HK40006608B - Esomeprazole-containing complex capsule and preparation method therefor - Google Patents

Description

Compound capsule containing esomeprazole and preparation method thereof

Technical Field

The present disclosure relates to an esomeprazole-containing composite capsule and a preparation method thereof, and more particularly, to an esomeprazole-containing composite capsule, which is enteric-soluble in that an active ingredient thereof is insoluble in the stomach and exhibits dual release characteristics in the intestine, thereby being capable of releasing the active ingredient over a prolonged period of time and maintaining the pharmaceutical effect, and a method of preparing the same.

Background

Esomeprazole ((S) -5-methoxy-2- [ (4-methoxy-3, 5-dimethylpyridin-2-yl) methylsulfinyl ] -3H-benzimidazole) is a (S) -optical isomer known to have excellent safety and efficacy among two optical isomers of omeprazole, and is a Proton Pump Inhibitor (PPI).

As PPI, esomeprazole has the effect of inhibiting gastric acid secretion in mammals (including humans) by regulating gastric acid secretion at the final stage of the acid secretion pathway. Therefore, esomeprazole is well known for the prevention and treatment of diseases associated with gastric acid hypersecretion, such as gastroesophageal reflux disease including reflux esophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer, peptic ulcer, and the like.

PPIs including esomeprazole are easily degraded or modified under acidic conditions. Therefore, enteric formulations have been developed, which can prevent the drug from being decomposed by introducing an enteric coating layer, which prevents exposure to gastric acid in the stomach, and can be dissolved and absorbed in the intestine.

Furthermore, it has been found that esomeprazole agents in the art have problems in that: due to the short duration, gastric acid is secreted 12 hours or more after the administration of one dose of esomeprazole, and symptoms such as heartburn are observed due to the decrease in pH in the stomach. To prevent this phenomenon, the frequency of administration of the drug may be increased. However, increasing the frequency of drug administration may cause problems due to reduced drug compliance of patients.

Disclosure of Invention

Technical problem

Therefore, there is a need to develop an esomeprazole-containing oral dosage form having acid resistance while exhibiting more sustained drug efficacy.

Provided is an esomeprazole-containing composite capsule which is resistant to acid so that it is not degraded in the stomach, and has dual release characteristics, resulting in sustained drug efficacy.

A method for preparing a compound capsule containing esomeprazole is provided.

Technical scheme

One aspect of the present disclosure provides a composite capsule comprising:

a first dissolution fraction comprising: a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient; an inner coating layer over the core; and a first enteric coating layer over the inner coating layer; and

a second dissolution fraction comprising: a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient; an inner coating layer over the core; and a second enteric coating layer on the inner coating layer,

wherein the first enteric coating layer comprises methacrylic acid copolymer LD as a coating base material in an amount of about 5% (w/w) to about 50% (w/w) of the core on which the inner coating layer is formed, and

the second enteric coating layer comprises, 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(w/w) to about 3.5:1(w/w) in an amount of about 15% (w/w) to about 40% (w/w) of the core on which the inner coating layer is formed.

Another aspect of the present disclosure provides a method of preparing the composite capsule according to any one of claims 1 to 13, the method comprising:

preparing a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive;

coating the core with an inner coating layer;

obtaining a first dissolved fraction by coating a first enteric coating layer on the inner coating layer;

separately, a second dissolved fraction is obtained by coating a second enteric coating layer on the inner coating layer; and

filling a capsule with the first and second dissolved fractions together,

wherein the first enteric coating layer comprises methacrylic acid copolymer LD as a coating base material in an amount of about 5% (w/w) to about 50% (w/w) of the core on which the inner coating layer is formed, and

the second enteric coating layer comprises, 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(w/w) to about 3.5:1(w/w) in an amount of about 15% (w/w) to about 40% (w/w) of the core on which the inner coating layer is formed.

Advantageous effects

The esomeprazole-containing composite capsule according to the embodiment has acid resistance and is not easily degraded by exposure to gastric juice, and further, can exhibit sustained drug efficacy for a long time by including a first dissolution part which can be immediately released upon reaching the intestine and a second dissolution part which can delay the release. Therefore, the esomeprazole-containing composite capsule can exhibit sustained pharmaceutical efficacy when administered once a day without any heartburn side effects including 12 hours after once a day administration.

Drawings

Fig. 1 is a schematic view of a composite capsule according to an embodiment, wherein the core of the first dissolution portion (red) and the core of the second dissolution portion (blue) are both mini-tablets.

Fig. 2 and 3 are graphs showing the results of dissolution tests of mini-tablets formed with the first enteric coating layer of examples 1 to 3 and comparative examples 1 and 2, respectively.

