KR102060738B1 - Bitter taste masked pharmaceutical formulation comprising esomeprazole free base or alkali salt thereof and preparation method thereof - Google Patents

Abstract

The present invention is 1) an inert core; 2) a drug coating layer coated on the inert core, the drug coating layer comprising eomeprazole free base or an alkali salt thereof as an active ingredient and a water-soluble film forming polymer; 3) a separation layer coated on the drug coating layer and comprising a sweetener and a hydrophilic polymer; And 4) a pharmaceutical formulation comprising a enteric coating layer coated on the separation layer and comprising an enteric base and a pharmaceutically acceptable additive, wherein the pharmaceutical formulation of the present invention is an unpleasant and bitter taste of the active ingredient. In addition to effectively shielding, and can suppress the formation of the flexible material can be improved by the formulation of the disintegrating tablet or suspension in the oral cavity to increase the patient's compliance.

Description

Pharmaceutical masked pharmaceutical preparation comprising eomeprazole free base or alkali salt thereof and method for preparing the same

The present invention relates to a pharmaceutical preparation comprising eomeprazole free base or an alkali salt thereof masked with irritation and bitter taste and a method for preparing the same.

Patients with chronic peptic ulcer disease and gastroesophageal reflux disease have to take daily medications for a long time and have low medication compliance, so tablets that can disintegrate quickly in the oral cavity rather than in general tablets and capsules (for example, disintegrating tablets in the mouth) And suspending agents are preferred in terms of improving convenience and compliance when taken. In particular, oral disintegrating tablets and suspensions are one of the preferred formulations because they can be easily taken by elderly and children with weak swallowing ability.

Eomeprazole (chemical name: (S) -5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl] -3H-benzoimidazole) is a peptic ulcer, stomach Proton pump inhibitors used for esophageal reflux disease and the like, wherein the esomeprazole free base or its alkali salt has a strong bitter or unpleasant taste. Therefore, when formulated with oral disintegrating tablets, the medication compliance of the patient may be lowered, so when formulated with oral disintegrating tablets using the above ingredients, the irritating or bitter taste should be effectively masked.

Korean Patent Registration No. 10-1011278 discloses masking the bitter taste of the active ingredient by mixing the water-soluble sugars into granules as a sweetener. However, when taking pharmaceutical preparations such as pellets such as eomeprazole, the particles remaining in the mouth after taking the drug may be broken and bitter afterwards, so it is not easy to shield bitter rice in this way.

Orally disintegrating tablets or suspending agents containing active ingredients with a strong bitter or unpleasant taste can mask the bitter or unpleasant taste by the addition of sweetening agents. However, even if only a small amount of the pellet containing the active ingredient may be unpleasant taste even if it breaks in the mouth, the inside of the pellet is coated with a component containing a sweetener. However, when the sweetener is mixed with the active ingredient and coated with the same layer, the formation of the flexible material may be promoted, thereby reducing the stability.

Thus, the present inventors earnestly studied to prepare a pharmaceutical formulation in which the bitter or unpleasant taste of esomeprazole free base or its alkali salt is masked. As a result, by coating a separation layer containing a sweetener between the drug coating layer and the enteric coating layer containing esomeprazole effectively shields the bitter or unpleasant taste of the active ingredient, while contacting the esomeprazole free base or its alkali salts and sweeteners According to the present invention, the present invention has been found to be able to suppress the formation of a flexible substance according to the present invention, thereby preparing a pharmaceutical formulation having excellent stability. The pharmaceutical preparations thus prepared can be easily administered to patients with swallowing disorders, children, and the elderly by formulating with oral disintegrating tablets and suspending agents, so that the medication compliance can be improved.

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Republic of Korea Patent Registration No. 10-1011278

Accordingly, it is an object of the present invention to provide a pharmaceutical preparation with masked bitterness comprising eomeprazole free base or an alkali salt thereof.

Another object of the present invention is to provide a method for preparing the pharmaceutical formulation.

