KR20160076928A - A pharmaceutical formulation in the form of mini-tablets containing a fumaric acid ester - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation of a mini-tablet form, comprising: a mini-tablet core containing at least one fumaric acid ester or pharmaceutically acceptable salts thereof selected from fumaric acid di (C_1 to C_5) alkyl esters and mono-(C_1 to C_5) alkyl esters of fumaric acid and a pharmaceutically acceptable additive; a separability coating layer formed on the core and separating a hydrophilic polymer; and an enteric coating layer formed on the separability coating layer and containing an enteric base material, and to a producing method thereof.

Description

[0001] A pharmaceutical formulation in the form of a mini-tablets containing a fumaric acid ester,

The present invention relates to a controlled release formulation containing a fumaric acid ester as an active ingredient, and more particularly to a controlled release formulation of a fumaric acid ester or a pharmaceutically acceptable salt thereof, which is small in size and administered once per unit dosage form The present invention relates to a pharmaceutical preparation having high adherence and compliance and reduced gastrointestinal side effects and increased stability and bioavailability of an active ingredient, and a preparation method thereof.

Monomethyl fumarate represented by dimethyl fumarate or fumaric acid di (C ₁ -C ₅₎ alkylesters of fumaric acid and a mono - (C ₁ -C ₅₎ autoimmune diseases, such as fumaric acid ester of a drug alkyl ester type is multiple sclerosis ≪ / RTI >

Multiple Sclerosis (MS) is a neurological disease affecting over one million people worldwide. It is the most common cause of neurological disease in adolescents and middle-aged adults, and has serious and major physical, psychological, social, and economic impacts on patients, their families, and people around them. It is presumed that MS is triggered by infection and genetic predisposition is added and mediated by several types of autoimmune processes.

Chronic diseases such as multiple sclerosis require long-term administration of medicines for treatment, and the number of medicines and the size of the medicines have a considerable effect on the patient's compliance with the medicines. In order to improve patient compliance, it is necessary to develop medicines that are small in size and small in dosage so that they can be easily carried or taken.

Conventionally, oral preparations of fumaric acid ester drugs are released at a high concentration in the gastrointestinal tract during oral administration, thereby causing local irritation of the intestinal mucosa. Such local stimulation leads to a high concentration of TNF-a in a short period of time , Which causes gastrointestinal side effects. Thus, it has been known that oral formulations of fumaric acid ester drugs cause gastrointestinal side effects such as diarrhea, epigastric seizures, and nausea at the time of administration. Therefore, there is a need for the development of agents that reduce the gastrointestinal side effects of fumaric acid ester drugs.

Patent Document 1 is a fumaric acid di (C ₁ -C ₅₎ alkylesters of fumaric acid and a mono - (C ₁ -C ₅₎ delays the gastrointestinal release of active ingredient in order to reduce the gastrointestinal side effects of one or more fumaric acid esters selected from alkyl esters of drugs Thereby reducing the increase in the local concentration of the active ingredient at a particular site of the gastrointestinal tract and thereby reducing gastrointestinal side effects. Specifically, it discloses the use of various release-controlled drug delivery systems, including diffusion-controlled drug delivery systems, osmotic controlled drug delivery systems, or erodible drug delivery systems, to delay gastrointestinal release of active ingredients.

Patent Document 2 discloses an oral preparation in which a dialkyl fumarate drug is made into an enteric coated micro-tablet and then filled into capsules. According to this, micro-tablets in capsules are released from the gastrointestinal tract, and micro-tablets are gradually passed through the small intestine by intestinal peristalsis to distribute the active ingredient, so that the local concentration of the active ingredient in the intestinal epithelial cells increases . Therefore, it is possible to avoid the fear of adverse effects due to an increase in local concentration in intestinal epithelial cells.

WO 2006/037342 US 6,509,376

It is an object of the present invention to provide an oral pharmaceutical preparation of a fumaric acid ester drug which is small in side effects of gastrointestinal tract and high in stability of an active ingredient and small in size but small in the number of administration once and can be improved in compliance.

It is another object of the present invention to provide a process for preparing an oral pharmaceutical preparation of the above-mentioned fumaric acid ester drug.

One aspect of the present invention is

At least one fumaric acid ester selected from fumaric acid di (C ₁ -C ₅ ) alkyl esters and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof, Mini-tablet cores;

A separable coating layer formed on the core and containing a hydrophilic polymer; And

A pharmaceutical formulation in the form of a mini-tablet comprising an enteric coating layer formed on the separable coating layer and containing a nutritive base.

In another aspect of the present invention,

At least one fumaric acid ester selected from fumaric acid di (C ₁ -C ₅ ) alkyl esters and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof, A core-making step of producing a mini-tablet core;

A separable coating layer forming step of coating the mini-tablet core with a hydrophilic polymer-containing coating liquid; And

And a step of forming an enteric coating layer for coating the separable coating layer with an enteric coating solution containing a nutrient-based base, to prepare a pharmaceutical preparation in the mini-tablet form according to an aspect of the present invention.

