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 5 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, an enteric coating solution prepared by dissolving hydroxypropylmethylcellulose phthalate and acetylate monoglyceride in a 1: 1 mixture of ethanol and acetone was sprayed onto the granules to coat the granules to prepare second enteric granules. The prepared second enteric granules were put into a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the granules. Then, magnesium stearate was added and finally mixed with a V-type mixer.

4) Three-layer tableting

In this process, the tablet was compressed using a multi-layer tablet press (Sejong, Korea). That is, the first enteric granule composition is fed into a first powder feeder, the second enteric granule composition into a second powder feeder, and the quick release granule composition into a third powder feeder, mg, and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a 1,200 mg three-layered tablet at a predetermined ratio.

Example 18: Preparation of a three-layer tablet

1) Preparation of quick-release granules

As shown in Table 5, vitamin B12, vitamin B6, vitamin B9 and hydrogen stearate choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Manufacture of first enteric granule

Vitamin D was mixed with lactose and microcrystalline cellulose as shown in Table 5 below, sieved through a No. 35 sieve, and mixed in a high-speed mixer. Granules were prepared in a high-speed mixer (Diosna, Germany) using a binding solution prepared by dispersing hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate in a 1: 1 mixture of water and ethanol. After the association, the mixture was granulated using a 25-well, dried at 60 ° C using a dryer (Jayutec, Korea), and dried at 25 ° C to form first enteric granules. The prepared primary enteric granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed in a V-type mixer.

3) Manufacture of second enteric granule

Vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 5 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Secondary enteric granules were prepared by spraying the granules with an enteric coating solution prepared by dissolving Eudragit L100-55 and triethyl citrate in a 1: 1 mixture of ethanol and acetone. The prepared second enteric granules were put into a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the granules. Then, magnesium stearate was added and finally mixed with a V-type mixer.

4) Three-layer tableting

In this process, the tablet was compressed using a multi-layer tablet press (Sejong, Korea). That is, the first enteric granule composition is fed into a first powder feeder, the second enteric granule composition into a second powder feeder, and the quick release granule composition into a third powder feeder, mg, and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a 1,200 mg three-layered tablet at a predetermined ratio.

Example 19: Preparation of a three-layer tablet

1) Preparation of quick-release granules

As shown in Table 5, vitamin B12, vitamin B6, vitamin B9 and hydrogen stearate choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Manufacture of first enteric granule

Vitamin D was mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 5 below. The mixture was prepared by dispersing hydroxypropyl cellulose and hydroxypropylmethylcellulose phthalate in a 1: 1 mixture of water and ethanol to prepare granules in a high-speed mixer. After the association, the mixture was granulated using a 25-well, dried at 60 ° C using a dryer (Jayutec, Korea), and dried at 25 ° C to form first enteric granules. The prepared primary enteric granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed in a V-type mixer.

3) Manufacture of second enteric granule

Vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 5 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Then, an enteric coating solution in which Eudragit L100 and triethyl citrate were dissolved in a 1: 1 mixture of ethanol and acetone was sprayed onto the granules to coat the granules to prepare second enteric granules. The prepared second enteric granules were put into a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the granules. Then, magnesium stearate was added and finally mixed with a V-type mixer.

4) Three-layer tableting

In this process, the tablet was compressed using a multi-layer tablet press (Sejong, Korea). That is, the first enteric granule composition is fed into a first powder feeder, the second enteric granule composition into a second powder feeder, and the quick release granule composition into a third powder feeder, mg, and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a tablet having a sugar content of 1,200 mg per tablet.

Example 20: Preparation of three-layer tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Sejong, Korea) as shown in Table 5 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Manufacture of first enteric granule

Vitamin D was mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 5 below. The mixture was prepared by dispersing hydroxypropyl cellulose and hydroxypropylmethylcellulose phthalate in a 1: 1 mixture of water and ethanol to prepare granules in a high-speed mixer. After the association, the mixture was granulated using a 25-well, dried at 60 ° C using a dryer (Jayutec, Korea), and dried at 25 ° C to form first enteric granules. The prepared primary enteric granules were placed in a V-type mixer (Erweka, Germany), mixed with sodium starch glycolate and silicon dioxide, and then mixed with magnesium stearate and finally mixed in a V-type mixer.

3) Manufacture of second enteric granule

Vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose and sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) as shown in Table 5 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Secondary enteric granules were prepared by spraying the granules with an enteric coating solution in which Eudragit S100 and triethyl citrate were dissolved in a 1: 1 mixture of ethanol and acetone. The prepared second enteric granules were put into a V-type mixer, and then sodium starch glycolate and silicon dioxide were mixed with the granules. Then, magnesium stearate was added and finally mixed with a V-type mixer.

4) Three-layer tableting

In this process, the tablet was compressed using a multi-layer tablet press (Sejong, Korea). That is, the first enteric granule composition is fed into a first powder feeder, the second enteric granule composition into a second powder feeder, and the quick release granule composition into a third powder feeder, mg, and then a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a tablet having a sugar content of 1,200 mg per tablet.

5) Eudragit S100: poly (methacrylic acid-methyl methacrylate) 1: 2 copolymer

Example 21: Preparation of three-layer tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 6 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Preparation of delayed-release granules

Vitamin D was mixed with lactose and microcrystalline cellulose as shown in Table 6 below, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). The granules were prepared in a high-speed mixer by using a binding solution prepared by dispersing hydroxypropyl cellulose and hydroxypropylmethylcellulose in a 1: 1 mixture of water and ethanol. After the association, the mixture was granulated using a 25-well, dried at 60 ° C using a dryer (Jayutec, Korea) and dried at 25 ° C to form a delayed-release granule. The prepared delayed-release granules were placed in a V-type mixer (Erweka, Germany), and then sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate and finally mixed in a V-type mixer.