Fig. 4 and 5 are graphs showing the results of dissolution tests of mini-tablets formed with the second enteric coating layer of examples 4 to 7 and comparative examples 3 to 8, respectively.

Fig. 6 is a graph showing the measurement results of the dissolution test of the composite capsules of example 8 and example 9 and comparative example 9.

Detailed Description

Hereinafter, the present disclosure will be described in detail.

Unless otherwise defined, all technical terms used in the present invention are the same as those commonly understood by one of ordinary skill in the art. In addition, preferred methods or samples are described in this specification, but similar or equivalent methods or samples are also included within the scope of the invention. Further, numerical values set forth herein are considered to include the meaning of "about", even if not explicitly stated. The contents of all publications mentioned in this specification are herein incorporated by reference in their entirety.

According to one embodiment, there is provided a composite capsule comprising:

a first stripping section comprising: a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient; an inner coating layer over the core; and a first enteric coating layer on the inner coating layer; and

a second stripping section comprising: a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient; an inner coating layer over the core; and a second enteric coating layer on the inner coating layer,

wherein the first enteric coating layer may comprise methacrylic acid copolymer LD as a coating base material in an amount of about 5% (w/w) to about 50% (w/w) of the core on which the inner coating layer is formed, and

the second enteric coating layer may comprise, 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(w/w) to about 3.5:1(w/w) in an amount of about 15% (w/w) to about 40% (w/w) of the core on which the inner coating layer is formed.

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 (Mg), strontium (Sr), lithium, sodium, potassium, calcium, and the like, or an ammonium salt. However, the pharmaceutically acceptable salt of esomeprazole is not limited thereto. In one embodiment, the pharmaceutically acceptable salt thereof may be a Mg salt of esomeprazole or a Sr salt of esomeprazole.

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

The core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, may be any solid agent that may be contained in a capsule, and for example, may be selected from the group consisting of pills, mini-tablets, and combinations thereof. In one embodiment, the core may comprise mini-tablets, and more particularly, may have a nearly spherical mini-tablet form. Thus, the first and/or second dissolution fraction as a Multiple Unit Spherical Tablet (MUST) may be filled in a composite capsule. In one embodiment, the core of the first dissolution fraction and the core of the second dissolution fraction may both be in mini-tablet form, and as a MUST, both cores may be filled in a composite capsule (fig. 1).

Mini-tablets may be 1mm to 4mm in diameter, and more specifically, 1.5mm to 3mm in diameter. The first and second dissolved portions in the capsule inner space may each be filled with mini-tablets separated by at least 4, more particularly 4 to 40, separate layers. Mini-tablets may be prepared according to methods known in the art.

The core may contain any suitable pharmaceutical additive useful in the art for preparing the core, along with esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient. For example, the core may additionally comprise one or more additives selected from diluents, binders, disintegrants, lubricants, surfactants, antioxidants, preservatives, stabilizers, and combinations thereof. However, the additive is not limited thereto.

For use as a diluent, one or more diluents may be selected from mannitol, microcrystalline cellulose, lactose, cellulose and its derivatives, calcium hydrogen phosphate or tricalcium phosphate, erythritol, low-substituted hydroxypropylcellulose (HPC-L), pregelatinized starch, sorbitol, xylitol, and combinations thereof, but the diluent is not limited thereto. In one embodiment, for use as a diluent, mannitol and/or microcrystalline cellulose may be used.

For use as a binder, one or more binders may be selected from hydroxypropyl cellulose (HPC), copovidone (copolymer of vinylpyrrolidone and other vinyl derivative), hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (povidone), pregelatinized starch, HPC-L, and combinations thereof, but the binder is not limited thereto. In one embodiment, for use as a binder, HPC may be used.

For use as a disintegrant, the one or more disintegrants may be croscarmellose sodium, corn starch, crospovidone, HPC-L, pregelatinized starch, and combinations thereof, but the disintegrant is not limited thereto. In one embodiment, for use as a disintegrant, croscarmellose sodium may be used.

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

The inner coating layer formed on the core can prevent interaction between the core and the enteric coating layer, and may comprise, as a coating base material, a hydrophilic polymer that does not inhibit release of the active ingredient in the core when the enteric coating layer is collapsed after application of the composite capsule. The coating base of the inner coating layer may be, for example, at least one selected from HPMC, polyvinylpyrrolidone (PVP), HPC-L, starch, gelatin, Ethyl Cellulose (EC), and a combination thereof. In one embodiment, the inner coating layer may comprise HPMC as a coating base.