In order to achieve the above object, the present invention

1) inert core;

2) a drug coating layer coated on the inert core, the drug coating layer comprising eomeprazole free base or an alkali salt thereof as an active ingredient and a water-soluble film forming polymer;

3) a separation layer coated on the drug coating layer and comprising a sweetener and a hydrophilic polymer; And

4) Provides a highly shielded pharmaceutical formulation coated on the separation layer, the enteric coating layer comprising an enteric base and a pharmaceutically acceptable additive.

The present invention to achieve the above another object

(a) coating a surface of the inert core with an aqueous solution comprising esomeprazole free base or an alkali salt thereof as an active ingredient and a water-soluble film forming polymer to form a drug coating layer;

(b) coating a coating material comprising a sweetener and a hydrophilic polymer on the surface of the drug coating layer to form a separation layer; And

(c) coating the enteric coating material comprising an enteric base and a pharmaceutically acceptable additive to form an enteric coating layer on the surface of the separation layer, thereby providing a method for preparing the high-shielding pharmaceutical preparation. .

The pharmaceutical preparations according to the present invention can effectively mask the unpleasant taste of esomeprazole while also suppressing the formation of flexible substances produced by sweeteners, so when formulated with oral disintegrating tablets or suspensions, patients with swallowing disorders, children and the elderly It can be expected to improve medication compliance.

Figure 1 shows the results of evaluation of the taste of pharmaceutical preparations according to the addition of sweeteners.
Figures 2 and 3 show the maximum analog and total analog produced after the harsh conditions (60 ℃) storage of the pharmaceutical formulations of Comparative Examples 4 and 5, and Example 4, respectively.
Figures 4 and 5 show the maximum amount and total amount of analogues produced after the accelerated exposure conditions (45 ℃ and 75%) storage of the pharmaceutical formulation of Comparative Examples 4 and 5, and Example 4, respectively.

The present invention is 1) an inert core; 2) a drug coating layer coated on the inert core, the drug coating layer comprising eomeprazole free base or an alkali salt thereof as an active ingredient and a water-soluble film forming polymer; 3) a separation layer coated on the drug coating layer and comprising a sweetener and a hydrophilic polymer; And 4) an enteric coating layer coated over the separation layer, the enteric coating layer comprising an enteric base and a pharmaceutically acceptable additive.

According to the present invention, the active ingredient is coated with an eomeprazole free base or an alkali salt thereof on a spherical inert core, and the coated particles are coated with a separation layer using a polymer containing a sweetener, and then once again with an enteric coating. Not only can it effectively mask unpleasant taste, but it can also solve the problem of deterioration in stability. Therefore, by formulating the pharmaceutical formulations in the form of oral disintegrating tablets or suspending agents, it can contribute to improve patient compliance.

1) inert core

In the case of high-shielding particles, it is necessary to minimize the size of the particles because if the size of the particles is too large, the particles may feel gritty in the oral cavity and cause a rejection of taking. Therefore, the pharmaceutical preparation according to the present invention preferably has an average particle diameter of 500 µm or less, preferably 400 µm or less, more preferably 300 µm or less.

Accordingly, in the present invention, the inert core has a size of 50 to 300 μm, preferably 80 to 250 μm, more preferably 100 to 180 μm, taking into account the preferred final particle size (about 500 μm or less) of the pharmaceutical formulation. It is good to have.

The inert core may be used as long as it is a pharmaceutically acceptable material having the appropriate size and firmness as mentioned above, and in the present invention, white sugar, mannitol, sorbitol, lactose, potato starch, corn starch, hydroxyethyl It can be selected from the group consisting of cellulose, microcrystalline cellulose, white lead, carnauba wax, microcrystalline wax and mixtures thereof.

2) drug coating layer

In the present invention, the drug coating layer is coated on an inert core, and includes, as active ingredients, omeprazole free base or an alkali salt thereof, and a water-soluble film forming polymer. In the present invention, the viscosity of the water-soluble film-forming polymer, the ratio of the drug and the water-soluble film-forming polymer, and the total coating amount of the drug coating layer can be adjusted to achieve rapid drug release of the drug.

