EA044361B1 - COMPOSITE CAPSULE CONTAINING EZOMEPRAZOLE AND METHOD FOR ITS PREPARATION - Google Patents

Description

Field of invention

The present invention relates to a compound capsule containing esomeprazole and a method for preparing the same and, more particularly, to a compound capsule containing esomeprazole which is enteric because its active ingredient is insoluble in the stomach and dual release characteristics occur in the intestine, allowing releasing the active ingredient over a long period of time and maintaining the therapeutic effect, and a method for preparing a compound capsule containing esomeprazole.

Prior Art

Esomeprazole ((S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)-methylsulfinyl]-3H-benzoimidazole), which is an (S)-optical isomer known to have superior safety and efficacy among the two optical isomers of omeprazole, is a type of proton pump inhibitor (PPI).

As a PPI, esomeprazole has gastric acid secretion inhibiting effects in mammals, including humans, by regulating gastric acid secretion at the last stage of the acid secretion pathway. Accordingly, the use of esomeprazole for the prevention and treatment of diseases associated with hypersecretion of gastric acid, such as gastroesophageal reflux disease, including reflux esophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer, and the like, is widely known.

PPIs, including esomeprazole, are easily degraded or modified under acidic conditions. Therefore, enteric drugs have been developed that can prevent the degradation of drugs by including an enteric coating layer that prevents the action of gastric acid in the stomach, and which can be dissolved and absorbed in the intestine.

Additionally, it has been found that the use of prior art esomeprazole agents is associated with problems due to the short period of action in that gastric acid is secreted 12 hours or more after dosing of the esomeprazole agent and symptoms such as heartburn are observed due to decreased pH in the stomach. To prevent this phenomenon, the frequency of drug administration can be increased. However, increasing the frequency of drug administration may pose a problem in terms of reducing the patient's ease of administration of the drug.

Description of embodiments, technical task

Therefore, there is a need to develop an oral dosage form containing esomeprazole that is acid-resistant while exhibiting longer-lasting drug efficacy.

A compound capsule containing esomeprazole is provided that is acid stable so that it is not destroyed in the stomach and has dual release characteristics resulting in long-term efficacy of the drug.

A method for producing a composite capsule containing esomeprazole is proposed.

Technical solution

In one aspect of the present invention, there is provided a compound capsule for the prevention or treatment of diseases associated with hypersecretion of gastric acid selected from gastroesophageal reflux disease, gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer, which contains:

a first dissolving portion including a core containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, an inner coating layer on the core, and a first enteric coating layer on the inner coating layer; and a second dissolving portion comprising a core containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, an inner coating layer on the core, and a second enteric coating layer on the inner coating layer, wherein said first enteric coating layer comprises a copolymer as a coating base material. LD of methacrylic acid in an amount of from about 5% (w/w) to about 50% (w/w) relative to the core on which this inner coating layer is formed, and said second enteric coating layer contains as a coating base material a mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of from about 1.5:1 (w/w) to about 3.5:1 (w/w), in an amount of from about 15% ( w/w) to about 40% (w/w) relative to the core on which the inner coating layer is formed, wherein each of the first dissolving portion and the second dissolving portion contains esomeprazole free base or a pharmaceutically acceptable salt thereof in in a weight ratio ranging from about 2:1 to about 1:2, wherein the cores of the first dissolving portion and the second dissolving portion are mini-tablets,

- 1 044361 wherein the inner coating layer is contained in the core on which the inner coating layer is formed in an amount of from about 3% (w/w) to about 5% (w/w), and where the inner coating layer contains hydroxypropyl methylcellulose (HPMC).

In another aspect of the present invention, there is provided a method for producing the above compound capsule of the present invention, comprising:

obtaining a core containing esomeprazole or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive;

applying a layer of internal coating to the core;

providing a first dissolving portion by applying a layer of a first enteric coating to said inner coating layer;

separately obtaining a second dissolving portion by applying a layer of a second enteric coating to this inner coating layer; and filling the capsule together with a first dissolving portion and a second dissolving portion, wherein said first enteric coating layer comprises a methacrylic acid LD copolymer as a coating base material in an amount of from about 5% (w/w) to about 50% (w/w) .) relative to the core on which this inner coating layer is formed, and said second enteric coating layer contains, as a coating base material, a mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of about 1.5:1 (wt./ wt.) to about 3.5:1 (wt./wt.), in an amount of from about 15% (wt./wt.) to about 40% (wt./wt.) relative to the core on which the layer is formed inner coating, wherein each of the first dissolving portion and the second dissolving portion contains esomeprazole free base or a pharmaceutically acceptable salt thereof in a weight ratio ranging from about 2:1 to about 1:2, wherein the cores of the first dissolving portion and the second dissolving portion are are minitablets, wherein the inner coating layer is contained in the core on which the inner coating layer is formed in an amount of from about 3% (w/w) to about 5% (w/w), and wherein the inner coating layer contains hydroxypropyl methylcellulose (HPMC).

Beneficial effects of the invention

The composite capsule containing esomeprazole according to an embodiment of the present invention is acid-resistant and is not subject to degradation by gastric acid, and is also capable of exhibiting long-term medicinal effectiveness over a long period of time due to the inclusion of both a first dissolving part, which provides immediate release upon entry into the intestine, and a second dissolving part that provides sustained release. Therefore, when administered once daily, the compound capsule containing esomeprazole can exhibit long-term medicinal efficacy without any side effects, including heartburn, 12 hours after once daily administration.

Brief description of graphic materials

In fig. 1 is a schematic diagram of a composite capsule according to one embodiment, in which both the core (indicated in red) of the first dissolving portion and the core (indicated in blue) of the second dissolving portion are mini-tablets.

In fig. 2 and 3 are graphs showing the results of the dissolution test of the first enteric coated minitablets of Examples 1 to 3 and Comparative Examples 1 and 2, respectively.

In fig. 4 and 5 are graphs showing the dissolution test results of the second enteric coated minitablets of Examples 4 to 7 and Comparative Examples 3 to 8, respectively.

