KR102193989B1 - Pharmaceutical Composition and Method for Manufacturing the same - Google Patents

Abstract

The pharmaceutical composition according to the present invention includes adenine, carnitine and cyanocobalamin, and provides a pharmaceutical composition capable of securing the stability of adenine by using a blocking agent or a blocking structure, and a method for preparing the same. The pharmaceutical composition according to the present invention secures the stability of adenine so that the adenine content is maintained at 95% or more after 6 months in a stability test under accelerated conditions (40±2°C/75±5%RH).

Description

Pharmaceutical composition and method for manufacturing the same {Pharmaceutical Composition and Method for Manufacturing the same}

The present invention relates to a pharmaceutical composition and a method for preparing the same, and more particularly, to a pharmaceutical composition capable of securing the stability of adenine in a pharmaceutical composition containing adenine, carnitine and cyanocobalamin, and a method for preparing the same.

Adenine is one of the purine bases that make up nucleic acids and is used as a precursor to ATP or ADP, which are energy sources in the body. It is also used for cAMP formation, which is involved in cell signal transduction occurring in the body. In the brain, it is used as a neurotransmitter inhibitor and is involved in inducing sleep and suppressing arousal. (Journal of Alzheimer's Disease 20 (2010) S3-S15 S3 DOI 10.3233/JAD-2010-1379) In the liver, it is involved in vasoconstriction, increasing the breakdown of glycogen into glucose and inhibiting the production of fatty liver. (Nature 204, 1196-1197 (19 December 1964); DOI 10.1038/2041196a0)

Adenine hydrochloride (molecular formula C ₅ H ₅ N ₅ ·HCl: Relative molecular weight 171.59) is a white crystalline powder and is well soluble in water. As a representative drug of a pharmaceutical composition containing adenine, there are Godex capsules, which contain adenine hydrochloride, riboflavin, pyridoxine hydrochloride, anti-toxic soy extract, carnitine orotate, biphenyldimethyldicarboxylate, and cyanocobalamin Contains.

Korean Patent Registration No. 0294329 discloses a pharmaceutical composition containing adenine hydrochloride for the purpose of treating and preventing liver disease, but when the Godex pharmaceutical composition is prepared by the method according to the patent, the content of adenine is significantly reduced. A problem occurred.

Accordingly, there is a need for a pharmaceutical composition capable of securing the stability of adenine when preparing a pharmaceutical composition containing adenine and a method for preparing the same.

An object of the present invention is to provide a pharmaceutical composition capable of securing the stability of adenine in a pharmaceutical composition comprising adenine, carnitine and cyanocobalamin, and a method for preparing the same.

The present inventors found that the stability of adenine was significantly reduced by carnitine and cyanocobalamin while studying a method for improving the stability of adenine. Accordingly, a method for stabilizing adenine was studied in various ways, and as a result of preparing a pharmaceutical composition containing adenine, carnitine and cyanocobalamin using a blocking agent or a blocking structure, the stability of adenine was significantly secured.

In one embodiment of the present invention, the pharmaceutical composition is a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin, and a blocking agent, wherein the adenine or It includes a pharmaceutically acceptable salt thereof, and a pharmaceutical composition in which physical contact with carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin is inhibited.

In one embodiment of the present invention, carnitine comprises D,L-carnitine or L-carnitine.

In one embodiment of the present invention, the cyanocobalamin comprises an embryoid form.

In one embodiment of the present invention, the blocking agent is maltodextrin, corn starch, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, gelatin, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol and poly It contains at least one selected from vinyl acetate.

In one embodiment of the present invention, the blocking agent may be 0.8 to 500 parts by weight based on 1 part by weight of adenine.

In one embodiment of the present invention, the pharmaceutical composition may form granules with adenine or a pharmaceutically acceptable salt thereof and a blocking agent.

In one embodiment of the present invention, the pharmaceutical composition may form granules with one or more active ingredients selected from carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin, and a blocking agent.

In one embodiment of the present invention, the pharmaceutical composition is a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin, wherein the adenine or a pharmaceutically acceptable salt thereof The salt includes the carnitine or a pharmaceutically acceptable salt thereof and a pharmaceutical composition that is spatially separated so that physical contact with cyanocobalamin is inhibited by a barrier structure.

In one embodiment of the present invention, the barrier structure may include a layer-separated capsule, a nucleated tablet, a two-layer tablet, or a multi-layer tablet.

In one embodiment of the present invention, carnitine or a pharmaceutically acceptable salt thereof and cyanocobalimin may be included in the same zone or in a zone separated from each other.

In one embodiment of the present invention, the pharmaceutical composition contains at least one active ingredient selected from anti-toxic liver extract, biphenyldimethyldicarboxylate, pyridoxine or a pharmaceutically acceptable salt thereof, and riboflavin or a pharmaceutically acceptable salt thereof. It may contain additionally.

In one embodiment of the present invention, when the pharmaceutical composition is stored in an airtight container for 6 months under accelerated conditions of 40° C. and 75% relative humidity, the adenine content is maintained at 95% or more.

The pharmaceutical composition according to the present invention can excellently secure the stability of adenine by using a blocking agent or a blocking structure.

[Pharmaceutical composition]

The pharmaceutical composition according to an embodiment of the present invention comprises adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin, and a blocking agent, and the component adenine or a pharmaceutical composition thereof by the blocking agent It inhibits physical contact with the acceptable salt and the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin.

In one embodiment of the present invention, adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof or cyanocobalamin is a pharmaceutically acceptable hydrate, solvate, isomer, polymorph, ester thereof. Or it may include a prodrug.

In one embodiment of the present invention, a solvate refers to a complex or aggregate formed by one or more molecules of a solute, that is, a compound according to the present invention or a pharmaceutically acceptable salt thereof, and one or more molecules of a solvent. The solvate is typically a crystalline solid having a fixed molar ratio of solute and solvent. Representative solvents include water, ethanol, and isopropanol.

In one embodiment of the present invention, an isomer refers to a compound having the same molecular formula but not the same linkage method or spatial arrangement of members in a molecule.

In one embodiment of the present invention, polymorph refers to a material that is crystallized in one or more crystal lattice arrangements.

In one embodiment of the present invention, ester means that an organic radical is substituted at the hydrogen molecule site of an acid.

In one embodiment of the present invention, a prodrug refers to a compound that changes into a target compound in vivo after administration.

In one embodiment of the present invention, the pharmaceutical composition comprises adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin, and accelerating conditions (40±2°C/75±5%RH) ), the content of adenine is maintained above 95% after 6 months in the stability test.

Adenine or a pharmaceutically acceptable salt thereof

In one embodiment of the present invention, the pharmaceutically acceptable salt of adenine is hydrochloride, sulfate, acetate, lactate, maleate, fumarate, succinate, tartrate, oxalate, citrate, benzenesulfonate, carbonate Or borate. More specifically, it may be hydrochloride or sulfate, but is not limited thereto.

In one embodiment of the present invention, adenine or a pharmaceutically acceptable salt thereof may be included in an amount of 0.05 to 5% by weight or 0.1 to 2.5% by weight based on 100% by weight of the total pharmaceutical composition.

Carnitine or a pharmaceutically acceptable salt thereof

In one embodiment of the present invention, carnitine comprises D,L-carnitine or L-carnitine.

In one embodiment of the present invention, the pharmaceutically acceptable salt of carnitine is orotate, napadicylate, tartrate, fumarate, tartrate, succinate, hydrochloride, aspartate, aspartate, citrate, phosphate , Lactate, maleate, oxalate, pamoate, sulfate, mucolate, 2-amino-ethanesulfonic acid salt, mesansulfonate, trichloroacetate or trifluoroacetate. More specifically, it may be orotate, napadicylate, tartrate, or fumarate, but is not limited thereto.

Examples of pharmaceutically acceptable salts of D,L-carnitine include D,L-carnitine orotate, D,L-carnitine napadisylate, D,L-carnitine tartrate, D,L-carnitine fumarate, D ,L-carnitine tartrate, D,L-carnitine succinate, D,L-carnitine hydrochloride, D,L-carnitine aspartate, D,L-carnitine aspartate, D,L-carnitine citrate, D,L- Carnitine phosphate, D,L-carnitine lactate, D,L-carnitine maleate, D,L-carnitine oxalate, D,L-carnitine pamoate, D,L-carnitine sulfate, D,L-carnitine mucolate, D , L-carnitine 2-amino-ethanesulfonate, D,L-carnitine mesansulfonate, D,L-carnitine trichloroacetate or D,L-carnitine trifluoroacetate. These may be used alone or may be used in combination.

