RU2786364C1 - Dimethyl fumarate-containing enteric tablet - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a tablet with an enteric coating, including: a core containing dimethyl fumarate or a pharmaceutically acceptable salt thereof as an active ingredient; and a layer of an enteric coating, and to production of a tablet exhibiting the same effect as the currently marketed capsule dosage form, following a simple technology, constituting a dosage form with excellent storage stability and ease of administration, therefore applicable for various groups of patients.

EFFECT: production of tablets for use in various groups of patients.

15 cl, 11 dwg, 17 tbl

Description

State of the art

The present invention relates to a pharmaceutical preparation containing dimethyl fumarate. In particular, the present invention relates to an enteric tablet containing dimethyl fumarate and an enteric coating layer, and the tablet of the present invention provides stable delivery of dimethyl fumarate to the site of absorption and rapidly disintegrates, so that a desirable therapeutic effect can be achieved in vivo . The tablet of the present invention, which has the same effect as the capsule dosage form currently commercially available, has advantages in terms of productivity and economy, since the preparation procedure is simpler than for the capsule dosage form currently available. is currently on sale and is smaller than a capsule so that patient compliance can be improved. In particular, the tablet of the present invention does not contain ingredients of animal origin, so that it can be used for groups of patients for whom capsules are contraindicated for religious reasons.

Dimethyl fumarate (DMF), the active ingredient of the present invention, is a compound having the following formula 1, which was proposed by a German chemist in the 1950s. for the treatment of psoriasis and has been used to treat psoriasis for many years. In 1994 Fumaderm® (Fumapharm AG), a mixture of the calcium, magnesium and zinc salts of dimethyl fumarate (DMF) and monoethyl fumarate (MEF), was approved in Germany for the treatment of psoriasis.

[Formula 1]

In addition to these uses for the treatment of psoriasis, U.S. No. US6509376 discloses that the dialkyl fumarate compound, to which dimethyl fumarate belongs, is useful for the treatment of autoimmune diseases such as multiple arthritis, multiple sclerosis, juvenile diabetes mellitus, systemic lupus erythematosus (SLE), psoriasis, psoriatic arthritis, and neurodermatitis. In particular, in the U.S. No. US7320999 discloses that dimethyl fumarate is effective in multiple sclerosis. Dimethyl fumarate was approved by the FDA as a therapeutic for multiple sclerosis in March 2013 and is currently available under the trade name Tekfidera® in the US and Korea. In addition, Korean Patent Publication No. 2009-0028047 discloses that dimethyl fumarate has an inhibitory effect on the proliferation of vascular smooth muscle cells, and Korean Patent No. 1379427 discloses that it contributes to the prevention or treatment of renal fibrosis.

US6355676 and US6509376 disclose pharmaceutical compositions in the form of enteric-coated microtablets or micropellets containing dimethyl fumarate, and WO2010/126605 discloses a pharmaceutical composition containing dimethyl fumarate in the form of a capsule containing an enteric-coated microtablet. The currently commercially available ^tecfidera® is a hard gelatin extended release capsule filled with micropellets containing the active ingredient dimethyl fumarate.

However, the technique of filling enteric-coated microtablets or micropellets into a capsule base or producing microtablets has the disadvantage that the production cost is increased due to the additional procedure and the production equipment is required, and there is also a difficulty in that, in the process of producing pellets, due to the sublimation of dimethyl fumarate, loss of the main component. In addition, since the capsule base contains an animal component (bovine cartilage), microbial contamination is possible, and there is also the problem that administration is not possible for a group of patients who are religiously contraindicated for animal components. Therefore, it is necessary to develop a preparation that overcomes the difficulties associated with the capsule dosage form and has the same effect in vivo as the capsule dosage form currently commercially available.

It is generally known that the enteric coating layer is applied in an amount of 10 to 12% by weight based on the total weight of the tablet core (Singh Deep Hussan et al., 2012, IOSR Journal of Pharmacy, A review on recent advances of enteric coating) . Meanwhile, the inventors of the present invention, in solving existing problems by adjusting the weight of the enteric coating layer, have found an enteric tablet having an optimal weight of the enteric coating layer with excellent bioavailability.

PRIOR ART LITERATURE

PATENT LITERATURE

US Patent No. US6509376

US Patent No. US7320999

US Patent No. US6355676

International Publication No. WO2010/126605

Korean Patent Publication No. 2009-0028047

Korean Patent No. 1379427

NON-PAtent LITERATURE

Singh Deep Hussan et al., 2012.

The essence of the invention

Accordingly, the present inventors have investigated the solution of the above problems, and as a result, the present inventors have completed the present invention by confirming that if the enteric coating layer surrounding the core containing dimethyl fumarate is used in an optimal amount, the difficulties associated with the dosage form in capsule form, such as sublimation of active ingredients and complicated production technology, and tablets of the drug having excellent in vivo bioavailability can be obtained.

An object of the present invention is to provide an enteric tablet for preventing or treating inflammatory or autoimmune diseases or disorders, diseases caused by proliferation of vascular smooth muscle cells, kidney fibrosis, and the like. More specifically, an object of the present invention is to provide an enteric tablet containing dimethyl fumarate as an active ingredient, and containing an enteric coating layer in an amount of 6 to 9% by weight, based on the weight of the core containing the active ingredient, so that dimethyl fumarate can be stably delivered to the site of absorption and rapidly distributed, the desired therapeutic effect can be expected in vivo .

In addition, another object of the present invention is to provide a drug that has excellent storage stability, ease of administration, applicability to different patient groups and bioavailability equivalent to that of a commercially available drug capsule, while maintaining a low production cost due to the simplicity of the production method.

To solve the above problems, one object of the present invention is an enteric-coated tablet comprising a core containing dimethyl fumarate or a pharmaceutically acceptable salt thereof as an active ingredient; and an enteric coating layer, where the enteric coating layer is included in an amount equal to from 6 to 9 wt.part. in terms of 100 wt.chast. kernels.

Another object of the present invention is a method for producing an enteric-coated tablet comprising the following steps:

a step of preparing a mixture by mixing dimethyl fumarate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive;

the step of preparing the core by directly tableting the mixture; and

the step of applying an enteric coating to the core,

where the application of enteric coating is carried out using from 6 to 9 wt.part. layer enteric coating in terms of 100 wt.chast. kernels.

The enteric tablet of the present invention has a preventive or therapeutic effect in inflammatory or autoimmune diseases or disorders, diseases caused by vascular smooth muscle cell proliferation, kidney fibrosis, and the like. More precisely, a tablet, a dosage form, which has excellent storage stability, ease of administration, and which can be used for different groups of patients, can be obtained in a simple way of obtaining without the loss of active ingredients that can occur during the production of micropellets. In particular, the enteric tablet of the present invention can provide a drug release mode equivalent to that of a commercially available drug capsule in vivo , and thus has excellent bioavailability.