In the present invention, the water-soluble film forming polymer serves to help the drug effectively attach to the inert core, and may be used in an amount sufficient to bind the drug to the inert core.

The water-soluble film-forming polymer is a water-soluble hydrophilic polymer having a low viscosity for rapid release of the drug, for example, a hydrophilic polymer having a viscosity of 50 cps or less, preferably a water-soluble hydrophilic having a viscosity of 3 to 15 cps Polymers can be used.

The water-soluble film-forming polymer used in the present invention is methyl cellulose, hydroxyalkyl cellulose having 1 to 3 carbon atoms, hydroxyalkyl alkyl cellulose having 1 to 3 carbon atoms, carboxyalkyl cellulose having 1 to 3 carbon atoms, and carboxyalkyl having 1 to 3 carbon atoms. Alkali metal salts of cellulose, carboxyalkyl cellulose esters of 1 to 3 carbon atoms, starch, pectin, chitin derivatives, polysaccharides, polyacrylic acid and salts thereof, polymethacrylic acid and salts thereof, polyvinyl alcohol, polyvinylpyrrolidone , Polyalkylene oxide and mixtures thereof, and preferably hydroxypropylmethyl cellulose (hypromellose) can be used.

The water-soluble film forming polymer may be used in an amount of 0.05 to 1 parts by weight, preferably 0.1 to 0.5 parts by weight, more preferably 0.12 to 0.25 parts by weight, based on 1 part by weight of esomeprazole free base or an alkali salt thereof.

3) Separation layer

In the present invention, the separation layer is coated on the drug coating layer, and includes a sweetening agent and a hydrophilic polymer. The separation layer serves to separate the drug so that the drug is not released until swallowed in the mouth as a bite shielding layer.

According to one embodiment of the present invention, when the active ingredient is mixed with eomeprazole free base or an alkali salt on the inert core and has a gummy shielding effect, as a flexible material produced by the direct contact of eomeprazole with the sweetener It was found that the stability is very low. Accordingly, in the present invention, a pharmaceutical formulation was prepared by coating a separation layer containing a sweetener between a drug coating layer containing esomeprazole free base or an alkali salt thereof and an enteric coating layer to release the drug in the intestine. In addition, the pharmaceutical formulation of the present invention having such a configuration can suppress the production of a flexible substance while at the same time masking an unpleasant or bitter taste.

In the present invention, the sweetener may be selected from the group consisting of saccharin, sodium saccharin, aspartame, acesulfame potassium, sucralose, stevia, stevioside, somartin and mixtures thereof, preferably sucralose, stevioside , Saccharin, aspartame and mixtures thereof may be used.

The sweetening agent may be used in an amount of 0.05 to 1 parts by weight, preferably 0.1 to 0.8 parts by weight, based on 1 part by weight of esomeprazole free base or an alkali salt thereof, and an amount of 20 to 80% by weight based on the total weight of the separation layer. It may be included as.

In the present invention, the hydrophilic polymer is polyvinylpyrrolidone, polyalkylene glycol (for example, polyethylene glycol, polypropylene glycol, etc.), polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives (hydroxypropylmethylcellulose, hydroxypropyl Cellulose) and mixtures thereof, and preferably polyethylene glycol or hydroxypropylmethylcellulose.

In the present invention, the separation layer is characterized in that it is included in an amount of 5 to 30% by weight based on the total weight of the formulation.

4) Enteric coating layer

Since eomeprazole decomposes very quickly under acidic conditions, an enteric coating of pharmaceutical preparations is essential to shield against unpleasant or bitter tastes in the oral cavity. Accordingly, the pharmaceutical formulation of the present invention comprises an enteric coating layer, wherein the enteric coating layer is coated on the separation layer, characterized in that it comprises an enteric base and a pharmaceutically acceptable additive.

In the present invention, the final pharmaceutical formulation containing esomeprazole due to the enteric coating layer has elasticity, and even if it is formulated in the form of disintegrating tablet in the oral cavity, the pharmaceutical formulation is not broken by compression. In addition, if the drug is released before swallowing in the oral cavity, the drug may be irritating and bitter taste, because the enteric coating does not release the drug in the stomach and the release of the drug only in the intestine to enable the shielding of bitter taste do.