The pharmaceutical preparations for oral use according to the present invention are in the form of enteric-coated mini-tablets, in which the mini-tablets sequentially reach the small intestine by peristalsis of the small intestine and sequentially reach the small intestine and dissolve the enteric coating As a result, the release of the drug can be avoided, and the rapid release of the fumaric acid ester drug in the intestine can be avoided, thereby avoiding an increase in the local concentration of the active ingredient on the intestinal epithelial cells. Therefore, there is low concern about gastrointestinal side effects, and patient compliance is high. In addition, the mini-tablet has a separable coating layer between the mini-tablet core and the enteric coating layer to prevent contact between the active ingredient and the enteric coating layer to increase the storage stability of the active ingredient, High bioavailability of the component can be maintained. In addition, the oral combination preparation according to the present invention can be administered in a very small capsule and can be administered once a unit dosage form. Therefore, it is possible to provide a drug for a patient taking a fumaric acid ester drug requiring long- There is an advantage that compliance can be remarkably increased.

1 is a graph showing the initial dissolution rate of Example 1 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
2 is a graph showing the initial dissolution rate of Example 2 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
3 is a graph showing the initial dissolution rate of Example 3 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
4 is a graph showing the initial dissolution rate of Example 4 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
5 is a graph showing the initial dissolution rate of Example 5 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
6 is a graph showing the initial dissolution rate of Example 6 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
7 is a graph showing the initial dissolution rate of Example 7 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
8 is a graph showing the initial dissolution rate of Comparative Example 1 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
9 is a graph showing the initial dissolution rate of Comparative Example 2 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
10 is a graph showing the initial dissolution rate of Comparative Example 4 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
11 is a graph showing the initial dissolution rate of Comparative Example 6 and the dissolution rate after storage at a temperature of 40 ° C and 75% moisture.
12 is a graph showing changes in bioavailability of monomethyl fumarate over time for the formulation of Example 1 and Comparative Example 6. Fig.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect of the present invention is

At least one fumaric acid ester selected from fumaric acid di (C ₁ -C ₅ ) alkyl esters and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof, Mini-tablet cores;

A separable coating layer formed on the core and containing a hydrophilic polymer; And

A pharmaceutical formulation in the form of a mini-tablet comprising an enteric coating layer formed on the separable coating layer and containing a nutritive base.

As used herein, the term " fumaric acid ester " has the chemical name mono - (C ₁ -C ₅ ) alkyl ester of fumaric acid di (C ₁ -C ₅ ) alkyl ester or fumaric acid and is used in the treatment or amelioration of autoimmune diseases including multiple sclerosis Means any effective drug.

As used herein, "mini-tablet" refers to tablets having a diameter of about 1-10 mm and a mass of about 2-20 mg. In one embodiment, the mini-tablet has a diameter of about 1-5 mm and a mass of about 5-15 mg.

As used herein, the term "mini-tablet core" refers to any core that may be the size and mass range of the mini-tablet, including an additional coating layer, as the core containing the active ingredient for making the mini- do.

As used herein, " pharmaceutical formulation in the form of a mini-tablet " means any form of formulation comprising a plurality of mini-tablets to contain a single dose of the fumaric acid ester, The tablet itself, or the plurality of mini-tablets, may be in the form of a capsule or sachet filled.

The mini-tablet core comprises at least one fumaric acid ester selected from the group consisting of fumaric acid di (C ₁ -C ₅ ) alkyl esters and mono - (C ₁ -C ₅ ) alkyl esters of fumaric acid or a pharmaceutically acceptable salt thereof . Such pharmaceutically acceptable salts include salts of metal cations. The metal cation may include, but is not limited to, an alkali metal, an alkaline earth metal, or a transition metal ion, for example, Li, K, Na, Mg, Ca, Sr, Zn, Fe, or Mn.

In one embodiment, the fumaric acid ester is monomethyl fumarate or dimethyl fumarate.

The mini-tablet core may comprise a fumaric acid ester or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and may be prepared according to the conventional method of manufacturing mini-tablets known in the art. The direct compression method or the granular compression method can be used as a method for producing mini-tablets.

The direct compression method is a method for preparing tablets by mixing the additives or active ingredients such as excipients, binders and disintegrants into tablets or powders by directly kneading the dried mixture in a tablet machine. There is no advantage. However, fumaric acid esters, particularly monomethyl fumarate or pharmaceutically acceptable salts thereof, are poor in compressibility and fluidity, so that even after mixing with other pharmaceutical additives, the fluidity is poor inside the tablet machine, Not only the productivity is lowered but also there may be a limit in producing tablets having the desired mass and size (see Test Example 1, Table 8, Comparative Example 5).