In fig. 6 is a graph showing the measurement results of the dissolution tests of the composite capsules of Examples 8 and 9 and Comparative Example 9.

Detailed Description of the Invention

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless otherwise specified, have the same meaning as commonly understood by one skilled in the art. Additionally, preferred methods or examples are provided herein, but similar or equivalent methods or examples are included within the scope of the present invention. Additionally, numerical values stated herein are considered to include approximately even if not specifically stated. The contents of all publications referred to herein are incorporated herein by reference in their entirety.

According to one embodiment, a composite capsule is provided for the prevention or treatment of diseases associated with hypersecretion of gastric acid selected from gastroesophageal reflux disease, gastritis, duodenitis, gastric ulcers, duodenal ulcers and peptic ulcers, comprising a first dissolving portion including a core containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, an inner coating layer on the core and a first enteric coating layer on the inner coating layer; and a second dissolving portion comprising a core containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, an inner coating layer on the core, and a second enteric coating layer on the inner coating layer, wherein said first enteric coating layer comprises a copolymer as a coating base material. LD of methacrylic acid in an amount of from about 5% (w/w) to about 50% (w/w) relative to the core on which this inner coating layer is formed, and said second enteric coating layer contains as a coating base material a mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of from about 1.5:1 (w/w) to about 3.5:1 (w/w), in an amount of from about 15% ( w/w) to about 40% (w/w) relative to the core on which the inner coating layer is formed, wherein each of the first dissolving portion and the second dissolving portion contains esomeprazole free base or a pharmaceutically acceptable salt thereof in in a weight ratio ranging from about 2:1 to about 1:2, wherein the cores of the first dissolving portion and the second dissolving portion are minitablets, wherein the inner coating layer is contained in the core on which the inner coating layer is formed in an amount of about 3% (wt./wt.) to about 5% (wt./wt.), and where the inner coating layer contains hydroxypropyl methylcellulose (HPMC).

The pharmaceutically acceptable salt of esomeprazole may be any pharmaceutically acceptable salt available in the art and, for example, may be a metal salt such as magnesium salt (Mg), strontium salt (Sr), lithium salt, sodium salt, potassium salt, calcium salt or the like, or ammonium salt. However, the pharmaceutically acceptable salt of esomeprazole is not limited to them. In one embodiment, the pharmaceutically acceptable salt thereof may be the Mg salt of esomeprazole or the Sr salt of esomeprazole.

Additionally, esomeprazole or a pharmaceutically acceptable salt thereof can be used in the form of an anhydride or hydrate.

The core containing esomeprazole or a pharmaceutically acceptable salt thereof may be a solid agent which may be included in a capsule and may be in the form of mini-tablets. In one embodiment, the core may include a mini-tablet, and more specifically, may have a mini-tablet shape that is approximately spherical. Therefore, the first dissolving portion and/or the second dissolving portion in the form of multi-unit spherical tablets (MUSTs) can be placed in a composite capsule. In one embodiment, both the first dissolving portion core and the second dissolving portion core may be in the form of mini-tablets, and as a MUST, both cores may be contained in a composite capsule (FIG. 1).

The mini-tablet may have a diameter from 1 mm to 4 mm and, more specifically, a diameter from 1.5 mm to 3 mm. The first dissolving part and the second dissolving part in the internal space of the capsule can be filled with mini-tablets divided into at least 4, more specifically 4-40 independent layers, respectively. The mini-tablet can be manufactured in accordance with methods known in the art.

Along with esomeprazole or a pharmaceutically acceptable salt thereof, which is the active ingredient, the core may contain any suitable pharmaceutical additive available in the art to prepare the core. For example, the core may further contain one or more additives selected from a diluent, a binder, a disintegrant, a lubricant, a surfactant, an antioxidant, a preservative, a stabilizer, and combinations thereof. However, the supplement is not limited to them.

For use as a diluent, one or more diluents may be selected from mannitol, microcrystalline cellulose, lactose, cellulose and derivatives thereof, dibasic or tribasic calcium phosphate, erythritol, low-substituted hydroxypropyl cellulose (HPC-L), pregelatinized starch, sorbitol , xylitol and combinations thereof, but the diluent is not limited to them. In one embodiment, mannitol and/or microcrystalline cellulose can be used as a diluent.

For use as a binder, one or more than one binder may be selected from hydroxypropylcellulose (HPC), copovidone (copolymer of vinylpyrrolidone with other vinyl derivatives), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (povidone), pregelatinized starch, HPC-L and combinations thereof, but the binder is not limited to them. In one embodiment, HPC can be used as a binder.

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For use as a disintegrant, the one or more disintegrants may be, but are not limited to, croscarmellose sodium, corn starch, crospovidone, HPC-L, pregelatinized starch, and a combination thereof. In one embodiment, croscarmellose sodium can be used as a leavening agent.

For use as a lubricant, one or more of sodium stearyl fumarate, magnesium stearate, talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil and combinations thereof may be selected, but the lubricant is not limited to them. In one embodiment, sodium stearyl fumarate can be used as a lubricant.

The inner coating layer formed on the core is capable of preventing interaction between the core and the enteric coating layer and may include a hydrophilic polymer as a coating base material that does not inhibit the release of the active ingredient in the core upon destruction of the enteric coating layer after administration of the composite capsule. The inner coating layer includes HPMC as a coating base material.

In the present description, the core on which the inner coating layer is formed is also referred to as an inner-coated core. The amount of the inner coating layer can be suitably selected by one skilled in the art, but in one embodiment, the amount of the inner coating layer can be in the range of from about 3% by weight to about 5% by weight relative to the inner-coated core.