Brief description of the drawings

In FIG. 1 is a diagram illustrating the results of observation with a scanning electron microscope to confirm the thickness of the primary coating layer (protective coating layer) and the coating layers of Examples 11 and 12 and Comparative Example 4.

In FIG. 2 is a graph illustrating the results of confirming the release rates for the enteric coating of the tablet of Examples 1-3 to compare and analyze the release rates from the tablet as a function of the content of the enteric coating.

In FIG. 3 is a graph illustrating the validation results for the enteric coating tablet release rates of Examples 2 and 4 to compare and analyze the release rates from the tablet as a function of the copolymer content of the enteric coating base.

In FIG. 4 is a graph showing the results of validating the release rates for the enteric coating tablet of Examples 4 and 5 to compare and analyze the release rates from the tablet as a function of the coating content of the enteric coating base.

In FIG. 5 is a graph illustrating the results of evaluating the weight loss (%) of dimethyl fumarate (the main ingredient) and a mixture containing dimethyl fumarate and a pharmaceutically acceptable additive to determine the appropriate temperature range for the drying step by evaluating the weight loss during coating.

In FIG. 6 is a graph illustrating the results of validating the release rates for the enteric coating of the tablet of Examples 5 and 6 to evaluate the release rate as a function of dimethyl fumarate particle size.

In FIG. 7 is a graph illustrating the results of confirming the release rates for the preparations of Examples 5 and 7 and Comparative Example 1 for evaluating the release rate depending on the use of an alkalizing agent.

In FIG. 8 is a graph illustrating the results of confirming release rates for the preparations of Example 5 and Comparative Example 1 using a pH 1.2 solution (artificial gastric juice, leavening solution 1, The Korean Pharmacopoeia) to evaluate the release rate for a preparation containing 120 mg of dimethyl fumarate.

In FIG. 9 is a graph illustrating the results of validating release rates for the formulations of Example 5 and Comparative Example 1 using a pH 6.8 solution (artificial gastric juice) to evaluate the release rate for a formulation containing 120 mg of dimethyl fumarate.

In FIG. 10 is a graph illustrating the release rate verification results for the enteric coating tablets of Examples 5 and 8 to confirm the release rate for a tablet containing 240 mg dimethyl fumarate.

In FIG. 11 is a graph illustrating the results of in vivo validation of drug kinetics by oral administration of the preparations of Example 11 and Comparative Examples 1-4 in beagle dogs for a pharmacokinetic study of the enteric coating of the tablet of the present invention.

Detailed description of the invention

Below, the present invention is described in detail.

One object of the present invention is an enteric-coated tablet containing a core containing dimethyl fumarate or a pharmaceutically acceptable salt thereof as an active ingredient; and an enteric coating layer, where the enteric coating layer is included in an amount equal to from 6 to 9 wt.part. in terms of 100 wt.chast. kernels.

In the case of commercially available capsule preparations, losses of dimethyl fumarate may occur during preparation, and there is a difficulty that administration is not possible for patient groups that are contraindicated for religious reasons for taking animal components, for convenience of administration, etc. On the other hand, an enteric-coated tablet coating according to the present invention is obtained on the basis that dimethyl fumarate is stably delivered to the site of absorption and distributed quickly, providing a therapeutic effect by adjusting the content of the enteric coating layer. In particular, the enteric coating layer is typically used in an amount of 10 to 12% by weight or 10 to 13% by weight, based on the total weight of the tablet core. In the present invention, when using from 6 to 9 wt.part. in terms of 100 wt.chast. the tablet core containing dimethyl fumarate or a pharmaceutically acceptable salt thereof is rapidly dissolved at the site of absorption and thus provides excellent bioavailability.

In this case, the active ingredient can be included in an amount equal to from 20 to 60 wt.%, preferably from 25 to 55 wt.%, from 30 to 50 wt.%, from 35 to 45 wt.%, from 40 to 45 wt.% , from 43 to 45 wt.% or about 44 wt.% in terms of the core.

In addition, the active ingredient may be included in the core in an amount of 50 mg to 500 mg, preferably 60 mg to 480 mg, 100 mg to 400 mg, 50 mg to 400 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 150 mg, 200 mg to 250 mg, 330 mg to 400 mg, 330 mg to 480 mg, 50 mg to 100 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, about 480 mg, more preferably 60 mg, 120 mg, 240 mg, 360 mg or 480 mg. A dose-proportional, linear elimination kinetic of dimethyl fumarate or a pharmaceutically acceptable salt thereof has been demonstrated over the range of 120 mg to 360 mg.

The core includes one or more pharmaceutically acceptable additives selected from the group consisting of the following: excipients, disintegrants and lubricants. Pharmaceutically acceptable additives are not limited to excipients, disintegrants, and lubricants, and can be used as long as they are commonly used pharmaceutical additives. For example, additives such as excipients, binders, disintegrants, antioxidants, surfactants, lubricants, plasticizers, and pigments may be included.

Examples of the excipient include starch, lactose, lactose anhydrous, microcrystalline cellulose, silicified microcrystalline cellulose, hypromellose, silicic anhydride, calcium phosphate, calcium phosphate anhydrous, calcium hydrogen phosphate, calcium hydrogen phosphate anhydrous, calcium silicate, dextrin, dextrose, dextrate, mannitol, maltose, sorbitol, sucrose, polyethylene glycol, sodium chloride, and the like, and may be used alone or in combination of two or more. Preferably, silicified microcrystalline cellulose can be used.

The disintegrant may include crospovidone, croscarmellose sodium, starch glycolate sodium, pregelatinized starch, low substituted hydroxypropyl cellulose, corn starch, and the like, and may be used alone or in combination of two or more. Preferably, croscarmellose sodium salt can be used.

Examples of the lubricant include magnesium stearate, stearic acid, talc, silicon dioxide, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, poloxamer, and the like, and they can be used alone or in combination of two or more. Preferably, colloidal silicon dioxide or magnesium stearate can be used, and most preferably, colloidal silicon dioxide and magnesium stearate can be used.

Examples of the plasticizer include triethyl citrate, acetyl tributyl citrate, glycerol acetate, triacetin, dibutyl phthalate, polysorbate 80, polyethylene glycol, propylene glycol, and the like, and they can be used alone or in combination of two or more.

Examples of the binder include povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum, and the like, and may be used alone or in combination of two or more.

Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxytoluene, butylhydroxyanisole, t-butylhydroquinone, propyl gallate, vitamin C, and the like, and they can be used alone or in combination of two or more.

Examples of the surfactant include sodium lauryl sulfate, sodium stearate, polysorbate 80, poloxamer, and the like, and may be used alone or in combination of two or more.