The enteric base in the present invention is a methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate And mixtures thereof It is characterized in that it is selected from the group consisting of.

According to one embodiment of the present invention, a methacrylic acid copolymer is prepared by mixing with polyethylene glycol, glyceryl monostearate, talc, triethyl citrate, polysorbate and citric acid and purified water The enteric coating layer can be formed by coating an inert core coated with a separation layer with an aqueous suspension.

The pharmaceutical preparations of the present invention may be formulated into various forms of oral preparations such as pellets, capsules, tablets, powders, granules, oral disintegrating tablets or suspensions, and oral disintegrating tablets or suspensions are preferred.

Intraoral disintegrating tablets refers to tablets that disintegrate within 2 minutes (preferably within 1 minute) by saliva without ingesting water. According to one embodiment of the invention, the pharmaceutical preparations prepared above may be formulated in the form of intraoral disintegrating tablets by mixing with a pharmaceutically acceptable additive (for example a diluent) and then tableting.

The diluent may be selected from the group consisting of xylitol, trehalose, sorbitol, maltose, sorbitol, erythritol, glucose, maltitol, mannitol, sucrose, lactose and hydrates thereof, and mannitol may be used as a specific example. The diluent may be used in an amount of 0.5 to 5 parts by weight, preferably 1 to 2 parts by weight, based on 1 part by weight of the pharmaceutical formulation.

In addition to the above components, the oral disintegrating tablet of the present invention may include disintegrants, acidulants, flavors, lubricants, combinations thereof, and the like, which are commonly used as pharmaceutically acceptable additives, and may further include sweetening agents. .

The disintegrant may be selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, low substituted hydroxypropyl cellulose, starch, alginic acid or its sodium salt and mixtures thereof, preferably crospovidone, Sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose or a mixture thereof can be used, and more preferably crospovidone can be used.

The acidulant may be citric anhydride, tartaric acid, malic acid and the like, and the fragrance may be peppermint flavor, strawberry flavor, peppermint flavor powder, menthol, lemon flavor powder, orange flavor powder and the like.

The glidant comprises magnesium stearate, calcium stearate, white sugar, fatty acid stearate, sucrose fatty acid ester, talc, hydrogenated vegetable oil, high melting point wax, glyceryl fatty acid esters, glyceryl behenate and mixtures thereof Can be selected from the group.

The pharmaceutical preparation according to the present invention comprises the steps of: (a) coating a surface of an inert core with an aqueous solution comprising esomeprazole free base or an alkali salt thereof as an active ingredient and a water-soluble film forming polymer to form a drug coating layer; (b) forming a separation layer by coating a coating material including a sweetener and a hydrophilic polymer on the surface of the drug coating layer; And (c) coating an enteric coating material comprising an enteric base and a pharmaceutically acceptable additive on the surface of the separation layer to form an enteric coating layer.

Further, in order to formulate the pharmaceutical preparation, further processes, for example, further mixing with a pharmaceutically acceptable additive and then tableting to prepare orally disintegrating tablets, or mixing with excipients for pharmaceutically acceptable suspensions Thereby preparing a suspension so that the pharmaceutical formulation can be formulated.

Coating in the manufacturing method of the present invention can be made using any conventional method used for coating the drug in the art, for example, without limitation, fan coating method, fluidized bed coating method or compression coating method, coating the fluidized bed coating apparatus A fluidized bed coating method is preferred in which a formulation is sprayed and then sprayed with air blown down to spray the coating solution.

EXAMPLE

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

<Drug coating layer>

Comparative Example 1 Preparation of Composition Coated with Eomeprazole Free Base

The coating solution was dissolved by dissolving 320 g of eomeprazole free base, 48 g of hydroxypropylmethylcellulose, 160 g of sucralose, 64 g of talc, 4 g of polysorbate, and 80 g of magnesium oxide in a mixture of 480 g of purified water and 1920 g of acetone. Prepared. While flowing 200 g of spherical microcrystalline cellulose (average diameter 150 μm) in a fluid bed granulator (GR-XP70), the coating solution prepared above was sprayed to prepare a core coated with esomeprazole free base.