Both the first dissolving portion and the second dissolving portion of the composite capsule include enteric coating layers, and thus acid resistance in the stomach can be maintained. In addition, upon entering the intestine after passage through the stomach, a first release of the active ingredient from the first dissolving portion occurs rapidly, and after a delay period, a second release of the active ingredient from the second dissolving portion occurs sequentially. Therefore, the composite capsule can avoid destruction in the stomach and, due to the rapid dissolution of the drug upon entering the intestine, can quickly exhibit drug efficacy, and this drug efficacy can then be maintained for a long time through dual release of the drug.

The enteric coating layer included in the first dissolving portion may include methacrylic acid copolymer LD as coating base materials. Methacrylic acid LD copolymer is an anionic copolymer comprising methacrylic acid and ethyl acrylate in a ratio of approximately 1:1 and is present in the form of a solution. The LD methacrylic acid copolymer is commercially available under the trade name Eudragit L30 D-55 and its IUPAC name is poly(methacrylic acid-co-ethyl acrylate) 1:1.

The enteric coating layer included in the first dissolving portion may include, as coating base materials, a mixture comprising methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of from about 1.5:1 (w/w) to about 3.5 :1 (wt/wt), for example from about 2:1 (wt/wt) to about 3:1 (wt/wt).

Methacrylic acid copolymer S is an anionic copolymer comprising methacrylic acid and methyl methacrylate in a ratio of approximately 1:2. Methacrylic acid copolymer S is commercially available under the trade name Eudragit S-100 and its IUPAC name is poly(methacrylic acid-co-methyl methacrylate) 1:2.

Methacrylic acid copolymer L is an anionic copolymer comprising methacrylic acid and methyl methacrylate in a ratio of approximately 1:1. Methacrylic acid copolymer L is commercially available under the trade name Eudragit L-100 and its IUPAC name is poly(methacrylic acid-co-methyl methacrylate) 1:1.

The methacrylic acid copolymer LD, which is the base material of the coating layer of the enteric coating layer of the first dissolving part (also called the first enteric coating layer), is a solid powder included in an amount of from about 5% (w/w) to about 50% (w/w) wt./wt.), for example from about 8% (wt./wt.) to about 30% (wt./wt.) relative to the inner coated core of the first dissolving part. When the amount of such solid powder is less than 5% (w/w) relative to the inner-coated core, it is difficult to maintain acid resistance in a 0.1N aqueous solution. HCl, despite the rapid dissolution of the solid powder. In this regard, when administered orally, the active ingredient may be degraded due to the nature of the PPI, and accordingly, achieving medicinal efficacy may be problematic. In addition, when the methacrylic acid copolymer LD is used in the form of a solid powder to coat in an amount of more than 50% (w/w) relative to the inner-coated core of the first dissolving portion, sufficient acid resistance can be maintained in a 0.1 N aqueous solution. HCl, but after passing through the stomach, the dissolution of the active ingredient is excessively slowed in the intestine, which leads to a delay in the absorption of the drug in a living body and delayed drug effectiveness.

S methacrylic acid copolymer and L methacrylic acid copolymer, which represent

- 4 044361 are the base coating materials of the enteric coating layer of the second dissolving portion (also referred to as the second enteric coating layer), can be mixed in a ratio of from about 1.5:1 (w/w) to about 3.5:1 (w/w). /wt.), and for example from about 2:1 (wt./wt.) to about 3:1 (wt./wt.). When the coating base materials are mixed in a ratio less than the above ratio, the proportion of methacrylic acid copolymer L that dissolves at a relatively low pH becomes relatively high, and accordingly, it may be rapidly released when reaching the intestines after passing the stomach, resulting in difficulty in developing dual release characteristics. In addition, when the coating base materials are mixed in a ratio greater than the above ratio, the proportion of S methacrylic acid copolymer, which is a relatively insoluble substance, increases, resulting in excessively delayed release of drugs. In this regard, coating base materials may be excreted without achieving complete drug release, resulting in low bioavailability.

As a solid powder, the mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L can be used in an amount of 15% (w/w) to 40% (w/w), for example 20% (w/w). wt.) up to 35% (wt./wt.) relative to the core with an internal coating. When the mixture is contained in an amount less than the above amount, the second dissolving portion may not be able to maintain the desired delay in dissolution, and due to the rapid dissolution upon entry into the intestines, the dual release characteristics may not be maintained due to the difficulties involved. In addition, when the mixture is contained in an amount greater than the above amount, the enteric coating layer may become thicker, so that the second release of drugs from the dissolving portion may be excessively delayed. Consequently, drugs in the compound capsule may be excreted without achieving complete drug release, resulting in low bioavailability.

The composite capsule may include the active ingredient separately in a first dissolving portion and a second dissolving portion in a suitable ratio, and such suitable ratio can be selected by one skilled in the art depending on the desired dissolution characteristics. In one embodiment, esomeprazole free base or a pharmaceutically acceptable salt thereof may be included in a weight ratio of first dissolving portion to second dissolving portion in the composite capsule of 2:1 to 1:2.

The capsule constituting the composite capsule may be a hard capsule, and any hard capsule available in the art may be used. The hard capsule base material may be selected from, for example, gelatin, hypromellose, pullulan (NP caps TM or the like from Capsugel Company), polyvinyl alcohol, and combinations thereof, but the base material is not limited to them.

For use as a hard capsule, any conventionally sized capsule available in the art can be used. Depending on the size of the capsule, capsules of different sizes are used. A large capsule size, such as a size 00 capsule (having a capsule cap diameter of 8.5 mm and a capsule length of 23.3 mm) is not suitable for elderly patients or small children who have small body sizes, and may also have poor mobility due to increased capsule volume. In one embodiment, taking into account the weight limitations of the tablets or granules that fill the capsule, a size 0, size 1, size 2, size 3 or size 4 capsule, for example a size 1, size 2 or size 3, can be used.

In a compound capsule, the active ingredient is difficult to release under very acidic conditions. However, the first release of the active ingredient occurs rapidly from the first intestinal dissolving portion at a pH of 5.5 or less, and the second release of the active ingredient occurs from the second intestinal dissolving portion at a pH of 6.5 to 7.0.

