KR20140076998A - Bitter taste masked pharmaceutical formulation comprising esomeprazole free base or alkali salt thereof and preparation method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation consisting of 1) an inactive core; 2) a drug coating layer which is coated on the inactive core and which comprises esomeprazole free base or alkali salt thereof, as an active ingredient, and a water soluble film forming polymer; 3) a separation layer which is coated on the drug coating layer and which comprises a sweetener and a hydrophilic polymer; and 4) a glutoid coating layer which is coated on the separation layer and which comprises a glutoid base material and a pharmaceutically acceptable additive, and a method for producing the same. Since the pharmaceutical formulation in the present invention effectively masks an unpleasant bitter taste of the active ingredient and also inhibits formation of impurities, being formulated as oral disintegrating tablets or suspension, thereby increasing patient compliance.

Description

FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition which is shielded from gummy taste and which contains S-omeprazole free base or an alkali salt thereof and a preparation method thereof,

The present invention relates to a pharmaceutical preparation comprising S-omeprazole free base or an alkali salt thereof which is shielded from irritation and bitter taste, and a process for producing the same.

Patients with chronic peptic ulcer, stomach and esophageal reflux disease should be treated with tablets that can be rapidly disintegrated in the oral cavity (for example, in oral cavity) rather than general tablets and capsules, And the improvement in convenience and compliance when taking the suspension. Particularly, oral disintegrating agents and suspensions are one of the preferred formulations because they can be easily taken by elderly people and children who have weak softening power.

S-omeprazole (chemical name: (S) -5-methoxy-2 - [(4-methoxy-3,5-dimethylpyridin- 2- yl) methylsulfinyl] -3H-benzoimidazole) And esophageal reflux disease. The S-omeprazole free base or its alkali salt is very strong in writing or having an unpleasant taste. Therefore, when formulated into a buccal cavity in the oral cavity, the patient's medication compliance may be lowered. Therefore, when the composition is formulated into a buccal cavity using the above-mentioned ingredients, it should be effectively shielded from irritating or bitter taste.

Korean Patent Registration No. 10-1011278 discloses that a bitter taste of an active ingredient is shielded by mixing a water-soluble saccharide with a granule as a sweetening agent. However, when a pharmaceutical preparation containing pellet such as S-omeprazole is taken, the particles remaining in the mouth after taking the medicine may be broken up later, resulting in a bitter taste.

In general, mouthwashes or suspensions containing active ingredients with a high or disagreeable taste can be worn off by adding sweeteners or may mask offensive flavors. However, even when only a small amount of the pellet containing the active ingredient remains in the mouth, it may taste unpleasant, so 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 production of the soft material is promoted, and the stability may be deteriorated accordingly.

Accordingly, the inventors of the present invention have made intensive studies to prepare a pharmaceutical preparation in which S-omeprazole free base or an alkali salt thereof is shielded from writing or unpleasant taste. As a result, by coating a separation layer containing a sweetener between the drug coating layer containing S-omeprazole and the enteric coating layer, it is possible to effectively prevent the writing or unpleasant taste of the active ingredient and to prevent the contact between the S- omeprazole free base or its alkali salt and the sweetener It is possible to produce a pharmaceutical preparation excellent in stability, and completed the present invention. The pharmaceutical preparations thus prepared can be easily administered to patients suffering from dysphagia, children and the elderly by formulating them with oral disintegrating agents and suspensions, so that compliance with medicines is expected to be improved.

[Patent Document 1] Korean Patent Registration No. 10-1011278

Accordingly, it is an object of the present invention to provide a pharmaceutical formulation which is shielded from the germs comprising S-omeprazole free base or an alkali salt thereof.

Another object of the present invention is to provide a method for producing the above pharmaceutical preparation.

In order to achieve the above object,

1) an inert core;

2) a drug coating layer coated on the inert core, comprising a S-omeprazole 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

And 4) an enteric coating layer coated on the separation layer, wherein the enteric coating layer comprises a nutrient base and a pharmaceutically acceptable additive.