A protective coating layer may optionally be included between the core and the enteric coating layer. Here, the protective coating layer is also referred to as an intermediate coating layer, a primary coating layer, or a non-enteric coating layer. The protective coating layer may include, but is never limited to, a cellulose-based polymer, preferably hydroxypropyl methylcellulose, and is not particularly limited as long as it is the basis of a non-enteric coating. The cellulose-based polymer may be at least one selected from the group consisting of the following: polyvinyl alcohol (PVA), polyethylene glycol, polyvinyl alcohol-polyethylene glycol graft copolymer (for example, Kollicoat-IR), ethyl cellulose, hydroxypropyl cellulose (HPC), lactose, and mannitol. The protective coating layer can be included in an amount equal to from 1 to 3 parts by weight. in terms of 100 wt.chast. core, preferably from 1 to 2 parts by weight, about 1.5 parts by weight. or about 2 wt.part.

The core may further include an alkalizing agent, where the ratio of the mass of the active ingredient to the mass of the alkalizing agent may be from 12:0.5 to 12:2, from 12:0.7 to 12:1.8, from 12:0.8 to 12 :1.5, 12:0.9 to 12:1.3 or 12:0.9 to 12:1.1, and may preferably be 12:1.

The alkalizing agent can be included in an amount equal to 2 to 5 wt.%, 2.5 to 4.5 wt.%, 3 to 4 wt.%, 3.5 to 4 wt.%, or about 3.7 wt.% in terms of the core.

As an alkalizing agent, a known alkalizing agent can be used to increase the water solubility of the active ingredient. Preferably, meglumine or a pharmaceutically acceptable salt thereof can be used as an alkalizing agent to improve compression moldability, adsorption, disintegration, stability, and the like suitable for a tablet.

One or more enteric coating polymers selected from the group consisting of the following can be used for the enteric coating layer: acrylic acid-based enteric copolymers selected from the group consisting of the following: styrene-acrylic acid copolymer, methacrylic acid-ethyl methacrylate copolymer, copolymer methyl acrylate, methacrylic acid and octylacrylate and a copolymer of methacrylic acid and ethyl acrylate; cellulose-based enteric polymers selected from the group consisting of the following: hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate maleate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, propionate -cellulose phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalate, carboxymethylethylcellulose and ethylhydroxyethylcellulose phthalate; Enteric copolymers based on maleic acid selected from the group consisting of the following: vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ester-maleic anhydride copolymer, ethylene-maleic anhydride copolymer , a copolymer of vinyl butyl ether - maleic anhydride, a copolymer of acrylonitrile - methyl acrylate - maleic anhydride and a copolymer of butyl acrylate - styrene - maleic anhydride; and polyvinyl-based enteric polymers selected from the group consisting of the following: polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, and polyvinyl acetal phthalate; but the enteric coating polymer is not particularly limited as long as it is a pharmaceutically acceptable enteric coating base. The enteric tablet of the present invention can eliminate batch-to-batch quality differences due to mixing unevenness that can occur when two or more types of coating bases are mixed by mixing non-enteric coating base additives.

The enteric coating layer can be formed using an enteric coating base containing an enteric coating polymer in an amount of 20 to 80% by weight. At the same time, the polymer included in the base of the enteric coating can be included in an amount equal to from 20 to 60 wt.%, from 40 to 80 wt.%, from 40 to 60 wt.%, from 35 to 45 wt.%, from 55 up to 65 wt.%, about 40 wt.% or about 60 wt.%.

If the layer of enteric coating is 5 wt.part. or less in terms of 100 wt.chast. nucleus, there may be difficulty in that the drug is released and decomposed in the stomach. On the other hand, if the enteric coating layer is 9 parts by weight. or more in terms of 100 wt.chast. nucleus, the absorption rate of the drug in the body is reduced and it takes a long time to establish an effective concentration, which can lead to the difficulty that the therapeutic effect cannot be properly manifested. The content range of the enteric coating layer of the present invention is preferable for controlling the release rate such that the dimethyl fumarate drug or pharmaceutically acceptable salt thereof is stably released at the in vivo absorption site and dissolution is possible so that the therapeutic effect can be sufficiently manifested.

The particle size distribution of dimethyl fumarate or a pharmaceutically acceptable salt thereof is such that (a) less than 90% of the average particle size (D90) is 100 µm or less; (b) less than 50% average particle size (D50) is 50 µm or less; and (c) less than 10% average particle size (D10) is 20 µm or less, (a) less than 90% average particle size (D90) is 80 µm or less; (b) less than 50% average particle size (D50) is 40 µm or less; and (c) less than 10% average particle size (D10) is 15 µm or less, or (a) less than 90% average particle size (D90) is 50 µm or less; (b) less than 50% average particle size (D50) is 30 µm or less; and (c) less than 10% average particle size (D10) is 10 µm or less.

The thickness of the applied layer of the enteric coating of the tablet can be from 20 µm to 90 µm, from 30 µm to 80 µm, from 30 µm to 50 µm, from 60 µm to 80 µm, from 35 µm to 50 µm, from 65 µm to 80 µm, 35 µm to 80 µm, or 40 µm to 75 µm. In this case, the thickness of the applied layer of the enteric coating of the tablet can be the thickness of the enteric coating layer or the thickness of the applied layer includes the thickness of the protective coating layer and the enteric coating layer.

An enteric-coated tablet can be prepared by a conventional tableting process such as a conventional dry/wet granulation process, a direct powder compression process, or a direct compression process, and preferably can be prepared by a direct compression process.

The enteric-coated tablet can be used to prevent or treat organ fibrosis, neurodegenerative disease, psoriasis, polyarthritis, juvenile diabetes, Hashimoto's disease, Graves' disease, systemic lupus erythematosus, Sjögren's syndrome, pernicious anemia, chronic active hepatitis, lupus-type hepatitis, rheumatoid arthritis, autoimmune disease, inflammatory disease, vascular smooth muscle cell proliferation disease, or optic neuritis. Wherein, organ fibrosis is at least one selected from the group consisting of the following: kidney fibrosis, cardiac fibrosis, pancreatic fibrosis, pulmonary fibrosis, vascular fibrosis, skin fibrosis, bone marrow fibrosis, liver fibrosis, scleroderma, cystic fibrosis, fibrosis pancreas and intestinal fibrosis; renal fibrosis is at least one selected from the group consisting of the following: renal failure, diabetic nephropathy, glomerulosclerosis, renal tubular fibrosis, glomerulonephritis, chronic renal failure, acute kidney injury, chronic kidney disease, end stage renal disease and albuminuria; liver fibrosis is at least one selected from the group consisting of the following: cirrhosis, hepatic nephropathy, hepatic purpura, metabolic liver disease, chronic liver disease, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, alcoholic liver disease, non-alcoholic fatty hepatitis, obesity, diabetes, protein deficiency, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1 antitrypsin deficiency, and primary biliary cirrhosis; pulmonary fibrosis is at least one selected from the group consisting of the following: bronchitis, acute bronchitis, diffuse panbronchiolitis (DPB), bronchiolitis, idiopathic pulmonary fibrosis (IPF), acute interstitial pneumonia, lung transplantation, radiation-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, pulmonary tuberculosis, pneumonia, pneumoconiosis, hypersensitivity pneumonia, pulmonary edema and sarcoidosis; skin fibrosis is at least one selected from the group consisting of the following: scarring, hypertrophic scarring, keloid scarring, skin fibrous disorder, wound healing, delayed wound healing, psoriasis and scleroderma; and neurodegenerative diseases are at least one selected from the group consisting of the following: multiple sclerosis, systemic sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, acute transverse myelitis, acute multiple encephalomyelitis, optic neuritis, acute necrotizing retinitis, transverse myelitis, chronic progressive myelopathy, progressive multifocal leukoencephalopathy, radiation myelopathy, central pontine myelinolysis, leukodystrophy, chronic inflammatory demyelinating polyneuropathy (CIDP), and acute inflammatory demyelinating polyneuropathy (AIDP). However, they are only examples and indications for enteric coating of tablets are not necessarily limited to them.