To test the solubility of a compound capsule, the compound capsule is left for 2 hours in an aqueous solution of 0.1 N. HCl and then this solution is transferred to artificial intestinal juice with a pH of 6.7 to 6.9. In the solubility test, virtually no release occurs during the first two hours, but release begins in the artificial intestinal juice. 150 minutes after the start of the dissolution test, the first release from the first dissolving portion occurs, in which approximately 90% (w/w) or more of the active ingredient from the first dissolving portion is released. After a delay period of 180 minutes from the start of the dissolution test, dissolution of the active ingredient from the second dissolving portion begins, and then, at time point 360 minutes, a second release at which dissolution is complete (approximately 99% or more). During a delay period of 180 minutes, a release of 5% of the active ingredient, preferably 2% of the active ingredient, from the second dissolving part can be achieved.

In one embodiment, when the solubility test is carried out continuously for 240 minutes in artificial intestinal juice having a pH of 6.7 to 6.9, after dissolving in an aqueous solution of 0.1 N. HCl at 100 revolutions per minute (rpm) for 120 min at 37 ± 0.5°C according to the United States Pharmacopoeia (USP) paddle method II, compound capsule

- 5 044361 has an acid resistance of 0.1 N. HCl for 120 minutes, about 55% or less of the active ingredient dissolves in artificial intestinal juice within 60 minutes, and about 95% or more of the active ingredient dissolves in artificial intestinal juice within 240 minutes (see Experimental Example 4).

Thus, considering that a compound capsule can have sufficient bioavailability and duration of action to avoid dissolution of the active ingredient in the stomach but provide dual release of the active ingredient in the intestine, the compound capsule can be used effectively while reducing the frequency of administration.

The composite capsule may include esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient. Such an active ingredient is known to be effective or can be used for any treatment or prevention of diseases for which the effectiveness of the drug will be discovered in the future. Therefore, according to one embodiment of the present invention, the composite capsule can be used for the prevention or treatment of diseases associated with hypersecretion of gastric acid selected from gastroesophageal reflux disease, gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer.

In one embodiment, the composite capsule can be administered once daily.

In another aspect of the present invention, there is provided a method for preparing a composite capsule of the present invention, comprising:

obtaining a core containing esomeprazole or a pharmaceutically acceptable salt and pharmaceutical additive thereof;

applying a layer of internal coating to the core;

providing a first dissolving portion by applying a layer of a first enteric coating to said inner coating layer;

separately obtaining a second dissolving portion by applying a layer of a second enteric coating to this inner coating layer; and filling the capsule together with a first dissolving portion and a second dissolving portion, wherein said first enteric coating layer comprises a methacrylic acid LD copolymer as a coating base material in an amount of from about 5% (w/w) to about 50% (w/w) .) relative to the core on which this inner coating layer is formed, and said second enteric coating layer contains, as a coating base material, a mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of about 1.5:1 (wt./ wt.) to about 3.5:1 (wt./wt.), in an amount of from about 15% (wt./wt.) to about 40% (wt./wt.) relative to the core on which the layer is formed inner coating, wherein each of the first dissolving portion and the second dissolving portion contains esomeprazole free base or a pharmaceutically acceptable salt thereof in a weight ratio ranging from about 2:1 to about 1:2, wherein the cores of the first dissolving portion and the second dissolving portion are are mini-tablets, wherein the inner coating layer is contained in a core on which the inner coating layer is formed in an amount of from about 3% (w/w) to about 5% (w/w), and wherein the inner coating layer coating contains hydroxypropyl methylcellulose (HPMC).

The details of the method for preparing the oral solid preparation according to one embodiment may be applicable as such to the oral solid preparation according to one aspect of the present invention, and any preparation method known in the art can be used for refinement.

When the cores of the first dissolving portion and the second dissolving portion of the composite capsule are mini-tablets (MUST), the cores may be manufactured by direct compression or indirect compression. For direct pressing, dry granules or wet granules can be used.

In one embodiment, manufacturing the core may include the following steps:

(a) mixing diluents with esomeprazole or a pharmaceutically acceptable salt thereof;

(b) mixing the mixture from step (a) with a disintegrant, a binder and a lubricant; and (c) dry granulating the mixture from step (b) and then tableting the resulting product to form a mini-tablet.

Any mini-tablet coating method may be used to coat the mini-tablet with an inner coating layer, a first enteric coating layer and a second enteric coating layer. For example, a fluidized bed coater may be used for coating.

Hereinafter, the present invention will be described in more detail with reference to the following

- 6 044361 below Examples. However, the following Examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

Examples

Preparation Example 1: Formation of a core containing esomeprazole magnesium salt and an inner coating layer.

Using the compositions from table. 1 below, esomeprazole magnesium salt and mannitol were mixed and the mixture was sieved using a 30 mesh round sieve. The resulting product was added to an empty blender along with microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose and sodium stearyl fumarate to blend for 15 minutes, thereby obtaining the final mixture. The final mixture was placed in a roller press and then dry granulated. The resulting granules were screened using a 20 mesh round sieve.

Next, a MUST punch with a diameter of 2.0 mm was used to tablet 10 mini-tablets, each of which had a compression ratio of about 1 kPa to about 2 kPa and a weight of 7.5 mg, thereby obtaining a MUST.

Table 1

Compositions of the core containing esomeprazole magnesium salt

Ingredient Weight (mg/10 tablets) Weight (%) Core Magnesium salt of esomeprazole 21.7 28.9 Microcrystalline cellulose 15.0 20.0 Mannitol 30.5 40.7 Croscarmellose sodium 2.4 3.2 Hydroxypropyl cellulose 2.4 3.2 Sodium stearyl fumarate h,o 4.0 Sum 75.0 100.0

The resulting MUSTs were coated with a coating liquid having the composition according to table. 2 below in a fluidized bed coater, thereby producing internally coated mini-tablets having a weight of 7.88 mg per tablet.

table 2

Composition of the inner coating layer

Ingredient Weight (mg/10 tablets) Weight (%) Removable coating layer Hydroxypropyl methylcellulose 3.8 4.82 Purified water (appropriate quantity, q.s.) - Sum 78.8 100.0

q.s. - how much is required

Preparation Example 2: Examples 1-3 and Comparative Examples 1 and 2.