3) Manufacture of enteric granules

Vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose, sieved through a No. 35 sieve, and mixed with a V-type mixer (Erweka, Germany) as shown in Table 6 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Then, an enteric coating solution in which Eudragit L100-55 and triethyl citrate were dissolved in a 1: 1 mixture of ethanol and acetone was sprayed on the granules to prepare enteric granules. The prepared enteric-coated granules were put into a V-shaped mixer, and then sodium starch glycolate and silicon dioxide were mixed with the granules. Then, magnesium stearate was added thereto and the mixture was finally mixed with a V-type mixer.

4) Three-layer tableting

In this process, the tablet was compressed using a multi-layer tablet press (Sejong, Korea). That is, the delayed-release granule composition is placed in a primary powder feeder, the enteric granule composition is fed into a secondary powder feeder, and the quick-release granule composition is fed into a tertiary powder feeder, After tableting, a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a 1,200 mg three-layered tablet at a predetermined ratio.

Example 22: Preparation of three-layer tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 6 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Preparation of delayed-release granules

Vitamin D was mixed with lactose and microcrystalline cellulose as shown in Table 6 below, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). The mixture was prepared by dispersing hydroxypropyl cellulose and polyvinylpyrrolidone in a 1: 1 mixture of water and ethanol to prepare granules in a high-speed mixer. After the association, the mixture was granulated using a 25-well, dried at 60 ° C using a dryer (Jayutec, Korea) and dried at 25 ° C to form a delayed-release granule. The prepared delayed-release granules were placed in a V-type mixer (Erweka, Germany), followed by mixing sodium starch glycolate and silicon dioxide, and then magnesium stearate was added thereto, followed by final mixing with a V-type mixer.

3) Manufacture of enteric granules

As shown in Table 6, vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose, sieved through a No. 35 sieve and mixed with a V-type mixer (Erweka, Germany) (GPCG 1: Glatt), and hydroxypropyl methylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, a 1: 1 mixture was prepared by dissolving Eudragit L100-55 and triethyl citrate in a mixed solution to prepare enteric granules. The enteric granules thus prepared were placed in a V-type mixer, Then, sodium starch glycolate and silicon dioxide were mixed and then magnesium stearate was added thereto, followed by final mixing with a V-type mixer.

4) Three-layer tableting

In this process, the tablet was compressed using a multi-layer tablet press (Sejong, Korea). That is, the delayed-release granule composition is placed in a primary powder feeder, the enteric granule composition is fed into a secondary powder feeder, and the quick-release granule composition is fed into a tertiary powder feeder, After tableting, a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a 1,200 mg three-layered tablet at a predetermined ratio.

Example 23: Preparation of a three-layer tablet

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 6 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Preparation of delayed-release granules

Vitamin D was mixed with lactose and microcrystalline cellulose as shown in Table 6 below, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). Granules were prepared in a high-speed mixer using a binding solution prepared by dissolving hydroxypropylcellulose and polyvinyl alcohol in purified water. After the association, the mixture was granulated using a 25-well, dried at 60 ° C using a dryer (Jayutec, Korea) and dried at 25 ° C to form a delayed-release granule. The prepared delayed-release granules were placed in a V-type mixer (Erweka, Germany), and then sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate and finally mixed in a V-type mixer.

3) Manufacture of enteric granules

Vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose, sieved through a No. 35 sieve, and mixed with a V-type mixer (Erweka, Germany) as shown in Table 6 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, an enteric coating solution in which Eudragit L100-55 and triethyl citrate were dissolved in a 1: 1 mixture of ethanol and acetone was sprayed on the granules to coat the granules to prepare enteric granules. The prepared granular admixture granules were put into a V-type mixer, and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate, followed by final mixing with a V-type mixer.

4) Three-layer tableting

In this process, the tablet was compressed using a multi-layer tablet press (Sejong, Korea). That is, the delayed-release granule composition is placed in a primary powder feeder, the enteric granule composition is fed into a secondary powder feeder, and the quick-release granule composition is fed into a tertiary powder feeder, After tableting, a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a 1,200 mg three-layered tablet at a predetermined ratio.

Example  24: Three-ply  Produce

1) Preparation of quick-release granules

Vitamin B12, vitamin B6, vitamin B9, and hydrogenated choline powder were mixed with lactose, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany) as shown in Table 6 below. Separately, hydroxypropylcellulose was dissolved in water to prepare a binding solution, which was then combined with the mixture in the high-speed mixer. After completion of the association, the granules were granulated using a 25-point tumbler and dried at 60 ° C using a dryer (Jayutec, Korea). After completion of the drying, the granules were formulated with a No. 25 sieve to produce quick-release granules. The prepared quick-release granules were placed in a V-type mixer (Erweka, Germany), and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by addition of magnesium stearate and final mixing with a V-type mixer.

2) Preparation of delayed-release granules

Vitamin D was mixed with lactose and microcrystalline cellulose as shown in Table 6 below, sieved through a No. 35 sieve, and mixed in a high-speed mixer (Diosna, Germany). The mixture was prepared by dispersing hydroxypropyl cellulose and methyl cellulose in a 1: 1 mixture of water and ethanol to prepare granules in a high-speed mixer. After the association, the mixture was granulated using a 25-well, dried at 60 ° C using a dryer (Jayutec, Korea) and dried at 25 ° C to form a delayed-release granule. The prepared delayed-release granules were placed in a V-type mixer (Erweka, Germany), and then sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate and finally mixed in a V-type mixer.