Example 1 Preparation of a Composition Coated with Esomeprazole Free Base

A core coated with esomeprazole freebase was prepared in the same manner as described in Comparative Example 1 except that sucralose was not added.

Example 2 Preparation of a Composition Coated with Eomeprazole Free Base

A core coated with esomeprazole freebase was prepared in the same manner as described in Example 1, except that spherical white sugar was used instead of spherical microcrystalline cellulose.

In Comparative Example 1, Examples 1 and 2, the content of the components corresponding to 40 mg of esomeprazole (oral disintegrating tablets or a suspension of suspension formulation) is shown in Table 1 below.

ingredient Comparative Example 1 Example 1 Example 2 Someprazole free base 40.00 mg 40.00 mg 40.00 mg Spherical Microcrystalline Cellulose 25.00 mg 25.00 mg - Spherical white sugar - - 25.00 mg Hydroxypropylmethylcellulose (HPMC) 6.00 mg 6.00 mg 6.00 mg Sucralose 20.00 mg - - Talc 8.00 mg 8.00 mg 8.00 mg Polysorbate 0.50 mg 0.50 mg 0.50 mg Magnesium oxide 10.00 mg 10.00 mg 10.00 mg Purified water ^* 60.00 mg ^* 60.00 mg ^* 60.00 mg ^* Acetone ^* 240.00 mg ^* 240.00 mg ^* 240.00 mg ^{* *} : These components are not present in the final product.

<Formation of Separation Layer>

Comparative Example 2: Preparation of High Shielding Coated Composition

160 g of hydroxypropylmethylcellulose and 16 g of talc were dissolved or dispersed in a mixed solution of 400 g of purified water and 1600 g of ethanol to prepare a coating solution. While flowing the core particles prepared in Comparative Example 1 in a fluidized bed granulator (GR-XP70), the coating liquid prepared above was sprayed to perform high-shielding (separation layer) coating.

Example 3: Preparation of High Barrier Coated Compositions

160 g of hydroxypropylmethylcellulose, 16 g of talc and 160 g of sucralose were dissolved or dispersed in a mixed solution of 400 g of purified water and 1600 g of ethanol to prepare a coating solution. While flowing the core particles prepared in Example 1 in a fluidized bed granulator (GR-XP70), the coating liquid prepared above was sprayed to perform high-shielding (separation layer) coating.

Comparative Example 3: Preparation of Unshielded Uncoated Composition

The coating was carried out in the same manner as described in Comparative Example 2, except that the core particles prepared in Example 1 were used.

In Comparative Examples 2 and 3, and Example 3, the content of components corresponding to 40 mg of esomeprazole (oral disintegrating tablets or suspensions in suspension) is shown in Table 2 below.

ingredient Comparative Example 2 Example 3 Comparative Example 3 core
(Someprazole) Comparative Example 1
109.5 mg (40 mg) Example 1
89.50 mg (40 mg) Example 1
89.50 mg (40 mg) HPMC 20.00 mg 20.00 mg 20.00 mg Talc 2.00 mg 2.00 mg 2.00 mg Sucralose - 20.00 mg - Purified water 50.00 mg ^* 50.00 mg ^* 50.00 mg ^* Acetone 200.00 mg ^* 200.00 mg ^* 200.00 mg ^{* *} : These components are not present in the final product.

<Formation of enteric coating layer>

Comparative Example 4: Enteric Coating of Gummy Shielded Compositions

1066.4 g of methacrylic acid copolymer, 7.2 g of polyethylene glycol, 50 g of triethyl citric acid, 20 g of glyceryl monostearate, 6.4 g of polysorbate and 0.32 g of citric acid were dissolved or dispersed in 783.2 g of purified water to prepare a coating solution. Entering coating by spraying the coating solution prepared above while flowing the particles prepared in Comparative Example 2 in a fluid bed granulator.