The granule compression method is a method in which granules are first prepared by mixing an active ingredient with a pharmaceutical additive and then granulating the granules. The granulation method may be divided into a wet granulation method and a dry granulation method depending on whether a bonding liquid is used or not. The wet granulation method is a method in which an excipient, disintegrant, etc. is added to the active ingredient, granulation is carried out by adding a binding liquid, and the mixture is dried, and the size of the granules is made constant by using a sizing machine and then mixed with a lubricant. Is a method of making a slug using a slug purifier or using a roller compactor to make granules in a sheet form, pulverizing and sizing it, and then mixing the slug with a lubricant.

In one embodiment of the invention, the method of making the mini-tablet core is a granular compression method. When granulated by the granular compression method, granules having excellent fluidity and flowability can be formed, which is preferable for tableting. Thus, unlike the direct compression method, the granule-compression method can make the mini-tablet core small in size and yet have a sufficiently high mass of active ingredient, and therefore, a single dose can be contained in one unit dosage form And can be administered once per unit dosage form (see Test Example 1, Table 8).

In one embodiment of the present invention, the granulation method is a dry granulation method. When mini-tablets are prepared using the wet granulation method in the production of the mini-tablet cores, there may be a problem of deterioration of dissolution which does not show the dissolution rate of the active ingredient to a desired extent during long-term storage, . Further, there is a problem that the storage stability of the active ingredient is reduced (see Test Example 2, Fig. 10, and Comparative Example 4). On the other hand, when the mini-tablet cores were prepared using the dry granulation method, there was no decrease in the dissolution rate of the active ingredient, indicating excellent efficacy (Test Example 2, Fig. 1-7) And it contributes to productivity improvement. As the dry granulation method, any dry granulation method known in the art can be used. For example, the dry granulation method is not limited to the roller compression method or the slugging method.

The mini-tablet cores, together with the active ingredient, comprise a pharmaceutically acceptable additive which can be routinely used in the preparation of mini-tablets. The pharmaceutically acceptable excipient may be a component selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and any combination thereof. In general, in the case of pharmaceutical additives, And can be used in any suitable amount customary for formulation. Specifically, pharmaceutically acceptable diluents include starch, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, dextrin, mannitol, sorbitol, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, other saccharides and any mixtures thereof Hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, ≪ / RTI > and mixtures thereof. The disintegrant may be selected from the group consisting of croscarmellose sodium, crospovidone, pregelatinized starch, low-substituted hydroxypropylcellulose, sodium starch glycolate, and any mixture thereof. As the lubricant, Wherein the polymer is selected from the group consisting of stearic acid, magnesium stearate, talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white lead, titanium oxide, microcrystalline cellulose, macrogol, Can be used.

The separable coating layer is a layer separating the mini-tablet core from the enteric coating layer, and serves to block the interaction between the active ingredient contained in the core and the enteric coating layer. The separating coating layer is capable of blocking the interaction between the core and the enteric coating layer and is capable of preventing the release of the drug in the mini-tablet core upon collapse of the enteric coating layer after administration of the pharmaceutical preparation, to be.

Wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, polyethylene glycol, dextrin, But it is not limited thereto.

As a result of the test, a mini-tablet prepared by forming a separable coating layer on a mini-tablet core of a fumaric acid ester drug and forming an enteric coating layer was filled in capsules and then subjected to a dissolution test after 6 months of initial and acceleration conditions. As a result, When the separable coating layer was not formed in sufficient amount, the active ingredient dissolution rate after 6 months of accelerated condition was significantly lower than the initial dissolution rate. Accordingly, the separable coating layer prevents the interaction between the active ingredient and the enteric coating layer, thereby increasing the stability of the active ingredient. As a result, the dissolution rate of the active ingredient is maintained after prolonged storage, It can be done.

The amount of the separable coating layer should be at least a certain ratio in order to achieve the desired effect. However, if the amount is too large, it is disadvantageous in preparing a desired small-sized preparation (Test Example 1, Table 8) The stability of the active ingredient is lowered and the dissolution rate of the active ingredient after storage for a long period of time is lowered (Test Example 2, Figs. 8 and 9). The content of the separable coating layer may vary depending on the kind of the hydrophilic polymer constituting the separable coating layer, but it may be about 3-15% by weight, more specifically 5-10% by weight, based on the core in one embodiment .

The enteric coating layer can be prepared by a method in which the active ingredient present in the mini-tablet is not eluted at once, even when a plurality of mini-tablets filled in a capsule or the like are simultaneously discharged from the stomach when the pharmaceutical preparation of the mini-tablet form is orally administered, When the mini-tablet of the present invention reaches the small intestine sequentially by peristaltic motion of the intestinal tract, the enteric coating layer is dissolved and the active ingredient can be eluted. By such a method, elution of the active ingredient can be gradually released without showing a high local concentration at a specific site in the intestinal tract, and gastrointestinal side effects of the fumaric acid ester drug can be avoided. In addition, the bioavailability of the fumaric acid ester drug can be increased by the presence of an enteric coating layer (Table 9 and Figure 12).

The enteric coating layer may be any enteric coating agent known in the art. The enteric coating agent may be selected from the group consisting of cellulose derivatives, gums, hydrophilic or hydrophobic (meth) acrylate copolymers, methacrylic acid copolymers, hydroxypropylcellulose phthalate, hydroxypropylcellulose acetate succinate, But it is not limited thereto.