Examples of pharmaceutically acceptable salts of L-carnitine include L-carnitine orotate, L-carnitine napadicylate, L-carnitine tartrate, L-carnitine fumarate, L-carnitine tartrate, L-carnitine succinate. , L-carnitine hydrochloride, L-carnitine aspartate, L-carnitine aspartate, L-carnitine citrate, L-carnitine phosphate, L-carnitine lactate, L-carnitine maleate, L-carnitine oxalate, L-carnitine pamo Acid salts, L-carnitine sulfate, L-carnitine mucolate, L-carnitine 2-amino-ethanesulfonic acid salt, L-carnitine mesansulfonate, L-carnitine trichloroacetate or L-carnitine trifluoroacetate. . These may be used alone or may be used in combination.

In one embodiment of the present invention, D,L-carnitine, a pharmaceutically acceptable salt of D,L-carnitine, or a pharmaceutically acceptable salt of L-carnitine or L-carnitine, is a solvate thereof, a crystalline form, etc. Can include.

In one embodiment of the present invention, D,L-carnitine, a pharmaceutically acceptable salt of D,L-carnitine, L-carnitine, a pharmaceutically acceptable salt of L-carnitine, or a mixture thereof is a total of 100 pharmaceutical compositions. It may be included in 1 to 80% by weight or 10 to 50% by weight based on the weight%.

Cyanocobalamin

In one embodiment of the present invention, the cyanocobalamin comprises an embryoid form. The use of cyanocobalamin glycosides may contribute to stabilization of pharmaceutical compositions.

In one embodiment of the present invention, the cyanocobalamin vesicle means that cyanocobalamin is distributed in an appropriate excipient. More specifically, it means that a small amount of cyanocobalamin is distributed through physical mixing or spray drying in one or more excipients selected from lactose, corn starch, mannitol, gelatin and maltodextrin. As an example of the cyanocobalamin vesicle, the cyanocobalamin 100 douches may contain 1% by weight of cyanocobalamin and 99% by weight of maltodextrin based on 100% by weight of the total cyanocobalamin vesicle.

In one embodiment of the present invention, cyanocobalamin may be included in an amount of 0.001 to 10% by weight or 0.005 to 5% by weight based on 100% by weight of the total pharmaceutical composition.

Blocker

In one embodiment according to the present invention, the blocking agent inhibits physical contact with adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin to accelerate conditions (40±2°C/ 75±5%RH) refers to a substance capable of maintaining a content of adenine above 95% after 6 months in a stability test.

In one embodiment of the present invention, the blocking agent is maltodextrin, corn starch, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, gelatin, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol and It may include one or more selected from polyvinyl acetate, but is not limited thereto.

In one embodiment of the present invention, the blocking agent may be included in 0.5 to 90% by weight, 1 to 80% by weight, or 3 to 70% by weight based on the total 100% by weight of the pharmaceutical composition. When the blocking agent is included in an amount of less than 0.5% by weight, the stability of adenine is not secured.

In one embodiment of the present invention, the content of the blocking agent is characterized in that 0.8 to 500 parts by weight, 2 to 400 parts by weight, or 5 to 300 parts by weight based on 1 part by weight of adenine or a pharmaceutically acceptable salt thereof. However, the content of the blocking agent does not exceed 90% by weight based on 100% by weight of the total pharmaceutical composition. If the blocker is less than 0.8 parts by weight, the stability of adenine is significantly reduced, and if it exceeds 500 parts by weight, the total mass of the formulation is greatly increased, causing dysphagia in patients or the elderly taking the formulation. have.

In another embodiment of the present invention, the pharmaceutical composition comprises adenine or a pharmaceutically acceptable salt thereof and a granule containing a blocking agent, or at least one selected from carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin It includes granules containing powder and blockers.

More specifically, the pharmaceutical composition contains at least one active ingredient selected from the adenine or a pharmaceutically acceptable salt thereof and a granule containing the blocking agent, and the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin It may contain a final product obtained by uniformly mixing one mixture.

As another example, a final product obtained by uniformly mixing a mixture containing adenine or a pharmaceutically acceptable salt thereof, the carnitine or a pharmaceutically acceptable salt thereof, and a granule containing the cyanocobalamin and the blocking agent It may include.

In another example, the adenine or a pharmaceutically acceptable salt thereof and a granule containing the blocking agent, the carnitine or a pharmaceutically acceptable salt thereof and at least one active ingredient selected from the cyanocobalamin and the blocking agent are contained. It may contain a final product obtained by uniformly mixing one granule.

In another example, a granule containing the adenine or a pharmaceutically acceptable salt thereof and the blocking agent, and the carnitine or a pharmaceutically acceptable salt thereof and a granule containing the blocking agent and the cyanocobalamin It may contain a final product obtained by uniformly mixing one mixture.

In another example, a mixture containing the adenine or a pharmaceutically acceptable salt thereof and the blocking agent, a mixture containing the carnitine or a pharmaceutically acceptable salt thereof, and the cyanocobalamin and the blocking agent It may include a final product obtained by uniformly mixing the granules, but is not limited thereto.

In another example, a mixture containing the adenine or a pharmaceutically acceptable salt thereof, a granule containing the carnitine or a pharmaceutically acceptable salt thereof and the blocking agent, and the cyanocobalamin and the blocker It may include a final product obtained by uniformly mixing the granules, but is not limited thereto.

When the carnitine or a pharmaceutically acceptable salt thereof is granulated with the blocking agent, the blocking agent is 80 parts by weight or more relative to 100 parts by weight of the carnitine or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the granules are granulated to increase particle size, increase density, and improve fluidity, and may include dry granules or wet granules. The dry granule means granulation using a pressing force without using a solvent, and the wet granule means granulation using a shear force or cohesive force using a solvent.

In one embodiment of the present invention, the average particle diameter of the granules may be 100 to 850㎛. More specifically, it may be 200 to 710 μm, but is not limited thereto.

In one embodiment of the present invention, the final product may be formulated into tablets, capsules, granules, and the like.

In one embodiment of the present invention, the tablet may be a compressed tablet, a single layer tablet, a multilayer tablet, a nucleated tablet, a dragee, a film-coated tablet, a gelatin-coated tablet, an enteric tablet, a chewable tablet, a fast disintegrating tablet, and the like. More specifically, it may be a compressed tablet, a single-layer tablet, a multi-layer tablet, or a nucleated tablet, but is not limited thereto.

The pharmaceutical composition of the present invention may further contain another physiologically active substance or a pharmaceutically acceptable additive as defined in the following additional active ingredients.

Blocking structure

The pharmaceutical composition according to an embodiment of the present invention comprises adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin, and the adenine or pharmaceutically acceptable salt thereof by a blocking structure The salt is inhibited from physical contact with the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin.

In one embodiment of the present invention, the blocking structure is spatially separated so that physical contact with the adenine or a pharmaceutically acceptable salt thereof is suppressed with the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin, and accelerated conditions ( 40±2℃/75±5%RH) refers to a structure capable of maintaining the adenine content above 95% after 6 months in the stability test.

In one embodiment of the present invention, the blocking structure may be more specifically a layer-separated capsule, a nucleated tablet, a two-layer tablet or a multi-layer tablet, but is not limited thereto.

In one embodiment of the present invention, the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalimin may be included in the same zone or in a zone separated from each other.

In one embodiment of the present invention, the blocking structure is a first layer portion containing the adenine or a pharmaceutically acceptable salt thereof, and the second layer containing the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin Includes wealth.

In one embodiment of the present invention, the blocking structure is a first layer portion containing the adenine or a pharmaceutically acceptable salt thereof, the second layer portion containing the carnitine or a pharmaceutically acceptable salt thereof, and the cyanocobalamin It includes a third layer including a.

The first to third layer portions may further include a blocking agent, and may further include another physiologically active substance or a pharmaceutically acceptable additive defined in the following additional active ingredients.

In one embodiment of the present invention, the adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin are each, or the carnitine or a pharmaceutically acceptable salt thereof and the cyano Cobalamin may be mixed to form granules or mixtures, and these may be formulated as layered capsules, nucleated tablets, double-layered tablets or multi-layered tablets.

Additional active ingredient

In one embodiment of the present invention, the pharmaceutical composition may further contain another physiologically active substance in addition to adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin.

The pharmaceutical composition of the present invention may contain vitamins, liver extracts (eg, antitoxic liver extract, Liver extract antitoxic fraction), amino acid preparations, or mixtures thereof, which are adjuvants commonly used in the treatment of liver diseases, if necessary. The vitamin or amino acid preparation is not particularly limited.

In one embodiment of the present invention, antitoxic soy extract, biphenyldimethyldicarboxylate, vitamins or mixtures thereof may be further included as the physiologically active substance.

In one embodiment of the present invention, the anti-toxic liver extract means an animal liver extract, for example, a hot water extract of cattle liver. The anti-toxic soy extract may mainly contain amino acids (ie, 50 to 100% by weight of the total weight of the anti-toxic soy extract). When anti-toxic soy extract is included as an additional active ingredient, mixing adenine or a pharmaceutically acceptable salt thereof with anti-toxic soy extract first is more effective in maintaining adenine stability.