Example 4: Enteric Coating of Gummy Masked Compositions

1066.4 g of methacrylic acid copolymer, 7.2 g of polyethylene glycol, 50 g of triethyl citric acid, 20 g of glyceryl monostearate, 6.4 g of polysorbate and 0.32 g of citric acid were dissolved or dispersed in 783.2 g of purified water to prepare a coating solution. While the particles prepared in Example 3 were flowed in a fluidized bed granulator, the coating solution prepared above was sprayed and enterically coated.

Comparative Example 5: Enteric Coating of Gummy Unshielded Compositions

The enteric coating was carried out in the same manner as in Comparative Example 4 except that the particles prepared in Comparative Example 3 were flowed.

In Comparative Examples 4 and 5, and Example 4, the content of components corresponding to 40 mg of esomeprazole (one tablet of oral disintegrating tablet or suspension of suspension formulation) is shown in Table 3 below.

Comparative Example 4 Example 4 Comparative Example 5 core
(Someprazole) Comparative Example 2
131.50 mg (40 mg) Example 3
131.50 mg (40 mg) Comparative Example 3
111.50 mg (40 mg) Methacrylic acid copolymer 133.3 mg
(40 mg as dry) 133.3 mg
(40 mg as dry) 133.3 mg
(40 mg as dry) Polyethylene glycol 0.90 mg 0.90 mg 0.90 mg Triethyl citrate 6.25 mg 6.25 mg 6.25 mg Glyceryl Monostearate 2.50 mg 2.50 mg 2.50 mg Poly sorbate 0.80 mg 0.80 mg 0.80 mg Citric acid 0.04 mg 0.04 mg 0.04 mg Purified water 97.9 mg ^* 97.9 mg ^* 97.9 mg ^{* *} : These components are not present in the final product.

<Preparation of Disintegrating Tablets>

Example  5: Gummy  Of the masked composition Intraoral Disintegrating tablet  Produce

Intraoral disintegrating tablets of the Komi masked composition were prepared using the ingredients and contents shown in Table 4 below. Specifically, the composition of Example 4, mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, crospovidone, citric acid and aspartame were mixed using a high speed mixer (Sejung, SM-50), followed by further magnesium stearate, Saccharin and peppermint flavors were added and mixed again. The granules thus prepared were compressed using a tableting machine (Sejung, GRC-18) to prepare oral disintegrating tablets.

Comparative Example 6 Preparation of Intraoral Disintegrating Tablet of Gummy-unshielded Composition

Except for using the composition prepared in Comparative Example 5 instead of the composition of Example 4, using the ingredients and contents shown in Table 4 below to prepare the oral disintegrating tablets of the Gomi-unshielded composition.

ingredient Example 5 Comparative Example 6 Composition
(Someprazole) Composition of Example 4
182.0 mg (40 mg) Composition of Comparative Example 5
162.0 mg (40 mg) Mannitol 262.0 mg 262.0 mg Low Substituted Hydroxypropyl Cellulose 38.6 mg 38.6 mg Microcrystalline cellulose 38.6 mg 38.6 mg Crospovidone 19.3 mg 19.3 mg Citric acid 0.93 mg 0.93 mg Aspartame 11.6 mg 11.6 mg Magnesium stearate 7.7 mg 7.7 mg saccharin 10.0 mg 10.0 mg Peppermint flavor 5.0 mg 5.0 mg

Preparation of Suspension Formulation

Example 6: Preparation of Suspending Agents of Gummy Masked Compositions

A binding solution was prepared by dissolving 75.0 g of crospovidone, 4.92 g of citric acid, 30.0 g of hydroxypropyl cellulose, and 1.8 g of yellow iron oxide in 300 g of ethanol. 2814.0 g of mannitol and 75.0 g of xanthan gum were placed in a high speed mixer (Sejung, SM-50), and the binder solution prepared above was added while mixing. And further proceeding the mixing process to prepare a granule.