3) Manufacture of enteric granules

Vitamin E, vitamin C, silymarin and biphenyldimethyldicarboxylate were mixed with lactose and microcrystalline cellulose, sieved through a No. 35 sieve, and mixed with a V-type mixer (Erweka, Germany) as shown in Table 6 below. The above mixture was put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose was separately dissolved in a 1: 1 mixture of water and ethanol to form granules, followed by drying. Thereafter, an enteric coating solution obtained by dissolving Eudragit L100-55 and triethyl citrate in a 1: 1 mixture of ethanol and acetone was sprayed onto the granules to coat the granules to produce enteric granules. The prepared final composition was put in a V-type mixer, and sodium starch glycolate and silicon dioxide were mixed with the mixture, followed by magnesium stearate, followed by final mixing with a V-type mixer.

4) Three-layer tableting

In this process, the tablet was compressed using a multi-layer tablet press (Sejong, Korea). That is, the delayed-release granule composition is placed in a primary powder feeder, the enteric granule composition is fed into a secondary powder feeder, and the quick-release granule composition is fed into a tertiary powder feeder, After tableting, a film coating layer was formed using a high-coater (Sejong, Korea) to prepare a 1,200 mg three-layered tablet at a predetermined ratio.

Example  25: Preparation of a single composition

The following ingredients in Table 7 were weighed and mixed in the stated amounts to prepare a single composition (A1-A3).

Component (unit) A1 A2 A3 Vitamin D3
(DSM, Germany) (IU) 2,000 5,000 10,000 Vitamin B12
(Lycored) (mg) One One One Vitamin B6
(DSM, Germany) (mg) 60 60 60 Vitamin B9
(DSM, Switzerland) (mg) 0.4 0.4 0.4 Hydrogen stearate choline
(Balchem, Italy) (mg) 50 50 50 Vitamin E
(DSM, Switzerland) (IU) 100 100 100 Vitamin C
(DSM, UK) (mg) 100 100 100 Milk Thistle Extract
(Monteloeder, Spain) (mg) 130 130 130 Omija extract
(Cho Eun Foodtec, Korea) (mg) 400 400 400

In addition, the following components in Table 8 were weighed and mixed in the stated amounts to prepare a single composition (B1-B3).

Component (unit) B1 B2 B3 Vitamin D3
(DSM, Germany) (IU) 2,000 5,000 10,000 Vitamin B12
(Lycored) (mg) One One One Vitamin B6
(DSM, Germany) (mg) 60 60 60 Vitamin B9
(DSM, Switzerland) (mg) 0.4 0.4 0.4 Hydrogen stearate choline
(Algry) (mg) 50 50 50 Vitamin E
(DSM, Switzerland) (IU) 100 100 100 Vitamin C
(DSM, UK) (mg) 100 100 100 Silymarin
(Teva) (mg) 420 420 420 Biphenyldimethyldicarboxylate
(Zhejiang Hisoar) (mg) 150 150 150

The A1-A3 and B1-B3 compositions thus prepared were weighed according to the dosages in Table 9 and dissolved in sterile water for injection of 0.5% carboxymethylcellulose (CMC) to prepare dosage compositions, which were then refrigerated. In the case of the above dose, 10 times dose based on mg per kg (kg) of the animal without conversion of the body surface area was set at the dose as follows.

A1 A2 A3 B1 B2 B3 Dose
(mg / head / day) 152.9 154.7 157.7 235.1 276.6 315.5 Dosage amount
(ml / head / day) 3 3 3 3 3 3

Experimental Example 1: Single tablet elution test

A dissolution test of the single tablet prepared according to Example 1 was carried out. In the case of fast-release granules, vitamin B6 (pyridoxine hydrochloride) is used as an index component in pH 1.2 and pH 6.8, and enteric granules are prepared from vitamin D (cholecalciferol) as an index component in pH 1.2 and pH 6.8 Respectively.

[Vitamin B6 (pyridoxine) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, disintegration time 2 liquid

4) Analysis method: HPLC method

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength = maximum 270 nm)

- Column: Column with a diameter of about 4.6 mm and a length of about 25 cm and filled with porous silica particles of 5 to 10 μm in diameter

- Mobile phase: Add 0.4 mL of triethylamine, 15.0 mL of acetic acid (100), and 350 mL of methanol into a 2000 mL volumetric flask, add 0.008 mol / L sodium hexanesulfonate to 2000 mL,

[Vitamin D (cholecalciferol) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, Disintegration test liquid 2

4) Analysis method: HPLC method

- Detector: Ultraviolet absorptiometer (detection wavelength = max 265nm)

- Column: Column packed with aminopropylsilyl porous silica gel for liquid chromatography of 10 μm in stainless steel pipe with inner diameter of about 4.6 mm and length of about 15 cm

- mobile phase: n-hexane isopropanol (99: 1)

As a result, the disintegration completion time on the single tablet dissolution tester produced according to Example 1 was about 12 minutes. As can be seen from Figs. 1 and 2, vitamin B6, which is an index component of fast-releasing granule, was eluted at pH 1.2 for 5 minutes and pH 6.8 for 5 minutes. Vitamin D, an index component of enteric granules, was eluted 60 minutes after pH 1.2 and 10 minutes after starting the test at pH 6.8, and the main component was detected.

As described above, the single tablet of the present invention is an agent that is optimized when the immediate-release granule releases the drug first and the enteric granule releases the drug in the small intestine, taking into consideration the physiological absorption order of each ingredient.

Experimental Example 2: Single tablet elution test

A dissolution test of the single tablet prepared according to Example 5 was performed. In the case of fast - release granules, vitamin B6 (pyridoxine hydrochloride) was used as an index component and delayed - release granules were tested for dissolution in pH 1.2 solution using vitamin D (cholecalciferol) as an index component.