In one embodiment of the present invention, the biphenyldimethyldicarboxylate is a poorly soluble drug, and the dissolution rate thereof is improved.

In addition, as the biphenyldimethyl dicarboxylate, a solvate or crystal form thereof may be used.

In one embodiment of the present invention, the weight ratio of adenine to biphenyldimethyldicarboxylate may be 1:0.01 to 1:50, 1:1 to 1:20, or 1:5 to 1:15.

In one embodiment of the present invention, the vitamin may be riboplasmin or a pharmaceutically acceptable salt thereof, pyridoxine or a pharmaceutically acceptable salt thereof, or a mixture thereof.

In one embodiment of the present invention, the weight ratio of adenine to vitamin may be 1:0.01 to 1:50, 1:1 to 1:20, or 1:5 to 1:15.

Pharmaceutically acceptable additives

In one embodiment of the present invention, the pharmaceutical composition may further include a pharmaceutically acceptable additive in addition to adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin.

The pharmaceutically acceptable additives in the pharmaceutical composition according to an embodiment of the present invention are excipients, binders, disintegrants, lubricants, stabilizers, antioxidants, flavoring agents, brightening agents, coloring agents, pH adjusting agents, coating agents, sweetening agents, adsorbents. , A solvent, a shielding agent, and a surfactant, and the like may be included, but the present invention is not limited thereto.

In the pharmaceutical composition according to an embodiment of the present invention, the blocking agent may be additionally included as a pharmaceutically acceptable additive.

[Method of manufacturing pharmaceutical composition]

Blocker

A method for preparing a pharmaceutical composition according to an embodiment of the present invention is a method for preparing a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin, and a blocker,

Preparing a granule comprising the adenine or a pharmaceutically acceptable salt thereof and a blocker, or preparing a granule comprising the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin and the blocker Includes.

In the method for preparing a pharmaceutical composition according to an embodiment of the present invention, the granules may be prepared using dry granules, high shear granules, fluid bed granules or spray drying methods. Dry granules can use a roller compactor or a punching method, wet granules can use a high shear granulator or a low shear granulator, and fluidized bed granules are Worster method, Top spray method, or Tangential spray. A granulator such as spray) method can be used. For spray drying, a spray dryer such as a two fluid nozzle, a rotary atomizer nozzle, a pressure nozzle, or an ultrasonic nozzle can be used. The method for producing the granules is described in more detail below, but is not limited thereto.

More specifically, a method for preparing a pharmaceutical composition according to an embodiment of the present invention is a method for preparing a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin, and a blocker As,

A first step of preparing a granule containing the adenine or a pharmaceutically acceptable salt thereof and the blocking agent; A second step of preparing a mixture containing the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin; And a third step of preparing a final product by mixing the granules of the first step and the mixture of the second step.

In another example, a first step of preparing a mixture containing the adenine or a pharmaceutically acceptable salt thereof; A second step of preparing a granule containing the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin and the blocker; And a third step of preparing a final product by mixing the mixture of the first step and the granule of the second step.

In another example, a first step of preparing a granule containing the adenine or a pharmaceutically acceptable salt thereof and the blocking agent; A second step of preparing a granule containing the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin and the blocker; And a third step of preparing a final product by mixing the granules of the first step and the granules of the second step.

In another example, a first step of preparing a granule containing the adenine or a pharmaceutically acceptable salt thereof and the blocking agent; A second step of preparing a granule containing the carnitine or a pharmaceutically acceptable salt thereof and the blocking agent; A third step of preparing a mixture containing the cyanocobalamin; And a fourth step of preparing a final product by mixing the granules of the first step, the granules of the second step, and the mixture of the third step.

In another example, a first step of preparing a granule containing the adenine or a pharmaceutically acceptable salt thereof and the blocking agent; A second step of preparing a mixture containing the carnitine or a pharmaceutically acceptable salt thereof; A third step of preparing a granule containing the cyanocobalamin salt and the blocking agent; And a fourth step of preparing a final product by mixing the granules of the first step, the mixture of the second step, and the granules of the third step.

The method for preparing a pharmaceutical composition according to an embodiment of the present invention may be prepared by additionally including another physiologically active substance defined in the additional active ingredient. When anti-toxic soy extract is included as an additional active ingredient, mixing adenine or a pharmaceutically acceptable salt thereof with anti-toxic soy extract first is more effective in maintaining adenine stability.

The method for preparing a pharmaceutical composition according to an embodiment of the present invention may be prepared by additionally including the pharmaceutically acceptable additive.

In the method for preparing a pharmaceutical composition according to an embodiment of the present invention, the blocking agent may be prepared by further including as a pharmaceutically acceptable additive.

The method for preparing a pharmaceutical composition according to an embodiment of the present invention may further include preparing the final product into capsules or tablets.

In one embodiment of the present invention, the capsule may be prepared by filling the final product into a hard capsule using a capsule filler according to the manufacturing method of the capsule section of the Korean Pharmacopoeia.

In one embodiment of the manufacturing method, the tablet may be manufactured using a tablet press according to the manufacturing method of the tablet section of the Korean Pharmacopoeia. The tablet may further include coating with a coating agent.

Blocking structure

A method for preparing a pharmaceutical composition according to an embodiment of the present invention is a method for preparing a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin,

The adenine or a pharmaceutically acceptable salt thereof,

The carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin may be prepared in the form of a layer-separated capsule, a nucleated tablet, a double tablet, a double-layer tablet or a multi-layer tablet. More specifically, it may be prepared as a layer-separated capsule or two-layer tablet, but is not limited thereto.

In one embodiment of the present invention, the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalimin may be included in the same zone or in a zone separated from each other.

In the same region, the adenine or a pharmaceutically acceptable salt thereof and the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalimin are spatially separated so that the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalimin are It means to be located in one area.

More specifically, a method for preparing a two-layer tablet of a pharmaceutical composition according to an embodiment of the present invention is a method for preparing a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin As,

Injecting the adenine or a pharmaceutically acceptable salt thereof, the carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin into a double-layer tablet press and tableting.

A method for preparing a layered capsule of a pharmaceutical composition according to another embodiment of the present invention is a method for preparing a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin. ,

A first step of filling a capsule with the adenine or a pharmaceutically acceptable salt thereof, and a second step of filling the capsule with the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin after the first step. .

A method for preparing a nucleated tablet of a pharmaceutical composition according to another embodiment of the present invention is a method for preparing a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin,

The adenine or its pharmaceutically acceptable salt (nucleus, core) and the carnitine or its pharmaceutically acceptable salt and cyanocobalamin (outer layer, shell) are added to a nucleated tablet tablet press and tableting.

In one embodiment of the present invention, the method of manufacturing the double-layer tablet, the layer-separated capsule or the nucleated tablet includes the adenine or a pharmaceutically acceptable salt thereof, the carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin are granulated. Can form a sieve or a mixture, but is not limited thereto

In one embodiment of the present invention, the two-layer tablet, layer-separated capsule or nucleated tablet manufacturing method may be prepared by additionally including a blocking agent, and another physiologically active substance or a pharmaceutically acceptable additive defined in the additional active ingredient It may be manufactured by additionally including, but is not limited thereto.

In another embodiment of the present invention, the method of preparing the layer-separated capsule further comprises preparing a tablet of the adenine or a pharmaceutically acceptable salt thereof, the carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin as a tablet. It can, but is not limited thereto.

[Method and use of pharmaceutical composition]

In an embodiment of the present invention, the pharmaceutical composition may be used for the treatment or prevention of liver diseases, such as cirrhosis of the liver, alcoholic cirrhosis, fatty liver, addictive liver disease, acute and chronic viral hepatitis.

The therapeutic or prophylactic use of the pharmaceutical composition of the present invention is not limited to the above diseases, and may include all of the therapeutic or prophylactic use of each or a mixture of the physiologically active substances of the present invention known before the present application.

The pharmaceutical composition may be used for primary or secondary carnitine deficiency, myocardial metabolic disorders due to ischemic heart disease (angina pectoris, acute myocardial infarction or chronic heart failure), intermittent claudication, chronic obstructive pulmonary disease, Alzheimer's, mild depression, hypercholesterolemia, glaze Hyperactivity in Fragile X Syndrome, chronic fatigue syndrome, arrhythmia, liver dysfunction, alcoholic fatty liver, nonalcoholic fatty liver, chronic fatigue, hypertriglyceridemia, diabetes, Down's syndrome, muscular dystrophy, sperm motility disorder, or AIDS It provides use for the treatment or prevention of AZT toxicity, which is a therapeutic agent.

The concentration of other components, including adenine or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is as described above, and the total mass of the pharmaceutical composition may be 100 mg to 1,800 mg, 150 mg to 1,500 mg, or 200 mg to 1,200 mg. have.

