CN111132665A

CN111132665A - Pharmaceutical composition and preparation method thereof

Info

Publication number: CN111132665A
Application number: CN201880061300.7A
Authority: CN
Inventors: 李丙勋; 韩恩志; 权翅鞍; 朴丹必; 尹索罗; 徐恩主; 南东延; 吴东骏; 文炳官; 朴永濬
Original assignee: Setron Pharmaceutical Co Ltd
Current assignee: Setron Pharmaceutical Co Ltd
Priority date: 2017-08-10
Filing date: 2018-08-09
Publication date: 2020-05-08
Anticipated expiration: 2038-08-09
Also published as: PH12020500278A1; KR20190017690A; WO2019031898A2; WO2019031898A3; KR102193989B1; CN111132665B

Abstract

The pharmaceutical composition according to the present invention comprises adenine, carnitine and cyanocobalamin, and the present invention provides a pharmaceutical composition capable of ensuring 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 can ensure the stability of adenine so that the content of adenine is maintained at 95% or more after 6 months in a stability test under accelerated conditions (40 + -2 ℃/75 + -5% RH).

Description

Pharmaceutical composition and preparation method thereof

Technical Field

The invention relates to a pharmaceutical composition and a preparation method thereof; and, more particularly, to a pharmaceutical composition comprising adenine, carnitine and cyanocobalamin in which the stability of adenine is ensured, and a method for preparing the same.

Background

Adenine is one of purine bases constituting nucleic acids, and serves as a precursor of ATP and ADP as energy sources in vivo. Adenine is also used in the formation of cAMP, which is involved in cell signaling in vivo. Adenine acts as a neurotransmitter inhibitor in the brain and is involved in the induction of sleep and inhibition of arousal (Journal of Alzheimer' S Disease 20(2010) S3-S15S 3DOI 10.3233/JAD-2010-1379). In the liver, adenine is involved in vasoconstriction, thereby increasing the breakdown of glycogen to glucose and inhibiting the development of fatty liver (Nature 204,1196-1197(19 Decumber 1964); DOI10.1038/2041196a 0).

Adenine hydrochloride (formula: C) is commonly used₅H₅N₅HCl, relative molecular weight: 171.59) is a white crystalline powder and is readily soluble in water. Representative drugs of adenine-containing pharmaceutical compositions are Godex capsules containing adenine hydrochloride, riboflavin, pyridoxine hydrochloride, antitoxic liver extract, carnitine orotate, dimethyl bibenzoate, and cyanocobalamin as main ingredients.

Korean patent No.0294329 discloses a pharmaceutical composition for the treatment and prevention of liver diseases comprising the above-mentioned adenine hydrochloride. However, when the Godex pharmaceutical composition is prepared by the method according to the above patent, a problem of a significant decrease in the amount of adenine occurs.

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

Disclosure of Invention

Technical problem

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

Technical scheme

The present inventors have studied a method for improving the stability of adenine and determined that carnitine and cyanocobalamin significantly reduce the stability of adenine. Therefore, based on the results of various studies on a method for stabilizing adenine, it can be found that the preparation of a pharmaceutical composition comprising adenine, carnitine and cyanocobalamin using a blocking agent or a blocking structure can remarkably ensure the stability of adenine.

In an embodiment of the invention, a pharmaceutical composition comprises adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin and a blocking agent, wherein said blocking agent inhibits the physical interaction of said adenine or a pharmaceutically acceptable salt thereof with said carnitine or a pharmaceutically acceptable salt thereof and said cyanocobalamin.

In an embodiment of the present invention, carnitine includes D, L-carnitine or L-carnitine.

In an embodiment of the invention, cyanocobalamin is included in the form of a dispersion.

In an embodiment of the present invention, the blocking agent includes at least one selected from the group consisting of maltodextrin, corn starch, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and polyvinyl acetate.

In an embodiment of the present invention, the amount of the blocking agent may be 0.8 parts by weight to 500 parts by weight with respect to 1 part by weight of adenine.

In the pharmaceutical composition according to an embodiment of the present invention, the adenine or a pharmaceutically acceptable salt thereof and the blocking agent may form a particulate phase.

In the pharmaceutical composition according to an embodiment of the present invention, at least one active ingredient selected from the group consisting of the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin and the blocking agent may form a granular phase.

In an embodiment of the invention, a pharmaceutical composition comprises: a pharmaceutical composition comprising adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin, wherein said adenine or a pharmaceutically acceptable salt thereof is spatially separated from said carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin by a blocking structure, thereby inhibiting physical interaction therebetween.

In embodiments of the invention, the blocking structure may comprise a layered capsule, a press-coated tablet, a bilayer tablet or a multilayer tablet.

In an embodiment of the present invention, the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin may be contained in the same region or different regions.

In an embodiment of the present invention, the pharmaceutical composition may further comprise: at least one active ingredient selected from the group consisting of an anti-toxic liver extract, dimethyl bibenzoate, pyridoxine or a pharmaceutically acceptable salt thereof, and riboflavin or a pharmaceutically acceptable salt thereof.

In an embodiment of the present invention, the pharmaceutical composition is capable of maintaining the amount of adenine at 95% or more after storage in a closed container for 6 months under accelerated conditions of 40 ℃ and 75% relative humidity.

Advantageous effects

According to the present invention, the pharmaceutical composition can ensure excellent adenine stability using a blocking agent or a blocking structure.

Detailed Description

[ pharmaceutical composition ]

According to an embodiment of the present invention, a pharmaceutical composition comprises adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin and a blocking agent, wherein said blocking agent inhibits the physical interaction of said adenine or a pharmaceutically acceptable salt thereof with said carnitine or a pharmaceutically acceptable salt thereof and said cyanocobalamin.

In an embodiment of the present invention, adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, or cyanocobalamin may comprise a pharmaceutically acceptable hydrate, solvate, isomer, polymorph, ester or prodrug thereof.

In an embodiment of the invention, a solvate refers to a complex or aggregate formed by at least one molecule of solute (i.e. a compound or a pharmaceutically acceptable salt according to the invention) and at least one molecule of solvent. Solvates are typically crystalline solids with a fixed solute to solvent molar ratio. Representative solvents include water, ethanol, isopropanol, and the like.

In embodiments of the invention, isomers refer to compounds having the same molecular formula but with different linkages or different spatial arrangements of the constituent atoms in the molecule.

In an embodiment of the present invention, polymorph refers to a material that crystallizes into at least one lattice arrangement.

In an embodiment of the present invention, an ester refers to an organic group in which the hydrogen molecule position of the acid is substituted.

In an embodiment of the present invention, a prodrug refers to a compound that becomes the target compound in vivo after administration.

In an 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, wherein the amount of adenine remains 95% or higher after 6 months in a stability test under accelerated conditions (40 ± 2 ℃/75 ± 5% RH).

Adenine or a pharmaceutically acceptable salt thereof

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

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

Carnitine or pharmaceutically acceptable salt thereof

In an embodiment of the present invention, the pharmaceutically acceptable salt of carnitine may include orotate, napadisylate, tartrate, fumarate, stannate, succinate, hydrochloride, aspartate, citrate, phosphate, lactate, maleate, oxalate, pamoate, sulfate, mucate, 2-amino-ethanesulfonate, methanesulfonate, trichloroacetate or trifluoroacetate. More specifically, the pharmaceutically acceptable salt of carnitine may be orotate, napadisylate, tartrate or fumarate, but is not limited thereto.