[Vitamin B6 (pyridoxine) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Dispersion test liquid 1

4) Analysis method: HPLC method

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength = maximum 270 nm)

- Column: Column with a diameter of about 4.6 mm and a length of about 25 cm and filled with porous silica particles of 5 to 10 μm in diameter

- Mobile phase: Add 0.4 mL of triethylamine, 15.0 mL of acetic acid (100), and 350 mL of methanol into a 2000 mL volumetric flask, add 0.008 mol / L sodium hexanesulfonate to 2000 mL,

[Vitamin D (cholecalciferol) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Dispersion test liquid 1

4) Analysis method: HPLC method

- Detector: Ultraviolet absorptiometer (detection wavelength = max 265nm)

- Column: Column packed with aminopropylsilyl porous silica gel for liquid chromatography of 10 μm in stainless steel pipe with inner diameter of about 4.6 mm and length of about 15 cm

- mobile phase: n-hexane isopropanol (99: 1)

As a result, the disintegration completion time on the dissolution tester of the single tablet produced according to Example 5 was about 15 minutes. As can be seen from Fig. 3, vitamin B6, which is an index component of fast-releasing granule, eluted after 5 minutes in pH 1.2 and 30 minutes in pH 1.2, the index component of delayed-release granules, Was detected.

As described above, the single tablet of the present invention is optimized when the quick release granules release the drug first and the delayed release granules sequentially release the drug, taking the physiological absorption order of each component into consideration.

Experimental Example 3: Two-layer tablet elution test

The elution test of the two-layer tablet produced according to Example 9 was carried out. In the case of the immediate release layer, vitamin B6 (pyridoxine hydrochloride) is used as an index component in pH 1.2 and pH 6.8, and the enteric layer is composed of vitamin D (cholecalciferol) as an index component and pH 1.2 and pH 6.8 Elution test was carried out.

[Vitamin B6 (pyridoxine) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, disintegration time 2 liquid

4) Analysis method: HPLC method

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength = maximum 270 nm)

- Column: Column with a diameter of about 4.6 mm and a length of about 25 cm and filled with porous silica particles of 5 to 10 μm in diameter

- Mobile phase: Add 0.4 mL of triethylamine, 15.0 mL of acetic acid (100), and 350 mL of methanol into a 2000 mL volumetric flask, add 0.008 mol / L sodium hexanesulfonate to 2000 mL,

[Vitamin D (cholecalciferol) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, Disintegration test liquid 2

4) Analysis method: HPLC method

- Detector: Ultraviolet absorptiometer (detection wavelength = max 265nm)

- Column: Column packed with aminopropylsilyl porous silica gel for liquid chromatography of 10 μm in stainless steel pipe with inner diameter of about 4.6 mm and length of about 15 cm

- mobile phase: n-hexane isopropanol (99: 1)

As a result, the disintegration completion time on the dissolution tester of the two-layer tablet produced according to Example 9 was about 15 minutes. As can be seen from Figs. 4 and 5, vitamin B6, which is an index component of quick-release granules, was eluted at pH 5 in 1.2 and eluted at pH 6.8 in 5 min. Vitamin D, an index component of enteric granules, was eluted 60 minutes after pH 1.2 and eluted 10 minutes after starting the test at pH 6.8.

Thus, the two-layer tablets of the present invention are optimized when the immediate-release layer releases the drug first and the enteric layer releases the drug in the small intestine, taking into account the physiological absorption order of each component.

Experimental Example 4: Two-layer tablet elution test

The elution test of the two-layer tablet produced according to Example 13 was carried out. In the case of fast - release granules, vitamin B6 (pyridoxine hydrochloride) was used as an index component and delayed - release granules were tested for dissolution in pH 1.2 solution using vitamin D (cholecalciferol) as an index component.

[Vitamin B6 (pyridoxine) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Dispersion test liquid 1

4) Analysis method: HPLC method

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength = maximum 270 nm)

- Column: Column with a diameter of about 4.6 mm and a length of about 25 cm and filled with porous silica particles of 5 to 10 μm in diameter

- Mobile phase: Add 0.4 mL of triethylamine, 15.0 mL of acetic acid (100), and 350 mL of methanol into a 2000 mL volumetric flask, add 0.008 mol / L sodium hexanesulfonate to 2000 mL,

[Vitamin D (cholecalciferol) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Dispersion test liquid 1

4) Analysis method: HPLC method

- Detector: Ultraviolet absorptiometer (detection wavelength = max 265nm)

- Column: Column packed with aminopropylsilyl porous silica gel for liquid chromatography of 10 μm in stainless steel pipe with inner diameter of about 4.6 mm and length of about 15 cm

- mobile phase: n-hexane isopropanol (99: 1)

As a result, the disintegration completion time on the elution tester of the two-layer tablet produced according to Example 13 was about 15 minutes. As can be seen from FIG. 6, vitamin B6, which is an index component of fast-release granules, eluted after 5 minutes at pH 1.2 and 30 minutes at pH 1.2, which is an index component of delayed-release granules, Was detected.

As described above, the two-layer tablet of the present invention is optimized when the quick-releasing granule releases the drug first and the delayed-release granule sequentially releases the drug, taking into consideration the physiological absorption order of each ingredient.

Experimental Example 5: Three-layer tablet elution test

The elution test of the three-layer tablet prepared according to Example 17 was performed. In the case of the immediate release layer, vitamin B6 (pyridoxine hydrochloride) is used as an index component, the first enteric layer is vitamin D (cholecalciferol) as an index component, and the second enteric layer is vitamin E (tocopherol acetate) The elution test was carried out at pH 1.2 and pH 6.8, respectively.