In an embodiment of the present invention, adenine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be contained in an amount of 0.1 mg to 20 mg or 1 mg to 10 mg.

The dosage and timing of administration of the pharmaceutical composition may vary depending on the type of disease, the severity and course of the disease, the patient's health and response to treatment, and the judgment of the treating doctor. Not limited. For example, one or three products containing the pharmaceutical composition may be administered 1 to 3 times a day.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only to illustrate a pharmaceutical composition and a manufacturing method capable of securing the stability of adenine when preparing a pharmaceutical composition containing adenine, and the scope of the present invention is not limited thereto.

Example 1: Preparation of tablets containing adenine granules

Example 1.1

With the components and contents shown in Table 1 below, tablets were prepared according to the following method.

Preparation of the first ingredient

The first component components of Table 1 are uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20). The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Second ingredient manufacturing

The second component of Table 1 was uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component granule and the second component mixture in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseong acid group, KT10SS) to a hardness of 10 to 20 kP. Tablets were prepared.

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Examples 1.2 to 1.6

Tablets were prepared in the same manner as in the preparation method of Example 1.1 using the ingredients and contents shown in Table 1 below.

Example 1.7

Tablets were prepared in the same manner as in the preparation method of Example 1.1, except that a fluidized bed granulator was used to prepare the first ingredient with the ingredients and contents shown in Table 1 below.

Preparation of the first ingredient

Adenine hydrochloride and microcrystalline cellulose were put in a fluidized bed granulator (top spray method, Glat, Midi-Glatt), flowed at an inlet temperature of 70° C., and preheated to a product temperature of 35 to 38° C. Gelatin was dissolved in purified water to form a binding solution, and a pump speed of 5 to 8 rpm and an atomization pressure of 0.6 bar were used to appropriately control the amount of the binding solution to be sprayed to maintain a product temperature of 30 to 32°C. After spraying was completed, the moisture of the granules was measured for 10 minutes at 105°C using a halogen moisture analyzer (Metler Toledo, HB43-S) and dried until the loss on drying became 0.5 to 1.5%. The dried granules were pulverized at 1000 rpm with a cone mill equipped with a 1.2 mm sieve (Woosung, CR3-160) to prepare granules having an average particle diameter of 100 to 850 μm.

Example 1.8

Tablets were prepared in the same manner as in Example 1.7, except that pregelatinized starch instead of microcrystalline cellulose and hydroxypropyl cellulose instead of gelatin were used in the ingredients and contents shown in Table 1 below.

Example 1.9

Tablets were prepared in the same manner as in Example 1.7, except that maltodextrin instead of microcrystalline cellulose and hypromellose instead of gelatin were used in the ingredients and contents shown in Table 1 below.

Example 1.10

Tablets were prepared in the same manner as in Example 1.1, except that a high-shear granulator was used to prepare the first component with the ingredients and contents shown in Table 1 below.

Preparation of the first ingredient

Add adenine hydrochloride and corn starch to a high shear granulator (Bosch, Mycromix 2.5L) and mix for 10 minutes at an impeller speed of 150 rpm. Polyvinyl alcohol was dissolved in purified water to form a binder, added to the mixture for 2 minutes at an impeller speed of 150 rpm and a chopper speed of 2000 rpm, and then kneaded for 3 minutes at the same speed. After passing the resulting granules through a 10-mesh sieve, dry them at 60°C using a fluid bed dryer (Retsch, TG200), and measure the moisture of the dried products at 105°C using a halogen moisture analyzer (Metler Toledo, HB43-S). It was measured for minutes and dried until the loss on drying became 0.5 to 1.5%. The dried granules were pulverized at 1000 rpm using a cone mill equipped with a 1.2 mm sieve (Woosung, CR3-160) to prepare granules having an average particle diameter of 100 to 850 μm.

Example 1.11

Tablets were prepared in the same manner as in Example 1.10, except that microcrystalline cellulose instead of corn starch and polyvinyl acetate instead of polyvinyl alcohol were used in the ingredients and contents shown in Table 1 below.

The components and contents of the tablets prepared in Examples 1.1 to 1.11 are shown in Table 1 below.

Ingredients Content(mg) Example 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.11



My
One
castle
minute Adenine hydrochloride 2.50 2.50 5.00 5.00 5.00 5.00 2.50 2.50 5.00 5.00 5.00 Maltodextrin 70.00 - - - 70.00 - - - 70.00 - - Corn starch - 70.00 - - - 70.00 - - - 70.00 - Microcrystalline cellulose - - 70.00 - - - 70.00 - - - 70.00 Pregelatinized starch - - - 70.00 - - - 70.00 - - - Croscarmellose Sodium - - - - 20.00 - - - - - - Sodium starch glycolate - - - - - 20.00 - - - - - gelatin - - - - - - 20.00 - - - - Hydroxypropyl
cellulose - - - - - - - 20.00 - - - Hypromellose - - - - - - - - 20.00 - - Polyvinyl alcohol - - - - - - - - - 20.00 - Polyvinyl acetate - - - - - - - - - - 20.00



My
2
castle
minute Cyanocobalamin 0.125 0.125 - - - - 0.125 0.125 - - - Cyanocobalamin
Diploid - - 25.00 25.00 25.00 25.00 - - 25.00 25.00 25.00 DL-Carnitine
Orotate 150.00 150.00 - - - - 150.00 150.00 - - - L-carnitine
Orotate - - 150.00 - - - - - 150.00 - - L-carnitine
Napadicylate - - - 144.34 144.34 144.34 - - - 144.34 144.34 D-sorbitol 118.175 118.175 117.800 116.460 116.460 116.460 118.175 118.175 117.800 116.460 116.460 Lactose 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 Colloidal
Silicon dioxide 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Magnesium stearate 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 nose
Ting Opadry
88A640014 16.00 16.00 17.00 17.00 18.00 18.00 17.00 17.00 18.00 18.00 18.00 sum 416.00 416.00 444.00 437.00 458.00 458.00 437.00 437.00 465.00 458.00 458.00

Example 2: Preparation of tablets containing carnitine and cyanocobalamin granules

Example 2.1

With the ingredients and contents shown in Table 2 below, tablets were prepared according to the following method.

Preparation of the first ingredient

The first component of Table 2 was uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture.

Second ingredient manufacturing

The second component of Table 2 is uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20). The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component mixture and the second component granules in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseong acid group, KT10SS) to a hardness of 10 to 20 kP. Tablets were prepared.

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Examples 2.2 to 2.6

With the ingredients and contents shown in Table 2 below, tablets were prepared in the same manner as in Example 2.1.

Example 2.7

Tablets were prepared in the same manner as in Example 2.1, except that a fluidized bed granulator was used to prepare the second component with the ingredients and contents shown in Table 2 below.

Second ingredient manufacturing

Put cyanocobalamin, DL-carnitine orotate, and microcrystalline cellulose into a fluidized bed granulator (top spray method, glat, Midi-Glatt) and flow at an inlet temperature of 70℃, and the product temperature is 35 It was preheated to a to 38 ℃. Gelatin was dissolved in purified water to form a binding solution, and a pump speed of 5 to 8 rpm and an atomization pressure of 0.6 bar were used to appropriately control the amount of the binding solution to be sprayed to maintain a product temperature of 30 to 32°C. After spraying was completed, the moisture of the granules was measured for 10 minutes at 105°C using a halogen moisture analyzer (Metler Toledo, HB43-S) and dried until the loss on drying became 0.5 to 1.5%. The dried granules were pulverized at 1000 rpm with a cone mill equipped with a 1.2 mm sieve (Woosung, CR3-160) to prepare granules having an average particle diameter of 100 to 850 μm.

Example 2.8

Tablets were prepared in the same manner as in Example 2.7, except that pregelatinized starch instead of microcrystalline cellulose and hydroxypropyl cellulose instead of gelatin were used in the ingredients and contents shown in Table 2 below.

Example 2.9

Tablets were prepared in the same manner as in Example 2.7, except that maltodextrin instead of microcrystalline cellulose and hypromellose instead of gelatin were used in the ingredients and contents shown in Table 2 below.

Example 2.10

Tablets were prepared in the same manner as in the preparation method of Example 2.1, except that a high shear granulator was used as the second component with the ingredients and contents shown in Table 2 below.

Second ingredient manufacturing

Cyanocobalamin vesicle, L-carnitine napadisylate, and corn starch are put in a high shear granulator (Bosch, Mycromix 2.5L) and mixed for 10 minutes at an impeller speed of 150 rpm. Polyvinyl alcohol was dissolved in purified water to form a binder, added to the mixture for 2 minutes at an impeller speed of 150 rpm and a chopper speed of 2000 rpm, and then kneaded for 3 minutes at the same speed. After passing the resulting granules through a 10-mesh sieve, dry them at 60°C using a fluid bed dryer (Retsch, TG200), and measure the moisture of the dried products at 105°C using a halogen moisture analyzer (Metler Toledo, HB43-S). It was measured for minutes and dried until the loss on drying became 0.5 to 1.5%. The dried granules were pulverized at 1000 rpm using a cone mill equipped with a 1.2 mm sieve (Woosung, CR3-160) to prepare granules having an average particle diameter of 100 to 850 μm.