Examples of the pharmaceutically acceptable salt of D, L-carnitine may include D, L-carnitine orotate, D, L-carnitine napadisylate, D, L-carnitine tartrate, D, L-carnitine fumarate, D, L-carnitine stannate, D, L-carnitine succinate, D, L-carnitine hydrochloride, 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 mucate, D, L-carnitine 2-amino-ethane sulfonate, D, L-carnitine hydrochloride, D, L-carnitine maleate, D, L-carnitine oxalate, D, L-carnitine pamoate, D, L-carnitine sulfate, D, L-carnitine mucate, D, L-carnitine 2-amino, D, L-carnitine mesylate, D, L-carnitine trichloroacetate and D, L-carnitine trifluoroacetate, examples of which may be used alone or in combination.

Examples of the pharmaceutically acceptable salt of L-carnitine may include L-carnitine orotate, L-carnitine napadisylate, L-carnitine tartrate, L-carnitine fumarate, L-carnitine stannate, L-carnitine succinate, L-carnitine hydrochloride, L-carnitine aspartate, L-carnitine citrate, L-carnitine phosphate, L-carnitine lactate, L-carnitine maleate, L-carnitine oxalate, L-carnitine pamoate, L-carnitine sulfate, L-carnitine mucate, L-carnitine 2-aminoethane sulfonate, L-carnitine methanesulfonate, L-carnitine trichloroacetate and L-carnitine trifluoroacetate, the above salts may be used alone or in combination.

In an embodiment of the present invention, D, L-carnitine, a pharmaceutically acceptable salt of D, L-carnitine or a pharmaceutically acceptable salt of L-carnitine may include solvates, crystals, and the like thereof.

In an embodiment of the present invention, the amount of D, L-carnitine, a pharmaceutically acceptable salt of L-carnitine, or a mixture thereof may be comprised in an amount of 1 wt% to 80 wt%, or 10 wt% to 50 wt%, based on a total of 100 wt% of the pharmaceutical composition.

Cyanocobalamin

In an embodiment of the invention, cyanocobalamin comprises the form of a dispersion. When cyanocobalamin is used, it may contribute to the stability of the pharmaceutical composition.

In an embodiment of the invention, cyanocobalamin microdispersion means that cyanocobalamin is microdispersed in a suitable excipient. More specifically, cyanocobalamin double dispersion means that a small amount of cyanocobalamin is double-dispersed in at least one excipient selected from lactose, corn starch, mannitol, gelatin and maltodextrin by physical mixing or spray drying. Examples of the cyanocobalamin double dispersion may be cyanocobalamin double dispersion containing 1 wt% of cyanocobalamin and 99 wt% of maltodextrin on the basis of 100 wt% of the total.

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

Blocking agent

In an embodiment of the present invention, the blocking agent refers to a substance that inhibits physical interaction of adenine or a pharmaceutically acceptable salt thereof with carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin, so that the amount of adenine can be maintained at 95% or more after 6 months in a stability test under accelerated conditions (40 ± 2 ℃/75 ± 5% RH).

In the embodiment of the present invention, the blocking agent may include at least one selected from the group consisting of maltodextrin, corn starch, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and polyvinyl acetate, but is not limited thereto.

In an embodiment of the present invention, the blocking agent may be included in an amount of 0.5 wt% to 90 wt%, 1 wt% to 80 wt%, or 3 wt% to 70 wt%, based on 100 wt% of the total pharmaceutical composition. If the amount of the blocking agent is less than 0.5 wt%, the stability of adenine cannot be ensured.

In an embodiment of the present invention, the amount of the blocking agent is 0.8 to 500 parts by weight, 2 to 400 parts by weight, or 5 to 300 parts by weight, relative to 1 part by weight of adenine or a pharmaceutically acceptable salt thereof. Herein, the amount of the blocking agent does not exceed 90 wt% based on 100 wt% of the total pharmaceutical composition. If the amount of the blocking agent is less than 0.8 parts by weight, the stability of adenine is significantly reduced. On the other hand, if the amount of the blocking agent exceeds 500 parts by weight, the total mass of the resulting preparation is greatly increased, undesirably causing a problem of dysphagia in patients or the elderly who take the preparation.

In another embodiment of the present invention, a pharmaceutical composition comprises: a particulate phase comprising adenine or a pharmaceutically acceptable salt thereof and a blocking agent; or a particulate phase comprising at least one active ingredient selected from carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin and a blocking agent.

More specifically, the pharmaceutical composition may include a final product obtained by homogeneously blending a granule phase containing adenine or a pharmaceutically acceptable salt thereof and a blocking agent with a mixture phase containing at least one active ingredient selected from carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin.

Alternatively, the pharmaceutical composition may comprise the final product obtained by homogeneously blending a mixture phase comprising adenine or a pharmaceutically acceptable salt thereof with a particulate phase comprising carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin and a blocking agent.

Alternatively, the pharmaceutical composition may comprise a final product obtained by homogeneously blending a granular phase comprising adenine or a pharmaceutically acceptable salt thereof and a blocking agent with a granular phase comprising at least one active ingredient selected from carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin and a blocking agent.

Alternatively, the pharmaceutical composition may include a final product obtained by homogeneously blending a granular phase containing adenine or a pharmaceutically acceptable salt thereof and a blocking agent, a granular phase containing carnitine or a pharmaceutically acceptable salt thereof and a blocking agent, and a mixture phase containing cyanocobalamin.

Alternatively, the pharmaceutical composition may include a final product obtained by homogeneously blending a granular phase containing adenine or a pharmaceutically acceptable salt thereof and a blocking agent, a mixture phase containing carnitine or a pharmaceutically acceptable salt thereof, and a granular phase containing cyanocobalamin and a blocking agent, but is not limited thereto.

Alternatively, the pharmaceutical composition may include a final product obtained by homogeneously blending a mixture phase containing adenine or a pharmaceutically acceptable salt thereof, a granule phase containing carnitine or a pharmaceutically acceptable salt thereof and a blocking agent, and a granule phase containing cyanocobalamin and a blocking agent, but is not limited thereto.

When carnitine or a pharmaceutically acceptable salt thereof and a blocking agent are granulated together, the amount of the blocking agent may be 80 parts by weight or more with respect to 100 parts by weight of carnitine or a pharmaceutically acceptable salt thereof.

In an embodiment of the present invention, the above particulate phase is obtained by granulation to increase particle size, density and flowability, and may comprise a dry particulate phase or a wet particulate phase. The dry particulate phase is obtained by granulation using a pressing force in the absence of a solvent; whereas the wet granular phase is obtained by granulation using shear or cohesion in the presence of a solvent.

In the embodiment of the present invention, the average particle diameter of the particulate phase may be 100 μm to 850 μm, and particularly 200 μm to 710 μm, but is not limited thereto.

In embodiments of the invention, the final product may be formulated as tablets, capsules, granules, and the like.