In order to obtain the desired effect, the enteric coating layer should be present at a certain ratio or more. However, when too much is formed, it is disadvantageous in preparing a desired small-sized preparation (Test Example 1, Table 8) There is a possibility that the bioavailability of the component is lowered (Test Example 3, Table 9, and Fig. 12). The content of the enteric coating layer may vary depending on the kind of the enteric coating agent constituting the composition, but may be present in an amount of about 8 to 25% by weight, more specifically 13 to 20% by weight, based on the sum of the core and the separable coating layer .

In one embodiment, the pharmaceutical preparation in the mini-tablet form exhibits a dissolution rate of less than or equal to 10% by weight for 2 hours in the artificial gastric juice of pH 1.2 during the dissolution test according to the United States Pharmacopoeia second method paddle method, It shows a dissolution rate of 80% or more within 30 minutes in the intestinal fluid.

The pharmaceutical preparations in the form of mini-tablets may be in the form of a plurality of mini-tablets themselves, or a plurality of mini-tablets filled in capsules or sacks. The capsule or sachet may contain about 10-100 mini-tablets per unit dosage form, more specifically about 20-90, more specifically about 30-80.

In one embodiment, the capsule has a size of no greater than zero, and may contain about 10-100 mini-tablets, more specifically about 20-90, more specifically about 30-80 . ≪ / RTI > No. 0 capsules are small capsules of about 20.5 to 23.5 mm in length, which can increase patient compliance due to their small size.

The mini-tablet form of the pharmaceutical preparation may contain a single dose of the fumaric acid ester drug per unit dosage form such as a capsule or sachet, so that a unit dosage form may be administered once. Thus, the pharmaceutical preparations in the mini-tablet form can contain a single dose of the active ingredient in a capsule of small size, and the small size of the preparation and the administration of one unit dosage form can improve the patient's compliance .

The dosage of fumaric acid ester drug may vary depending on the type of drug, but in the case of monomethyl fumarate, about 230 to 480 mg can be administered per 60 kg adult male, 1-2 times a day, 1 One unit dosage form may be administered.

In another aspect of the present invention,

At least one fumaric acid ester selected from fumaric acid di (C ₁ -C ₅ ) alkyl esters and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof, A core-making step of producing a mini-tablet core;

A separable coating layer forming step of coating the mini-tablet core with a hydrophilic polymer-containing coating liquid; And

And a step of forming an enteric coating layer on the separable coating layer by coating with an enteric coating solution containing a nutrient-based base material.

Details of the method for preparing the pharmaceutical preparation in the mini-tablet form can be applied as it is in the description of the pharmaceutical preparation in the mini-tablet form according to one aspect of the present invention.

In one embodiment, the step of preparing the mini-tablet core comprises the steps of: preparing a dry granule containing the fumaric acid ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; And

And tableting the mini-tablet by granular compression method using the dry granules.

In one embodiment, the production of the dry granules may be carried out by roller compression or slugging.

The method for producing the pharmaceutical preparation in the mini-tablet form may further include filling the capsule or sack with the mini-tablet in which the enteric coating layer is formed, thereby preparing a preparation filled in a capsule or a sack .

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  1 to 4 and Comparative Example  1 to 3

With varying proportions of separable coating layers, Dry granulation method  By compression Endurance  Manufacture of mini-tablets

(1) granulation using dry granulation

The monomethyl fumarate is thoroughly mixed with the siliconized microcrystalline cellulose, croscarmellose sodium and talc in advance. The mixed powders were compacted using a roller compactor with a minimum denuding force. The thus obtained flake granules were made into a powder having a size of not more than 600 μm (30 mesh) using a sizing machine.

(2) Preparation of mini-tablets by granulation method

Magnesium stearate was added to the prepared granules and mixed for about 5 minutes. After mixing, the final mixed powder is transferred to a tablet machine that has been previously prepared so that the mini-tablet can be tableted. Shaped tablet-like mini-tablet having a size of about 2 mm in diameter on a tabletting machine.

(3) Formation of separable coating layer on mini-tablet core

The coating solution was prepared by previously mixing hydroxypropyl methylcellulose and talc in an appropriate ratio. The produced mini-tablets were put in a coater and coated. When the weight of the mini-tablet at the start of the coating is measured and the coating weight is increased by about 3%, 5%, 10, 15% at the initial refining weight, the coating operation is stopped, Mini-tablets containing 3% (Example 1), 5% (Example 2), 10% (Example 3) and 15% (Example 4)

As a comparative example to this embodiment, it was found that when the separable coating layer was not present in sufficient amount (Comparative Example 2), when the separable coating layer was present in excess (Comparative Example 3), and when the separable coating layer was not present (Comparative Example 1) was also prepared.