To achieve these and other advantages and in accordance with the purpose of the present invention,

(a) coating a surface of an inert core with an aqueous solution containing an S-omeprazole 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 surface of the drug coating layer with a coating material comprising a sweetener and a hydrophilic polymer to form a separation layer; And

(c) coating the surface of the separation layer with an enteric coating material comprising a nutritive base and a pharmaceutically acceptable additive to form an enteric coating layer, .

The pharmaceutical preparations according to the present invention can effectively inhibit the unpleasant taste of S-omeprazole and inhibit the generation of the sweetening agent-induced soft substances. Therefore, when formulated into oral cavity disintegrating agents or suspensions, Which is the most common drug in the world.

FIG. 1 shows the results of evaluation of the pharmaceutical preparations according to the addition of sweeteners.
FIGS. 2 and 3 show the maximum amount of the flexible substance and the total amount of the flexible substance produced after the storage of the pharmaceutical preparations of Comparative Examples 4 and 5 and Example 4 at the severe condition (60 ° C), respectively.
Figures 4 and 5 show the maximum amount of the suppositories and total suppositories produced after storage of the accelerated exposure conditions (45 ° C and 75%) of the pharmaceutical preparations of Comparative Examples 4 and 5 and Example 4, respectively.

The present invention relates to: 1) an inert core; 2) a drug coating layer coated on the inert core, comprising a S-omeprazole 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, wherein the enteric coating layer comprises a nutrient base and a pharmaceutically acceptable additive.

According to the present invention, the S-omeprazole free base or an alkali salt thereof is coated on a spherical inert core, the coated particles are coated with a separating layer using a polymer including a sweetener, and then coated once with an enteric coating, It is possible not only to effectively block the unpleasant taste of the food, but also to solve the problem of lowering the stability. Therefore, the pharmaceutical preparation may be formulated into a form such as an oral cavity disintegrating tablet or a suspending agent, thereby contributing to improvement of patient compliance with medicines.

1) Inert core

In the case of gum-screened particles, if the size of the particles is too large, it is necessary to minimize the size of the particles, because the particles may feel gritty in the mouth and may cause a resistance to take. Therefore, the pharmaceutical preparation according to the present invention preferably has an average particle size of 500 mu m or less, preferably 400 mu m or less, more preferably 300 mu m or less.

Accordingly, in the present invention, the inert core has a size of 50 to 300 탆, preferably 80 to 250 탆, more preferably 100 to 180 탆, in consideration of the desired final particle size (about 500 탆 or less) .

The inert core may be any pharmaceutically acceptable substance having the appropriate size and firmness as mentioned above. In the present invention, the inert core may be selected from the group consisting of white sugar, mannitol, sorbitol, lactose, potato starch, corn starch, 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 S-omeprazole free base or an alkali salt thereof as an active ingredient, and a water-soluble film-forming polymer. In the present invention, rapid drug release of the drug can be achieved by controlling the viscosity of the water-soluble film-forming polymer, the ratio of the drug to the water-soluble film-forming polymer, and the total coating amount of the drug coating layer.

In the present invention, the water-soluble film-forming polymer serves to help the drug effectively adhere to the inert core and can be used in an amount sufficient for the drug to bind 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 polymer having a viscosity of 3 to 15 cps Polymers may be used.

The water-soluble film-forming polymer to be used in the present invention is selected from the group consisting of methylcellulose, hydroxyalkylcellulose having 1 to 3 carbon atoms, hydroxyalkylalkylcellulose having 1 to 3 carbon atoms, carboxyalkylcellulose having 1 to 3 carbon atoms, carboxyalkyl Alkali metal salts of cellulose, carboxyalkylcellulose esters of 1 to 3 carbon atoms, starch, pectin, chitin derivatives, polysaccharides, polyacrylic acid and its salts, polymethacrylic acid and its salts, polyvinyl alcohol, polyvinylpyrrolidone , Polyalkylene oxide, and mixtures thereof. Hydroxypropylmethylcellulose (Hypromellose) may be preferably used.

The water-soluble film-forming polymer may be used in an amount of 0.05 to 1 part by weight, preferably 0.1 to 0.5 part by weight, more preferably 0.12 to 0.25 part by weight based on 1 part by weight of the S-omeprazole 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 sweetener and a hydrophilic polymer. The separating layer serves as an antiseptic shielding layer and separates the drug so that release of the drug does not occur until swallowing in the oral cavity.