 [Vitamin B6 (pyridoxine) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, disintegration time 2 liquid

4) Analysis method: HPLC method

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength = maximum 270 nm)

- Column: Column with a diameter of about 4.6 mm and a length of about 25 cm and filled with porous silica particles of 5 to 10 μm in diameter

- Mobile phase: Add 0.4 mL of triethylamine, 15.0 mL of acetic acid (100), and 350 mL of methanol into a 2000 mL volumetric flask, add 0.008 mol / L sodium hexanesulfonate to 2000 mL,

[Vitamin D (cholecalciferol) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, Disintegration test liquid 2

4) Analysis method: HPLC method

- Detector: Ultraviolet absorptiometer (detection wavelength = max 265nm)

- Column: Column packed with aminopropylsilyl porous silica gel for liquid chromatography of 10 μm in stainless steel pipe with inner diameter of about 4.6 mm and length of about 15 cm

- mobile phase: n-hexane isopropanol (99: 1)

[Vitamin E (tocopherol acetate) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, Disintegration test liquid 2

4) Analysis method: HPLC method

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength = 254 nm at maximum)

- Column: A column packed with octadecylsilyl porous silica gel or liquid ceramic microparticles for liquid chromatography of 5 to 10 μm in a stainless steel pipe having an inner diameter of about 8 mm and a length of about 10 cm

- mobile phase: mixture of water and methanol (5:95)

As a result, the disintegration completion time on the elution tester of the three-layer tablet produced according to Example 17 was about 15 minutes. As can be seen from Figs. 7 and 8, vitamin B6, which is an index component of the rapid-release granule, was eluted at pH 5.8 after 5 minutes at pH 1.2, and the major component was detected. Vitamin D, the indicator component of the first enteric granule, was eluted at 60 minutes after pH 1.2 and at pH 6.8 after 10 minutes from the start of the test. In addition, vitamin E, an index component of the second enteric granule, eluted about 90 minutes after the start of the test at pH 1.2 and about 15 minutes after the start of the test at pH 6.8, and the main component was detected.

As described above, the three-layered tablet of the present invention disintegrates and elutes first from the immediate-release layer first, releases the drug from the top, and the first enteric and the second enteric layer emit drugs with time differences in the small intestine, Is an optimized formulation.

Experimental Example 6: Three-layer tablet elution test

The elution test of the three-layer tablet prepared according to Example 21 was carried out. In the case of the immediate release layer, vitamin B6 (pyridoxine hydrochloride) as an index component, the delayed release layer as vitamin D (cholecalciferol) as an index component, and the enteric layer as vitamin D (tocopherol acetate) And a dissolution test was carried out in a solution of 1.2 and a solution of pH 6.8.

 [Vitamin B6 (pyridoxine) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, disintegration time 2 liquid

4) Analysis method: HPLC method

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength = maximum 270 nm)

- Column: Column with a diameter of about 4.6 mm and a length of about 25 cm and filled with porous silica particles of 5 to 10 μm in diameter

- Mobile phase: Add 0.4 mL of triethylamine, 15.0 mL of acetic acid (100), and 350 mL of methanol into a 2000 mL volumetric flask, add 0.008 mol / L sodium hexanesulfonate to 2000 mL,

[Vitamin D (cholecalciferol) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, Disintegration test liquid 2

4) Analysis method: HPLC method

- Detector: Ultraviolet absorptiometer (detection wavelength = max 265nm)

- Column: Column packed with aminopropylsilyl porous silica gel for liquid chromatography of 10 μm in stainless steel pipe with inner diameter of about 4.6 mm and length of about 15 cm

- mobile phase: n-hexane isopropanol (99: 1)

[Vitamin E (tocopherol acetate) test method]

1) Dissolution test basis: In the 11th revision of Korea Pharmacopoeia, the dissolution test method of General Test Methods

2) Elution test method: Paddle method, 50 revolutions per minute

3) Elution test liquid: Disintegration test liquid 1, Disintegration test liquid 2

4) Analysis method: HPLC method

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength = 254 nm at maximum)

- Column: A column packed with octadecylsilyl porous silica gel or liquid ceramic microparticles for liquid chromatography of 5 to 10 μm in a stainless steel pipe having an inner diameter of about 8 mm and a length of about 10 cm

- mobile phase: mixture of water and methanol (5:95)

As a result, the disintegration completion time on the elution tester of the three-layer tablet produced according to Example 21 was about 15 minutes. As can be seen from Figs. 9 and 10, vitamin B6, which is an index component of fast-releasing granule, eluted 5 minutes after pH 1.2 and 5 minutes after pH 6.8, and the main component was detected. Vitamin D, the index component of the delayed-release granules, eluted 30 minutes after the start of the test at pH 1.2 and 30 minutes after the start of the test at pH 6.8. In addition, vitamin E, which is an index component of enteric granules, eluted about 90 minutes after pH 1.2 and eluted about 15 minutes after pH 6.8.

As described above, the three-layered tablet of the present invention disintegrates and elutes first from the immediate-release layer first to release the drug from the top, and the delayed release layer and the enteric layer release the drug with a time difference. Lt; / RTI &gt;

Experimental Example  7: side effects of administration of a single composition Occurrence  And the damage between the damaged

1) administration of single composition and induction of liver damage

Animals that had undergone a one-week purification period as in Reference Example 2 were divided into groups as shown in Table 10, and the single compositions A1-A3 and B1-B3 prepared according to Example 25 were orally administered (G3-G8) . The dose was administered once / day (7 times / week) for 42 days. All doses were performed before 15:00 and autopsy was performed after 6 weeks. The weight of the animals determined to be healthy during the refinement period was ranked and randomly distributed so that the average body weight of each group was evenly distributed.

For the excipients to be administered to the G1 and G2 groups, sterile injectable water of 0.5% carboxymethylcellulose (CMC) used for preparing the composition in Example 25 was used.