In the present specification, a core having an inner coating layer formed thereon is also referred to as an inner-coated core. The amount of the inner coating layer may be appropriately selected by one of ordinary skill in the art, but in one embodiment, the amount of the inner coating layer may be in the range of about 3% to about 5% by weight based on the inner coated core.

Both the first and second dissolution parts of the composite capsule include an enteric coating layer, so that acid resistance can be secured in the stomach. Furthermore, upon reaching the intestine through the stomach, a first release of the active ingredient is carried out rapidly from the first dissolution section and, after a delayed time, a second release of the active ingredient is carried out subsequently from the second dissolution section. Accordingly, the composite capsule can prevent the drug from being degraded in the stomach, and can exhibit a rapid drug efficacy since the drug is rapidly dissolved upon reaching the intestine, and then can sustain the drug efficacy over a long period of time by the dual release of the drug.

The enteric coating layer contained in the first dissolution part may contain methacrylic acid copolymer LD as a coating base material. Methacrylic acid copolymer LD is an anionic copolymer comprising methacrylic acid and ethyl acrylate in a ratio of about 1:1 and is present in the form of a solution. Methacrylic acid copolymer LD is commercially available under the trade name Eudragit L30D-55 and its IUPAC name is poly (methacrylic acid-co-ethyl acrylate) 1: 1.

The enteric coating layer comprised in the first dissolution part may comprise as coating base a mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of about 1.5:1(w/w) to about 3.5:1(w/w), for example about 2:1(w/w) to about 3:1 (w/w).

The methacrylic acid copolymer S is an anionic copolymer comprising methacrylic acid and methyl methacrylate in a ratio of about 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.

The methacrylic acid copolymer L is an anionic copolymer comprising methacrylic acid and methyl methacrylate in a ratio of about 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 as a coating base material of the enteric coating layer of the first dissolution part (also referred to as the first enteric coating layer) is a solid powder having a content of about 5% (w/w) to about 50% (w/w), for example about 8% (w/w) to about 30% (w/w), relative to the inner coated core of the first dissolution part. When the amount of such solid powder is less than 5% (w/w) relative to the inner-coated core, it is difficult to ensure acid resistance in 0.1N aqueous HCl solution although the solid powder is rapidly dissolved. In this regard, when administered orally, the active ingredient may degrade due to the nature of PPIs, and thus may be difficult to exhibit medical efficacy. Further, when the methacrylic acid copolymer LD is used as the solid powder for coating in an amount of more than 50% (w/w) relative to the inner coated core of the first dissolution part, sufficient acid resistance in a 0.1N HCl aqueous solution can be ensured, but after passing through the stomach, dissolution of the active ingredient is excessively slow in the intestine, resulting in delay of drug absorption and delay of medical efficacy in the living body.

The methacrylic acid copolymer S and the methacrylic acid copolymer L as coating substrates of the enteric coating layer of the second dissolution part (also referred to as the second enteric coating layer) may be mixed at a ratio of about 1.5:1(w/w) to about 3.5:1(w/w), and for example, about 2:1(w/w) to about 3:1 (w/w). When the coating base material is mixed at a ratio lower than the above ratio, the proportion of the methacrylic acid copolymer L dissolved at a relatively low pH becomes relatively high, and therefore, rapid release thereof may occur when it reaches the intestine through the stomach, resulting in difficulty in expressing the dual release property. Further, when the coating base is mixed at a ratio higher than the above ratio, the proportion of the methacrylic acid copolymer S as a relatively insoluble substance increases, resulting in excessively delayed release of the drug. In this regard, the coated substrate may be excreted without achieving complete release of the drug, resulting in low bioavailability.

As a solid powder, the mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L may be used in an amount of 15% (w/w) to 40% (w/w), for example 20% (w/w) to 35% (w/w), relative to the inner coated core. When the content of the mixture is less than the above amount, the second dissolution part may not be able to ensure a desired dissolution delay, and it may be difficult to ensure a dual release profile due to rapid dissolution upon reaching the intestine. Further, when the content of the mixture is more than the above amount, the enteric coating layer may become thicker, so that the second release of the drug from the dissolution member may be excessively delayed. Therefore, the drug in the composite capsule may be excreted without achieving complete release of the drug, resulting in low bioavailability.

The composite capsule may contain the active ingredient in the first and second dissolution fractions, respectively, in appropriate ratios, and such appropriate ratios may be selected by one of ordinary skill in the art depending on the desired dissolution characteristics. In one embodiment, as a free base, esomeprazole or a pharmaceutically acceptable salt thereof may be contained between the first and second dissolution parts in the composite capsule in a weight ratio 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 substrate of the hard capsule may be, for example, selected from gelatin, hypromellose, pullulan (NP caps TM, etc., Capsugel Company), polyvinyl alcohol, and combinations thereof, but the substrate is not limited thereto.