Preparation of a mini-tablet with a formed layer of the first enteric coating.

The internally coated mini-tablet was coated using the formulations in Table 1. 3 in a fluidized bed granulator so as to obtain a mini-tablet having formed a layer of first enteric coating according to Examples 1-3 and Comparative Examples 1 and 2. In Examples 1-3, Eudragit L30 D-55, which is the base material the first enteric coating was applied in an amount of from 5% (wt./wt.) to 50% (wt./wt.) by weight relative to the inner-coated mini-tablet. In each of Comparative Examples 1 and 2, Eudragit L30 D-55 was applied at 4% (w/w) and 51% (w/w) by weight, respectively.

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Table 3

Compositions of the first enteric coating layer

Ingredient Weight (mg/10 tablets) Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Eudragit L30 D-55 (solid form) powder) 26.35 (7.88) 13.18 (3.94) 131.80 (39.40) 10.54 (3.15) 132.59 (40.19) Triethyl citrate 2.35 1.18 11.80 0.94 12.59 Diacetylated monoglyceride 0.43 0.22 2.20 0.17 2.99 Polysorbate 80 0.18 0.09 0.90 0.07 1.69 Purified water (q s.) (qs.) (qs) (qs.) (qs.) Sum 108.11 93.47 225.50 90.52 228.66

Preparation Example 3: Examples 4-7 and Comparative Examples 3-8.

Preparation of a mini-tablet with a formed layer of a second enteric coating.

The internally coated mini-tablet from Preparation Example 1 was coated using the formulations in Table 1. 4 and 5 below in a fluidized bed granulator so as to produce the mini-tablets of Examples 4-7 and Comparative Examples 3-8, forming a second enteric coating layer.

In Examples 4 and 5, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a 2:1 ratio was applied in a mass ratio of 25% (w/w) to 35% (w/w) relative to the mini - tablets with internal coating. In Examples 6 and 7, a mixture of Eudragit S-100 and L-100 mixed in a 3:1 ratio was applied in a mass ratio of 20% (w/w) to 30% (w/w) relative to the minimum internally coated tablets.

Table 4

Compositions of the layers of the second enteric coating from examples 4-7

Ingredient Weight (mg/10 tablets) Eudragit S/L in a ratio of 2/1 Eudragit S/L in a ratio of 3/1 Example 4 Example 5 Example 6 Example 7 Eudragit S-100 13.3 18.6 12.0 18.0 Eudragit L-100 6.7 9.4 4.0 6.0 Triethyl citrate 2.0 2.8 1.6 2.4 Talc 10.0 14.0 8.0 12.0 Ethanol (qs.) (qs.) (q.s.) (q.s.) Purified water (qs.) (q.s.) (q.s.) (q.s.) Sum 110.8 123.6 104.4 117.2

In Comparative Examples 3 and 4, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a 2:1 ratio was applied in an amount of 10.15% (w/w) and 40.61% (w/w). ) by weight, respectively, relative to the mini-tablet with an internal coating. In Comparative Examples 5 and 6, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a 3:1 ratio was applied in an amount of 10.15% (w/w) and 40.61% (w/w). ) by weight, respectively, relative to the mini-tablet with an internal coating. In Comparative Examples 7 and 8, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a 6:1 ratio was applied in an amount of 10.15% (w/w) and 20.30% (w/w). ) by weight, respectively, relative to the mini-tablet with an internal coating.

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Table 5

Compositions of the Second Enteric Coating Layers of Comparative Examples 3-8

Ingredient Weight (mg/10 tablets) Eudragit S/L in a ratio of 2/1 Eudragit S/L in a ratio of 3/1 Eudragit S/L in a ratio of 6/1 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Eudragit S-100 5.3 21.2 6.0 24.0 6.86 13.7 Eudragit L-100 2.7 10.8 2.0 8.0 1.14 2.3 Triethyl citrate 0.8 3.2 0.8 3.2 0.8 1.6 Talc 4.0 16.0 4.0 16.0 4.0 8.0 Ethanol (q.s.) (q.s.) (q.s.) (q.s.) (q.s.) (q.s.) Purified water (q.s.) (q.s.) (q.s.) (q.s.) (q.s.) (q.s.) Sum 91.6 130.0 91.6 130.0 91.6 104.4

Preparation Example 4: Examples 8 and 9 and Comparative Example 9.

Preparation of a mini-tablet with a formed layer of the first enteric coating and a mini-tablet with a formed layer of the second enteric coating.

In hard gelatin capsule No. 2, the main base material of which is gelatin, 10 tablets representing mini-tablets formed by a layer of the first enteric coating from Example 1 and 10 tablets representing mini-tablets forming a layer of the second enteric coating from Example 4 were placed together, so to prepare the compound capsule of Example 8 (comprising 40 mg of esomeprazole). In the same manner, the mini-tablets of Examples 1 and 7 were filled into a capsule so as to obtain the composite capsule of Example 9. Additionally, in the same manner, the mini-tablets of Example 1 and Comparative Example 3 were filled into a capsule so as to obtain the composite capsule of Comparative Example 9 .

Preparation Example 5: Preparation of composite capsules according to capsule types.

A composite capsule was prepared in the same manner as in Preparation Example 4, except that the mini-tablets were filled into a hypromellose capsule, which is a hard capsule whose main base material is hypromellose. Additionally, a composite capsule was prepared in the same manner as in Preparation Example 4, except that the mini-tablets were filled into a pullulan capsule, which is a hard capsule whose main base material is pullulan.

Experimental Example 1: Solubility test of mini-tablets with a first enteric coating layer formed.

Using the first enteric coated mini-tablets of Examples 1 to 3 and Comparative Examples 1 and 2, the dissolution levels of esomeprazole magnesium salts as a function of time were measured under the following conditions.