On the other hand, 200 mg / kg of D-galactosamine was intraperitoneally administered to all but the G1 group at 1 hour after administration of the first single composition to induce liver damage in the animal model.

group gender Number of animals Animal number Dosage amount
(mL / head / day) Dosing substance G1 cock 6 1-6 3 Excipient G2 cock 6 7-12 3 Excipient G3 cock 6 13-18 3 A1 G4 cock 6 19-24 3 A2 G5 cock 6 25-30 3 A3 G6 cock 6 31-36 3 B1 G7 cock 6 37-42 3 B2 G8 cock 6 43-48 3 B3

(G1: normal group, G2: vehicle control group, G3-8: single composition administration group)

2) Confirmation of occurrence of side effects by administration of single composition

To determine whether a single composition exhibited adverse effects on animal models, the presence or absence of abnormal symptoms, the date of onset, the severity of symptoms, and the mortality during the observation period were observed once a day when the single composition was administered. The first single composition administration day was set to Day 1, and autopsy was performed after 6 weeks of observation.

Weights of the animal models were measured at the time of arrival, at the time of separation, once / week, and at the date of the autopsy, and the weights of the liver, heart and kidney were measured after completion of blood collection at the date of autopsy.

Calcium ion (Ca ²⁺ ) levels were measured by autopsy and blood biochemical tests.

As a result of observing general symptoms during the test period, no animals died from the first administration day of the single composition until the day of the autopsy, and no animals exhibiting abnormal symptoms due to the administration of the single composition were observed (Table 11).

Work Symptom group G1 G2 G3 G4 G5 G6 G7 G8 1-43 normal 6/6 6/6 6/6 6/6 6/6 6/6 6/6 6/6 43 Autopsy 6/6 6/6 6/6 6/6 6/6 6/6 6/6 6/6

Body weight measurements of animal models during the test period did not reveal significant differences in body weight in all groups (Table 12, Figure 11)

G1 G2 G3 G4 G5 G6 G7 G8 0 weeks 298.91 + - 8.54 300.66 + - 9.85 299.90 + - 8.74 301.39 ± 9.14 299.97 ± 5.97 298.93 + - 7.46 299.58 +/- 7.53 302.73 + - 5.43 1 week 348.76 + - 11.64 345.84 + - 9.98 345.23 + - 9.83 347.30 ± 15.26 344.12 + - 9.14 345.89 ± 18.23 349.36 ± 14.22 348.40 ± 8.64 2 weeks 386.73 + - 13.11 384.61 + - 10.15 384.17 + - 11.75 387.03 + - 20.19 389.56 ± 17.21 387.45 +/- 29.18 395.42 + - 24.18 381.68 + - 21.84 3 weeks 415.99 ± 9.94 412.34 + - 13.14 407.75 ± 12.88 418.66 ± 25.34 415.91 + - 23.98 411.55 + 33.54 420.50 ± 30.34 405.01 + - 20.55 4 weeks 445.82 + - 13.14 442.05 ± 15.29 431.18 ± 18.69 447.16 +/- 29.81 440.16 + 26.85 434.87 +/- 40.84 447.54 +/- 37.40 428.65 + - 24.44 5 weeks 468.66 ± 13.26 467.23 + - 18.65 451.16 + - 18.78 471.93 + - 31.67 464.22 + - 33.19 458.40 ± 49.08 475.01 + - 40.03 450.59 ± 26.25 6 weeks 487.67 ± 16.14 485.19 + - 24.52 469.57 ± 22.28 492.49 + - 34.82 481.72 + - 34.55 478.94 + - 53.61 493.57 ± 45.47 468.79 ± 29.51 Autopsy 459.25 + 15.91 457.74 ± 23.87 445.85 + - 22.36 463.70 ± 32.35 451.04 + - 33.80 448.76 ± 51.64 467.04 + - 43.11 444.49 ± 28.62

As a result of measuring the weight of the liver after the completion of the test, there was no significant difference between the single composition administration groups and the excipient control groups (FIG. 12 and Table 13). As a result of measuring the weight of the kidneys, (Fig. 13, Table 13). As a result of measuring the weight of the heart, it was confirmed that there was no significant difference in all groups (Fig. 14 and Table 13).

Weight of organ (g) liver Height (left) Height (right) Heart G1 13.265 ± 1.277 ^** 1.652 + 0.142 1.692 + 0.122 1.552 + 0.086 G2 16.870 + 1.795 1.665 + 0.082 1.666 + 0.109 1.434 + 0.088 G3 15.545 ± 1.249 1.623 + 0.129 1.650 + 0.135 1.442 + 0.084 G4 17.185 ± 3.312 1.772 + 0.130 1.741 + 0.091 1.499 + 0.123 G5 16.194 ± 2.283 1.644 + 0.107 1.615 + 0.075 1.494 + 0.158 G6 16.156 ± 3.030 1.715 + 0.125 1.730 + 0.187 1.515 + 0.110 G7 16.927 + 1.450 1.767 + 0.155 1.814 + 0.177 1.522 + 0.165 G8 15.429 ± 2.228 1.873 + - 0.185 ^* 1.876 + - 0.236 ^* 1.441 + 0.180

(* And ** mean statistical significance with G2, representing P <0.05 and P <0.01, respectively)

Also, as a result of the measurement of the calcium ion level, it was confirmed that all the single composition administration groups did not show any significant difference compared with the excipient control group (Table 14).

G1 G2 G3 G4 G5 G6 G7 G8 Calcium ion
(mg / dL) 10.02 0.08 9.92 + - 0.12 10.17 ± 0.16 10.25 + 0.09 10.02 ± 0.16 10.09 + - 0.11 10.17 ± 0.19 10.25 + - 0.10

Thus, it was confirmed that the single composition does not cause side effects such as hepatotoxicity even when administered in the body, and is a safe substance that does not cause toxic action even when containing a high dose of vitamin D in particular.