Example 2.11

Tablets were prepared in the same manner as in Example 2.10, except that microcrystalline cellulose instead of corn starch and polyvinyl acetate instead of polyvinyl alcohol were used in the ingredients and contents shown in Table 2 below.

The components and contents of the tablets prepared in Examples 2.1 to 2.11 are shown in Table 2 below.

Ingredients Content(mg) Example 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 My
One
castle
minute Adenine hydrochloride 2.50 2.50 5.00 5.00 5.00 5.00 2.50 2.50 5.00 5.00 5.00 D-sorbitol 70.00 70.00 69.625 68.285 68.285 68.285 70.00 70.00 69.625 68.285 68.285 My
2
castle
minute Cyanocobalamin 0.125 0.125 - - - - 0.125 0.125 - - - Cyanocobalamin
Diploid - - 25.00 25.00 25.00 25.00 - - 25.00 25.00 25.00 DL-Carnitine
Orotate 150.00 150.00 - - - - 150.00 150.00 - - - L-carnitine
Orotate - - 150.00 - - - - - 150.00 - - L-carnitine
Napadicylate - - - 144.34 144.34 144.34 - - - 144.34 144.34 Maltodextrin 158.175 - - - 158.175 - - - 158.175 - - Corn starch - 158.175 - - 158.175 - - - 158.175 - Microcrystalline cellulose - - 158.175 - - - 158.175 - - - 158.175 Pregelatinized starch - - - 158.175 - - - 158.175 - - - Croscarmellose Sodium - - - - 20.00 - - - - - - Starch glycolic acid
salt - - - - - 20.00 - - - - - gelatin - - - - - - 20.00 - - - - Hydroxypropyl
cellulose - - - - - - - 20.00 - - - Hypromellose - - - - - - - - 20.00 - - Polyvinyl alcohol - - - - - - - - 20.00 Polyvinyl
acetate - - - - - - - - - - 20.00 Colloidal
Silicon dioxide 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Stearic acid
magnesium 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 nose
Ting Opadry 88A640014 16.00 16.00 17.00 17.00 18.00 18.00 17.00 17.00 18.00 18.00 18.00 sum 416.00 416.00 444.00 437.00 458.00 458.00 437.00 437.00 465.00 458.00 458.00

Example 3: Preparation of tablets containing adenine granules and carnitine and cyanocobalamin granules

Example 3.1

With the components and contents shown in Table 3 below, tablets were prepared according to the following method.

Preparation of the first ingredient

The first component of Table 3 is uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20).

The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Second ingredient manufacturing

The second component of Table 3 is uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20). The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component granules and the second component granules in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseong acid group, KT10SS) with a hardness of 10 to 20 kP Tablets were prepared with

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Example 3.2

With the ingredients and contents shown in Table 3 below, tablets were prepared in the same manner as in Example 3.1.

The components and contents of the tablets prepared in Examples 3.1 to 3.2 are shown in Table 3 below.

Ingredients Content(mg) Example 3.1 3.2
First ingredient Adenine hydrochloride 2.50 5.00 Maltodextrin 70.00 - Corn starch - 70.00




Second ingredient Cyanocobalamin 0.125 - Cyanocobalamin glycoside - 25.000 DL-carnitine orotate 150.00 - L-carnitinenapadicylate - 144.340 Maltodextrin 78.175 - Corn starch - 76.46 Microcrystalline cellulose - 80.00 Pregelatinized starch 80.00 - Colloidal silicon dioxide 8.00 8.00 Magnesium stearate 11.20 11.20 coating Opadry 88A640014 16.00 17.00 sum 416.000 437.000

Comparative Example 1. Preparation of tablets containing adenine, carnitine and cyanocobalamin mixture

Comparative Example 1.1.

With the components and contents shown in Table 4 below, tablets were prepared according to the following method.

The components of Table 4 were uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture. The mixture was prepared in a tablet with a hardness of 10 to 20 kP using a tablet press (Geumseong acid group, KT10SS). Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Ingredients Content(mg) Comparative example 1.1


ingredient Adenine hydrochloride 2.50 Cyanocobalamin 0.125 DL-carnitine orotate 150.00 D-sorbitol 118.175 Lactose 40.00 Colloidal silicon dioxide 8.00 Magnesium stearate 11.20 coating Opadry 88A640014 13.00 sum 343.00

Comparative Example 2. Preparation of a tablet comprising adenine and carnitine mixed/granular part or adenine and cyanocobalamin mixed/granular part

Comparative Example 2.1

With the ingredients and contents shown in Table 5 below, tablets were prepared according to the following method.

Preparation of the first ingredient

The first component of Table 5 was uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture.

Second ingredient manufacturing

The second component of Table 5 was uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20) to prepare a mixture.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component mixture and the second component mixture in a mixer (empty mixer, Innotek, LM-20) for 10 minutes is purified to a hardness of 10 to 20 kP using a tablet press (Geumseong acid group, KT10SS) Was prepared.

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Comparative Example 2.2

Comparative Example 2.1 and Using the same ingredients and contents, tablets were prepared in the same manner as in Example 1.1.

Comparative Example 2.3

In the ingredients and contents listed in Table 5 below Tablets were prepared in the same manner as in Example 2.1.

Comparative Example 2.4

With the ingredients and contents shown in Table 5 below, tablets were prepared in the same manner as in Comparative Example 2.1.

Comparative Example 2.5

With the same ingredients and contents as Comparative Example 2.4, tablets were prepared in the same manner as in Example 1.1.

Comparative Example 2.6

Tablets were prepared in the same manner as in Example 2.1 with the same ingredients and contents as Comparative Example 2.4.

Comparative Example 2.7

With the ingredients and contents shown in Table 5 below, tablets were prepared in the same manner as in Comparative Example 2.1.

Comparative Example 2.8

Tablets were prepared in the same manner as in Example 1.1, with the same ingredients and contents as Comparative Example 2.7.

Comparative Example 2.9

Tablets were prepared in the same manner as in Example 2.1 with the same ingredients and contents as Comparative Example 2.7.

The components and contents of the tablets prepared in Comparative Examples 2.1 to 2.9 are shown in Table 5 below.

Ingredients Content(mg) Comparative example 2.1 2.3 2.4 2.7


First ingredient Adenine hydrochloride 2.50 2.50 2.50 5.0 Cyanocobalamin 0.125 0.125 - - DL-Carnitine Orotate - - 150.00 - L-carnitinenapadicylate - - - 144.340 D-sorbitol 70.00 - 70.00 - Maltodextrin - 70.00 - - Corn starch - - 70.00


Second ingredient DL-carnitine orotate 150.00 150.00 - - Cyanocobalamin - 0.125 - Cyanocobalamin glycoside - - 25.00 D-sorbitol 118.175 118.175 118.175 116.460 Lactose 40.000 40.000 40.000 40.000 Colloidal silicon dioxide 8.00 8.00 8.00 8.00 Magnesium stearate 11.20 11.20 11.20 11.20 coating Opadry 88A640014 16.00 16.00 16.00 17.00 sum 416.000 416.000 416.000 437.000

Comparative Example 3. Preparation of tablets containing various types of blocking agents

Comparative Examples 3.1 to 3.5

With the ingredients and contents shown in Table 6 below, tablets were prepared in the same manner as in Example 1.1.

The components and contents of the tablets prepared in Comparative Examples 3.1 to 3.5 are shown in Table 6 below.