The enteric-coated tablet may include a powder form and is preferably prepared as an enteric-coated tablet in solid form, but it is not impossible to obtain it in liquid form and this is not excluded from the scope of rights.

The enteric-coated tablet may be administered as a single therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times.

The term "administration" as used herein means administering an enteric tablet to a patient by any suitable method. The enteric tablet can be administered by various routes, orally or parenterally, until it reaches the target tissue. Preferably, the enteric tablet may be administered orally. In addition, the enteric tablet can be prepared in a variety of dosage forms depending on the desired route of administration.

The frequency of administration of the enteric-coated tablet is not particularly limited, but it may be administered once or twice a day, or may be administered multiple times by divided dose. For example, a 120 mg tablet may be administered as one tablet in the morning and afternoon, or a 240 mg tablet may be administered as one tablet in the morning and afternoon. The administered subject may be any animal, including humans, and the animal may be a mammal such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, cats, etc., but they are not always limited only to them.

Another object of the present invention is a method for producing an enteric-coated tablet comprising the following steps:

a step of preparing a mixture by mixing dimethyl fumarate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive;

the step of preparing the core by directly tableting the mixture; and

the step of applying an enteric coating to the core.

When this application enteric coating is carried out using from 6 to 9 wt.chast. layer enteric coating in terms of 100 wt.chast. kernels.

The method may further include the step of applying a protective coating to the step of applying an enteric coating.

Meanwhile, the enteric coating step and/or the protective coating step can be carried out at a temperature of 20°C to 50°C, 20°C to 40°C, and preferably at a temperature of about 25°C to 35°C.

The enteric coating layer may further include additives such as excipients, binders, disintegrants, antioxidants, surfactants, lubricants, plasticizers, and pigments.

The enteric coating step can be carried out with a coating solution in which the enteric coating base and/or pharmaceutically acceptable additive is dissolved in a solvent. The solvent may be used as one or a combination of two or more selected from the group consisting of the following: purified water, alcohol, alkyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, anisole, acetic acid, butyl methyl ether, ethyl ether, ethyl formate, formic acid, pentane, heptane, methyl ethyl ketone and methyl isobutyl ketone.

The coating can be carried out by known means. For example, in the case of spraying, a tank coater, a drum coater, a fluidized bed coater, or an agitated fluidized bed coater can be used. The nebulizer attached to such a device can be an air nebulizer, an airless nebulizer, or a 3-fluid nebulizer. In the case of the dry type, for example, a centrifugal fluidized bed coater, a tank coater, a fluidized bed coater, a motor driven centrifugal fluidized bed coater, and the like can be used.

In the method of obtaining an enteric coating of a tablet, the above content for an enteric coating tablet can be used.

Below, the present invention is described in detail using the following examples and experimental examples.

However, the following examples and experimental examples are provided only to illustrate the present invention, and the content of the present invention is not limited thereto.

Example: Obtaining an enteric-coated tablet

Table 1 Component Dose (mg/tablet) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Core Main component dimethyl fumarate 120.0 120.0 120.0 120.0 120.0 120.0 120.0 alkalizing agent Meglumine 10.0 10.0 10.0 10.0 10.0 10.0 - Inert filler (silicified microcrystalline cellulose), baking powder (croscarmellose sodium and/or crospovidone), lubricant (colloidal silicon dioxide and/or magnesium stearate) 140.0 140.0 140.0 140.0 140.0 140.0 140.0 uncoated tablet 270.0 270.0 270.0 270.0 270.0 270.0 260.0 Primary Coating OPADRY 03K19229 5.4 5.4 5.4 5.4 5.4 5.4 5.2 secondary coating ACRYL-EZE MP 93O18508 10.8 16.2 21.6 - - - - ACRYL-EZE MP 93O18509 - - - 16.2 21.6 21.6 20.8

table 2 Component Dose (mg/tablet) Example 8 Example 9 Example 10 Example 11 Example 12 Core Main component dimethyl fumarate 240.0 240.0 240.0 120.0 120.0 alkalizing agent meglumine 20.0 - - - - Inert filler (silicified microcrystalline cellulose), baking powder (croscarmellose sodium and/or crospovidone), lubricant (colloidal silicon dioxide and/or magnesium stearate) 280.0 300.0 300.0 150.0 150.0 uncoated tablet 540.0 540.0 540.0 270.0 270.0 Primary Coating OPADRY 03K19229 10.8 8.0 8.0 4.0 4.0 secondary coating ACRYL-EZE MP 93O18508 - 43.2 54.0 16.2 22.0 ACRYL-EZE MP 93O18509 43.2 - - - -

Preparation of an enteric-coated tablet containing dimethyl fumarate

The angle of repose of a mixture containing dimethyl fumarate is 40° or less, and it is generally considered that flowability is good enough to allow direct tabletting if the angle of repose is less than 40°. On the other hand, spruces use a wet granulation technique to improve flowability, there may be a problem due to the sublimation of dimethyl fumarate caused by the use of a solvent and drying. Therefore, an enteric-coated tablet comprising dimethyl fumarate is prepared as follows by minimizing contact with water and using a direct tabletting technique in a simple manufacturing technique.

With the compositions of Tables 1 and 2, an enteric coating of the tablets of Examples 1-12 was obtained using the following steps:

preparation of the core (uncoated tablets, i.e. tablets in a compacted state without coating) by mixing dimethyl fumarate and pharmaceutically acceptable additives (inert fillers (silicified microcrystalline cellulose), disintegrants (croscarmellose sodium and/or crospovidone), lubricants (colloidal dioxide silicon and/or magnesium stearate) and alkalizing agents (meglumine)) and thickening the mixture;

applying a primary coating (protective coating) to the core with a coating solution in which the non-enteric coating base is dissolved in a solvent; and

applying a secondary coating to the core with a coating solution in which the enteric coating base is dissolved in a solvent.