According to one embodiment of the present invention, when an S-omeprazole free base or its alkali salt is mixed with an sweetener as an active ingredient and coated on an inert core, there is an effect of shielding the gum. However, since S-omeprazole is a soft substance produced by direct contact with a sweetener It was found that the stability was very poor. Accordingly, in the present invention, a pharmaceutical preparation is prepared by coating a drug coating layer containing S-omeprazole free base or an alkali salt thereof and an enteric coating layer for releasing the drug from the intestine, by coating a separation layer containing a sweetener , The pharmaceutical preparation of the present invention having such a constitution can block the unpleasant or bitter taste and inhibit the production of the soft substance.

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

The sweetener may be used in an amount of 0.05 to 1 part by weight, preferably 0.1 to 0.8 part by weight, based on 1 part by weight of the S-omeprazole free base or its alkali salt, and the amount of 20 to 80% by weight ≪ / RTI >

In the present invention, the hydrophilic polymer may be at least one selected from the group consisting of polyvinyl pyrrolidone, polyalkylene glycols (e.g., polyethylene glycol, polypropylene glycol, etc.), polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives such as hydroxypropylmethylcellulose, Cellulose, etc.) and mixtures thereof. Preferably, polyethylene glycol or hydroxypropylmethylcellulose can be used.

In the present invention, the separation layer is contained in an amount of 5 to 30% by weight based on the total weight of the preparation.

4) Long coat layer

Because S-omeprazole is degraded very quickly in acidic conditions, intestinal coatings of pharmaceutical preparations are essential to mask offensive or bitter taste in the mouth. Accordingly, the pharmaceutical preparation of the present invention includes an enteric coating layer, wherein the enteric coating layer is coated on the separation layer, and comprises a nutrient-based base and a pharmaceutically acceptable additive.

In the present invention, the final pharmaceutical preparation containing S-omeprazole has elasticity due to the enteric coating layer, and even if it is formulated in the form of a buccal cavity in the oral cavity, the pharmaceutical preparation is not broken by the static pressure. In addition, when the drug is released before oral swallowing, the drug may cause irritation and bitter taste due to the intestinal coating. Because of the intestinal coating, the release of the drug does not occur from above and the drug is released from the intestine. do.

In the present invention, the nutrient-based base is selected from the group consisting of methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate And mixtures thereof And the like.

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

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

Oral intracorporeal tablets mean tablets that do not ingest water but actually disintegrate within 2 minutes (preferably within 1 minute) of saliva. According to one embodiment of the present invention, the pharmaceutical preparation prepared as described above may be formulated into an oral disintegrating tablet by mixing it with a pharmaceutically acceptable additive (for example, a diluent or the like) and then tableting it.

The diluent may be selected from the group consisting of xylitol, trehalose, sorbitol, maltose, sorbitol, erythritol, glucose, maltitol, mannitol, saccharose, lactose and a hydrate thereof, and specific examples thereof include mannitol. 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 preparation.

In addition to the above-mentioned components, the intra-oral fracture disintegration device of the present invention may further include disintegrants, acidifiers, fragrances, lubricants, and combinations thereof, which are conventionally used as pharmaceutically acceptable additives, and may further include a sweetening agent .

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

The acidulant may be anhydrous citric acid, tartaric acid or malic acid. Examples of the flavor include peppermint, strawberry, peppermint powder, menthol, lemon flavor powder, orange flavor powder and the like.

The lubricant may be selected from the group consisting of 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, Can be selected from the group.

The pharmaceutical preparation according to the present invention comprises: (a) coating a surface of an inert core with an aqueous solution containing an S-omeprazole 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 surface of the separation layer with an enteric coating material comprising a nutrient base and a pharmaceutically acceptable additive to form an enteric coating layer.

In addition, in order to formulate the above pharmaceutical preparations, it is also possible to prepare oral buccal solutions by further processing, for example, by mixing with a pharmaceutically acceptable additive and then tableting or mixing with a pharmaceutically acceptable excipient for suspension To thereby prepare a suspension, whereby the pharmaceutical preparation can be formulated.