Dissolution conditions.

Eluate: 300 ml 0.01 N. HCl (2 hours) ^ 1000 ml artificial intestinal juice (pH 6.8).

Appliance: USP paddle mixer (method), 100 rpm.

Temperature: 37°C.

Time point at which the dissolution level was measured: 60 min, 120 min, 125 min, 130 min, 135 min, 150 min, 165 min and 180 min.

Analysis conditions.

Equipment used: HPLC (Hitachi 5000 series, Japan).

Detector: Ultraviolet spectrophotometer (measured wavelength: 302 nm).

Column: A stainless steel tube having an internal diameter of approximately 4.0 mm and a length of approximately 10 cm, a 5 µm column packed with liquid chromatography grade silica gel.

Mobile phase - sodium phosphate buffer (pH 7.3): acetonitrile: purified water = 50:35:15.

Flow rate: 1.0 ml/min.

Column temperature: 30°C.

The results of measuring the level of dissolution of mini-tablets with the formed layer of the first enteric coating from examples 1-3 are shown in table. 6 and FIG. 2.

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Table 6

Dissolution rate (%) Example 1 Example 2 Example 3 Time (minutes) Average Standard deviation Average Standard deviation Average Standard deviation 0 θ,θ oh oh oh oh oh oh oh oh oh oh 60 oh oh oh oh oh oh oh oh oh oh oh oh 120 0.0 0.0 0.0 0.0 0.0 0.0 125 50.7 6.9 70.8 2.7 30.6 3.8 130 86.4 1.5 95.9 1.1 61.0 1.8 135 100.3 1.3 100.6 0.3 85.1 1.9 150 100.0 1.9 99.8 0.6 95.6 1.2 165 100.1 1.2 101.1 1.4 100.6 1.3 180 100.9 1.3 101.3 0.8 100.0 1.0

As shown in table. 6 and FIG. 2, mini-tablets from examples 1-3 have an acid resistance of 0.1 N. HCl during the first 2 hours. Further, the mini-tablets demonstrated a dissolution rate of 90% or more in artificial intestinal juice (pH 6.8) within 30 minutes (i.e., 150 minutes after the start of the solubility test), indicating that mini-tablets exhibit immediate release.

The dissolution level measurement results of Comparative Examples 1 and 2 are shown in Table. 7 and fig. 3.

Table 7

Dissolution rate (%) Comparative Example 1 Comparative Example 2 Time (minute) Average Standard deviation Average Standard deviation 0 oh oh oh oh oh oh oh oh 60 0.0 oh oh oh oh oh oh 120 10.0 6.4 oh oh oh oh 125 65.4 2.7 10.6 1.8 130 86.9 3.6 30.3 4.8 135 89.9 1.5 61.8 1.3 150 90.6 0.8 85.6 1.2 165 90.2 1.1 95.7 0.5 180 90.1 0.9 100.7 0.8

As shown in table. 7 and fig. 3, the mini-tablets of Comparative Example 1, in which Eudragit L30 D-55 was used as the first enteric coating layer with a weight of 4% (w/w) relative to the weight of the inner-coated mini-tablet, it was difficult to achieve sufficient acid resistance from - for a low coating fraction compared to an internally coated mini-tablet, and demonstrated a 10% release at 0.1 N. HCl for 120 min. In addition, the mini-tablet of Comparative Example 1 did not exhibit a final dissolution rate of 100% due to the properties of esomeprazole, which degrades in an acidic environment.

Additionally, the mini-tablet of Comparative Example 2, in which Eudragit L30 D-55 was used as the first enteric coating layer at 51% (w/w) relative to the weight of the inner-coated mini-tablet, maintained sufficient acid resistance but exhibited dissolution level 85% after 150 min. Consequently, the absorption of esomeprazole was slowed down, and accordingly, the manifestation of drug efficacy was also possibly delayed.

Experimental Example 2: Acid resistance test of mini-tablets with a first enteric coating layer formed.

Using the first enteric coated mini-tablets of Examples 1 to 3 and Comparative Examples 1 and 2, the mini-tablets were left for 2 hours under the acidic conditions described below, and the acid resistance was measured based on the amount of esomeprazole magnesium salts. Is

- 10 044361 used 10 mini-tablets and the results are shown in the table. 8.

Conditions for determining acid resistance.

Test solution: 0.01 N. HCl.

Apparatus: USP paddle method, 100 rpm.

Temperature: 37°C.

Time: left for 2 hours.

Analysis conditions.

Device used: HPLC (Hitachi 5000 series, Japan).

Detector: Ultraviolet spectrophotometer (measured wavelength: 302 nm).

Column: A stainless steel tube having an internal diameter of approximately 4.0 mm and a length of approximately 10 cm.

Column 5 µm filled with silica gel for liquid chromatography.

Mobile phase - sodium phosphate buffer (pH 7.3): acetonitrile: purified water = 50:35:15.

Flow rate: 1.0 ml/min.

Column temperature: 30°C.

Table 8

Acid resistance test results

Amount before test (%) Quantity after test (%) Example 1 100.9 ± 1.3 101.2 ±0.5 Example 2 101.3 ±2.5 100.6 ± 1.2 Example 3 100.6 ±0.9 100.1 ± 1.1 Comparative Example 1 100.6 ± 1.6 90.4 ± 2.4 Comparative Example 2 100.7 ±0.7 101.3 ± 1.7

As a result of the acid resistance test in 0.1 N. HCl mini-tablets from examples 1-3 and comparative examples 1 and 2, as shown in table. 8, Comparative Example 1, in which the coating ratio was low, showed a difference in the amount of esomeprazole magnesium salt before and after the test of approximately 10.0%. However, the remaining samples, with the exception of Comparative Example 1, were found to have amounts similar to the original amounts of the active ingredient after the acid resistance test.

Experimental Example 3: Dissolution test of mini-tablets with a second enteric coating layer formed.