3) Confirmation of improvement of surface element

(AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN), which are components that increase the expression level of liver damage, are measured And the antioxidant activity (SOD activity) was measured in order to confirm the recovery effect of liver function.

Specifically, D-galactosamine was administered, followed by fasting for 24 hours. Jugular vein sampling was performed, and serum was separated using a vacutainer tube containing a clot activator. Blood biochemical tests for AST, ALT, and BUN were performed on the day of the autopsy.

In addition, after autopsy, some tissues were cut and the tissue was disrupted, and the SOD activity was measured using an SOD kit.

As a result of the AST measurement, it was confirmed that the AST level was increased in the excipient control group in which hepatic injury was induced compared to the normal control group. On the other hand, the single composition administration groups were found to have decreased AST levels compared with the vehicle control group. Specifically, the single composition A1-A3 treated groups (G3-G5) showed about 74.18, 80.62 and 77.90% improvement compared to the vehicle control group, and the single composition B1-B3 treated groups (G6-G8) , It was confirmed that the improvement rate was about 84.98, 77.42 and 89.34% (FIG. 15 and Table 15).

As a result of the ALT measurement, it was confirmed that the ALT level was increased in the excipient control group in which hepatic injury was induced compared to the normal group. On the other hand, the single composition administration groups were found to have decreased ALT levels compared with the vehicle control group. Specifically, the single composition A1-A3 administration groups (G3-G5) showed improvement rates of about 77.40, 82.90 and 82.15% compared to the vehicle control group and the single composition B1-B3 administration groups (G6-G8) , It was confirmed that the improvement rate was about 90.35, 88.35 and 92.95% (FIG. 16 and Table 15).

As a result of BUN measurement, it was confirmed that the BUN value of the excipient control group in which hepatic injury was induced was increased as compared with the normal group. On the other hand, the single composition administration groups were found to have decreased BUN levels compared to the vehicle control group (Table 15).

In addition, SOD measurement showed that SOD was decreased in the excipient control group induced liver damage compared with the normal group. On the other hand, the single composition administration groups were found to have increased SOD compared to the vehicle control group (Fig. 17 and Table 15).

Through this, it was confirmed that the single composition showed an improvement effect on liver damage and a recovery effect of liver function.

AST (U / L) ALT (U / L) BUN (mg / dL) SOD activity (%) G1 172.60 ± 6.19 ^* 34.55 ± 2.13 ^* 12.02 + - 0.25 ^* 52.90 + - 5.39 ^* G2 2936.42 + - 770.25 2000.60 ± 526.22 14.40 0.95 41.31 8.31 G3 758.42 + - 315.79 ^* 452.68 ± 203.78 ^* 12.68 ± 1.01 57.91 + - 2.32 ^** G4 569.17 ± 112.02 ^* 342.00 ± 132.52 ^* 11.80 ± 0.59 63.32 + - 6.55 ^** G5 649.86 + - 216.02 ^* 357.10 + - 141.14 ^* 13.82 ± 1.68 62.46 + - 6.45 ^** G6 441.22 + ^- 121.11 ^* 193.34 ± 70.66 ^* 11.44 + - 0.58 ^* 57.20 ± 5.66 ^** G7 663.15 ± 410.18 ^* 293.63 + ^- 217.14 ^* 11.02 + - 0.22 ^** 51.22 + - 8.13 G8 313.52 + - 158.91 ^* 141.93 + - 101.30 ^* 12.12 + - 0.44 49.17 ± 3.47

(* And ** mean statistical significance with G2, representing P <0.05 and P <0.01, respectively)

Claims (48)