If a protective coating (primary coating) is applied before the enteric coating, there is an advantage that adhesion to the tablet surface of the enteric coating base can be increased and acid resistance can be increased. However, a polyvinyl alcohol (PVA) base can be used as a protective coating base, but when using a PVA base, the polymer content of the coating base is low, so it must be applied in an amount equal to about 6 to 10% based on the weight of the tablet. uncoated, more than HPMC backing. In addition, in this case, there is a high possibility that the enteric coating film is applied unevenly depending on the surface and curvature of the tablet, so that deterioration of acid resistance is highly likely. The PVA base should be applied in a water based coating using water as a solvent and drying for a long time at a high temperature of 45°C or higher. Therefore, water-based coating is not a suitable coating technique.

On the other hand, in the case of a protective coating based on hydroxypropyl methylcellulose (HPMC), a thin coating can be applied with a coating content of about 1.5 to 3%, based on the weight of the uncoated tablet, and an oil-based coating can be applied using an organic solvent. ethanol. Loss of dimethyl fumarate can be minimized by drying for a short time at a low temperature of about 25 ~ 35°C. In addition, when using the HPMC base, there is an advantage that the enteric coating film is stably maintained and the enteric coating base containing the copolymer bonds well to the surface of the protective coating film. Therefore, in the enteric-coated tablet containing dimethyl fumarate according to the example, OPADRY 03K19229, mainly composed of HPMC, was used as the base of the protective coating.

ACRYL-EZE MP, which is the base of the enteric coating, is divided into ACRYL-EZE MP 93O18508 and ACRYL-EZE MP 93O18509 depending on the content of the copolymer of methacrylic acid and ethyl acrylate. As shown in Table 3, if the mass content of methacrylic acid and ethyl acrylate is 60 wt./wt.%, it is referred to ACRYL-EZE MP 93O18508, and if the mass content of methacrylic acid and ethyl acrylate is 40 wt./wt.%, it is referred to ACRYL-EZE MP 93O18509. In addition to the methacrylic acid/ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate coating base is also used as the enteric coating base. On the other hand, the coating base based on hydroxypropyl methylcellulose phthalate has a large content of organic solvent, so that it is very possible to detect residual solvent and the coating time is also longer than that of the coating base based on hydroxypropyl methylcellulose phthalate, so that it is usually unusable.

Table 3 Component w/w% Trademark Copolymer of methacrylic acid and ethyl acrylate 60 ACRYL-EZE MP 93O18508 40 ACRYL-EZE MP 93O18509

<Comparative Example>

In Comparative Example 1, 120 mg of a commercially available reference drug tecpider capsule (tecfidera®, Eisai Korea Inc.) was used. In Comparative Examples 2-4, tablets were prepared in the same manner as described in the example, according to the list of ingredients in Table 4.

Table 4 Component Dose (mg/tablet) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Core Main component dimethyl fumarate 120.0 120.0 120.0 120.0 alkalizing agent Meglumine - - - - Inert filler (silicified microcrystalline cellulose), baking powder (croscarmellose sodium and/or crospovidone), lubricant (colloidal silicon dioxide and/or magnesium stearate) The right amount 150.0 150.0 150.0 uncoated tablet 270.0 270.0 270.0 Primary Coating OPADRY 03K19229 - 4.0 4.0 4.0 secondary coating ACRYL-EZE MP 93O18508 - 13.5 28.0 33.0 ACRYL-EZE MP 93O18509 - - - -

<Experimental example 1> Coating layer thickness measurement

To measure the thickness of the enteric coating layer of the enteric-coated tablet of Example 11, Example 12, and Comparative Example 4, the primary coating layer (protective coating), the coating layers of the tablet of Example 11, Example 12, and Comparative Example 4 were examined using a scanning electron microscope (SEM) with using ESEM (Thermo Fisher, Quattro S). The weight of the enteric coating layer (secondary coating layer) of the tablet of example 11 was 6% based on the total weight of the core, 8% in example 12 and 12% in comparative example 4. For SEM examination, the primary coating layer (protective coating), the tablet coating layers of Example 11, Example 12, and Comparative Example 4 were pre-treated by depositing a layer of Os with a thickness of 10 nm or less using an Os deposition apparatus. The results are shown in Table 5 and in FIG. one.

Table 5 Primary coating layer (protective coating) Example 11 Example 12 Comparative Example 4 Average measured value (µm) 17±6 43±6 71±10 109±6

According to the results of Table 5, the film thickness of the enteric coating layer of Examples 11, 12 and Comparative Example 4 is the value obtained by subtracting the thickness of the primary coating layer (protective coating layer) from each average measured value. As shown by the above results, the thickness of the enteric coating layer of Example 11 was the smallest, while Example 12 and Comparative Example 4 were thicker. Thus, the enteric coating layer was thinner the lower the ratio of weight to total weight of the core. It was confirmed that the results of determining the degree of release and pharmacokinetic study influenced the thickness of the applied layer. Therefore, it was confirmed that the results of the determination of the degree of release and the pharmacokinetic study were influenced by the thickness of the applied layer.

<Experimental Example 2> Examination of the release rate depending on the content of the enteric coating

2-1. Release rate for tablet at pH 6.8 as a function of enteric coating content

To determine the release rate for a tablet as a function of the enteric coating content, the release rate of the enteric coating of the tablet of Examples 1-3 was calculated in pH 6.8 solution. The tablets of Examples 1-3 contained 10.8 mg/tablet, 16.2 mg/tablet, and 21.6 mg/tablet ACRYL-EZE MP 93O18508 (methacrylic acid/ethyl acrylate copolymer 60% w/w) as an enteric base. coverage, respectively.

To determine the degree of release, a pH 6.8 buffer (McIlvain's buffer) was prepared and the dissolution of each eluate was examined by a second method (paddle method). Specifically, the volume of the buffer solution was maintained at 900 ml, the stirring speed was maintained at 75 rpm, and the temperature of the buffer solution was maintained at 37±0.5°C. After the start of the dissolution study, the end time was set based on the typical residence time in the internal organ (intestine) at pH 6.8, and the solution was sampled by setting the intermediate time at regular intervals. The collected solution sample was filtered through a filter and analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 6 and in FIG. 2.

Table 6 Release rate (%) minutes Example 1 Example 2 Example 3 0 0.0 0.0 0.0 five 28.0 18.2 2.3 10 86.1 88.0 55.6 fifteen 89.0 90.9 88.0 thirty 89.5 89.4 89.6 45 87.4 87.8 91.0 60 87.6 87.1 90.3 90 84.0 85.1 87.4 120 83.3 82.7 85.6

As shown in Table 6 and FIG. 2, it was confirmed that the greater the content of the enteric coating, the more delayed the initial release from the tablet. Thus, the dissolution of the tablet of Example 1 containing 10.8 mg/tablet ACRYL-EZE MP 93O18508 (methacrylic acid/ethyl acrylate copolymer 60% w/w) as the enteric coating base was the fastest.