The granules prepared above were dried using ethanol, and then the enteric-coated composition prepared in Example 4 was added thereto and mixed to prepare a suspension formulation.

ingredient content Particles Prepared in Example 4 82.0 mg (Someprazole 40 mg) Mannitol 2814.0 mg Xanthan Gum 75.0 mg Crospovidone 75.0 mg Citric acid 4.92 mg Hydroxypropyl cellulose 30.0 mg Yellow iron oxide 1.8 mg ethanol 300.0 mg ^{* *} : These components are not present in the final product.

Experimental Example 1: Evaluation of Gomi Shield

The degree of bitterness of the oral disintegrating tablet of Example 5, which performed the separation layer coating containing the sweetening agent, and the oral disintegrating tablet of Comparative Example 6, which did not include the sweetening agent, was surveyed for 50 people. It is shown in Table 6 and FIG.

Example 5 Comparative Example 6 I do not write (one point) 21 people - Slightly write (2 points) 27 people - Write (three points) 2 people 21 people Very use (four points) - 29 people Average (points) 1.62 3.58

As can be seen from the above results, those who took the disintegrating tablet of the present invention that performed the separation layer coating containing the sweetener did not use or slightly used the opinion, while the disintegrating tablet of Comparative Example 6 containing no sweetener was used. Most people who took the drug were very bitter. Therefore, the disintegrating tablet of the present invention exhibits an excellent effect on bitumen shielding.

Experimental Example 2: Comparison of Severe Condition Stability

Each of the pharmaceutical formulation of Example 4 including a separation layer coating including a sweetener, the pharmaceutical formulation of Comparative Example 4 by mixing and coating a sweetener together on a drug layer, and the pharmaceutical formulation of Comparative Example 5 without a sweetener, respectively, were HDPE bottles. After storage for 2 weeks in harsh conditions (60 ℃) and the amount of the maximum amount (single max) and total total (total) produced was analyzed by HPLC. The peak area of the flexible material relative to the peak area of the principal component in percentage (%) is shown in Table 7, 2 and 3 below.

For the measurement of the analogue, about 10 mg of the corresponding amount of eosmeprazole was accurately weighed from each of the pharmaceutical formulations, and placed in a 100 mL brown flask, and 10 mL of methanol and 20 mL of 0.25M NaOH were added and stirred. Thereafter, 40 mL of phosphate buffer solution (pH 11.0) was used for sonication. Subsequently, 100 mL of the phosphate buffer solution (pH 11.0) was added to accurately adjust the amount, and the amount of the flexible substance was measured according to the following HPLC conditions using the solution filtered through a 0.45 μm filter. At this time, the peak area of less than 0.05% was not included.

[HPLC condition]

Detector: UV absorbance photometer (wavelength: 302 nm)

Column: Inertsil ODS-2, 5 μm, 150 x 4.6 mm

Mobile Phase A: Acetonitrile / Phosphate Buffer (pH 7.6) / Water = 10/10/80 Mixture (v / v / v)

Mobile Phase B: Acetonitrile / Phosphate Buffer (pH7.3) / Water = 80/1/19 Mixture (v / v / v)

Injection volume: 20 μL

Flow rate: 1.0mL / min

sample Early 1 week 2 weeks maximum
Leading substance gun
Leading substance maximum
Leading substance gun
Leading substance maximum
Leading substance gun
Leading substance Comparative Example 4 0.199 0.542 1.237 3.543 3.141 9.503 Example 4 0.073 0.350 0.314 1.082 0.815 2.224 Comparative Example 5 0.062 0.290 0.287 0.842 0.637 1.842

As shown in Table 7, Example 4 in which the sweetener was added to the separation layer showed excellent stability compared to Comparative Example 4 in which the sweetener was added to the drug coating layer.