For use as hard capsules, any conventional size capsule available in the art may be used. Various capsule sizes are used depending on the size of the capsule. Large size capsules, for example size 00 capsules (capsule cap diameter 8.5mm and capsule length 23.3mm) are inconvenient for elderly patients or small children and may also have poor portability due to increased capsule volume. In one embodiment, size 0, size 1, size 2, size 3 or size 4, e.g., size 1, size 2 or size 3 composite capsules may be used in view of the mass limitations of the tablets or granules to be filled in the capsule.

In the composite capsule, the active ingredient is hardly released in a strongly acidic environment. However, the first release of the active ingredient proceeds rapidly from the first dissolved portion in the intestine at a pH of 5.5 or less, and the second release of the active ingredient proceeds from the second dissolved portion in the intestine at a pH of 6.5 to 7.0.

For dissolution test on the composite capsules, the composite capsules were left in 0.1N HCl aqueous solution for 2 hours, and then the solution was transferred to artificial intestinal juice of pH6.7 to 6.9. In the dissolution test, almost no release occurred during the first two hours, but release began in the artificial intestinal fluid. A first release from the first dissolution fraction is performed 150 minutes after the start of the dissolution test, wherein about 90% (w/w) or more of the active ingredient of the first dissolution fraction is released. After a delay time of 180 minutes from the start of the dissolution test, the dissolution of the active ingredient is started from the second dissolution part, and then at 360 minutes, a second release is achieved completing the dissolution (about 99% or more). During a delay time of 180 minutes, a 5% active ingredient, preferably 2% active ingredient, of the second dissolved fraction can be achieved.

In one embodiment, when dissolution testing is performed continuously in artificial intestinal fluid having a pH of 6.7 to 6.9 for 240 minutes after dissolution at 100 revolutions per minute (rpm) in 0.1N aqueous HCl for 120 minutes at a temperature of 37 ± 0.5 ℃ according to paddle method II described in United States Pharmacopeia (USP),

the composite capsules have acid resistance in 0.1N HCl over 120 minutes,

about 55% or less of the active ingredient was dissolved in 60 minutes in the artificial intestinal juice, and about 95% or more of the active ingredient was dissolved in 240 minutes in the artificial intestinal juice (see experimental example 4).

Therefore, considering that the composite capsule can have sufficient bioavailability and duration by allowing the active ingredient not to be dissolved in the stomach but to be doubly released in the intestine, the composite capsule can be effectively used while reducing the frequency of administration.

The composite capsule may include esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient. Such active ingredients are known to be effective or may be used for any treatment or prevention of diseases for which newly developed drugs are effective in the future. Thus, according to one embodiment, the composite capsule may be used for preventing or treating a disease associated with gastric hyperacidity, selected from the group consisting of gastroesophageal reflux disease, gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer.

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

Another aspect of the present disclosure provides a method of preparing the composite capsule according to any one of claims 1 to 13, the method comprising:

preparing a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive;

coating the core with an inner coating layer;

obtaining a first dissolved fraction by coating a first enteric coating layer on the inner coating layer;

separately, a second dissolved fraction is obtained by coating a second enteric coating layer on the inner coating layer; and

filling a capsule with the first and second dissolved fractions together,

wherein the first enteric coating layer comprises methacrylic acid copolymer LD as a coating base material in an amount of about 5% (w/w) to about 50% (w/w) of the core on which the inner coating layer is formed, and

the second enteric coating layer comprises, 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(w/w) to about 3.5:1(w/w) in an amount of about 15% (w/w) to about 40% (w/w) of the core on which the inner coating layer is formed.

The details of the method of preparing an oral solid formulation according to one embodiment may be applied as such to the oral solid formulation according to the above aspect of the present disclosure, and may be detailed using any preparation method known in the art.

When the core of the first and second dissolution fractions of the composite capsule is a mini-tablet (MUST) or a conventional tablet, the core may be prepared according to direct compression or indirect compression. For direct compression, dry granules or wet granules may be used.

In one embodiment, the preparation of the core may comprise the steps of:

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

(b) mixing the mixture of step (a) with a disintegrant, a binder and a lubricant; and

(c) dry granulating the mixture of step (b) and then tabletting the obtained product to obtain mini-tablets or tablets.

For coating the mini-tablets or tablets with the inner coating layer, the first enteric coating layer and the second enteric coating layer, any coating method of coating the mini-tablets or tablets may be applied. For example, a fluidized bed coater may be used for coating.