(4) Formation of an enteric coating layer

A coating solution of a nutrient-based base was prepared by mixing Eudragit L30 D-55 with a plasticizer and dissolving in water. The mini-tablets containing the ready-to-use separating coating layer were then placed in a coater and coated. At the start of coating, the weight of the mini-tablets was measured, and the coating operation was stopped when the coating weight was increased by about 15% at the initial tablet weight, so that the enteric coating layer was contained at a ratio of about 15% ≪ / RTI > was prepared.

The components and the content (unit: mg) used in the preparation of enteric mini- tablets of Examples 1 to 4 and Comparative Examples 1 to 3 are shown in Tables 1 to 3 below.

Example 1 Example 2 Example 3 Example 4 Core component Monomethyl fumarate (MMF) 240.0 240.0 240.0 240.0 Siliconized microcrystalline cellulose 105.0 105.0 105.0 105.0 Cross camelose sodium 38.2 38.2 38.2 38.2 Talc 12.0 12.0 12.0 12.0 Magnesium stearate 4.8 4.8 4.8 4.8 Core amount 400.0 400.0 400.0 400.0 The inner coating component Hydroxypropylmethylcellulose 8.4 14.0 28.0 42.0 Talc 3.6 6.0 12.0 18.0 Purified water Proper amount Proper amount Proper amount Proper amount Total amount of separable coating layer 12.0 20.0 40.0 60.0 Enteric coating component Eudragit L30D-55 (solid content) 55.5 56.6 59.3 62.0 Triethyl citrate 4.9 5.0 5.2 5.5 Glyceryl monostearate 1.0 1.0 1.1 1.1 Polysorbate 80 0.4 0.4 0.4 0.4 Purified water Proper amount Proper amount Proper amount Proper amount Total amount of enteric coating layer 61.8 63.0 66.0 69.0 Total amount 473.8 483.0 506.0 529.0

Comparative Example 2 Comparative Example 3 Core component Monomethyl fumarate 240.0 240.0 Siliconized microcrystalline cellulose 105.0 105.0 Cross camelose sodium 38.2 38.2 Talc 12.0 12.0 Magnesium stearate 4.8 4.8 Core amount 400.0 400.0 The inner coating component Hydroxypropylmethylcellulose 5.6 47.6 Talc 2.4 20.4 Purified water Proper amount Proper amount Total amount of separable coating layer 8.0 68.0 Enteric coating component Eudragit L30D-55 (solid content) 55.0 63.0 Triethyl citrate 4.9 5.6 Glyceryl monostearate 1.0 1.1 Polysorbate 80 0.4 0.5 Purified water Proper amount Proper amount Total amount of enteric coating layer 61.2 70.2 Total amount 469.2 538.2

Comparative Example 1 Core component Monomethyl fumarate 240.0 Siliconized microcrystalline cellulose 105.0 Cross camelose sodium 38.2 Talc 12.0 Magnesium stearate 4.8 Core amount 400.0 The inner coating component Hydroxypropylmethylcellulose 0.0 Talc 0.0 Purified water Proper amount Total amount of separable coating layer 0.0 Enteric coating component Eudragit L30D-55 (solid content) 53.9 Triethyl citrate 4.8 Glyceryl monostearate 1.0 Polysorbate 80 0.4 Purified water Proper amount Total amount of enteric coating layer 60.0 Total amount 460.0

Comparative Example  4: Wet granulation method  By compression Endurance  Manufacture of mini-tablets

(1) Granulation using wet granulation

The monomethyl fumarate was thoroughly mixed with the microcrystalline cellulose, croscarmellose sodium and talc beforehand and added to the high-shear mixer. The wet granules were then prepared using about 10% by weight of purified water relative to the powder part. The prepared wet granules were completely dried with a fluid bed drier and then transferred to a sizing machine to form the wet granules.

(2) Preparation of mini-tablets by granulation method

Magnesium stearate was added to the prepared granules and mixed for about 5 minutes. After mixing, the final mixed powder is transferred to a tablet machine that has been previously prepared so that the mini-tablet can be tableted. Shaped tablet-like mini-tablet having a size of about 2 mm in diameter on a tabletting machine.

(3) Formation of separable coating layer and enteric coating layer on mini-tablet core

In the same manner as in Example 2, a separable coating layer was formed on the mini-tablet, and then an enteric coating layer was formed.

The ingredients and the content (unit: mg) used in the preparation of the enteric mini- tablets of Comparative Example 4 are shown in Table 4 below.

Comparative Example 4 Core component Monomethyl fumarate 240.0 Siliconized microcrystalline cellulose 105.0 Cross camelose sodium 38.2 Talc 12.0 Purified water Proper amount Magnesium stearate 4.8 Core amount 400.0 The inner coating component Hydroxypropylmethylcellulose 14.0 Talc 6.0 Purified water Proper amount Total amount of separable coating layer 20.0 Enteric coating component Eudragit L30D-55 (solid content) 56.6 Triethyl citrate 5.0 Glyceryl monostearate 1.0 Polysorbate 80 0.4 Purified water Proper amount Total amount of enteric coating layer 63.0 Total amount 483.0

Comparative Example  5: Direct compression method Endurance  Mini-Tablet Manufacture

(1) Preparation of mini-tablets using direct compression method

Monomethyl fumarate was thoroughly mixed with the siliconized microcrystalline cellulose, croscarmellose sodium and talc. Then, magnesium stearate was added and mixed for about 5 minutes. After the mixing, the final mixed powder was transferred to a tablet machine which had been previously prepared so that the mini-tablet could be tableted. Shaped tablet-like mini-tablet having a size of about 2 mm in diameter on a tabletting machine.