Experimental Example 3: Stability Comparison of Accelerated Exposure Conditions

Example 4, Comparative Examples 4 and 5 in the HDPE bottle and stored in accelerated exposure conditions (45 ℃, 75%) for two weeks after the maximum amount of the resulting soft substance and total soft substance produced in Experimental Example 2 Measurements were made in the same manner as described in. The results are shown in Table 8, FIG. 3 and FIG.

sample Early 1 week 2 weeks maximum
Leading substance gun
Leading substance maximum
Leading substance gun
Leading substance maximum
Leading substance gun
Leading substance Comparative Example 4 0.199 0.542 0.873 2.164 1.302 5.049 Example 4 0.073 0.35 0.281 0.833 0.586 1.414 Comparative Example 5 0.062 0.29 0.172 0.509 0.306 0.973

As can be seen from the results of Tables 7 and 8 and FIGS. 2 to 5, the pharmaceutical formulation of Comparative Example 4 coated with a sweetener and esomeprazole was not very stable. On the other hand, the pharmaceutical formulation of Example 4, in which the separation layer containing the sweetener was coated between the drug coating layer and the enteric coating layer, showed little decrease in stability even when compared to Comparative Example 5 containing no sweetener. Therefore, when the sweetener is coated on the inert core, it was found that it is useful to prepare a pharmaceutical formulation having excellent stability by including the coating in a separation layer instead of the drug layer.

Claims (17)

1) inert core;
2) a drug coating layer coated on the inert core, the drug coating layer comprising eomeprazole free base or an alkali salt thereof as an active ingredient and a water-soluble film forming polymer;
3) a separation layer coated on the drug coating layer and comprising a sweetener and a hydrophilic polymer; And
4) an enteric coating layer coated on the separation layer, the enteric coating layer comprising an enteric base and a pharmaceutically acceptable additive,
The water-soluble film-forming polymer is hydroxypropylmethylcellulose,
The sweetener is sucralose,
Wherein said hydrophilic polymer is hydroxypropylmethylcellulose. The method according to claim 1,
The inert core is selected from the group consisting of white sugar, mannitol, sorbitol, lactose, potato starch, corn starch, hydroxyethyl cellulose, microcrystalline cellulose, white lead, carnauba wax, microcrystalline wax and mixtures thereof, Pharmaceutical preparations. The method according to claim 1,
Pharmaceutical formulation, characterized in that the inert core has a particle diameter of 50 to 300 ㎛. delete The method according to claim 1,
Pharmaceutical formulation, characterized in that the water-soluble film-forming polymer is included in an amount of 0.05 to 1 parts by weight based on 1 part by weight of eomeprazole free base or an alkali salt thereof. delete delete The method according to claim 1,
Pharmaceutical agent, characterized in that the sweetening agent is included in an amount of 0.05 to 1 parts by weight based on 1 part by weight of eomeprazole free base or an alkali salt thereof. The method according to claim 1,
Pharmaceutical preparation, characterized in that the sweetener is included in an amount of 20 to 80% by weight based on the total weight of the separation layer. delete The method according to claim 1,
Pharmaceutical formulation, characterized in that the separation layer is included in an amount of 5 to 30% by weight based on the total weight of the formulation. The method according to claim 1,
Pharmaceutical formulation, characterized in that the enteric base is selected from the group consisting of methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate and mixtures thereof. The method according to claim 1,
Pharmaceutical formulation, characterized in that the oral disintegrating tablet or suspension. The method according to claim 1,
Pharmaceutical formulation, characterized in that the pharmaceutical formulation has a size of 500 ㎛ or less. (a) coating a surface of an inert core with an aqueous solution comprising esomeprazole free base or an alkali salt thereof as an active ingredient and a water-soluble film forming polymer to form a drug coating layer;
(b) forming a separation layer by coating a coating material including a sweetener and a hydrophilic polymer on the surface of the drug coating layer; And
(c) coating an enteric coating material comprising an enteric base and a pharmaceutically acceptable additive on the surface of the separation layer to form an enteric coating layer,
The water-soluble film-forming polymer is hydroxypropylmethylcellulose,
The sweetener is sucralose,
The method of claim 1, wherein the hydrophilic polymer is hydroxypropylmethylcellulose. The method according to claim 15,
The method of manufacturing, characterized in that it further comprises the step of formulating into a disintegrating tablet in the mouth after mixing with a pharmaceutically acceptable additive. The method according to claim 15,
The preparation method is characterized in that it further comprises the step of formulating into a suspension by mixing with a pharmaceutically acceptable excipient for suspension.

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