In an embodiment of the present invention, the tablet may be a compressed tablet, a single layer tablet, a multi-layer tablet, a press-coated tablet, a sugar-coated tablet, a film-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a chewable tablet, an immediate release tablet, or the like. More specifically, the tablet may be a compressed tablet, a single layer tablet, a multilayer tablet or a press-coated tablet, but is not limited thereto.

The pharmaceutical composition of the present invention may further comprise a biologically active substance or pharmaceutically acceptable excipient as defined in the "additional active ingredient" below.

Blocking structure

A 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, wherein physical interaction of adenine or a pharmaceutically acceptable salt thereof with carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin is inhibited by blocking a structure.

In an embodiment of the present invention, the blocking structure refers to a structure in which adenine or a pharmaceutically acceptable salt thereof is spatially separated from carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin, thereby inhibiting physical interaction therebetween, thereby enabling the amount of adenine to be maintained at 95% or more after 6 months in a stability test under accelerated conditions (40 ± 2 ℃/75 ± 5% RH).

In the embodiment of the present invention, more specific examples of the blocking structure may be a layered capsule, a press-coated tablet, a bilayer tablet, a multilayer tablet, etc., but are not limited thereto.

In an embodiment of the present invention, carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin may be contained in the same region or different regions.

In an embodiment of the present invention, the blocking structure includes: a first layer portion comprising adenine or a pharmaceutically acceptable salt thereof; and, a second layer portion comprising carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin.

In an embodiment of the present invention, the blocking structure includes: a first layer portion comprising adenine or a pharmaceutically acceptable salt thereof; a second layer portion comprising carnitine or a pharmaceutically acceptable salt thereof; and, a third layer portion comprising cyanocobalamin.

The first layer portion to the third layer portion may further comprise a blocking agent, and may further comprise a biologically active substance or a pharmaceutically acceptable excipient as defined in "additional active ingredient" below.

In an embodiment of the present invention, adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin may be formed into respective granular phases or mixed phases, or carnitine or a pharmaceutically acceptable salt thereof may be mixed with cyanocobalamin to form granular phases or mixed phases, and they may be formulated into layered capsules, press-coated tablets, double-layered tablets, or multi-layered tablets.

Additional active ingredients

In an embodiment of the present invention, the pharmaceutical composition may further comprise a bioactive 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 (e.g., anti-toxic liver extracts, anti-toxic components of liver extracts), amino acid preparations, or mixtures thereof, which are generally used as supplements for treating liver diseases, as needed. There is no particular limitation on the vitamin or amino acid formulation.

In an embodiment of the present invention, an anti-toxic liver extract, dimethyl bibenzoate, vitamins or a mixture thereof may be further included as the bioactive substance.

In an embodiment of the invention, the anti-toxic liver extract is an extract of animal liver, such as a hydrothermal extract of bovine liver. The anti-toxic liver extract may comprise mainly amino acids (in an amount of 50 wt% to 100 wt% based on the total weight of the anti-toxic liver extract). When an anti-toxic liver extract is included as an additional active ingredient, blending adenine or a pharmaceutically acceptable salt thereof with the anti-toxic liver extract first more effectively maintains the stability of adenine.

In the embodiment of the present invention, since dimethyl bibenzoate is a poorly soluble drug, dimethyl bibenzoate having an improved dissolution rate can be used.

Further, dimethyl bibenzoate can be used in the form of a solvate, crystals, or the like.

In embodiments of the invention, the weight ratio of adenine to dimethyl bibenzoate may range from 1:0.01 to 1:50, 1:1 to 1:20, or 1:5 to 1: 15.

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

In embodiments of the invention, the weight ratio of adenine to vitamin may range from 1:0.01 to 1:50, 1:1 to 1:20, or 1:5 to 1: 15.

Pharmaceutically acceptable excipients

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

The pharmaceutically acceptable excipient in the pharmaceutical composition according to an embodiment of the present invention may include at least one selected from the group consisting of fillers, binders, disintegrants, lubricants, stabilizers, antioxidants, fragrances, polishing agents, colorants, pH adjusters, coating agents, sweeteners, adsorbents, solvents, taste-masking agents, and surfactants, but is not limited thereto.

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

[ Process for producing pharmaceutical composition ]

Blocking agent

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

forming a particulate phase comprising adenine or a pharmaceutically acceptable salt thereof and a blocking agent; alternatively, a particulate phase is formed comprising carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin and a blocking agent.

In the method of preparing a pharmaceutical composition according to an embodiment of the present invention, the particulate phase may be prepared by dry granulation, high shear granulation, fluidized bed granulation or spray drying. Here, the dry granulation may be performed using a roll press or a pulverizing process, the wet granulation may be performed using a high-shear granulator or a low-shear granulator, and the fluidized bed granulation may be performed using a granulator of Wurster type, top spray type, or tangential spray type. Further, the spray drying may be performed using a spray dryer of a two-fluid nozzle type, a rotary atomizer nozzle type, a pressure nozzle type, or an ultrasonic nozzle type. The method of forming the particulate phase will be described in detail below, but is not limited thereto.

More specifically, as 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 blocking agent, a method for preparing a pharmaceutical composition according to an embodiment of the present invention comprises:

step 1) preparing a particulate phase comprising adenine or a pharmaceutically acceptable salt thereof and a blocking agent; step 2), preparing a mixture phase comprising carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin; and, step 3) preparing a final product by blending the particulate phase of step 1) with the mixture of step 2).

In another embodiment, the method comprises: step 1) preparing a mixture phase comprising adenine or a pharmaceutically acceptable salt thereof; step 2) preparing a particulate phase comprising carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin and a blocking agent; and, step 3) preparing the final product by blending the mixture phase of step 1) with the particulate phase of step 2).

In another embodiment, the method comprises: step 1) preparing a particulate phase comprising adenine or a pharmaceutically acceptable salt thereof and a blocking agent; step 2) preparing a particulate phase comprising carnitine or a pharmaceutically acceptable salt thereof, cyanocobalamin and a blocking agent; and, step 3) preparing the final product by blending the particulate phase of step 1) with the particulate phase of step 2).

In another embodiment, the method comprises: step 1) preparing a particulate phase comprising adenine or a pharmaceutically acceptable salt thereof and a blocking agent; step 2), preparing a particulate phase comprising carnitine or a pharmaceutically acceptable salt thereof and a blocking agent; step 3), preparing a mixture phase containing cyanocobalamin; and step 4) preparing a final product by blending the particulate phase of step 1), the particulate phase of step 2) and the mixture of step 3).

In yet another embodiment, the method comprises: step 1) preparing a particulate phase comprising adenine or a pharmaceutically acceptable salt thereof and a blocking agent; step 2), preparing a mixture phase comprising carnitine or a pharmaceutically acceptable salt thereof; step 3) preparing a particulate phase comprising a salt of cyanocobalamin and a blocking agent; and step 4) preparing the final product by blending the particulate phase of step 1), the mixture phase of step 2) and the particulate phase of step 3).

According to an embodiment of the present invention, the method of preparing a pharmaceutical composition may further comprise adding a biologically active substance as defined in the "additional active ingredient" above. When an anti-toxic liver extract is included as an additional active ingredient, blending adenine or a pharmaceutically acceptable salt thereof first with the anti-toxic liver extract is more effective in maintaining the stability of adenine.