2-2. Release rate for a tablet at pH 6.8 as a function of copolymer content in the enteric coating base

To determine the release rate for a tablet as a function of the copolymer content of the enteric coating base, the pH 6.8 release rate of the enteric coating tablet of Examples 2 and 4 was calculated. The tablet of Example 2 contained 16.2 mg/tablet of ACRYL-EZE MP 93O18508 acid and ethyl acrylate 60% w/w) as the base of the enteric coating, and the tablet of example 4 contained 16.2 mg/tablet ACRYL-EZE MP 93O18509 (copolymer of methacrylic acid and ethyl acrylate 40% w/w) as the base enteric coating.

The release rate determination was carried out in the same manner as described in Example 2-1, and the results are shown in Table 7 and FIG. 3.

Table 7 Release rate (%) minutes Example 2 Example 4 0 0.0 0.0 five 18.2 80.1 10 88.0 90.5 fifteen 90.9 92.4 thirty 89.4 93.5 45 87.8 93.9 60 87.1 93.9 90 85.1 92.7 120 82.7 91.6

As shown in Table 7 and FIG. 3, it was confirmed that the initial release rate for the tablet of Example 2 containing ACRYL-EZE MP 93018508 having a high content of methacrylic acid-ethyl acrylate copolymer as the enteric coating base was relatively decreased. Thus, the tablets of example 2 and example 4 both contained 16.2 mg/tablet enteric coating base, while the dissolution of the enteric coating of the tablet of example 4 containing ACRYL-EZE MP 93018509, which has a relatively low content of a copolymer of methacrylic acid and ethyl acrylate (40% wt. ./wt.) was better.

2-3. Release rate for tablet at pH 6.8 depending on the content of the applied base of the enteric coating ACRYL-EZE MP 93018509

To determine the release rate for a tablet depending on the base content of the enteric coating ACRYL-EZE MP 93018509, which was confirmed to have relatively better dissolution in Example 2-2, the release rate at pH 6.8 of the enteric coating tablet of Examples 4 was calculated and 5. The tablets of Examples 4 and 5 contained 16.2 mg/tablet and 21.6 mg/tablet of ACRYL-EZE MP 93018509 (40% w/w methacrylic acid/ethyl acrylate copolymer) as the enteric coating base, respectively.

Determination of the release rate was carried out in the same manner as described in Example 2-1, and the results are shown in Table 8 and FIG. 4.

Table 8 Release rate (%) minutes Example 4 Example 5 0 0.0 0.0 five 80.1 83.3 10 90.5 93.8 fifteen 92.4 94.9 thirty 93.5 95.1 45 93.9 94.8 60 93.9 94.6 90 92.7 93.5 120 91.6 92.2

As shown in Table 8 and FIG. 4, it was confirmed that the release rates for the tablet of Example 4 with an enteric coating content of 6% and for the tablet of Example 5 with an enteric coating content of 8% were similar. However, when considering tablet stability, it is preferable to set the coating content to 8%. Therefore, based on the results for 2-1-2-3, it was confirmed that the tablet of Example 5, in which the content of ACRYL-EZE MP 93018509 enteric coating base was 8%, was the most optimal enteric coated tablet.

<Experimental Example 3> Establishing a Temperature Range by Evaluating Weight Loss During Coating

Depending on the storage temperature, there is a loss of dimethyl fumarate due to sublimation. Accordingly, in order to confirm the degree of weight loss of dimethyl fumarate and the mixture containing it, depending on the drying temperature of the coating, the degree of weight loss was re-determined after 2 weeks at a temperature of 60°C. Here, the dimethyl fumarate mixture was a mixture in which dimethyl fumarate and other pharmaceutically acceptable additives were mixed. The results are shown in FIG. five.

As shown in FIG. 5, dimethyl fumarate (the main component) and the mixture containing it continued to lose weight during drying and sublimation during the coating procedure. Therefore, to prevent losses of dimethyl fumarate, it is necessary to reduce the temperature of the supplied air. Meanwhile, if the supply air temperature during the coating procedure was about 55 to 60°C, the temperature of the product was about 35 to 40°C, thus stable and fast drying could be carried out during protective coating and enteric coating. although the temperature was too low to dry the coating. Therefore, a product temperature in the range of about 25 to 35°C was appropriate.

<Experimental Example 4> Investigation of the release rate depending on the particle size of dimethyl fumarate

The degree of solubilization of a poorly soluble drug increases with increasing particle size of the drug according to the "Noyes-Whitney" equation, and thus the solubility of the drug tends to increase. Therefore, the particle size of dimethyl fumarate was controlled under the conditions shown in Table 9, and comparative release patterns were investigated for the tablet of Example 5 containing micronized dimethyl fumarate (i.e., dimethyl fumarate finely divided to a D90 of 100 µm or less) and a tablet of Example 6 containing non-micronized dimethyl fumarate was tested at pH 6.8. In addition, the determination of the degree of release was carried out in the same manner as described in example 2-1. The results are shown in Table 10 and in FIG. 6.

Table 9 D10 D50 D90 Example 5 Less than 20 µm Less than 50 µm Less than 100 µm Example 6 More than 20 microns More than 50 microns More than 100 microns

Table 10 Release rate (%) minutes Example 5 Example 6 0 0.0 0.0 five 83.3 16.0 10 93.8 30.9 fifteen 94.9 44.4 thirty 95.1 69.1 45 94.8 79.6 60 94.6 84.5 90 93.5 88.2 120 92.2 88.9

As a result, it was confirmed that the release rate of the enteric coating for the tablet containing dimethyl fumarate in pH 6.8 solution was significantly affected by the particle size from the initial to the median time point. In particular, when D90 was greater than 100 μm (Example 6), the release rate was significantly reduced. Therefore, for fast initial release of the drug, it is preferable that the average particle size of less than 90% of dimethyl fumarate (D90) particles is 100 μm or less.

<Experimental Example 5> Investigation of release rate depending on the use of alkalizing agent

Since dimethyl fumarate is a highly basic drug with a pKa value of -6.5, its bioabsorption rate decreases at low pH as the ionization ratio increases according to the Henderson-Haselbach equation. Therefore, in order to increase the rate of bioabsorption of dimethyl fumarate, it is desirable to provide a rapid release of the drug from the drug in the pH range of 6.5 to 6.8 in the duodenum, a known site of drug absorption. Accordingly, the comparative release profile in pH 6.8 solution for the composition containing meglumine (C ₇ H ₁₇ NO ₅ ), the alkalizing agent (Example 5), the composition excluding meglumine (Example 7) and the commercially available control drug (comparative Example 1) from the enteric coating formulations of a tablet containing 120 mg dimethyl fumarate, Examples 1-7 and Comparative Example 1. The results are shown in Table 11 and FIG. 7.

Table 11 Release rate (%) minutes Example 5 Example 7 Comparative Example 1 0 0.0 0.0 0.0 five 83.3 67.0 0.5 10 93.8 83.5 24.2 fifteen 94.9 85.7 59.4 thirty 95.1 86.2 80.5 45 94.8 85.5 83.1 60 94.6 85.5 84.2 90 93.5 84.7 84.8 120 92.2 83.7 85.3

As a result, the composition of Example 5 containing the alkalizing agent had an increased initial release rate compared to the compositions of Example 7 and Comparative Example 1 not containing the alkalizing agent. Thus, the effect of rapidly increasing the initial rate of drug release from a tablet at pH 6.8 (artificial gastric juice) was confirmed in the presence of meglumine, which was used as an alkaline solubilizer among the additives included in the enteric-coated tablet of Example 5.