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are illustrative of embodiments and are not intended to otherwise limit the scope of embodiments in any way.

[ examples ]

Preparation example 1 formation of core and inner coating layer containing magnesium salt of esomeprazole

Using the compositions in table 1 below, the magnesium salt of esomeprazole and mannitol were mixed and the mixture was sieved using a 30 mesh circular sieve. The resultant product was added to an air blender having microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and sodium stearyl fumarate, and blended for 15 minutes, thereby preparing a final mixture. The final mixture was placed in a roller press and then dry granulated. The granules thus obtained were sieved using a 20 mesh circular sieve.

Next, 10 mini-tablets were compressed using a MUST punch with a diameter of 2.0mm, at a compression level of about 1kp to about 2kp per compression and a weight of 7.5mg, to form MUST.

[ Table 1] composition of cores containing esomeprazole magnesium salt

The prepared MUST was coated in a fluid bed coater with a coating fluid having the composition of table 2 below, to obtain inner coated mini tablets with a weight of 7.88mg per tablet.

[ Table 2] composition of inner coating layer

Preparation example 2 examples 1 to 3 and comparative examples 1 and 2

Preparation of mini-tablets formed with a first enteric coating layer

The internally coated mini-tablets were coated in a fluid bed granulator using the composition of table 3 to prepare mini-tablets formed with a first enteric coating layer according to examples 1 to 3 and comparative examples 1 and 2. In examples 1 to 3, Eudragit L30D-55 as the first enteric coating base material was coated at a weight of 5% (w/w) to 50% (w/w) relative to the internally coated mini-tablets. In comparative example 1 and comparative example 2, Eudragit L30D-55 was coated at 4% (w/w) and 51% (w/w), respectively.

TABLE 3 composition of the first enteric coating layer

Preparation example 3 example 4To example 7 and comparative examples 3 to 8

Preparation of mini-tablets having a second enteric coating layer formed thereon

The internally coated minitablets of preparation example 1 were coated in a fluid bed granulator using the compositions of tables 4 and 5 below to prepare mini-tablets of examples 4 to 7 and comparative examples 3 to 8 having a second enteric coating layer formed thereon.

In examples 4 and 5, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a ratio of 2:1 was coated in a weight ratio of 25% (w/w) to 35% (w/w) with respect to the inner coated mini-tablets. In examples 6 and 7, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a ratio of 3:1 was coated in a weight ratio of 20% (w/w) to 30% (w/w) with respect to the inner coated mini-tablets.

Table 4 composition of the second enteric coating layer of example 4 to example 7

In comparative example 3 and comparative example 4, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a ratio of 2:1 was coated at a weight of 10.15% (w/w) and 40.61% (w/w), respectively, relative to the internally coated mini-tablets. In comparative example 5 and comparative example 6, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a ratio of 3:1 was coated at a weight of 10.15% (w/w) and 40.61% (w/w), respectively, relative to the internally coated mini-tablets. In comparative example 7 and comparative example 8, a mixture of Eudragit S-100 and Eudragit L-100 mixed in a ratio of 6:1 was coated at a weight of 10.15% (w/w) and 20.30% (w/w), respectively, relative to the internally coated mini-tablets.

Table 5 composition of the second enteric coating layer of comparative examples 3 to 8

Preparation example 4 examples 8 and 9 and comparative example 9

Preparation of mini-tablets formed with a first enteric coating layer and mini-tablets formed with a second enteric coating layer

A No. 2 gelatin hard capsule whose main base material is gelatin was filled with 10 mini-tablets of example 1 formed with the first enteric coating layer and 10 mini-tablets of example 4 formed with the second enteric coating layer together to prepare a composite capsule of example 8 (including 40mg of esomeprazole). In the same manner, capsules were filled with the mini-tablets of example 1 and example 7 to prepare composite capsules of example 9. Further, in the same manner, the capsule was filled with the mini-tablets of example 1 and comparative example 3 to prepare a composite capsule of comparative example 9.

Preparation example 5 preparation of composite Capsule according to Capsule type

A composite capsule was prepared in the same manner as in preparation example 4, except that the hypromellose capsule filled with mini tablets was a hard capsule whose main base material was hypromellose. Further, a composite capsule was prepared in the same manner as in preparation example 4, except that the mini-tablet-filled pullulan capsule was a hard capsule whose main base was pullulan.