According to an embodiment of the present invention, the method of preparing a pharmaceutical composition may further comprise adding a pharmaceutically acceptable excipient.

In the method of preparing a pharmaceutical composition according to an embodiment of the present invention, a blocking agent may be further included as a pharmaceutically acceptable excipient.

According to an embodiment of the present invention, the method of preparing the pharmaceutical composition may further comprise manufacturing the final product into a capsule or a tablet.

In the embodiment of the present invention, the capsule can be manufactured by filling a hard capsule with a final product using a capsule filling machine according to a method for preparing a capsule defined in general requirements of pharmaceutical preparations of korean pharmacopoeia.

In an embodiment of the preparation method, the tablet may be manufactured from the final product using a tablet press according to a method for preparing a tablet defined in general requirements of pharmaceutical preparations of korean pharmacopoeia. The tablets may be further coated with a coating agent.

Blocking structure

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

Here, adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin may be formulated in the form of a layered capsule, a press-coated tablet, a two-layer tablet, a double-layer tablet, or a multi-layer tablet. More specifically, adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin may be prepared into a layered capsule or a bilayer tablet, but is not limited thereto.

The same region means that adenine or a pharmaceutically acceptable salt thereof is spatially separated from carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin so that carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin are located in the same region.

More specifically, as 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 method for manufacturing a bilayer tablet of the pharmaceutical composition according to an embodiment of the present invention includes:

adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin are tableted using a two-layer tablet press.

As 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 method for manufacturing a layered capsule of a pharmaceutical composition according to another embodiment of the present invention comprises:

step 1), filling capsules with adenine or a pharmaceutically acceptable salt thereof; and, step 2), filling the capsule with carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin.

As 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 method for manufacturing a press-coated tablet of the pharmaceutical composition according to still another embodiment of the present invention comprises:

adenine or a pharmaceutically acceptable salt thereof (core) is tableted with carnitine or a pharmaceutically acceptable salt thereof and cyanocobalamin (shell) using a press-coating tablet press.

In the method of manufacturing a bilayer tablet, a layered capsule, or a press-coated tablet according to an embodiment of the present invention, adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin may be formed into a granular phase or a mixed phase, but is not limited thereto.

The method of manufacturing a bilayer tablet, a layered capsule or a press-coated tablet according to an embodiment of the present invention may further comprise adding a blocking agent, or may further comprise adding a biologically active substance or a pharmaceutically acceptable excipient as defined in the above "additional active ingredient", but is not limited thereto.

In another embodiment of the present invention, the method of manufacturing the layered capsule may further comprise tableting adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin, but is not limited thereto.

[ method of Using and use of pharmaceutical composition ]

In embodiments of the invention, the pharmaceutical compositions may be used to treat or prevent liver diseases such as cirrhosis, alcoholic cirrhosis, fatty liver, addictive liver diseases, and acute and chronic viral hepatitis.

The therapeutic or prophylactic use of the pharmaceutical composition according to the present invention is not limited to the above-mentioned diseases, and may include the therapeutic or prophylactic use known before the present application of each bioactive substance of the present invention or a mixture thereof.

The pharmaceutical composition can be used for treating or preventing primary or secondary carnitine deficiency, myocardial metabolic disorder caused by ischemic heart disease (angina pectoris, acute myocardial infarction or chronic heart failure), intermittent claudication, chronic obstructive pulmonary disease, Alzheimer's disease, mild depression, hypercholesterolemia, fragile X syndrome hyperactivity disorder, chronic fatigue syndrome, arrhythmia, liver dysfunction, alcoholic fatty liver, non-alcoholic fatty liver, chronic fatigue, hypertriglyceridemia, diabetes, Down's syndrome, muscular dystrophy, sperm dyskinesia or toxicity associated with AZT (as a therapeutic agent for AIDS).

The concentration of the component comprising adenine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is as described above, and the total mass of the pharmaceutical composition is 100mg to 1800mg, 150mg to 1500mg, or 200mg to 1200 mg.

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

The dosage and dosage regimen for administering the pharmaceutical composition may vary depending on the type of disease, the severity and progression of the disease, the health and therapeutic response of the patient, and the judgment of the physician, and is not limited to a particular dosage and dosage regimen. For example, one or three products comprising the pharmaceutical composition may be taken from 1 to 3 times per day.

The invention will be better understood by the following examples. Here, these examples are listed only for illustrating the pharmaceutical composition comprising adenine capable of ensuring the stability of adenine and the method for preparing the same, and should not be construed as limiting the scope of the present invention.

Example 1: manufacture of tablets comprising an adenine particle fraction

Example 1.1

Tablets were manufactured according to the following method using the compositions in the amounts shown in table 1 below.

Preparation of the first composition

The components of the first composition in table 1 were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20). The resulting mixture was compressed using a roll press (Seoul High Tech, RC80) at a roll speed of 1.5rpm to 2.5rpm, a screw speed of 8rpm to 10rpm, and a pressure of 8MPa to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Preparation of the second composition

The mixture phase was prepared by homogeneously blending the components of the second composition in table 1 for 10 minutes using a blender (box blender, Innotek, LM-20).

Manufacture of film coated tablets

A final product obtained by uniformly blending the first constituent particle phase and the second constituent mixture phase using a blender (box blender, Innotek, LM-20) for 10 minutes was manufactured into tablets having hardness of 10kP to 20kP using a tablet press (Keum sun Machinery, KT10 SS).

The tablets were placed in a tablet coating machine (Keum sun Machinery, KC50F), and then sprayed with a coating solution in which Opadry 88a640014 (trade name of Colorcon corporation) was dispersed in purified water under the conditions of a pan rotation speed of 18rpm, a pump rotation speed of 3rpm to 5rpm, an atomization pressure of 3 bar, a distance between a coating gun and the bottom of the tablets of 20cm, an inlet temperature of 60 ± 5 ℃, and a product temperature of 40 ± 2 ℃.

Examples 1.2 to 1.6

Tablets were manufactured in the same manner as the method of example 1.1, using the compositions in the amounts shown in table 1 below.

Example 1.7

Tablets were manufactured in the same manner as the method of example 1.1, using the compositions in the amounts shown in table 1, except that a fluid bed granulator was used in preparing the first composition.

Preparation of the first composition

Adenine hydrochloride and microcrystalline cellulose were placed in a fluid bed granulator (top spray, Glatt, Midi-Glatt), fluidized at an inlet temperature of 70 ℃ and preheated to a product temperature of 35 ℃ to 38 ℃. Gelatin is dissolved in purified water to obtain a binding solution, and the binding solution is sprayed in an appropriately adjusted amount under conditions of a pump speed of 5rpm to 8rpm and an atomization pressure of 0.6 bar such that the product temperature is maintained in the range of 30 ℃ to 32 ℃. After the spraying was completed, the moisture content of the granules was measured at 105 ℃ for 10 minutes using a halogen moisture analyzer (Mettler Toledo, HB43-S), and then dried to a moisture content of 0.5% to 1.5%. The dried particles were milled using a cone mill (Woosung Tech, CR3-160) equipped with a 1.2mm screen at 1000rpm, thereby preparing a particulate phase having an average particle size of 100 μm to 850 μm.