<Experimental Example 6> Examination of the release rate of an enteric-coated tablet containing 120 mg of dimethyl fumarate

Comparison of release patterns in pH 1.2 solution (artificial gastric juice, disintegrant 1, The Korean Pharmacopoeia) and pH 6.8 solution (artificial gastric juice) for an enteric-coated tablet containing 120 mg dimethyl fumarate (Example 5) , which showed an excellent release rate in Experimental Example 5 and for the control drug (Comparative Example 1). The results are shown in Table 12, Table 13 and FIG. 8 and 9 respectively.

Table 12
pH 1.2 solution (artificial gastric juice) Release rate (%) minutes Example 5 Comparative Example 1 0 0.0 0.0 five 0.2 0.2 10 0.2 0.2 fifteen 0.2 0.2 thirty 0.3 0.2 45 0.4 0.2 60 0.5 0.3 90 0.7 0.3 120 0.8 0.4

Table 13
pH 6.8 solution (artificial gastric juice) Release rate (%) minutes Example 5 Comparative Example 1 0 0.0 0.0 five 83.3 0.5 10 93.8 24.2 fifteen 94.9 59.4 thirty 95.1 80.5 45 94.8 83.1 60 94.6 84.2 90 93.5 84.8 120 92.2 85.3

As a result, in the pH 1.2 artificial gastric juice, almost all of the enteric-coated tablets of Example 5 and the commercially available control drug of Comparative Example 1 did not release. On the other hand, in the pH 6.8 artificial gastric juice, both the preparations of Example 5 and Comparative Example 1 were released, the enteric-coated tablet of Example 5 released faster than the preparation of Comparative Example 1.

To confirm that the enteric-coated tablet of Example 5 had a release pattern similar to that observed for the commercial formulation of Comparative Example 1, the following experiment was performed.

Release Mode Similarity Study

To investigate the similarity of release patterns for the tablet of Example 5 (test drug) and the formulation of Comparative Example 1 (control drug) in pH 1.2 and pH 6.8 solutions, the similarity factor (f ₂ ) was calculated and compared. The similarity coefficient is the logarithm of the reciprocal of the square root of the sum of the squared errors, and its value is obtained by determining the similarity of the release rates (%) for the two dependencies and is calculated by the following mathematical formula.

[math formula]

n: number of time values

R _t : mean release rate for control drug

T _t : mean release rate for study drug.

Here, the appropriate point in time around the average release rate of the control drug (Comparative Example 1) of about 85% was taken as Ta, and the release rates for 1/4Ta, 2/4Ta, 3/4Ta and Ta were compared. The results are shown in Table 14. As a result, in pH 1.2 and pH 6.8 solutions, all formulations of Example 5 and Comparative Example 1 were pharmaceutically equivalent in terms of in vitro drug release characteristics.

Table 14 Test solution 1/4 Ta 2/4 Ta 3/4 Ta Ta f ₂ reference value f ₂ received value Grade pH 1.2 solution 30 minutes 60 min 90 min 120 min ≥55 99.2 Equivalent pH 6.8 solution 45 min 90 min 120 min 180 min ≥55 72.3 Equivalent

<Experimental Example 7> Examination of the release rate of an enteric-coated tablet containing 240 mg of dimethyl fumarate

Since a dose-proportional linear release kinetic of dimethyl fumarate has been shown over the range of 120 mg to 360 mg, a comparative release study according to the Standard on Pharmaceutical Equivalence Study of the Ministry of Food and Drug Safety is possible based on the dose of the active ingredient in the previously approved therapeutic dose range during development high dose drug. Therefore, for a comparative study of the released amount depending on the content of dimethyl fumarate, the released amounts were determined for the tablet of example 5 and example 8. The tablet of example 5 contained 120 mg of dimethyl fumarate and the tablet of example 8 contained 240 mg of dimethyl fumarate.

Determination of the release rate was carried out in the same manner as described in Example 2-1, and the results are shown in Table 15 and FIG. 10.

Table 15 Release rate (%) minutes Example 5 Example 8 0 0.0 0.0 five 83.3 84.3 10 93.8 93.3 fifteen 94.9 94.9 thirty 95.1 95.5 45 94.8 95.3 60 94.6 94.9 90 93.5 93.9 120 92.2 92.8

Release Mode Similarity Study

To investigate the similarity of release patterns for the tablet of Example 8 (test drug) and Example 5 (control drug) in pH 6.8 solution, the similarity factor (f ₂ ) was calculated and compared. The similarity evaluation was carried out according to the Standard on Pharmaceutical Equivalence Study of the Ministry of Food and Drug Safety as in Experimental Example 6. The similarity evaluation results for the tablet of Example 5 and Example 8 are shown in Table 16. As a result, in a solution with a pH of 6.8 , the in vitro release characteristics of the tablet of Example 8 were pharmaceutically equivalent to those of the tablet of Example 5.

Table 16 Test solution Example f ₂ reference value f ₂ received value Grade pH 6.8 solution Example 8 ≥50 98.6 Equivalent

<Experimental Example 8> In vivo study

After oral administration of the preparations of Example 11 and Comparative Examples 1-4 to beagle dogs, a non-clinical study was conducted to study in vivo drug kinetics. At the same time, the mass content of the enteric coating layer of the preparation of example 11 was 6% in terms of the total mass of the core, the mass content of the enteric coating layer of the preparation of comparative example 2 was 5%, the mass content of the enteric coating layer of the preparation of comparative example 3 was 10%, and the mass content of the enteric coating layer of the preparation of comparative example 3 was 10% and the mass content of the enteric coating layer coverage of the preparation of comparative example 4 was 12%. Specifically, 1 enteric tablet prepared in Example 11 and Comparative Examples 2 to 4 or 1 Comparative Example 1 was orally administered to beagle dogs, and blood samples were taken at a set time and analyzed by LC-MSMS. The results are shown in Table 17 and in FIG. 11. However, the values for Comparative Example 3 and Comparative Example 4 were too low to be calculated, so they are not shown in Table 17.

Table 17 Example 11 Comparative Example 1 Comparative Example 2 AUC
(ng.h/ml, _0-36 ) 14441.31±3009.19 15237.59±1375.36 10940.91±1357.99 AUC
(ng.h/ml, _inf ) 14539.73±3008.02 15517.56±1452.83 11073.94±1399.41 _Cmax (ng/ml) 6783.72±1746.61 6096.64±1962.29 5319.22±1071.96 T _max (h) 1.67±1.26 1.83±0.29 2.00±1.00

AUC: area under the plasma concentration-time curve

C _max : maximum plasma concentration

T _max : time to establish maximum plasma concentration.