(2) Formation of separable coating layer on mini-tablet core

The coating solution was prepared by previously mixing hydroxypropyl methylcellulose and talc in an appropriate ratio. The produced mini-tablets were put in a coater and coated. When the weight of the mini-tablet at the start of the coating is measured and the coating is proceeded, if the weight of each initial weight of the tablet increases by about 5%, the coating operation is stopped and the separable coating layer is formed at a ratio of about 5% ≪ / RTI > was prepared.

(3) Formation of separable coating layer and enteric coating layer on mini-tablet core

In the same manner as in Example 2, a separable coating layer was formed on the mini-tablet, and then an enteric coating layer was formed.

The ingredients and the content (unit: mg) used in the preparation of the enteric mini- tablets of Comparative Example 5 are shown in Table 5 below.

Comparative Example 5 Core component Monomethyl fumarate 240.0 Siliconized microcrystalline cellulose 105.0 Cross camelose sodium 38.2 Talc 12.0 Magnesium stearate 4.8 Core amount 400.0 The inner coating component Hydroxypropylmethylcellulose 14.0 Talc 6.0 Purified water Proper amount Total amount of separable coating layer 20.0 Enteric coating component Eudragit L30D-55 (solid content) 56.6 Triethyl citrate 5.0 Glyceryl monostearate 1.0 Polysorbate 80 0.4 Purified water Proper amount Total amount of enteric coating layer 63.0 Total amount 483.0

Example  5 to 7, and Comparative Example  6 and 7

Varying proportions of Endurance  Coating layer, by dry granulation compression method Endurance  Manufacture of mini-tablets

(One)  Preparation of Mini-Tablets with Separable Coating Layer

In the same manner as in the preparation of granules using (1) dry granulation method of the above Example 2, (2) preparation of a mini-tablet, and (3) preparation of a tablet including a separable coating layer, % ≪ / RTI > by weight.

(2) Formation of an enteric coating layer

A coating solution of a nutrient-based base was prepared by mixing Eudragit L30 D-55 with a plasticizer and dissolving in water. The mini-tablets containing the ready-to-use separating coating layer were then placed in a coater and coated. At the start of coating, the weight of mini-tablets was measured and the coating was stopped at the time of weight increase of about 7%, 8%, 20%, 25%, and 27% The coating layers were each applied in a weight ratio of 7% (Comparative Example 6), 8% (Example 5), 20% (Example 6), 25% (Example 7), and 27% (Comparative Example 7) ≪ / RTI > was prepared.

The components and the content (unit: mg) used in the preparation of the enteric mini- tablets of Examples 5 to 7 and Comparative Examples 6 and 7 are shown in Tables 6 and 7 below.

Example 5 Example 6 Example 7 Core component Monomethyl fumarate 240.0 240.0 240.0 Siliconized microcrystalline cellulose 105.0 105.0 105.0 Cross camelose sodium 38.2 38.2 38.2 Talc 12.0 12.0 12.0 Magnesium stearate 4.8 4.8 4.8 Core amount 400.0 400.0 400.0 The inner coating component Hydroxypropylmethylcellulose 14.0 14.0 14.0 Talc 6.0 6.0 6.0 Purified water Proper amount Proper amount Proper amount Total amount of separable coating layer 20.0 20.0 20.0 Enteric coating component Eudragit L30D-55 (solid content) 30.2 75.4 94.3 Triethyl citrate 2.7 6.7 8.3 Glyceryl monostearate 0.5 1.4 1.7 Polysorbate 80 0.2 0.5 0.7 Purified water Proper amount Proper amount Proper amount Total amount of enteric coating layer 33.6 84.0 105.0 Total amount 453.6 504.0 525.0

Comparative Example 6 Comparative Example 7 Core component Monomethyl fumarate 240.0 240.0 Siliconized microcrystalline cellulose 105.0 105.0 Cross camelose sodium 38.2 38.2 Talc 12.0 12.0 Magnesium stearate 4.8 4.8 Core amount 400.0 400.0 The inner coating component Hydroxypropylmethylcellulose 14.0 14.0 Talc 6.0 6.0 Purified water Proper amount Proper amount Total amount of separable coating layer 20.0 20.0 Enteric coating component Eudragit L30D-55 (solid content) 26.4 101.8 Triethyl citrate 2.3 9.0 Glyceryl monostearate 0.5 1.8 Polysorbate 80 0.2 0.7 Purified water Proper amount Proper amount Total amount of enteric coating layer 29.4 113.4 Total amount 449.4 533.4

Test Example  1: Capsules Chargeability  exam

The mini-tablets obtained in Examples 1 to 7 and Comparative Examples 1 to 7 were filled in gelatin capsules. As a result, the number of mini-tablets containing 240 mg of each monomethyl fumarate and the minimum size of the gelatin capsules capable of containing the mini-tablets are shown in Table 8 below.