Ingredients Content(mg) Comparative example 3.1 3.2 3.3 3.4 3.5

First ingredient Adenine hydrochloride 2.50 2.50 2.50 2.50 2.50 Calcium hydrogen phosphate hydrate 70.00 - - - - Low-substituted hydroxypropyl cellulose - 70.00 - - - Calcium carboxymethylcellulose - - 70.00 - - Crospovidone - - - 70.00 - Mannitol - - - - 70.00


Second ingredient Cyanocobalamin 0.125 0.125 0.125 0.125 0.125 DL-carnitine orotate 150.00 150.00 150.00 150.00 150.00 D-sorbitol 118.175 118.175 118.175 118.175 118.175 Lactose 40.000 40.000 40.000 40.000 40.000 Colloidal silicon dioxide 8.00 8.00 8.00 8.00 8.00 Magnesium stearate 11.20 11.20 11.20 11.20 11.20 coating Opadry 88A640014 16.00 16.00 16.00 16.00 16.00 sum 416.000 416.000 416.000 416.000 416.000

Test Example 1

Stability test method

Test conditions: Ministry of Food and Drug Safety Notice No. 2014-59, Accelerated conditions for stability test standards for pharmaceuticals (temperature/humidity: 40±2℃/75±5%RH)

Sample packaging form: airtight container

Test period: manufacturing date, 1 month, 3 months and 6 months from the date of manufacture

Analysis method: liquid chromatography

Column: Inertsil ODS-3V 4.6ｘ250 mm, 5 μm

Detector: absorbance detector (270nm)

Mobile phase: Acetonitrile: Phosphoric acid aqueous solution buffer = 80: 20

Flow rate: 1.0 mL/min

As the stability test method, stability evaluation of adenine contained in the pharmaceutical compositions of Examples 1.1 to 3.2 and Comparative Examples 1.1 to 3.5 was performed. The adenine content was measured at the date of manufacture of the pharmaceutical composition and at 1 month, 3 months and 6 months from the date of manufacture, and the results are shown in Table 7.

division Adenine content (%) Early 1 month 3 months 6 months








Example 1.1 100.0 99.9 98.2 97.7 1.2 100.0 99.1 98.8 98.2 1.3 100.0 99.4 99.0 98.1 1.4 100.0 99.2 98.4 97.6 1.5 100.0 99.0 98.9 98.3 1.6 100.0 99.3 99.0 97.8 1.7 100.0 99.7 98.6 97.9 1.8 100.0 99.8 99.5 99.1 1.9 100.0 99.8 99.3 99.0 1.10 100.0 99.5 99.0 98.4 1.11 100.0 99.1 98.9 98.0 2.1 100.0 99.7 97.5 96.0 2.2 100.0 99.4 98.7 96.5 2.3 100.0 99.2 98.1 97.1 2.4 100.0 99.0 98.0 96.2 2.5 100.0 99.5 98.2 96.8 2.6 100.0 99.6 98.5 97.2 2.7 100.0 99.8 99.2 98.0 2.8 100.0 99.2 98.7 98.3 2.9 100.0 99.5 99.0 98.2 2.10 100.0 99.5 98.9 97.9 2.11 100.0 99.2 98.7 96.8 3.1 100.0 100.4 99.8 98.9 3.2 100.0 100.3 100.1 99.3




Comparative example 1.1 100.0 95.4 89.2 78.2 2.1 100.0 97.5 92.9 83.3 2.2 100.0 98.1 94.8 85.7 2.3 100.0 98.6 95.2 88.3 2.4 100.0 97.7 93.4 81.5 2.5 100.0 97.2 91.9 79.6 2.6 100.0 97.8 92.8 82.1 2.7 100.0 98.3 94.7 84.4 2.8 100.0 97.9 92.6 82.7 2.9 100.0 98.5 94.3 85.4 3.1 100.0 95.0 83.5 70.3 3.2 100.0 95.8 91.6 80.1 3.3 100.0 96.9 92.0 81.2 3.4 100.0 96.5 90.7 77.4 3.5 100.0 98.7 94.2 87.6

As shown in Table 7, in the pharmaceutical composition comprising adenine, cyanocobalamin and carnitine as active ingredients, adenine is included in the first component and cyanocobalamin and carnitine are included in the second component. Examples 1.1 to 3.2 including a blocking agent while being separated from cobalamin and carnitine were confirmed that the content of adenine was maintained at 95% or more in the results of a 6 month stability test. On the other hand, it was confirmed that the content of adenine was significantly reduced in Comparative Examples 1.1 to 2.11, where adenine was located in the same ingredient as at least one active ingredient selected from cyanocobalamin and carnitine.

On the other hand, Comparative Examples 3.1 to 3.5 prepared using low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, crospovidone or mannitol as a blocking agent showed a content of adenine of about 90% or less in the results of a 6-month stability test. Was confirmed to be inappropriate.

Example 4. Preparation of tablets containing adenine granules, carnitine granules, and cyanocobalamin mixed parts

Example 4.1

With the components and contents shown in Table 8 below, tablets were prepared according to the following method.

Preparation of the first ingredient

The first component components of Table 8 are uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20). The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Second ingredient manufacturing

As the second component of Table 8, a granule was prepared in the same manner as the method for preparing the first component.

Third ingredient manufacturing

The third component of Table 8 was uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component granule, the second component granule, and the third component mixture in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseongsan, KT10SS) Thus, tablets were prepared with a hardness of 10 to 20 kP.

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Example 4.2

With the ingredients and contents shown in Table 8 below, tablets were prepared in the same manner as in the preparation method of Example 4.1.

The components and contents of the tablets prepared in Examples 4.1 to 4.2 are shown in Table 8 below.

Ingredients Content(mg) Example 4.1 4.2
First ingredient Adenine hydrochloride 5.00 5.00 Maltodextrin 70.00 - Pregelatinized starch - 70.00

Second ingredient L-carnitine orotate 150.000 - L-carnitinenapadicylate - 144.340 Corn starch 157.800 - Microcrystalline cellulose - 156.460 Colloidal silicon dioxide 8.00 8.00 Stearin magnesium 11.20 11.20 Third ingredient Cyanocobalamin glycoside 25.00 25.00 Croscarmellose Sodium 20.00 20.00 coating Opadry 88A640014 18.00 18.00 sum 465.000 458.000

Test Example 2

In the same manner as in Test Example 1, stability evaluation of adenine contained in the pharmaceutical compositions of Examples 4.1 and 4.2 was performed. The adenine content was measured at the date of manufacture of the pharmaceutical composition and at 1, 3 and 6 months from the date of manufacture, and the results are shown in Table 9.

division Adenine content (%) Early 1 month 3 months 6 months Example 4.1 100.0 100.2 100.0 99.0 4.2 100.0 100.4 100.1 99.5

As shown in Table 9 above, Examples 4.1 to 4.2 containing a blocking agent while adenine, carnitine and cyanocobalamin were separately constituted in the first component, the second component, and the third component, respectively, the content of adenine in the results of the 6-month stability test. It was confirmed that 95% or more was maintained.

Example 5. Preparation of tablets containing various amounts of blocking agent

Examples 5.1 to 5.8

With the ingredients and contents shown in Table 10 below, tablets were prepared in the same manner as in the preparation method of Example 1.1.

The components and contents of the tablets prepared in Examples 5.1 to 5.8 are shown in Table 10 below.

Ingredients Content(mg) Example 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 My
One
castle
minute Adenine hydrochloride 2.50 2.50 2.50 2.50 2.50 2.50 2.50 2.50 Corn starch - - - - 0.75 15.00 250.00 500.00 Microcrystalline cellulose 0.75 15.00 250.00 500.00 - - - - My
2
castle
minute
Cyanocobalamin 0.125 0.125 0.125 0.125 0.125 0.125 0.125 0.125 DL-Carnitine
Orotate 150.00 150.00 150.00 150.00 150.00 150.00 150.00 150.00 D-sorbitol 118.175 118.175 118.175 118.175 118.175 118.175 118.175 118.175 Lactose 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 Colloidal silicon dioxide 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Magnesium stearate 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 nose
Ting Opadry 88A640014 13.00 14.00 23.00 33.00 13.00 14.00 23.00 33.00 sum 343.75 359.00 603.00 863.00 343.75 359.00 603.00 863.00

Examples 5.9 to 5.14

With the ingredients and contents shown in Table 11 below, tablets were prepared in the same manner as in the preparation method of Example 2.1.

The components and contents of the tablets prepared in Examples 5.9 to 5.14 are shown in Table 11 below.

Ingredients Content(mg) Example 5.9 5.10 5.11 5.12 5.13 5.14 First
ingredient Adenine hydrochloride 2.50 2.50 2.50 2.50 2.50 2.50 D-sorbitol 70.175 70.175 70.175 70.175 70.175 70.175 Second
ingredient Cyanocobalamin 0.125 0.125 0.125 0.125 0.125 0.125 DL-carnitine orotate 150.00 150.00 150.00 150.00 150.00 150.00 Maltodextrin - - - 300.00 600.00 900.00 Pregelatinized starch 300.00 600.00 900.00 - - - Colloidal silicon dioxide 8.00 8.00 8.00 8.00 8.00 8.00 Magnesium stearate 11.20 11.20 11.20 11.20 11.20 11.20 coating Opadry 88A640014 22.00 34.00 46.00 22.00 34.00 46.00 sum 564.000 876.000 1188.000 564.000 876.000 1188.000

Test Example 3

In the same manner as in Test Example 1, the stability of adenine was evaluated in a pharmaceutical composition containing various amounts of a blocking agent. In the stability test result, it was confirmed that the content of adenine was maintained at 95% or more. From Examples 5.1 and 5.5, it was confirmed that when the blocking agent was less than 0.8 parts by weight, the adenine content was less than 90%, and the adenine stability was significantly reduced.