In the production process of the present invention, the coating may be carried out by any conventional method used for coating a pharmaceutical agent in the art, for example, without limitation, a fan coating method, a fluidized bed coating method or a compression coating method, It is preferable to use a fluidized bed coating method in which a coating liquid is sprayed by flowing the air into the air injected with the formulation to be sprayed.

[Example]

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

<Drug Coating Layer>

Comparative Example 1: Preparation of a composition coated with S-omeprazole free base

320 g of S-omeprazole free base, 48 g of hydroxypropylmethylcellulose, 160 g of sucralose, 64 g of talc, 4 g of polysorbate and 80 g of magnesium oxide were dissolved in a mixture of 480 g of purified water and 1920 g of acetone to prepare a coating solution . 200 g of spherical microcrystalline cellulose (average diameter 150 탆) was flown from a fluidized bed granulator (GR - XP70), and the coating solution prepared above was sprayed to prepare a core coated with S - omeprazole free base.

Example 1: Preparation of a composition coated with S-omeprazole free base

A core coated with S-omeprazole free base was prepared in the same manner as described in Comparative Example 1, except that sucraloose was not added.

Example 2: Preparation of a composition coated with S-omeprazole free base

A core coated with S-omeprazole free base was prepared in the same manner as described in Example 1, except that spherical white sugar was used in place of spherical microcrystalline cellulose.

The contents of the components corresponding to 40 mg of somemeprazol (1 tablet in the oral cavity or 1 capsule of the suspension) in Comparative Example 1 and Examples 1 and 2 are shown in Table 1 below.

ingredient Comparative Example 1 Example 1 Example 2 S-omeprazole 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 a gum-coated coating 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. In the fluidized bed granulator (GR-XP70), the core particles prepared in Comparative Example 1 were flowed, and the coating solution prepared above was sprayed to perform the grit-shielding (separation layer) coating.

Example 3: Preparation of a gum-coated coating composition

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. In the fluidized bed granulator (GR-XP70), the core particles prepared in Example 1 were flowed, and the coating solution prepared above was sprayed to perform an antifouling (separation layer) coating.

Comparative Example 3: Preparation of a composition not coated with a gum

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.

The contents of the components corresponding to 40 mg of somemeprazole (1 tablet of the intrabasal solution or 1 capsule of the suspension) in Comparative Examples 2 and 3 and Example 3 are shown in Table 2 below.

ingredient Comparative Example 2 Example 3 Comparative Example 3 core
(S-omeprazole) 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 Intestinal Coating Layer>

Comparative Example 4: Intestinal Coating of Gum-Shielded Compositions

1066.4 g of methacrylic acid copolymer, 7.2 g of polyethylene glycol, 50 g of triethyl citrate, 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. In the fluidized bed granulator, while the particles prepared in Comparative Example 2 were being flowed, the coating solution prepared above was sprayed for intestinal coating.

Example 4: Intestinal Coating of Gum-Shielded Compositions

1066.4 g of methacrylic acid copolymer, 7.2 g of polyethylene glycol, 50 g of triethyl citrate, 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. In the fluidized bed granulator, while the particles prepared in Example 3 were being flown, the coating solution prepared above was sprayed for enteric coating.

Comparative Example 5: Intestinal Coating of Anti-Shielded Compositions

Except that the particles prepared in Comparative Example 3 were flowed, in the same manner as in Comparative Example 4.

The contents of the components corresponding to 40 mg of somemeprazol (1 tablet in the oral cavity or 1 capsule of the suspension) in Comparative Examples 4 and 5 and Example 4 are shown in Table 3 below.

Comparative Example 4 Example 4 Comparative Example 5 core
(S-omeprazole) 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 dried product) 133.3 mg
(40 mg as dried product) 133.3 mg
(40 mg as dried product) 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 Polysorbate 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.

&Lt; Preparation of disintegrate &

Example  5: Gomi  Of the shielded composition Oral Bonghaejeong  Produce

Using the ingredients and the contents shown in Table 4 below, an intraoral buccal cavity of an oily composition was prepared. Specifically, the composition of Example 4, mannitol, low-substituted hydroxypropylcellulose, microcrystalline cellulose, crospovidone, citric acid and aspartame were mixed using a high-speed mixer (Sejung, SM-50), and further, magnesium stearate, Saccharin and peppermint flavor were added and mixed again. The granules thus formed were tabletted using a tabletting machine (Sejung, GRC-18) to prepare an intraoral buccal cavity.