Example 1.8

Tablets were manufactured in the same manner as the method of example 1.7, using the compositions in the amounts shown in table 1 below, except that pregelatinized starch was used instead of microcrystalline cellulose and hydroxypropyl cellulose was used instead of gelatin.

Example 1.9

Tablets were manufactured in the same manner as the method of example 1.7, using the compositions in the amounts shown in table 1 below, except that maltodextrin was used instead of microcrystalline cellulose and hydroxypropylmethylcellulose was used instead of gelatin.

Example 1.10

Tablets were manufactured in the same manner as the method of example 1.1, using the compositions in the amounts shown in table 1 below, except that a high shear granulator was used in preparing the first composition.

Preparation of the first composition

Adenine hydrochloride and corn starch were placed in a high shear granulator (Bosch, Mycromix 2.5L) and blended for 10 minutes at an impeller speed of 150 rpm. Polyvinyl alcohol was dissolved in purified water to obtain a binding solution, which was then added to the above mixture over 2 minutes at an impeller speed of 150rpm and a shear paddle speed of 2000rpm, followed by kneading at the same speed for 3 minutes. The resulting granules were passed through a 10-mesh screen, dried at 60 ℃ with a fluidized bed dryer (Retsch, TG200), and the moisture content of the dried product was measured at 105 ℃ for 10 minutes with a halogen moisture analyzer (Mettler Toledo, HB43-S), and then dried to a moisture content of 0.5% to 1.5%. The dried granules were milled using a cone mill (Woosung Tech, CR3-160) equipped with a 1.2mm screen at 1000rpm, thereby preparing a particulate phase having an average particle diameter of 100 μm to 850 μm.

Example 1.11

Tablets were manufactured in the same manner as the method of example 1.10, using the compositions in the amounts shown in table 1 below, except that microcrystalline cellulose was used instead of corn starch and polyvinyl acetate was used instead of polyvinyl alcohol.

The composition and amount of the tablets manufactured in example 1.1 to example 1.11 are shown in table 1 below.

[ Table 1]

Example 2: manufacture of tablets comprising carnitine and cyanocobalamin granulate fractions

Example 2.1

Tablets were manufactured according to the following method using the compositions in the amounts shown in table 2 below.

Preparation of the first composition

The mixture phase was prepared by homogeneously blending the components of the first composition in table 2 for 10 minutes using a blender (box blender, Innotek, LM-20).

Preparation of the second composition

The components of the second composition in table 2 were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20). The resulting mixture was compressed with a roll press (Seoul High Tech, RC80) at a roll speed of 1.5 to 2.5rpm, a screw speed of 8 to 10rpm and a pressure of 8 to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Manufacture of film coated tablets

A final product obtained by uniformly blending the first composition mixture phase and the second composition particle phase using a blender (box blender, Innotek, LM-20) for 10 minutes was manufactured into tablets having a hardness of 10kP to 20kP using a tablet press (Keum sun Machinery, KT10 SS).

Examples 2.2 to 2.6

Tablets were manufactured in the same manner as the method of example 2.1, using the compositions in the amounts shown in table 2 below.

Example 2.7

Tablets were manufactured in the same manner as in example 2.1, using the compositions in the amounts shown in table 2 below, except that a fluid bed granulator was used in preparing the second composition.

Preparation of the second composition

Cyanocobalamin, DL-carnitine orotate and microcrystalline cellulose were placed in a fluid bed granulator (top spray, Glatt, Midi-Glatt), fluidized at an inlet temperature of 70 ℃ and preheated to a product temperature of 35 ℃ to 38 ℃. Gelatin is dissolved in purified water to obtain a binding solution, and the binding solution is sprayed in an appropriately adjusted amount under conditions of a pump speed of 5rpm to 8rpm and an atomization pressure of 0.6 bar such that the product temperature is maintained in the range of 30 ℃ to 32 ℃. After the spraying was completed, the moisture content of the granules was measured at 105 ℃ for 10 minutes using a halogen moisture analyzer (Mettler Toledo, HB43-S), and then dried to a moisture content of 0.5% to 1.5%. The dried particles were milled using a cone mill (WoosungTech, CR3-160) equipped with a 1.2mm screen at 1000rpm, thereby preparing a particulate phase having an average particle size of 100 μm to 850 μm.

Example 2.8

Tablets were manufactured in the same manner as the method of example 2.7, using the compositions in the amounts shown in table 2 below, except that pregelatinized starch was used instead of microcrystalline cellulose and hydroxypropyl cellulose was used instead of gelatin.

Example 2.9

Tablets were manufactured in the same manner as the method of example 2.7, using the compositions in the amounts shown in table 2 below, except that maltodextrin was used instead of microcrystalline cellulose and hydroxypropylmethylcellulose was used instead of gelatin.

Example 2.10

Tablets were manufactured in the same manner as in example 2.1, using the compositions in the amounts shown in table 2 below, except that a high shear granulator was used in preparing the second composition.

Preparation of the second composition

The cyanocobalamin double dispersion, L-carnitine napadisylate and corn starch were placed in a high shear granulator (Bosch, Mycromix 2.5L) and blended for 10 minutes at 150rpm impeller speed. Polyvinyl alcohol was dissolved in purified water to obtain a binding solution, which was then added to the above mixture over 2 minutes at an impeller speed of 150rpm and a shear paddle speed of 2000rpm, followed by kneading at the same speed for 3 minutes. The resulting granules were passed through a 10-mesh screen, dried at 60 ℃ with a fluidized bed dryer (Retsch, TG200), and the moisture content of the dried product was measured at 105 ℃ for 10 minutes with a halogen moisture analyzer (Mettler Toledo, HB43-S), and then dried to a moisture content of 0.5% to 1.5%. The dried granules were milled using a cone mill (Woosung Tech, CR3-160) equipped with a 1.2mm screen at 1000rpm, thereby preparing a particulate phase having an average particle diameter of 100 μm to 850 μm.

Example 2.11

Tablets were manufactured in the same manner as the method of example 2.10, using the compositions in the amounts shown in table 2 below, except that microcrystalline cellulose was used instead of corn starch and polyvinyl acetate was used instead of polyvinyl alcohol.

The composition and amount of the tablets manufactured in example 2.1 to example 2.11 are shown in table 2 below.

[ Table 2]

Example 3: manufacture of tablets comprising an adenine granulate fraction and a carnitine and cyanocobalamin granulate fraction

Example 3.1

Tablets were manufactured according to the following method using the compositions in the amounts shown in table 3 below.

Preparation of the first composition

The components of the first composition in table 3 were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20).

The resulting mixture was compressed with a roll press (Seoul High Tech, RC80) at a roll speed of 1.5 to 2.5rpm, a screw speed of 8 to 10rpm and a pressure of 8 to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Preparation of the second composition

The components of the second composition in table 3 were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20). The resulting mixture was compressed with a roll press (Seoul High Tech, RC80) at a roll speed of 1.5 to 2.5rpm, a screw speed of 8 to 10rpm and a pressure of 8 to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Manufacture of film coated tablets

A final product obtained by uniformly blending the first constituent particle phase and the second constituent particle phase using a blender (box blender, Innotek, LM-20) for 10 minutes was manufactured into tablets having hardness of 10kP to 20kP using a tablet press (Keum sun Machinery, KT10 SS).