Fast-release compartment containing vitamin B12, vitamin B6, vitamin B9, choline and pharmaceutically acceptable additives, and vitamin D, vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, &Lt; / RTI &gt; wherein the controlled release compartment comprises a controlled release compartment. The combination preparation for oral administration according to claim 1, wherein the base for controlled release is a nutrient base or delayed release base. 3. The composition of claim 2, wherein the enteric base is selected from the group consisting of hydroxypropylmethylcellulose phthalate, Eudragit L (poly (methacrylic acid-methyl methacrylate) 1: 1 copolymer), Eudragit L100-55 (Methacrylic acid-methyl methacrylate) 1: 2 copolymer), cellulose acetate phthalate, polyvinyl acetate phthalate, and shellac. Or more. 3. The oral combined preparation according to claim 2, wherein the delayed-release base is at least one selected from a cellulose derivative, a dimethylaminoethyl methacrylate copolymer, a polyvinyl derivative, a polyethylene derivative, a carboxyvinyl polymer and gums. The oral preparation according to claim 4, wherein the cellulose derivative is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and carboxymethylcellulose sodium. 5. The oral combined preparation according to claim 4, wherein the dimethylaminoethyl methacrylate copolymer is Eudragit E. The oral preparation according to claim 4, wherein the polyvinyl derivative is at least one selected from polyvinyl alcohol and polyvinyl pyrrolidone. The oral preparation according to claim 4, wherein the polyethylene derivative is at least one selected from the group consisting of polyethylene glycol and polyethylene oxide. 5. The oral combined preparation according to claim 4, wherein the carboxyvinyl polymer is carbomer. 5. The oral combined preparation according to claim 4, wherein the gum is at least one selected from guar gum, locust bean gum, carrageenan, gum arabic, gellan gum and xanthan gum. The combination preparation for oral administration according to claim 1, wherein the pharmaceutically acceptable additive is at least one selected from a diluent, a binder, a disintegrant, and a lubricant. The oral preparation according to claim 1, wherein the vitamin D is vitamin D3. 13. The oral combined preparation according to claim 12, wherein the vitamin D3 is contained in an amount of 1,000 IU to 20,000 IU. 13. The oral combined preparation according to claim 12, wherein the vitamin D3 is contained in an amount of 2,000 IU to 20,000 IU. 13. The oral combined preparation according to claim 12, wherein the vitamin D3 is contained in an amount of 5,000 IU to 20,000 IU. 13. The oral combined preparation according to claim 12, wherein the vitamin D3 is contained in an amount of 2,000 IU to 10,000 IU. The combination formulation of claim 1, wherein the immediate release compartment and the controlled release compartment are in the form of granules or pellets, respectively. The combination preparation for oral administration according to claim 1, wherein the oral combination preparation is a single-dose, double-layered, multi-layered, coated tablet, or capsule. 19. The oral combined preparation according to claim 18, wherein the coated tablet comprises a coating layer composed of a coating agent, a coating aid or a mixture thereof. 20. The method according to claim 19, wherein the coating layer is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, polyvinyl derivatives, waxes, fatty acids, gelatin, polyethylene glycol, talc, titanium oxide and diethyl phthalate &Lt; / RTI &gt; 20. A pharmaceutical composition for the prevention or treatment of liver diseases comprising the combination oral preparation according to any one of claims 1 to 20. 22. The pharmaceutical composition according to claim 21, wherein the liver disease is any one of fatty liver, hepatitis, liver cirrhosis and liver cancer. 20. A health functional food composition for improving liver function comprising the combination preparation for oral administration according to any one of claims 1 to 20. A quick-release compartment comprising vitamin B12, vitamin B6, vitamin B9, choline and a pharmaceutically acceptable additive; A controlled release first compartment comprising vitamin D, a controlled release base, and a pharmaceutically acceptable additive; And a controlled release second compartment comprising vitamin E, vitamin C, silymarin, biphenyldimethyldicarboxylate, a controlled release base, and a pharmaceutically acceptable additive. 25. The oral combined preparation according to claim 24, wherein the controlled-release base is a nutrient-based or delayed-release base. 25. The combination preparation for oral administration according to claim 24, wherein the controlled release composition contained in the controlled release first compartment and the controlled-release second compartment is a nutritive base. 26. The combination formulation of claim 24, wherein the controlled release vehicle contained in the controlled release first compartment is a delayed release vehicle and the controlled release vehicle contained in the controlled release second compartment is a penetrating vehicle. 26. The composition of claim 25, wherein the enteric base is selected from the group consisting of hydroxypropylmethylcellulose phthalate, Eudragit L (poly (methacrylic acid-methyl methacrylate) 1: 1 copolymer), Eudragit L100-55 (Methacrylic acid-methyl methacrylate) 1: 2 copolymer), cellulose acetate phthalate, polyvinyl acetate phthalate, and shellac. Or more. 26. The oral combined preparation according to claim 25, wherein the delayed-release base is at least one selected from a cellulose derivative, a dimethylaminoethyl methacrylate copolymer, a polyvinyl derivative, a polyethylene derivative, a carboxyvinyl polymer and gums. 30. The combination preparation for oral administration according to claim 29, wherein the cellulose derivative is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and carboxymethylcellulose sodium. 30. The oral dosage form of claim 29, wherein the dimethylaminoethyl methacrylate copolymer is Eudragit E. 30. The combination preparation for oral administration according to claim 29, wherein the polyvinyl derivative is at least one selected from polyvinyl alcohol and polyvinylpyrrolidone. 30. The combination preparation for oral administration according to claim 29, wherein the polyethylene derivative is at least one selected from polyethylene glycol and polyethylene oxide. 30. The combination preparation of claim 29, wherein the carboxyvinyl polymer is a carbomer. 30. The combination preparation for oral administration according to claim 29, wherein the gum is at least one selected from guar gum, locust bean gum, carrageenan, gum arabic, gellan gum and xanthan gum. 25. The combination preparation for oral administration according to claim 24, wherein the pharmaceutically acceptable additive is at least one selected from a diluent, a binder, a disintegrant, and a lubricant. 26. The oral combined preparation according to claim 24, wherein the vitamin D is vitamin D3. 38. The oral combined preparation according to claim 37, wherein the vitamin D3 is contained in an amount of 1,000 IU to 20,000 IU. 38. The oral combined preparation according to claim 37, wherein the vitamin D3 is contained in an amount of 2,000 IU to 20,000 IU. 38. The oral combined preparation according to claim 37, wherein the vitamin D3 is contained in an amount of 5,000 IU to 20,000 IU. 38. The oral combined preparation according to claim 37, wherein the vitamin D3 is contained in an amount of 2,000 IU to 10,000 IU. 25. The combination formulation of claim 24, wherein the immediate release compartment, controlled release first compartment and controlled release second compartment are each in the form of granules or pellets. 26. The combination preparation for oral administration according to claim 24, wherein the oral combination preparation is a three-layered, multi-layered, coated or capsule. 44. The combination preparation for oral administration of claim 43, wherein the coated tablet comprises a coating layer composed of a coating agent, a coating aid, or a mixture thereof. 45. The method according to claim 44, wherein the coating layer is formed of at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, polyvinyl derivatives, waxes, fatty acids, gelatin, polyethylene glycol, talc, titanium oxide and diethyl phthalate &Lt; / RTI &gt; 45. A pharmaceutical composition for the prophylaxis or treatment of liver disease comprising the combination oral preparation according to any one of claims 24 to 45. 47. The pharmaceutical composition according to claim 46, wherein the liver disease is any one of fatty liver, hepatitis, liver cirrhosis and liver cancer. 45. A health functional food composition for improving liver function comprising the combination preparation for oral administration according to any one of claims 24 to 45.

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