Total mass MMF 240mg equivalent of
Mini - Number of tablets Capsuleable
Lowest capsule lake Example 1 473.80 46 ~ 49 # 0 Example 2 483.00 47 ~ 49 # 0 Example 3 506.00 47 to 50 # 0 Example 4 529.00 48 to 50 # 0 Example 5 453.60 46 ~ 48 # 0 Example 6 504.00 47 to 50 # 0 Example 7 525.00 48 to 50 # 0 Comparative Example 1 460.00 46 ~ 48 # 0 Comparative Example 2 469.20 46 ~ 49 # 0 Comparative Example 3 538.20 49-52 # 0 EL Comparative Example 4 483.00 47 ~ 49 # 0 Comparative Example 5 483.00 55 ~ 59 # 0 EL Comparative Example 6 449.40 44 to 46 # 0 Comparative Example 7 533.40 49 ~ 51 # 0 EL

As shown in Table 8 above, 240 mg of monomethyl fumarate, except for Comparative Example 3 (excess of separable coating layer content), Comparative Example 5 (direct mini tablet) and Comparative Example 7 (intolerable coating layer content gradient) The number of the corresponding mini-tablets could be filled into capsule No. 0.

The mini-tablets of Comparative Example 3 showed that the coating ratio of the separable coating layer was 17%, the total mass of the mini-tablets corresponding to 240 mg of the active ingredient exceeded 530 mg, and the larger capsule No. 0 EL . The capsule could be charged.

The mini-tablets of Comparative Example 7 had an excess of enteric coating layer, so that the total mass of mini-tablets corresponding to 240 mg of active ingredient was not suitable for filling capsule No. 0.

In contrast, the mini-tablet of Comparative Example 5 had a lower total mass of the mini-tablets corresponding to 240 mg of the active ingredient, but the density of the mini-tablets formed by the direct tableting method was so low that the mass of the individual mini- The capsule could not be charged to 0 due to the excessive increase in the number of the entire mini-tablets (i.e., due to the increase in volume).

From these results, it can be seen that, in order to formulate a mini-size capsule such as capsule No. 0, the mini-tablet core is prepared by granulation and the mini-tablet contains about 3-15% , And a formulation comprising about 8-25% by weight of an enteric coating layer for a mini-tablet core comprising a separable coating layer is preferred.

Test Example  2: dissolution test

The mini-tablets prepared in Examples 1 to 7 and Comparative Examples 1, 2, 4 and 6 were packed in No. 0 gelatin capsules, and samples were stored for 6 months under initial and accelerated conditions (40 ° C, 75% relative humidity) Method 2 of the United States Pharmacopoeia paddle method A dissolution test was conducted at a rotating speed of 100 rpm. 500 mL of the 0.1 N hydrochloric acid buffer solution (pH of about 1.2) is eluted for 2 hours, then 500 mL of phosphate buffer solution (65.4 g of sodium dihydrogenphosphate and 28.2 g of sodium hydroxide are dissolved in 4 L of water) An elution test was performed for an additional 2 hours at the serous condition (pH of about 6.8). The elution rate of monomethyl fumarate was measured by taking the eluate after about 5, 10, 15, 30, 60 and 120 minutes after the start of elution, and furthermore, the eluate after 125, 130, 135, 150, The dissolution rate of fumarate was measured and calculated. The graphs showing the results are shown in Figs.

In the case of Examples 1-7 (Figs. 1 to 7), in the case of capsules made with mini-tablets containing a suitable amount of separable coating layer, within 30 minutes from storage under artificial intestinal fluid conditions for initial and accelerated conditions for 6 months Showed a stable dissolution profile showing 80% or more release, and it was confirmed that the separable coating layer exhibited a sufficient dissolution rate without affecting the dissolution rate of the active ingredient.

Further, it was confirmed that the stability of the active ingredient was maintained for 6 months under accelerated conditions by the separable coating layer formed between the active ingredient-containing mini-tablet core and the enteric coating layer, .

On the other hand, as shown in Figs. 8 and 9, in Comparative Examples 1 and 2 including the detachable coating layer below the optimum amount, the dissolution rate was markedly lowered at the initial stage of storage for 6 months under accelerated conditions. Also, as shown in FIG. 10, when the mini-tablet core was prepared by the granular compression method by the wet granulation method (Comparative Example 4), the dissolution rate at the initial stage of 6 months storage was significantly lowered and the stability was poor . According to Fig. 11, when the enteric coating layer was less than the proper amount (Comparative Example 6), the dissolution rate in the artificial intestinal fluid condition exceeded 10% for 2 hours even after the initial and accelerated condition storage for 6 months, There is concern about gastrointestinal side effects.