Experimental example 1: dissolution test of mini-tablets formed with a first enteric coating layer

Using the mini-tablets of examples 1 to 3 and comparative examples 1 and 2 formed with the first enteric coating layer, the time-dependent dissolution rate of esomeprazole magnesium salt was measured under the following conditions:

dissolution conditions

Eluent: 300mL of 0.01N HCl (2 hours) → 1,000mL of artificial intestinal juice (pH6.8)

The device comprises the following steps: USP Paddle (Farad), 100rpm

Temperature: 37 deg.C

Time for measuring dissolution rate: 60 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 150 minutes, 165 minutes, and 180 minutes

Analysis conditions

The equipment used was: HPLC (Hitachi 5000 series, Japan)

A detector: ultraviolet spectrophotometer (measuring wavelength: 302nm)

Column: stainless steel tube having an inner diameter of about 4.0mm and a length of about 10cm

5 μm column packed with silica gel for liquid chromatography

Mobile phase-

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

Flow rate: 1.0mL/min

Column temperature: 30 deg.C

The results of measuring the dissolution rate of the mini-tablets of examples 1 to 3 in which the first enteric coating layer was formed are shown in table 6 and fig. 2.

[ Table 6]

As shown in table 6 and fig. 2, the mini-tablets of examples 1-3 have acid resistance in 0.1N HCl for the first 2 hours. Then, the mini-tablets showed a dissolution rate of 90% or more in the artificial intestinal fluid (pH6.8) within 30 minutes (i.e., 150 minutes after the start of the dissolution test), indicating that the mini-tablets showed immediate release.

The results of the dissolution rate measurements of comparative example 1 and comparative example 2 are shown in table 7 and fig. 3.

[ Table 7]

As shown in table 7 and fig. 3, the mini-tablet of comparative example 1, in which Eudragit L30D-55 was used as the first enteric coating layer at a weight of 4% (w/w) relative to the inner-coated mini-tablet, was difficult to have sufficient acid resistance due to a low coating rate compared to the inner-coated mini-tablet, and showed 10% release in 0.1N HCl within 120 minutes. In addition, the mini-tablet of comparative example 1 did not show a final dissolution rate of 100% due to the characteristics of esomeprazole degraded in an acidic environment.

Further, the mini-tablet of comparative example 2, in which Eudragit L30D-55 was used as the first enteric coating layer at a weight of 51% (w/w) relative to the inner coated mini-tablet, ensured sufficient acid resistance, but showed a dissolution rate of 85% within 150 minutes. Therefore, the absorption of esomeprazole is slowed, and thus the expression of medical efficacy may also be delayed.

Experimental example 2: acid resistance test of mini-tablets formed with a first enteric coating layer

Using the mini-tablets of examples 1 to 3 and comparative examples 1 and 2, in which the first enteric coating layer was formed, the mini-tablets were left under the following acid resistance conditions for 2 hours, and the acid resistance was measured based on the amount of the esomeprazole magnesium salt. 10 mini-tablets were used and the results are shown in table 8.

Acid resistance conditions

Test solutions: 0.01N HCl

The device comprises the following steps: USP Paddle method, 100rpm

Temperature: 37 deg.C

Time: standing for 2 hours

Analysis conditions

The equipment used was: HPLC (Hitachi 5000 series, Japan)

A detector: ultraviolet spectrophotometer (measuring wavelength: 302nm)

Column: stainless steel tube having an inner diameter of about 4.0mm and a length of about 10cm

5 μm column packed with silica gel for liquid chromatography

Mobile phase-

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

Flow rate: 1.0mL/min

Column temperature: 30 deg.C

TABLE 8 results of acid resistance test

	Amount before test (%)	Amount 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 shown in table 8, as a result of the acid resistance test in 0.1N HCl performed in examples 1 to 3 and comparative examples 1 and 2, comparative example 1, in which the coating layer ratio was low, showed a difference of about 10.0% in the amount of esomeprazole magnesium salt before and after the test. However, the remaining samples except comparative example 1 were found to have an amount similar to the amount of the original active ingredient after the acid resistance test.

Experimental example 3: dissolution test of Mini-tablets having formed thereon a second enteric coating layer

Using the mini-tablets of example 4 to example 7 and comparative examples 3 to 8, in which the second enteric coating layer was formed, the time-dependent dissolution rate of the esomeprazole magnesium salt was measured under the following conditions:

dissolution conditions

Eluent: 300mL of 0.01N HCl → 1,000mL of artificial intestinal juice (pH6.8)

The device comprises the following steps: USP Paddle (Farad), 100rpm

Temperature: 37 deg.C

Time for measuring dissolution rate: 60 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 300 minutes, and 360 minutes

Analysis conditions

The equipment used was: HPLC (Hitachi 5000 series, Japan)

A detector: ultraviolet spectrophotometer (measuring wavelength: 302nm)

Column: stainless steel tube having an inner diameter of about 4.0mm and a length of about 10cm

5 μm column packed with silica gel for liquid chromatography

Mobile phase-

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

Flow rate: 1.0mL/min

Column temperature: 30 deg.C

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

[ Table 9]

Referring to the results of table 9 and fig. 4, the mini tablets of examples 4 to 7 did not show any dissolution in 0.1N HCl for the first 2 hours, so that acid resistance was ensured. Then, the release of the drug in the artificial intestinal juice (pH6.8) is delayed for 60 minutes or more. However, once the drug begins to release, the release is quickly completed.