Comparative Example 6: Preparation of an intraoral buccal preparation of an unshielded composition

An intraoral buccal cavity of a composition that was not abraded was prepared using the components and the contents shown in Table 4, except that the composition prepared in Comparative Example 5 was used in place of the composition of Example 4.

ingredient Example 5 Comparative Example 6 Composition
(S-omeprazole) The composition of Example 4
182.0 mg (40 mg) The composition of Comparative Example 5
162.0 mg (40 mg) Mannitol 262.0 mg 262.0 mg Low substituted hydroxypropylcellulose 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 incense 5.0 mg 5.0 mg

&Lt; Preparation of suspension preparation >

Example 6: Preparation of suspensions of gum-coated compositions

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 were dissolved in 300 g of ethanol to prepare a binding solution. 2814.0 g of mannitol and 75.0 g of xanthan gum were placed in a high-speed mixer (Sejung, SM-50), and the binding solution prepared above was added while mixing. Then, the granulation process was further continued to prepare granules.

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

ingredient content The particles prepared in Example 4 82.0 mg (S-omeprazole 40 mg) Mannitol 2814.0 mg Xanthan gum 75.0 mg Crospovidone 75.0 mg Citric acid 4.92 mg Hydroxypropylcellulose 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 gummy shielding

The results of the questionnaire survey were conducted on 50 patients in the oral cavity disintegration tablet of Example 5 in which the separation layer coating containing the sweetening agent was applied and in the oral cavity disintegration tablet of Comparative Example 6 which did not include the sweetening agent. Are shown in Table 6 and Fig.

Example 5 Comparative Example 6 Not used (1 point) 21 people - Write a little (2 points) 27 people - Write (3 points) 2 people 21 people Very Useful (4 points) - 29 people Average (point) 1.62 3.58

As can be seen from the above results, the people taking the disintegrating tablet according to the present invention in which the separating layer coating containing the sweetener was used do not use or have a little bit of opinion, whereas the disintegrating tablet of Comparative Example 6 containing no sweetening agent Most of the people who took it were very uncomfortable. Accordingly, the Bronze Seal of the present invention exhibits an excellent effect on the gummy shielding.

Experimental Example 2: Comparison of Stability Conditions

The pharmaceutical preparation of Example 4 including a separation layer coating containing a sweetening agent, the pharmaceutical preparation of Comparative Example 4 in which a sweetener was mixed and coated on the drug layer, and the pharmaceutical preparation of Comparative Example 5 containing no sweetening agent, (60 ° C) for 2 weeks, and the amount of total single substance and total substance produced was analyzed by HPLC. The results shown in percentage (%) of the peak area of the flexible material with respect to the peak area of the main component are shown in Tables 7, 2 and 3.

For the measurement of the suppository, about 10 mg equivalent of S-omeprazole was precisely weighed from each of the above pharmaceutical preparations into a 100 mL capacity brown flask, and 10 mL of methanol and 20 mL of 0.25 M NaOH were added and stirred. Then, ultrasonication was performed using 40 mL of phosphate buffer (pH 11.0). Then, 100 mL of phosphate buffer solution (pH 11.0) was added to accurately adjust the amount of the suppositories. The supernatant was filtered with a 0.45 μm filter and the amount of the suppositories was measured according to the following HPLC conditions. At this time, those having a peak area of less than 0.05% were not included.

[HPLC conditions]

Detector: Ultraviolet absorptiometer (measuring wavelength: 302 nm)

Column: Inertsil ODS-2, 5 [mu] m, 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: 1.0 mL / min

sample Early 1 week 2 weeks maximum
Flexible material gun
Flexible material maximum
Flexible material gun
Flexible material maximum
Flexible material gun
Flexible material 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 placed in the separation layer, showed much better stability than Comparative Example 4 in which the sweetener was placed in the drug coating layer.