Example 3.2

Tablets were manufactured in the same manner as the method of example 3.1, using the compositions in the amounts shown in table 3 below.

The composition and amount of the tablets made in example 3.1 and example 3.2 are shown in table 3 below.

[ Table 3]

Comparative example 1 production of tablet comprising portion of mixture of adenine, carnitine and cyanocobalamin

Comparative example 1.1

Tablets were manufactured according to the following method using the compositions in the amounts shown in table 4 below.

The components in table 4 were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20) to prepare a mixture phase. The blend phase was fabricated into tablets having a hardness of 10 to 20kP using a tablet press (Keum Sung Machinery, KT10 SS). The tablets were placed in a tablet coating machine (Keum sun Machinery, KC50F), and then sprayed with a coating solution in which Opadry 88a640014 (trade name of Colorcon corporation) was dispersed in purified water under the conditions of a pan rotation speed of 18rpm, a pump rotation speed of 3 to 5rpm, an atomization pressure of 3 bar, a distance between a coating gun and the bottom of the tablets of 20cm, an inlet temperature of 60 ± 5 ℃, and a product temperature of 40 ± 2 ℃.

[ Table 4]

Comparative example 2 production of tablet comprising mixture part/granule part of adenine and carnitine or mixture part/granule part of adenine and cyanocobalamin

Comparative example 2.1

Tablets were manufactured according to the following method using the ingredients in the amounts shown in table 5 below.

Preparation of the first composition

The mixture phase was prepared by homogeneously blending the components of the first composition in table 5 for 10 minutes using a blender (box blender, Innotek, LM-20).

Preparation of the second composition

The mixture phase was prepared by homogeneously blending the components of the second composition in table 5 for 10 minutes using a blender (box blender, Innotek, LM-20).

Manufacture of film coated tablets

A final product obtained by uniformly blending the first and second compositional mixture phases using a blender (box blender, Innotek, LM-20) for 10 minutes was manufactured into tablets having a hardness of 10kP to 20kP using a tablet press (Keum sun Machinery, KT10 SS).

Comparative example 2.2

Tablets were made in the same manner as the method of example 1.1, using the same composition and amounts as described in comparative example 2.1.

Comparative example 2.3

Tablets were manufactured in the same manner as the method of example 2.1, using the compositions in the amounts shown in table 5 below.

Comparative example 2.4

Tablets were manufactured in the same manner as the method of comparative example 2.1, using the compositions in the amounts shown in table 5 below.

Comparative example 2.5

Tablets were made in the same manner as the method of example 1.1, using the same composition and amounts as described in comparative example 2.4.

Comparative example 2.6

Tablets were made in the same manner as the method of example 2.1, using the same composition and amounts as described in comparative example 2.4.

Comparative example 2.7

Comparative example 2.8

Tablets were made in the same manner as the method of example 1.1, using the same composition and amounts as described in comparative example 2.7.

Comparative example 2.9

Tablets were made in the same manner as the method of example 2.1, using the same composition and amounts as described in comparative example 2.7.

The composition and amount of tablets produced in comparative example 2.1 to comparative example 2.9 are shown in table 5 below.

[ Table 5]

Comparative example 3 production of tablets containing different blocking Agents

Comparative example 3.1 to comparative example 3.5

Tablets were manufactured in the same manner as the method of example 1.1, using the compositions in the amounts shown in table 6 below.

The composition and amount of the tablets manufactured in comparative example 3.1 to comparative example 3.5 are shown in table 6 below.

[ Table 6]

Test example 1

Stability testing method

And (3) testing conditions are as follows: KFDA Notification No. 2014-59 for acceleration conditions of stability test standards of drugs (temperature/humidity: 40. + -. 2 ℃/75. + -. 5% RH)

Packaging form of the sample: airtight container

And (3) testing date: day of manufacture and 1 month, 3 months and 6 months after day of manufacture

The analysis method comprises the following steps: liquid chromatography

Column: inertsil ODS-3V 4.6X 250mm, 5 μm

A detector: absorbance detector (270nm)

Mobile phase: 80:20 aqueous buffer of acetonitrile and phosphoric acid

Flow rate: 1.0mL/min

A stability test was performed to evaluate the stability of adenine contained in the pharmaceutical compositions of examples 1.1 to 3.2 and comparative examples 1.1 to 3.5. The amount of adenine was measured on the day of manufacture of the pharmaceutical composition and at 1 month, 3 months and 6 months after the day of manufacture. The results are shown in Table 7 below.

[ Table 7]

As is apparent from table 7, in the pharmaceutical composition comprising adenine, cyanocobalamin and carnitine as active ingredients, the first composition comprising adenine and the second composition comprising cyanocobalamin and carnitine were confirmed such that the amount of adenine remained 95% or more in the 6-month stability test in examples 1.1 to 3.2 in which adenine is provided separately from cyanocobalamin and carnitine and which comprises a blocking agent. In contrast, in comparative examples 1.1 to 2.11 in which adenine and at least one active ingredient selected from cyanocobalamin and carnitine were contained in the same composition, it was confirmed that the amount of adenine was greatly reduced.

Meanwhile, comparative examples 3.1 to 3.5 using low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, crospovidone, or mannitol as a blocking agent showed an amount of adenine of about 90% or less in a stability test for 6 months, indicating that the use of the above blocking agent is not suitable.

Example 4 production of a tablet comprising an adenine granulate fraction, a carnitine granulate fraction and a cyanocobalamin mixture fraction

Example 4.1

Tablets were manufactured according to the following method using the compositions in the amounts shown in table 8 below.

Preparation of the first composition

The components of the first composition in table 8 were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20). The resulting mixture was compressed with a roll press (Seoul High Tech, RC80) at a roll speed of 1.5 to 2.5rpm, a screw speed of 8 to 10rpm and a pressure of 8 to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Preparation of the second composition

The particulate phase was prepared in the same manner as described in the above "preparation of first composition" using the components of the second composition in table 8.

Preparation of the third composition

The mixture phase was prepared by homogeneously blending the components of the third composition in table 8 for 10 minutes using a blender (box blender, Innotek, LM-20).

Manufacture of film coated tablets

A final product obtained by uniformly blending the first constituent particle phase, the second constituent particle phase and the third constituent mixture phase using a blender (tank blender, Innotek, LM-20) for 10 minutes was manufactured into a tablet having a hardness of 10kP to 20kP using a tablet press (Keum sun Machinery, KT10 SS).

Example 4.2

Tablets were manufactured in the same manner as in example 4.1, using the compositions in the amounts shown in table 8 below.

The composition and amount of the tablets prepared in example 4.1 and example 4.2 are shown in table 8 below.

[ Table 8]

Test example 2

The stability of adenine contained in the pharmaceutical compositions of example 4.1 and example 4.2 was evaluated in the same manner as in test example 1. The amount of adenine was measured on the day of manufacture of the pharmaceutical composition and 1 month, 3 months and 6 months after the day of manufacture. The results are shown in Table 9 below.

[ Table 9]

As is apparent from table 9, for example 4.1 and example 4.2, which contained adenine, carnitine and cyanocobalamin provided in the first composition, the second composition and the third composition, respectively, and further contained a blocking agent, the amount of adenine remained 95% or more in the stability test for 6 months.