Although slightly different depending on the ratio of Eudragit S and Eudragit L, it is ensured that after 120 minutes of acid resistance in 0.1N HCl the esomeprazole magnesium salt is hardly released in 60 minutes in the artificial intestinal fluid, but is released rapidly over the past 60 minutes. Then, when a period of 360 minutes elapsed, an excellent release characteristic of releasing 99% or more of the esomeprazole magnesium salt was confirmed. When a dissolution rate of 90% or more is not ensured at a time of 360 minutes due to the properties of the formulation, the drug may be excreted without being dissolved out, and in this regard, it is confirmed that sufficient release can be achieved in examples 4 to 7.

In addition, the results of measuring the dissolution rate of the mini-tablets of comparative examples 3 to 8 in which the second enteric coating layer was formed are shown in table 10 and fig. 5.

[ Table 10]

Referring to the results shown in table 10 and fig. 5, in the case of the mini-tablets of comparative example 3, comparative example 5, and comparative example 7, it was difficult to secure acid resistance for 2 hours in 0.1N HCl because the weight ratio of the second enteric coating layer was low. In the case of the mini-tablets of comparative example 4, comparative example 6 and comparative example 8, not only acid resistance is ensured but also the release of the drug is excessively delayed in the artificial intestinal juice due to the high weight ratio of the second enteric coating layer. In these mini-tablets, more than 90% of drug release is not achieved even after 6 hours have passed, and therefore, the drug may be excreted without the release of the drug being sufficiently completed.

Experimental example 4: dissolution test of Compound Capsule

Using the composite capsules of example 8 and example 9 and comparative example 9, the time-dependent dissolution rate of esomeprazole magnesium salt was measured under the following conditions:

dissolution conditions

Eluent: 300mL of 0.1N HCl → 1,000mL of artificial intestinal juice (pH6.8)

The device comprises the following steps: USP Paddle (Farad), 100rpm

Temperature: 37 deg.C

Time for measuring dissolution rate: 60 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 150 minutes, 165 minutes, 180 minutes, 210 minutes, 240 minutes, 300 minutes, and 360 minutes

Analysis conditions

The equipment used was: HPLC (Hitachi 5000 series, Japan)

A detector: ultraviolet spectrophotometer (measuring wavelength: 302nm)

Column: stainless steel tube with inner diameter of about 4.0mm and length of about 10cm for a 5 μm column of liquid chromatography filled with silica gel

Mobile phase-

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

Flow rate: 1.0mL/min

Column temperature: 30 deg.C

The results of the dissolution rate measurement are shown in table 11 and fig. 6.

[ Table 11] dissolution rate of esomeprazole magnesium salt

Referring to the results of table 11 and fig. 6, the composite capsules of example 8 and example 9, which were prepared by mixing the mini-tablets including the first enteric coating layer and the mini-tablets including the second enteric coating layer at a ratio of 1:1, ensured acid resistance in 0.1N HCl for the first 2 hours. Then, after the first release in the artificial intestinal fluid, the release was delayed by about 45 minutes before the second release was initiated. This dual release characteristic has been clearly identified with reference to the graph of fig. 6. Therefore, the composite capsules of example 8 and example 9 showed sustained release of the drug for up to 6 hours after the start of the dissolution test due to the dual release characteristics in the artificial intestinal fluid.

In the mini-tablets of comparative example 9, acid resistance was ensured in 0.1N HCl within 2 hours. However, the release of the drug occurs immediately after the first release, without a delay before the second release begins. Thus, after 3 hours of dissolution testing, the release of most of the drug (98% or more) was complete.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the embodiments as defined by the following claims. The exemplary embodiments should be considered in descriptive sense only and not for purposes of limitation. Therefore, the scope of the embodiments is defined not by the detailed description of the embodiments but by the appended claims, and all differences within the scope will be construed as being included in the present invention.