Example 6. Preparation of tablets containing various combinations of blocking agents

Examples 6.1 to 6.3

Tablets were prepared in the same manner as in the preparation method of Example 1.1 using the ingredients and contents shown in Table 12 below.

Examples 6.4 to 6.5

With the ingredients and contents shown in Table 12 below, tablets were prepared in the same manner as in the preparation method of Example 2.1.

Examples 6.6 to 6.7

With the ingredients and contents shown in Table 12 below, tablets were prepared in the same manner as in Example 3.1.

The components and contents of the tablets prepared in Examples 6.1 to 6.7 are shown in Table 12 below.

Ingredients Content(mg) Example 6.1 6.2 6.3 6.4 6.5 6.6 6.7

First ingredient Adenine hydrochloride 2.50 2.50 2.50 2.50 2.50 2.50 2.50 D-sorbitol - - - 70.00 70.00 - - Maltodextrin 30.00 20.00 - - - - - Corn starch - 20.00 30.00 - - - 20.00 Microcrystalline cellulose 40.000 30.00 - - - 70.00 20.00 Pregelatinized starch - - 40.00 - - - 30.00




Second ingredient Cyanocobalamin 0.125 0.125 0.125 0.125 0.125 0.125 0.125 DL-Carnitine
Orotate 150.00 150.00 150.00 150.00 150.00 150.00 150.00 D-sorbitol 118.175 118.175 - - - - - Lactose 40.000 40.000 - - - - - Maltodextrin - - 158.175 80.000 50.000 - - Corn starch - - - - 50.000 80.000 50.000 Microcrystalline cellulose - - - 78.175 58.175 - 50.000 Pregelatinized starch - - - - - 78.175 58.175 Colloidal silicon dioxide 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Magnesium stearate 11.20 11.20 11.20 11.20 11.20 11.20 11.20 coating Opadry 88A640014 16.00 16.00 16.00 16.00 16.00 16.00 16.00 sum 416.00 416.00 416.00 416.00 416.00 416.00 416.00

Test Example 4

The stability of adenine was evaluated in a pharmaceutical composition containing various combinations of blocking agents in the same manner as in Test Example 1, and as a result, Examples 6.1 to 6.7 showed that the content of adenine was maintained at 95% or more in the results of the 6-month stability test. Confirmed.

Example 7. Preparation of capsules or tablets containing additional active ingredients

Based on the results of improving the adenine stability of Examples 1 to 6 and Comparative Examples 1 to 3, capsules or tablets additionally containing antitoxic soy extract, pyridoxine hydrochloride, riboflavin, and biphenyldimethyldicarboxylate were prepared.

Example 7.1

With the components and contents shown in Table 13 below, capsules were prepared according to the following method.

Preparation of the first ingredient

Adenine hydrochloride and anti-toxic soy sauce extract were uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes, and then uniformly mixed with the remaining components of the first component in Table 12 for an additional 10 minutes to prepare a mixture. .

Second ingredient manufacturing

The second component of Table 13 was uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20). The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Capsule manufacturing

The final product obtained by uniformly mixing the first component mixture and the second component granules in a mixer (empty mixer, Innotek, LM-20) for 10 minutes is filled in a hard capsule using a capsule filler (Geumseong acid group, KF). Capsules were prepared.

Examples 7.2 to 7.3

With the ingredients and contents shown in Table 13 below, a capsule was prepared in the same manner as in the manufacturing method of Example 7.1.

Example 7.4

With the components and contents shown in Table 13 below, tablets were prepared according to the following method.

Preparation of the first ingredient

Adenine hydrochloride and anti-toxic soy sauce extract were uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20), and then uniformly mixed with the remaining ingredients of the first component in Table 12 for an additional 10 minutes. The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Second ingredient manufacturing

The second component of Table 13 was uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20). The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component granules and the second component granules in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseong acid group, KT10SS) with a hardness of 10 to 20 kP Tablets were prepared with

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Examples 7.5 to 7.6

With the ingredients and contents shown in Table 13 below, tablets were prepared in the same manner as in the preparation method of Example 7.4.

Example 7.7

With the components and contents shown in Table 13 below, tablets were prepared according to the following method.

Preparation of the first ingredient

The first component components of Table 13 were uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20) to prepare a mixture.

Second ingredient manufacturing

Put cyanocobalamin vesicle, carnitine, anti-toxic soy sauce extract and corn starch in a fluidized bed granulator (top spray method, glat, Midi-Glatt) and flow at an inlet temperature of 70°C. Product temperature Was preheated to be 35 to 38 ℃. Gelatin was dissolved in purified water to form a binding solution, and a pump speed of 5 to 8 rpm and an atomization pressure of 0.6 bar were used to appropriately control the amount of the binding solution to be sprayed to maintain a product temperature of 30 to 32°C. After spraying was completed, the moisture of the granules was measured for 10 minutes at 105°C using a halogen moisture analyzer (Metler Toledo, HB43-S) and dried until the loss on drying became 0.5 to 1.5%. The dried granules were pulverized at 1000 rpm with a cone mill equipped with a 1.2 mm sieve (Woosung, CR3-160) to prepare granules having an average particle diameter of 100 to 850 μm.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component mixture and the second component granules in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseong acid group, KT10SS) to a hardness of 10 to 20 kP. Tablets were prepared.

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Example 7.8

With the components and contents shown in Table 13 below, tablets were prepared according to the following method.

Preparation of the first ingredient

Put adenine hydrochloride, riboflavin, biphenyldimethyldicarboxylate, and corn starch in a fluidized bed granulator (top spray method, Glatt, Midi-Glatt) and flow at an inlet temperature of 70°C. Was preheated to be 35 to 38°C. Hypromellose was dissolved in purified water to form a binder, and a pump speed of 5 to 8 rpm and an atomization pressure of 0.6 bar were used to properly control the amount of the binder to be sprayed to maintain a product temperature of 30 to 32°C. . After spraying was completed, the moisture of the granules was measured for 10 minutes at 105°C using a halogen moisture analyzer (Metler Toledo, HB43-S) and dried until the loss on drying became 0.5 to 1.5%. The dried granules were pulverized at 1000 rpm with a cone mill equipped with a 1.2 mm sieve (Woosung, CR3-160) to prepare granules having an average particle diameter of 100 to 850 μm.

Second ingredient manufacturing

The second component of Table 13 was uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component granule and the second component mixture in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseong acid group, KT10SS) to a hardness of 10 to 20 kP. Tablets were prepared.

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Example 7.9

With the components and contents shown in Table 13 below, tablets were prepared according to the following method.

Preparation of the first ingredient

The first component components of Table 13 are uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20). The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Second ingredient manufacturing

The second component of Table 13 was uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component granules and the second component granules in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseong acid group, KT10SS) with a hardness of 10 to 20 kP Tablets were prepared with

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Example 7.10

With the components and contents shown in Table 13 below, tablets were prepared according to the following method.

Preparation of the first ingredient

Adenine hydrochloride and anti-toxic soy sauce extract were uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20), and then uniformly mixed with the remaining components of the first component in Table 13 for an additional 10 minutes. The mixture was compressed using a roller compactor (Seoul Hi-Tech, RC80) at a roller speed of 1.5 to 2.5 rpm, a screw speed of 8 to 10 rpm, and a pressure of 8 to 12 MPa to prepare a compact. The compressed material was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm.

Second ingredient manufacturing

The second component of Table 13 was uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture.

Film coated tablet manufacturing

The final product obtained by uniformly mixing the first component granules and the second component granules in a mixer (empty mixer, Innotek, LM-20) for 10 minutes using a tablet press (Geumseong acid group, KT10SS) with a hardness of 10 to 20 kP Tablets were prepared with

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Example 7.11

Tablets were prepared in the same manner as in the preparation method of Example 7.10 with the ingredients and contents shown in Table 13 below.

The components and contents of the tablets prepared in Examples 7.1 to 7.11 are shown in Table 13 below.