Test Example  3: Evaluation of drug bioavailability

The mini-tablets of Example 1 and Comparative Example 6 were filled into gelatin capsules, each made into a formulation containing 120 mg of monomethyl fumarate, and the pre-vivo bioavailability was evaluated in beagle dogs. Six beagle dogs were randomly cross-studied, and the resulting pharmacokinetic parameter results are shown in Table 9 and FIG. 12, respectively.

FIG. 12 is a graph showing the plasma concentrations of monomethyl fumarate (ng / mL) obtained in the course of time (hour) as a result of administering the capsules prepared in Example 1 and Comparative Example 6 to beagle dogs Fig.

parameter Example 1 Comparative Example 6 AUC0-24 (ng.hr / mL) 8729.0 + - 3297.9 5043 ± 1729.7 Cmax (ng / mL) 6009.5 ± 2890.9 2751 + - 1127 Tmax (hr) 2.0 ± 1.6 1.4 ± 0.7

According to the results of Table 9 and FIG. 12, it was confirmed that the case of Example 1 including an appropriate amount of the enteric coating layer had a significantly higher bioavailability than that of Comparative Example 6 which did not sufficiently contain the enteric coating layer. It has been found that monomethyl fumarate exhibits a high bioavailability as well as a reduction in the risk of adverse effects by maintaining sufficient enteric properties. It can be seen that the thickness of the enteric coating layer in the pharmaceutical preparation of the present invention is large It is confirmed that it can affect.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (19)

At least one fumaric acid ester selected from fumaric acid di (C ₁ -C ₅ ) alkyl esters and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof, Mini-tablet cores;
A separable coating layer formed on the core and containing a hydrophilic polymer; And
And an enteric coating layer formed on the separable coating layer and containing a nutrient base. The pharmaceutical formulation according to claim 1, wherein the mini-tablet core is in the form of a mini-tablet made by granular compression of dry granules. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable additive is selected from the group consisting of a diluent, a disintegrant, a lubricant, and any combination thereof. [Claim 2] The method according to claim 1, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, polyethylene glycol, dextrin, ≪ / RTI > or any combination thereof. The pharmaceutical formulation of claim 1, wherein the separable coating layer is present in an amount of 3-15% by weight relative to the mini-tablet core. [2] The composition of claim 1, wherein the enteric base is selected from the group consisting of cellulose derivatives, gums, hydrophilic or hydrophobic (meth) acrylate copolymers, methacrylic acid copolymers, hydroxypropylcellulose phthalate, hydroxypropylcellulose acetate succinate, ≪ / RTI > or a combination thereof. The pharmaceutical formulation according to claim 1, wherein the enteric coating layer is present in an amount of 8-25% by weight based on the sum of the mini-tablet core and the separable coating layer. The pharmaceutical preparation according to claim 1, wherein the fumaric acid ester is monomethyl fumarate or dimethyl fumarate. The pharmaceutical preparation according to claim 1, wherein the composition exhibits a dissolution rate of not more than 10% by weight in the artificial gastric juice of pH 1.2 during the dissolution test for 2 hours and a dissolution rate of not less than 80% by weight in the artificial intestinal fluid of pH 6.8 within 30 minutes. The pharmaceutical preparation according to claim 1, wherein the mini-tablet is a mini-tablet having a mass of 5-15 mg. The pharmaceutical preparation according to claim 1, wherein the mini-tablet has a circular and convex or plate-like upper and lower surfaces, a columnar shape, and a diameter of 1-5 mm. 12. The pharmaceutical preparation according to any one of claims 1 to 11, wherein the mini-tablet is filled in a capsule or a sack. 13. The pharmaceutical preparation according to claim 12, wherein the capsule or sack contains 10-100 mini-tablets per unit dosage form. 13. The pharmaceutical preparation according to claim 12, wherein the capsule or sachet contains 230 to 250 mg of monomethyl fumarate per unit dosage form and is administered once a unit dosage form. 13. A pharmaceutical formulation according to claim 12 for the alleviation or treatment of multiple sclerosis. At least one fumaric acid ester selected from fumaric acid di (C ₁ -C ₅ ) alkyl esters and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof, A core-making step of producing a mini-tablet core;
A separable coating layer forming step of coating the mini-tablet core with a hydrophilic polymer-containing coating liquid; And
The method for producing a pharmaceutical preparation of the mini-tablet form according to any one of claims 1 to 11, comprising an enteric coating layer forming step of coating the separable coating layer with an enteric coating solution containing a long-acting base. 17. The method of claim 16, wherein the mini-
Preparing a dry granule containing the fumaric acid ester or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; And
And forming said mini-tablets by tableting said dry granules by granular compression. 18. The method according to claim 17, wherein the dry granulation is carried out by roller compression or slugging. 17. The method of claim 16, further comprising filling the mini-tablets formed with the enteric coating layer into a capsule or sack.

Images