Experimental Example 3: Comparison of stability of accelerated exposure conditions

The pharmaceutical preparations of Example 4 and Comparative Examples 4 and 5 were stored in an HDPE bottle under accelerated exposure conditions (45 ° C, 75%) for 2 weeks, Were measured in the same manner as described above. The results are shown in Tables 8, 3 and 4.

sample Early 1 week 2 weeks maximum
Flexible material gun
Flexible material maximum
Flexible material gun
Flexible material maximum
Flexible material gun
Flexible material 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 preparation of Comparative Example 4 in which the sweetener and S-omeprazole were mixed and coated was not very stable. On the other hand, the pharmaceutical preparation 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 compared to Comparative Example 5 which did not contain any sweetener at all. Therefore, when the sweetener is coated on the inert core, it is useful to prepare a pharmaceutical preparation having excellent stability by coating it in the separation layer instead of the drug layer.

Claims (17)

1) an inert core;
2) a drug coating layer coated on the inert core, comprising a S-omeprazole 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 antiseptic pharmaceutical formulation coated on said separation layer, comprising an enteric coating layer comprising a nutrient base and a pharmaceutically acceptable additive. The method according to claim 1,
Characterized in that the inert core is selected from the group consisting of white sugar, mannitol, sorbitol, lactose, potato starch, corn starch, hydroxyethylcellulose, microcrystalline cellulose, white spirit, carnauba wax, microcrystalline wax, Pharmaceutical formulation. The method according to claim 1,
Wherein the inert core has a particle size of 50 to 300 mu m. The method according to claim 1,
Wherein the water-soluble film-forming polymer is selected from the group consisting of methylcellulose, hydroxyalkylcellulose having 1 to 3 carbon atoms, carboxyalkylcellulose having 1 to 3 carbon atoms, hydroxyalkylalkylcellulose having 1 to 3 carbon atoms, alkaline metal of carboxyalkylcellulose having 1 to 3 carbon atoms Salts, carboxyalkylcellulose esters having 1 to 3 carbon atoms, starch, pectin, chitin derivatives, polysaccharides, polyacrylic acid and its salts, polymethacrylic acid and its salts, polyvinyl alcohol, polyvinylpyrrolidone, &Lt; / RTI &gt; and mixtures thereof. The method according to claim 1,
Wherein the water-soluble film-forming polymer is contained in an amount of 0.05 to 1 part by weight based on 1 part by weight of the S-omeprazole free base or an alkali salt thereof. The method according to claim 1,
Wherein the sweetener is selected from the group consisting of saccharin, saccharin sodium, aspartame, acesulfame potassium, sucralose, stevia, stevioside, bovine and mixtures thereof. The method of claim 6,
Wherein the sweetener is selected from the group consisting of sucralose, saccharin, aspartame or a mixture thereof. The method according to claim 1,
Characterized in that the sweetener is contained in an amount of 0.05 to 1 part by weight based on 1 part by weight of the S-omeprazole free base or its alkali salt. The method according to claim 1,
Characterized in that the sweetener is included in an amount of 20 to 80% by weight based on the total weight of the separating layer. The method according to claim 1,
Wherein the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, starch and derivatives thereof, hydroxypropylmethylcellulose, hydroxypropylcellulose, and mixtures thereof. Pharmaceutical formulation. The method according to claim 1,
Characterized in that the separating layer is contained in an amount of 5 to 30% by weight, based on the total weight of the preparation. The method according to claim 1,
Wherein the enteric base is selected from the group consisting of methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate, and mixtures thereof. The method according to claim 1,
Wherein the pharmaceutical preparation is an intraoral oral disintegrating agent or a suspending agent. The method according to claim 1,
Wherein the pharmaceutical preparation has a size of not more than 500 mu m. (a) coating a surface of an inert core with an aqueous solution containing an S-omeprazole 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 surface of the separation layer with an enteric coating material comprising a nutrient base and a pharmaceutically acceptable additive to form an enteric coating layer.
A method of preparing the pharmaceutical preparation of claim 1. 16. The method of claim 15,
The method according to claim 1, further comprising the step of mixing the mixture with a pharmaceutically acceptable additive and then tableting the mixture into an oral cavity disintegrating tablet. 16. The method of claim 15,
Characterized in that the method further comprises the step of mixing with a pharmaceutically acceptable excipient for a suspension and formulating it as a suspension.

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