Claims (10)

1. A composite capsule comprising:

a first dissolved fraction comprising: a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient; an inner coating layer over the core; and a first enteric coating layer on the inner coating layer; and

a second digested portion comprising: a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient; an inner coating layer over the core; and a second enteric coating layer on the inner coating layer,

wherein the first enteric coating layer comprises methacrylic acid copolymer LD as a coating base material in an amount of 5 to 50% w/w of the core on which the inner coating layer is formed,

the second enteric coating layer comprises, as a coating base material, a mixture containing a methacrylic copolymer S and a methacrylic copolymer L in a weight ratio ranging from 1.5:1 to 3.5:1 in an amount of 15% w/w to 40% w/w of the core on which the inner coating layer is formed,

wherein the inner coating layer comprises Hydroxypropylmethylcellulose (HPMC),

wherein the inner coating layer is included in the core having the inner coating layer formed thereon in an amount of 3% w/w to 5% w/w,

wherein the cores of the first and second dissolution fractions are all mini-tablets, and

wherein in an artificial intestinal juice having a pH value of 6.7 to 6.9 and a temperature of 37 + -0.5 ℃, the active ingredient of the first dissolved fraction is released into the artificial intestinal juice before the active ingredient of the second dissolved fraction is released.

2. The composite capsule of claim 1, wherein the second enteric coating layer comprises, as a coating base material, a mixture containing methacrylic acid copolymer S and methacrylic acid copolymer L in a weight ratio ranging from 2:1 to 3:1 in an amount of 20% w/w to 35% w/w of the core on which the inner coating layer is formed.

3. The composite capsule of claim 1, wherein the first and second dissolved portions each comprise esomeprazole, or a pharmaceutically acceptable salt thereof, as a free base in a weight ratio ranging from 2:1 to 1: 3.

4. The composite capsule of claim 1, wherein the core of the first and second dissolved portions each comprise one or more pharmaceutical additives selected from diluents, binders, disintegrants, lubricants, surfactants, antioxidants, preservatives, stabilizers, and combinations thereof.

5. The composite capsule of claim 1, wherein, when the dissolution test is continuously performed in artificial intestinal fluid having a pH of 6.7 to 6.9 for 240 minutes after dissolution at 100 revolutions per minute (rpm) in 0.1N aqueous HCl solution at a temperature of 37 ± 0.5 ℃ for 120 minutes according to Paddle method II described in United States Pharmacopeia (USP),

the composite capsules have acid resistance in 0.1N HCl over 120 minutes,

55% or less of the active ingredient is dissolved in the artificial intestinal juice within 60 minutes, and

95% or more of the active ingredient is dissolved in the artificial intestinal juice within 240 minutes.

6. The composite capsule of claim 1, wherein the pharmaceutically acceptable salt of esomeprazole comprises a magnesium esomeprazole salt or a strontium esomeprazole salt.

7. The composite capsule of claim 1, wherein the capsule base of the composite capsule is selected from the group consisting of gelatin, hypromellose, pullulan, polyvinyl alcohol, and combinations thereof.

8. The composite capsule according to claim 1, wherein the composite capsule is used for preventing or treating a disease associated with gastric acid hypersecretion selected from the group consisting of gastroesophageal reflux disease, gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer.

9. The composite capsule of claim 1, wherein said composite capsule is administered once daily.

10. A method of making a composite capsule according to any one of claims 1 to 9, the method comprising:

preparing a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive;

coating the core with an inner coating layer;

obtaining a first dissolved fraction by coating a first enteric coating layer on the inner coating layer;

separately, a second dissolution fraction is obtained by coating a second enteric coating layer on the inner coating layer; and

filling a capsule with the first and second dissolved fractions together to produce the composite capsule,

wherein the first enteric coating layer comprises methacrylic acid copolymer LD as a coating base material in an amount of 5 to 50% w/w of the core on which the inner coating layer is formed,

the second enteric coating layer comprises, as a coating base material, a mixture containing a methacrylic copolymer S and a methacrylic copolymer L in a weight ratio ranging from 1.5:1 to 3.5:1 in an amount of 15% w/w to 40% w/w of the core on which the inner coating layer is formed,

wherein the inner coating layer comprises Hydroxypropylmethylcellulose (HPMC),

wherein the inner coating layer is included in the core having the inner coating layer formed thereon in an amount of 3% w/w to 5% w/w,

wherein the cores of the first and second dissolved fractions are all mini-tablets, and

wherein in an artificial intestinal juice having a pH value of 6.7 to 6.9 and a temperature of 37 + -0.5 ℃, the active ingredient of the first dissolved fraction is released into the artificial intestinal juice before the active ingredient of the second dissolved fraction is released.