Ingredients Content(mg) Example 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11



My
One
castle
minute Adenine hydrochloride 2.50 2.50 2.50 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Anti-toxic soy sauce extract 12.50 12.50 12.50 25.00 25.00 25.00 - - - 25.00 25.00 Pyridoxine hydrochloride 25.00 25.00 25.00 50.00 - 50.00 50.00 - - - - Riboflavin - - 0.50 1.00 1.00 1.00 1.00 1.00 1.00 - - Biphenyl dimethyl
Dicarboxylate - - 25.00 - - 50.00 50.00 50.00 50.00 50.00 - Maltodextrin 75.00 - - - - - - - - - Corn starch - 75.00 - - - 75.00 - 75.00 - 75.00 - Microcrystalline cellulose - - 75.00 - - - 75.00 - 75.00 - 75.00 Pregelatinized starch - - - 75.00 75.00 - - - - - - Sodium starch glycolate - - - - - 20.00 - - - - - Hypromellose - - - - - - - 20.00 - - -









My
2
castle
minute Cyanocobalamin 0.125 - - - - - - - - - - Cyanocobalamin
Diploid - 12.50 12.50 25.00 25.00 25.00 25.00 25.00 25.00 25.00 25.00 DL-Carnitine
Orotate 150.00 150.00 150.00 - - - - - - - - L-carnitine
Orotate - - - 150.00 150.00 - 150.00 - 150.00 - - L-carnitine
Napadicylate - - - - - 144.34 - 144.34 - 144.34 144.34 Anti-toxic soy sauce extract - - - - - - 25.00 25.00 25.00 - - Pyridoxine hydrochloride - - - - 50.00 - - 50.00 50.00 50.00 50.00 Riboflavin 0.50 0.50 - - - - - - - 1.00 1.00 Biphenyl dimethyl
Dicarboxylate 25.00 25.00 - 50.00 50.00 - - - - - 50.00 Maltodextrin 140.175 - 70.000 - - - - - - - - Corn starch - - - 139.80 139.80 140.46 139.80 - 139.80 140.46 - Microcrystalline cellulose - 139.80 - - - - - 140.46 - - 140.46 Pregelatinized starch - - 69.80 - - - - - - - - Croscarmellose Sodium - - - 20.00 20.00 - - - 20.00 20.00 - Sodium starch glycolate - - - - - - - - - - 20.00 gelatin - - - - - - 20.00 - - - - Colloidal
Silicon dioxide 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Magnesium stearate 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 11.20 nose
Ting Opadry 88A640014 - - - 22.00 22.00 22.00 22.00 22.00 22.00 22.00 22.00 sum 450.0 462.0 462.0 582.0 582.0 577.0 582.0 577.0 582.0 577.0 577.0

Comparative Example 4. Preparation of tablets containing additional active ingredients (Example 1 of Korean Patent Registration No. 0294329)

Comparative Example 4.1

With the components and contents shown in Table 14 below, tablets were prepared according to the following method.

The components of Table 14 were uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20) to prepare a mixture. The mixture was prepared in a tablet with a hardness of 10 to 20 kP using a tablet press (Geumseong acid group, KT10SS). Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Ingredients Content(mg) Comparative example 4.1


ingredient Adenine hydrochloride 2.50 Anti-toxic soy sauce extract 12.50 Pyridoxine hydrochloride 25.00 Riboflavin 0.50 Biphenyldimethyldicarboxylate 25.00 Cyanocobalamin 0.125 DL-carnitine orotate 150.00 D-sorbitol 165.00 Colloidal silicon dioxide 43.00 Magnesium stearate 17.00 coating Opadry 88A640014 11.20 sum 451.825

Test Example 5

The stability of adenine was evaluated in a pharmaceutical composition containing an additional active ingredient in the same manner as in Test Example 1, and the results are shown in Table 15.

division Adenine content (%) Early 1 month 3 months 6 months



Example 7.1 100.0 99.6 98.6 97.8 7.2 100.0 99.4 99.0 98.1 7.3 100.0 99.6 98.8 98.0 7.4 100.0 99.4 98.8 98.1 7.5 100.0 99.5 99.0 98.8 7.6 100.0 99.6 99.1 97.8 7.7 100.0 99.1 98.1 96.1 7.8 100.0 99.3 98.2 97.3 7.9 100.0 98.7 97.8 96.7 7.10 100.0 99.5 98.9 98.0 7.11 100.0 99.8 99.7 99.1 Comparative example 4.1 100.0 93.3 87.6 73.4

As shown in Table 15 above, Examples 7.1 to 7.11 containing antitoxic soy extract, pyridoxine hydrochloride, riboflavin and biphenyldimethyldicarboxylate as additional active ingredients also contained adenine content of 95% or more in the 6-month stability test result. It was confirmed to be maintained. In addition, Examples 7.1 to 7.6 and Examples 7.10 to 7.11 in which adenine and anti-toxic soy extract were first mixed were confirmed that the stability of adenine was more excellent than in Examples 7.7 to 7.9 in which adenine and anti-toxic soy extract were not first mixed. It was found that antitoxic soy extract affects the stability of adenine.

On the other hand, in Comparative Example 4.1, which had the same composition as Example 1 of Korean Patent No. 0294329, that is, adenine, as well as cyanocobalamin and carnitine, as well as the additional active ingredient and the same ingredient, the stability of adenine was less than 75%. It was confirmed that it was significantly reduced. Considering the result that the stability of adenine of Comparative Example 4.1 is lower than that of Comparative Example 1.1, which does not contain an additional active ingredient, it can be seen that the additional active ingredient affects the stability of adenine. Although it is necessary to study, it can be seen through the present invention that in a pharmaceutical composition containing adenine, carnitine and cyanocobalamin, at least adenine must be formed separately from carnitine and cyanocobalamin so that the content of adenine does not decrease for a long time.

Example 8. Preparation of two-layer tablet

Example 8.1

With the components and contents shown in Table 16 below, a two-layer tablet was prepared according to the following method.

Preparation of the first ingredient

The first component components listed in Table 16 were uniformly mixed in a mixer (empty mixer, Innotek, LM-20) for 10 minutes to prepare a mixture.

Second ingredient manufacturing

The second component components listed in Table 16 were uniformly mixed for 10 minutes in a mixer (empty mixer, Innotek, LM-20) to prepare a mixture.

Film coated two-layer tablet manufacturing

The first component mixture and the second component mixture were prepared in a two-layer tablet with a hardness of 10 to 20 kP using a double-layer tablet press (Elizabeth Palette, EP200L AWC).

Put the tablets into a tablet coating machine (Geumseong Sangi, KC50F) and disperse Opadry 88A640014 (trade name of Colorcon) in purified water. Fan speed of 18 rpm, pump speed of 3 to 5 rpm, spraying pressure of 3 bar Film-coated tablets were prepared by spraying at a distance of 20cm, a supply air temperature of 60±5℃, and a product temperature of 40±2℃.

Ingredients Content(mg) Example 8.1 First ingredient Adenine hydrochloride 5.00 Corn starch 70.00

Second ingredient Cyanocobalamin glycoside 25.000 L-carnitinenapadicylate 144.340 Corn starch 76.46 Microcrystalline cellulose 80.00 Colloidal silicon dioxide 8.00 Magnesium stearate 11.20 coating Opadry 88A640014 17.00 sum 437.000

Test Example 6

In the same manner as in Test Example 1, the stability of adenine was evaluated in a pharmaceutical composition composed of two-layer tablets, and the results are shown in Table 17.

division Adenine content (%) Early 1 month 3 months 6 months Example 8.1 100.0 101.2 100.0 100.0

As shown in Table 17, in Example 8, which is a two-layer tablet, the physical contact between the first component including adenine and the second component including carnitine and cyanocobalamin is minimized, so that the change in the content of adenine in the results of the 6-month stability test It was confirmed that there were few. From the above results, it can be sufficiently seen that there will be no change in the adenine content even in the layer-separated capsule, the nucleated tablet, and the multi-layer tablet.

Claims (12)

As a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin, and a blocking agent,
Granules or mixtures containing the adenine or a pharmaceutically acceptable salt thereof and a blocking agent, and the separately formed carnitine or a pharmaceutically acceptable salt thereof, and a granule or mixture containing cyanocobalamin and a blocking agent A pharmaceutical composition having one or more sieves.
The method of claim 1
The pharmaceutical composition, characterized in that the carnitine is D,L-carnitine or L-carnitine.
The method of claim 1,
The cyanocobalamin is a pharmaceutical composition, characterized in that in the form of a glycoside.
The method of claim 1,
The blocking agent is one or more selected from maltodextrin, corn starch, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, starch glycolate sodium, gelatin, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol and polyvinyl acetate A pharmaceutical composition characterized in that.
The method of claim 1,
The pharmaceutical composition, characterized in that the blocking agent is 0.8 to 500 parts by weight based on 1 part by weight of the adenine.
delete delete The method of claim 1,
A pharmaceutical composition further comprising at least one active ingredient selected from antitoxic soy extract, biphenyldimethyldicarboxylate, pyridoxine or a pharmaceutically acceptable salt thereof, and riboflavin or a pharmaceutically acceptable salt thereof.
As a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin,
The adenine or a pharmaceutically acceptable salt thereof,
A pharmaceutical composition, characterized in that the carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin are spatially separated so that physical contact is suppressed by a blocking structure.
The method of claim 9,
The barrier structure is a pharmaceutical composition, characterized in that a layer-separated capsule, a nucleated tablet, a two-layer tablet or a multi-layer tablet.
The method of claim 9,
The pharmaceutical composition, characterized in that the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin are contained in the same zone or in a zone separated from each other.
delete