Example 5 preparation of tablets containing varying amounts of blocking agent

Example 5.1 to example 5.8

Tablets were manufactured in the same manner as the method of example 1.1, using the compositions in the amounts shown in table 10 below.

The composition and amount of the tablets manufactured in examples 5.1 to 5.8 are shown in table 10 below.

[ Table 10]

Example 5.9 to example 5.14

Tablets were manufactured in the same manner as the method of example 2.1, using the compositions in the amounts shown in table 11 below.

The composition and amount of the tablets manufactured in example 5.9 to example 5.14 are shown in table 11 below.

[ Table 11]

Test example 3

In the same manner as in test example 1, the stability of adenine in pharmaceutical compositions containing different amounts of the blocking agent was evaluated. In examples 5.1 to 5.14, in which the amount of the blocking agent is 0.8 to 500 parts by weight relative to 1 part by weight of adenine, the amount of adenine was maintained at 95% or more in the stability test for 6 months. In example 5.1 and example 5.5, when the amount of the blocking agent is less than 0.8 parts by weight, the amount of adenine is less than 90%, indicating that the stability of adenine is significantly reduced.

Example 6 preparation of tablets containing different combinations of blockers

Example 6.1 to example 6.3

Tablets were manufactured in the same manner as the method of example 1.1, using the compositions in the amounts shown in table 12 below.

Example 6.4 and example 6.5

Tablets were manufactured in the same manner as the method of example 2.1, using the compositions in the amounts shown in table 12 below.

Example 6.6 and example 6.7

Tablets were manufactured in the same manner as the method of example 3.1, using the compositions in the amounts shown in table 12 below.

The composition and amount of the tablets manufactured in example 6.1 to example 6.7 are shown in table 12 below.

[ Table 12]

Test example 4

In the same manner as in test example 1, stability of adenine in pharmaceutical compositions containing different combinations of blockers was evaluated. For example 6.1 to example 6.7, the amount of adenine remained 95% or higher in the stability test for 6 months.

Example 7 manufacture of capsules or tablets containing additional active ingredients

Based on the results of the improved adenine stability of examples 1 to 6 and comparative examples 1 to 3, a capsule or tablet further comprising an antitoxic liver extract, pyridoxine hydrochloride, riboflavin, and dimethyl bibenzoate was manufactured.

Example 7.1

Capsules were manufactured according to the following method using the compositions in the amounts shown in table 13 below.

Preparation of the first composition

The mixture phase was prepared by homogeneously blending adenine hydrochloride and the antitoxic liver extract for 10 minutes using a blender (box blender, Innotek, LM-20) and then further mixing with the remaining components of the first composition in table 12 for 10 minutes.

Preparation of the second composition

The components of the second composition in table 13 were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20). The resulting mixture was compressed with a roll press (Seoul High Tech, RC80) at a roll speed of 1.5 to 2.5rpm, a screw speed of 8 to 10rpm and a pressure of 8 to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Manufacture of capsules

A final product obtained by uniformly blending the first composition mixture phase and the second composition particle phase using a blender (box blender, Innotek, LM-20) for 10 minutes was loaded into a hard capsule using a capsule filling machine (KF), thereby manufacturing a capsule.

Example 7.2 and example 7.3

Capsules were manufactured in the same manner as in example 7.1, using the compositions in the amounts shown in table 13 below.

Example 7.4

Tablets were manufactured according to the following method using the compositions in the amounts shown in table 13 below.

Preparation of the first composition

Adenine hydrochloride and the antitoxic liver extract were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20) and then further homogeneously blended for 10 minutes with the remaining components of the first composition in table 12. The resulting mixture was compressed with a roll press (Seoul High Tech, RC80) at a roll speed of 1.5 to 2.5rpm, a screw speed of 8 to 10rpm and a pressure of 8 to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Preparation of the second composition

Preparation of film-coated tablets

Example 7.5 and example 7.6

Tablets were manufactured in the same manner as the method of example 7.4, using the compositions in the amounts shown in table 13 below.

Example 7.7

Preparation of the first composition

The mixture phase was prepared by homogeneously blending the components of the first composition in table 13 for 10 minutes using a blender (box blender, Innotek, LM-20).

Preparation of the second composition

Cyanocobalamin double powder, carnitine, antitoxic liver extract and corn starch were placed in a fluid bed granulator (top spray, Glatt, Midi-Glatt), fluidized at an inlet temperature of 70 ℃ and preheated to a product temperature of 35 ℃ to 38 ℃. Gelatin is dissolved in purified water to obtain a binding solution, and the binding solution is sprayed in an appropriately adjusted amount under conditions of a pump speed of 5rpm to 8rpm and an atomization pressure of 0.6 bar such that the product temperature is maintained in the range of 30 ℃ to 32 ℃. After the spraying was completed, the moisture content of the granules was measured at 105 ℃ for 10 minutes using a halogen moisture analyzer (Mettler Toledo, HB43-S), and then dried to a moisture content of 0.5% to 1.5%. The dried particles were milled using a cone mill (WoosungTech, CR3-160) equipped with a 1.2mm screen at 1000rpm, thereby preparing a particulate phase having an average particle size of 100 μm to 850 μm.

Manufacture of film coated tablets

Example 7.8

Preparation of the first composition

Adenine hydrochloride, riboflavin, dimethyl bibenzoate and corn starch were placed in a fluidized bed granulator (top spray, Glatt, Midi-Glatt), fluidized at an inlet temperature of 70 ℃ and preheated to a product temperature of 35 ℃ to 38 ℃. Hydroxypropyl methylcellulose was dissolved in purified water to obtain a binding solution, and the binding solution was sprayed in an appropriately adjusted amount under conditions of a pump speed of 5rpm to 8rpm and an atomization pressure of 0.6 bar such that the product temperature was maintained in the range of 30 ℃ to 32 ℃. After the spraying was completed, the moisture content of the granules was measured at 105 ℃ for 10 minutes using a halogen moisture analyzer (Mettler Toledo, HB43-S), and then dried to a moisture content of 0.5% to 1.5%. The dried granules were milled using a cone mill (Woosung Tech, CR3-160) equipped with a 1.2mm screen at 1000rpm, thereby preparing a particulate phase having an average particle diameter of 100 μm to 850 μm.

Preparation of the second composition

The mixture phase was prepared by homogeneously blending the components of the second composition in table 13 for 10 minutes using a blender (box blender, Innotek, LM-20).

Manufacture of film coated tablets

Example 7.9

Preparation of the first composition

The components of the first composition in table 13 were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20). The resulting mixture was compressed with a roll press (Seoul High Tech, RC80) at a roll speed of 1.5 to 2.5rpm, a screw speed of 8 to 10rpm and a pressure of 8 to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Preparation of the second composition

Manufacture of film coated tablets

Example 7.10

Preparation of the first composition

Adenine hydrochloride and the antitoxic liver extract were homogeneously blended for 10 minutes using a blender (box blender, Innotek, LM-20) and then further homogeneously blended for 10 minutes with the remaining components of the first composition in table 13. The resulting mixture was compressed with a roll press (Seoul High Tech, RC80) at a roll speed of 1.5 to 2.5rpm, a screw speed of 8 to 10rpm and a pressure of 8 to 12MPa to obtain a compressed product. The pressed product was passed through a 20-mesh screen, thereby preparing a particulate phase having an average particle diameter of 100 to 850 μm.