Using the second enteric coated mini-tablets of Examples 4-7 and Comparative Examples 3-8, dissolution levels of esomeprazole magnesium salts were measured as a function of time under the following conditions.

Dissolution conditions.

Eluate: 300 ml 0.01 N. HCl >1000 ml artificial intestinal juice (pH 6.8).

Device: USP paddle mixer (method), 100 rpm.

Temperature: 37°C.

Time point at which dissolution levels were measured: 60 min, 120 min, 150 min, 180 min, 210 min, 240 min, 300 min, and 360 min.

Analysis conditions.

Device used: HPLC (Hitachi 5000 series, Japan).

Detector: Ultraviolet spectrophotometer (measured wavelength: 302 nm).

Column: A stainless steel tube having an internal diameter of approximately 4.0 mm and a length of approximately 10 cm, a 5 µm column packed with liquid chromatography grade silica gel.

Mobile phase.

Sodium phosphate buffer (pH 7.3):acetonitrile:purified water = 50:35:15.

Flow rate: 1.0 ml/min.

Column temperature: 30°C.

The results of measuring the level of dissolution of mini-tablets with the formed layer of the second enteric coating from examples 4-7 are shown in table. 9 and FIG. 4.

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Table 9

Dissolution levels (%) Example 4 Example 5 Example 6 Example 7 Time (minutes) Average Standard deviation Average Standard deviation Average Standard deviation Average Standard deviation 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 60 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 120 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 150 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 180 0.0 0.0 0.0 0.0 1.8 3.1 0.0 0.0 240 64.6 2.1 0.0 0.0 65.5 2.6 5.9 1.5 300 94.4 0.2 76.4 7.7 83.2 6.6 51.1 9.7 360 1-1.2 2.1 98.8 2.0 99.2 9.7 101.7 11.1

Regarding the results presented in table. 9 and Fig. 4, the mini-tablets from examples 4-7 did not show any dissolution in the first 2 hours in 0.1 N. HCl, so that acid resistance was maintained. Drug release was then delayed for 60 min or longer in artificial intestinal juice (pH 6.8). However, once the drug release began, the release occurred quickly.

Despite slight differences depending on the ratio of Eudragit S and Eudragit L, after an acid resistance of 0.1 N. The HCl was retained for 120 min, the magnesium salt of esomeprazole was almost not released within 60 min in artificial intestinal juice, but was rapidly released after 60 min. Then, after a time of 360 minutes, excellent release characteristics were confirmed, amounting to the release of 99% or more of the magnesium salt of esomeprazole. When a dissolution level of 90% or more was not achieved at time point 360 minutes due to the nature of the drug, the drug could possibly be released undissolved, and in this regard, it was confirmed that sufficient release could be achieved in Examples 4-7.

Additionally, the results of measuring the dissolution level of mini-tablets with the formed layer of the second enteric coating from comparative examples 3-8 are shown in table. 10 and fig. 5.

Table 10

Dissolution rate (%) Comparative Example3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Time (minutes) Average Standard deviation Average Standard deviation Average Standard deviation Average Standard deviation Average Standard deviation Average Standard deviation 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 60 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 120 0.0 0.0 0.0 0.0 0.5 0.3 0.0 0.0 0.0 0.0 0.0 0.0 150 52.9 0.0 0.0 0.0 25.6 2.6 0.0 0.0 16.7 3.1 0.0 0.0 180 756, 10.6 0.0 0.0 65.1 13.8 0.0 0.0 33.5 4.0 0.0 0.0 210 86.4 2.3 0.0 0.0 74.1 3.2 0.0 0.0 52.4 3.0 0.0 0.0 240 93.6 7.0 0.0 0.0 82.1 4.8 0.0 0.0 62.6 4.2 3.0 5.1 300 99.0 1.1 0.0 0.0 96.0 10.1 0.0 0.0 87.8 8.2 44.5 8.0 360 91.5 0.8 56.4 7.7 100.4 3.9 16.5 2.3 95.8 9.3 61.2 6.2

Regarding the results shown in table. 10 and fig. 5, in the case of the mini-tablets of Comparative Examples 3, 5 and 7, it was difficult to maintain the acid resistance of 0.1N. HCl for 2 hours due to the low mass fraction of the second enteric coating layer. In the case of the mini-tablets of Comparative Examples 4, 6 and 8, due to the high mass fraction of the second enteric coating layer, not only was acid resistance maintained, but also drug release was excessively delayed in the artificial enteric juice. In these mini-tablets, drug release of more than 90% was not achieved even after 6 hours, and therefore the drug may possibly be excreted without releasing the drugs, that is, release does not occur to a sufficient extent.

Experimental Example 4: Dissolution Level Test of Compound Capsules.

Using the composite capsules of Examples 8 and 9 and Comparative Example 9, time-dependent dissolution levels of esomeprazole magnesium salts were measured under the following conditions.

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Dissolution conditions.

Eluate: 300 ml 0.1 N. HCl ^ 1000 ml artificial intestinal juice (pH 6.8).

Appliance: USP paddle mixer (method), 100 rpm.

Temperature: 37°C.

Time point at which dissolution levels were measured: 60 min, 120 min, 125 min, 130 min, 135 min, 150 min, 165 min, 180 min, 210 min, 240 min, 300 min, and 360 min.

Analysis conditions.

Device used: HPLC (Hitachi 5000 series, Japan).

Detector: Ultraviolet spectrophotometer (measured wavelength: 302 nm).

Column: A stainless steel tube having an internal diameter of approximately 4.0 mm and a length of approximately 10 cm.

Column 5 µm filled with silica gel for liquid chromatography.

Mobile phase - sodium phosphate buffer (pH 7.3): acetonitrile: purified water = 50:35:15.

Flow rate: 1.0 ml/min.

Column temperature: 30°C.

The results of measuring the dissolution level are shown in table. 11 and fig. 6.