As shown in Table 17 and FIG. 11, it was confirmed that the enteric tablet of Example 11 had a pharmacokinetic parameter similar to that of the commercially available product (Comparative Example 1), and that the preparations of Comparative Examples 2 to 4 in which the weight content of the enteric coating layer was 5%, 10% and 12%, respectively, based on the total weight of the core, did not have the same potency as the commercially available product (Comparative Example 1) in vivo .

In particular, as shown in Table 17 and FIG. 11, the tablet of example 11 had almost the same AUC and Cmax values with less than 10% deviations from the values for the preparation of comparative example 1, but were not similar to the values for the preparation of comparative example 2 with more than 10% deviations. In addition, the compositions of Comparative Example 3 and Comparative Example 4 resulted in substantially no drug absorption until approximately 12 hours had elapsed. The above results confirm that when the weight content of the enteric coating layer of the enteric tablet containing dimethyl fumarate as the main component was less than 6% or more than 9% based on the total weight of the core, excellent pharmacokinetic results could not be obtained.

The present invention has been described in detail above by way of preferred preparation examples, examples, and experimental examples, but the scope of the present invention is not limited to the specific example, and should be interpreted in accordance with the appended claims. In addition, those skilled in the art will appreciate that numerous modifications and variations are possible without departing from the scope of the present invention.

Claims (30)

1. Enteric-coated tablet for stable delivery of dimethyl fumarate, comprising: a core containing dimethyl fumarate as an active ingredient; an enteric coating layer containing enteric copolymers based on acrylic acid; and a protective coating layer containing a cellulose-based polymer between the core and the enteric coating layer, where, the active ingredient is included in the core in an amount equal to 60 mg to 480 mg, the enteric coating layer is included in an amount of 6 to 9 wt.h. in terms of 100 wt.h. core, the protective coating layer is included in an amount equal to from 1 to 3 wt.h. in terms of 100 wt.h. kernels, and the particle size distribution of dimethyl fumarate satisfies the following conditions: (a) less than 90% average particle size (D90) is 100 µm or less; (b) less than 50% average particle size (D50) is 50 µm or less; and (c) the average particle size of less than 10% (D10) is 20 µm or less. 2. An enteric-coated tablet according to claim 1, wherein the active ingredient is included in an amount equal to 20 to 60% by weight, based on the core. 3. An enteric-coated tablet according to claim 1, wherein the core contains pharmaceutically acceptable additives including excipients, disintegrants, and lubricants. 4. Enteric coated tablet according to claim 3, wherein the excipient is included in an amount of 30 to 45% by weight, the disintegrant is included in an amount of 10 to 20% by weight, and the lubricant is included in an amount of from 0.1 to 2 wt.% in terms of the core. 5. An enteric-coated tablet according to claim 1, wherein the core further comprises an alkalizing agent. 6. An enteric-coated tablet according to claim 5, wherein the ratio of the weight of active ingredient to the weight of alkalizing agent is from 12:0.5 to 12:2. 7. An enteric-coated tablet according to claim 5, wherein the alkalizing agent is included in an amount equal to 2 to 5% by weight, based on the core. 8. An enteric-coated tablet according to claim 5, wherein the alkalizing agent is meglumine or a pharmaceutically acceptable salt thereof. 9. The enteric coated tablet of claim 1, wherein the acrylic acid enteric copolymers are selected from the group consisting of the following: styrene-acrylic acid copolymer, methacrylic acid-ethyl methacrylate copolymer, methyl acrylate-methacrylic acid-octylacrylate copolymer, and methacrylic acid copolymer, and ethyl acrylate. 10. An enteric-coated tablet according to claim 1, wherein the thickness of the applied layer of the enteric-coated tablet is from 20 µm to 90 µm. 11. An enteric-coated tablet according to claim 1, wherein the core is obtained by direct compression. 12. The enteric-coated tablet of claim 1, wherein the tablet is used to prevent or treat organ fibrosis, neurodegenerative disease, psoriasis, polyarthritis, juvenile diabetes, Hashimoto's disease, Graves' disease, systemic lupus erythematosus, Sjögren's syndrome, pernicious anemia, chronic active hepatitis , lupus-type hepatitis, rheumatoid arthritis or optic neuritis. 13. An enteric-coated tablet according to claim 12, wherein the organ fibrosis is at least one selected from the group consisting of the following: renal fibrosis, cardiac fibrosis, pancreatic fibrosis, pulmonary fibrosis, vascular fibrosis, skin fibrosis, bone fibrosis brain, liver fibrosis, scleroderma, cystic fibrosis, pancreatic fibrosis and intestinal fibrosis; renal fibrosis is at least one selected from the group consisting of the following: renal failure, diabetic nephropathy, glomerulosclerosis, renal tubular fibrosis, glomerulonephritis, chronic renal failure, acute kidney injury, chronic kidney disease, end stage renal disease, and albuminuria; liver fibrosis is at least one selected from the group consisting of the following: cirrhosis, hepatic nephropathy, hepatic purpura, metabolic liver disease, chronic liver disease, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, alcoholic liver disease, non-alcoholic fatty hepatitis, obesity, diabetes, protein deficiency, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1 antitrypsin deficiency and primary biliary cirrhosis; pulmonary fibrosis is at least one selected from the group consisting of the following: bronchitis, acute bronchitis, diffuse panbronchiolitis (DPB), bronchiolitis, idiopathic pulmonary fibrosis (IPF), acute interstitial pneumonia, lung transplantation, radiation-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, pulmonary tuberculosis, pneumonia, pneumoconiosis, hypersensitivity pneumonia, pulmonary edema, and sarcoidosis; skin fibrosis is at least one selected from the group consisting of scarring, hypertrophic scarring, keloid scarring, dermal fibrotic disorder, wound healing, delayed wound healing, psoriasis, and scleroderma; and neurodegenerative diseases are at least one selected from the group consisting of the following: multiple sclerosis, systemic sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, acute transverse myelitis, acute disseminated encephalomyelitis, optic neuritis, acute necrotic retinitis, transverse myelitis, chronic progressive myelopathy, progressive multifocal leukoencephalopathy, radiation myelopathy, central pontine myelinolysis, leukodystrophy, chronic inflammatory demyelinating polyneuropathy (CIDP), and acute inflammatory demyelinating polyneuropathy (AIDP). 14. A method for producing an enteric-coated tablet according to claim 1, comprising the following steps: a step of preparing a mixture by mixing dimethyl fumarate and a pharmaceutically acceptable additive; the step of preparing the core by directly tableting the mixture; the step of applying a protective coating to the core; the step of applying an enteric coating to the core, and where the application of enteric coating is carried out using from 6 to 9 wt.h. layer enteric coating in terms of 100 wt.h. kernels. 15. The method for producing an enteric-coated tablet according to claim 14, wherein each protective coating step or enteric coating step is carried out at a temperature of 20°C to 50°C.

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