Preparation of the second composition

Manufacture of film coated tablets

A final product obtained after uniformly blending the first constituent particle phase and the second constituent particle phase for 10 minutes by using a blender (box blender, Innotek, LM-20) was manufactured into a tablet having a hardness of 10kP to 20kP using a tablet press (Keum sun Machinery, KT10 SS).

Example 7.11

Tablets were manufactured in the same manner as in example 7.10, using the compositions in the amounts shown in table 13 below.

The composition and amount of the tablets manufactured in example 7.1 to example 7.11 are shown in table 13 below.

[ Table 13]

Comparative example 4. production of tablet comprising additional active ingredient (example 1 of Korean patent No. 0294329)

Comparative example 4.1

Tablets were manufactured according to the following method using the compositions in the amounts shown in table 14 below.

The mixture phase was prepared by homogeneously blending the components of table 14 for 10 minutes using a blender (box blender, Innotek, LM-20). The blend phases were fabricated into tablets having a hardness of 10 to 20kP using a tablet press (Keum Sung Machinery, KT10 SS). The tablets were placed in a tablet coating machine (Keum sun Machinery, KC50F), and then sprayed with a coating solution in which Opadry 88a640014 (trade name of Colorcon corporation) was dispersed in purified water under the conditions of a pan rotation speed of 18rpm, a pump rotation speed of 3 to 5rpm, an atomization pressure of 3 bar, a distance between a coating gun and the bottom of the tablets of 20cm, an inlet temperature of 60 ± 5 ℃, and a product temperature of 40 ± 2 ℃.

[ Table 14]

Test example 5

In the same manner as in test example 1, the stability of adenine in the pharmaceutical composition containing the additional active ingredient was evaluated. The results are shown in Table 15 below.

[ Table 15]

As is apparent from table 15, for examples 7.1 to 7.11 containing the antitoxic liver extract, pyridoxine hydrochloride, riboflavin, and dimethyl bibenzoate as additional active ingredients, the amount of adenine remained 95% or more in the stability test for 6 months. Furthermore, the stability of adenine in examples 7.1 to 7.6 and examples 7.10 and 7.11, in which adenine and the anti-toxic liver extract were first blended, was higher than that in examples 7.7 to 7.9, in which adenine and the anti-toxic liver extract were not first blended, indicating that the anti-toxic liver extract affects the stability of adenine.

Meanwhile, for comparative example 4.1, which is the same as example 1 of korean patent No.0294329, in which adenine is contained in the same composition not only with cyanocobalamin and carnitine but also with an additional active ingredient, the stability of adenine is less than 75% and thus is significantly reduced. Based on the results that the stability of adenine of comparative example 4.1 is lower than that of comparative example 1.1 without additional active ingredient, the additional active ingredient affects the stability of adenine. Therefore, although further studies on the correlation between the additional active ingredient and the stability of adenine are required, it can be concluded that at least adenine must be provided separately from carnitine and cyanocobalamin in the pharmaceutical composition comprising adenine, carnitine and cyanocobalamin according to the present invention so that the amount of adenine does not decrease over a long period of time.

EXAMPLE 8 preparation of bilayer tablet

Example 8.1

Using the compositions in the amounts shown in table 16 below, bilayer tablets were manufactured as follows.

Preparation of the first composition

The mixture phase was prepared by homogeneously blending the components of the first composition in table 16 for 10 minutes using a blender (box blender, Innotek, LM-20).

Preparation of the second composition

The mixture phase was prepared by homogeneously blending the components of the second composition in table 16 for 10 minutes using a blender (box blender, Innotek, LM-20).

Manufacture of film-coated bilayer tablets

The first and second compositional blend phases were fabricated into bilayer tablets having a hardness of 10kP to 20kP using a bilayer tablet press (Elizabeth Parle, EP200L AWC).

The tablets were placed in a tablet coating machine (Keum sun Machinery, KC50F), and then sprayed with a coating solution in which Opadry 88a640014 (trade name of Colorcon corporation) was dispersed in purified water under the conditions of a pan rotation speed of 18rpm, a pump rotation speed of 3 to 5rpm, an atomization pressure of 3 bar, a distance between a coating gun and the bottom of the tablets of 20cm, an inlet temperature of 60 ± 5 ℃, and a product temperature of 40 ± 2 ℃.

[ Table 16]

Test example 6

In the same manner as in test example 1, the stability of adenine in the pharmaceutical composition for the bilayer tablet was evaluated. The results are shown in Table 17 below.

[ Table 17]

As is apparent from table 17, the bilayer tablet of example 8 showed that physical interaction between the first composition comprising adenine and the second composition comprising carnitine and cyanocobalamin was minimized, and thus the amount of adenine was hardly changed in the stability test for 6 months. Based on the above results, it can be understood that the amount of adenine in the layered capsule, the press-coated tablet and the multi-layered tablet was not changed.

Claims

1. 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 blocking agent inhibits the physical interaction of the adenine or a pharmaceutically acceptable salt thereof with the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin.

2. The pharmaceutical composition of claim 1, wherein said carnitine is D, L-carnitine or L-carnitine.

3. The pharmaceutical composition of claim 1, wherein the cyanocobalamin is in a form of a dilution.

4. The pharmaceutical composition according to claim 1, wherein the blocking agent is selected from at least one of maltodextrin, corn starch, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and polyvinyl acetate.

5. The pharmaceutical composition according to claim 1, wherein the amount of the blocking agent is 0.8 to 500 parts by weight with respect to 1 part by weight of the adenine.

6. The pharmaceutical composition of claim 1, wherein the adenine or pharmaceutically acceptable salt thereof and the blocker form a particulate phase.

7. The pharmaceutical composition of claim 1, wherein the carnitine or pharmaceutically acceptable salt thereof, the cyanocobalamin, and the blocking agent form a particulate phase.

8. The pharmaceutical composition of claim 1, further comprising: at least one active ingredient selected from the group consisting of an anti-toxic liver extract, dimethyl bibenzoate, pyridoxine or a pharmaceutically acceptable salt thereof, and riboflavin or a pharmaceutically acceptable salt thereof.

9. 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 is spatially separated from the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin by a blocking structure, thereby inhibiting a physical interaction between the adenine or a pharmaceutically acceptable salt thereof and the carnitine or a pharmaceutically acceptable salt thereof and the cyanocobalamin.

10. The pharmaceutical composition according to claim 9, wherein the blocking structure is a layered capsule, a press-coated tablet, a bilayer tablet or a multilayer tablet.

11. The pharmaceutical composition of claim 9, wherein the carnitine or pharmaceutically acceptable salt thereof and the cyanocobalamin are contained in the same region or different regions.

12. A pharmaceutical composition comprising:

adenine or a pharmaceutically acceptable salt thereof, carnitine or a pharmaceutically acceptable salt thereof, and cyanocobalamin,

wherein the amount of adenine is maintained at 95% or more after storage in a closed container for 6 months under accelerated conditions of 40 ℃ and 75% relative humidity.