Table 11

Dissolution levels of esomeprazole magnesium salt

Dissolution rate (%) Example 8 Example 9 Comparative Example 9 Time (minutes) Average Standard deviation Average Standard deviation Average Standard deviation 0 0.0 0.0 0.0 0.0 0.0 0.0 60 0.0 0.0 0.0 0.0 0.0 0.0 120 0.0 0.0 0.0 0.0 0.0 0.0 125 22.8 5.6 24.8 4.5 25.2 4.5 130 45.1 1.3 44.2 2.2 46.3 2.2 135 50.1 0.9 49.9 1.0 50.1 1.0 150 50.0 0.8 50.0 1.2 75.3 2.4 165 50.2 1.1 50.4 0.6 86.7 1.9 180 50.0 0.5 50.3 0.5 98.6 7.8 210 53.5 8.5 53.3 10.6 100.4 4.9 240 82.6 2.3 94.1 8.3 100.1 6.8 300 95.5 1.9 99.3 1.5 99.1 2.7 360 101.2 1.2 100.7 2.0 98.6 1.9

Regarding the results from table. 11 and fig. 6, the composite capsules of Examples 8 and 9, prepared by mixing a mini-tablet comprising a layer of a first enteric coating and a mini-tablet comprising a layer of a second enteric coating in a 1:1 ratio, maintained acid resistance for the first 2 hours in 0.1 N . HCl. Then, after the first release in artificial intestinal juice, the release was delayed by approximately 45 min before the start of the second release. According to the graph in Fig. 6, such dual release characteristics were clearly shown. Therefore, the composite capsules of Examples 8 and 9 exhibited sustained drug release up to 6 hours after the start of the dissolution test due to the dual release characteristics of artificial intestinal juice.

In the mini-tablet of Comparative Example 9, acid resistance was maintained at 0.1N. HCl for 2 hours. However, after the first release, drug release occurred immediately without a delay in release until the second release began. Thus, the release of most of the drugs (98% or more) was completed after 3 h of dissolution test.

While the present invention has been shown and described in detail with reference to exemplary embodiments thereof, one skilled in the art will appreciate that various changes may be made in its form and details without departing from the spirit and scope of the embodiments as defined in the appended appendix. formula. The exemplary embodiments are to be considered descriptive only and are not intended to limit the scope of the invention in any way. Therefore, the scope of the embodiments is determined not by the detailed description of the embodiments, but by the appended claims, and all differences within this scope are to be considered as being included in the present invention.

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Claims (6)

CLAIM 1. A compound capsule for the prevention or treatment of diseases associated with hypersecretion of gastric acid selected from gastroesophageal reflux disease, gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer, containing a first dissolving part including a core containing as an active ingredient esomeprazole or a pharmaceutically acceptable salt thereof, an inner coating layer on this core and a first enteric coating layer on this inner coating layer; and a second dissolving portion comprising a core containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, an inner coating layer on the core, and a second enteric coating layer on the inner coating layer, wherein said first enteric coating layer comprises a copolymer as a coating base material. LD of methacrylic acid in an amount of from about 5% (w/w) to about 50% (w/w) relative to the core on which this inner coating layer is formed, said second enteric coating layer contains a mixture as a coating base material , containing a methacrylic acid copolymer S and a methacrylic acid copolymer L in a ratio of from about 2:1 (wt./wt.) to about 3:1 (wt./wt.), in an amount of from about 15% (wt./wt.) ) to about 40% (w/w) relative to the core on which the inner coating layer is formed, wherein each of the first dissolving portion and the second dissolving portion contains esomeprazole free base or a pharmaceutically acceptable salt thereof in a weight ratio ranging from from about 2:1 to about 1:2, wherein the cores of the first dissolving portion and the second dissolving portion are minitablets, wherein the inner coating layer is contained in the core on which the inner coating layer is formed in an amount of from about 3% (w/w .) to about 5% (w/w), and wherein the inner coating layer contains hydroxypropyl methylcellulose (HPMC). 2. The composite capsule of claim 1, wherein the second enteric coating layer comprises as a base coating material a mixture comprising methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of from about 2:1 (w/w) to about 3: 1 (w/w), in an amount of from about 20% (w/w) to about 35% (w/w) relative to the core on which the inner coating layer is formed. 3. The compound capsule according to claim 1, wherein each of the cores of the first dissolving part and the second dissolving part contain one or more than one pharmaceutical additive selected from a diluent, a binder, a disintegrant, a lubricant, a surfactant, an antioxidant, a preservative, stabilizer and their combinations. 4. The compound capsule according to claim 1, wherein the pharmaceutically acceptable salt of esomeprazole includes magnesium salt of esomeprazole or strontium salt of esomeprazole. 5. The compound capsule according to claim 1, wherein the capsule base material of said compound capsule is selected from gelatin, hypromellose, pullulan, polyvinyl alcohol, and combinations thereof. 6. A method for producing a composite capsule according to any one of claims 1 to 5, including obtaining a core containing esomeprazole or a pharmaceutically acceptable salt thereof and a pharmaceutical additive; applying a layer of internal coating to the core; providing a first dissolving portion by applying a layer of a first enteric coating to said inner coating layer; separately obtaining a second dissolving portion by applying a layer of a second enteric coating to this inner coating layer; and filling the capsule together with the first dissolving portion and the second dissolving portion, thereby forming a composite capsule, wherein said first enteric coating layer contains, as a coating base material, a methacrylic acid copolymer LD in an amount of from about 5% (w/w) to about 50% (w/w) % (w/w) relative to the core on which this inner coating layer is formed, and said second enteric coating layer contains, as a coating base material, a mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of about 2:1 (w/w) to about 3:1 (w/w), in an amount of from about 15% (w/w) to about 40% (w/w) relative to the core on which the this inner coating layer, wherein each of the first dissolving portion and the second dissolving portion contains esomeprazole free base or a pharmaceutically acceptable salt thereof in a weight ratio ranging from about 2:1 to about 1:2, wherein the cores of the first dissolving portion and the second dissolving portion the parts are mini