KR102432084B1 - S-omeprazole tablet having improved stability and miniaturized size - Google Patents

Abstract

The present invention relates to a S-omeprazole formulation. The present invention is developed for the purpose of improving formulation stability, and is characterized in that general container packaging, not special packaging, is possible for the first time in the world. Furthermore, the present invention has an advantage that the convenience of taking medicine is increased by reducing the mixing amount of pharmaceutical additives and making the size smaller than conventional formulations.

Description

Improved stability and miniaturized tablet containing S-omeprazole {S-OMEPRAZOLE TABLET HAVING IMPROVED STABILITY AND MINIATURIZED SIZE}

The present invention relates to a tablet containing S-omeprazole as an active ingredient, and more particularly, to a tablet that can be packaged in an HDPE container with improved moisture stability and property stability.

[S-omeprazole]

S-omeprazole is (S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole for peptic ulcer , is one of the proton pump inhibitors used for gastroesophageal reflux disease.

S-omeprazole has very poor physical properties and storage stability of the component itself. Specifically, S-omeprazole has a fairly low melting point of about 45°C, making it difficult to formulate, and its stability is so low that the total amount of related substances becomes about 1% even after 2 months at 25°C and 60% RH storage conditions. do. In addition, the stability of S-omeprazole in acidic and neutral environments is very poor compared to stability in alkaline environments.

S-omeprazole uses S-omeprazole magnesium salt as a main ingredient to improve stability and physical properties. Korean Patent No. 10-0540720 discloses S-omeprazole magnesium salt trihydrate.

[S-omeprazole formulation]

Omeprazole is susceptible to decomposition or conversion in acidic and neutral media, and is also affected by moisture, heat, organic solvents or to some extent light. Therefore, in the solid preparation for oral administration of omeprazole, it is necessary to prevent the main ingredient from coming into contact with acidic gastric juice and to minimize the blocking of the external environment. In addition, packaging paper made of a special material that can block contact with the external environment is required even when packaging the formulation. This causes an increase in the overall unit price. Regarding the packaging, the paragraph is changed and the product design is introduced first.

Korean Patent Publication No. 10-0540721 describes the S-omeprazole formulation as follows.

Solid formulations for oral administration of omeprazole should be protected with an enteric layer to prevent contact of omeprazole with gastric juice. In addition, it is preferable to additionally mix an alkali salt in the formulation so that the alkaline environment can be maintained even after the coating layer is dissolved.

However, omeprazole may degrade or discolor during the coating process or during storage when in contact with an enteric polymer containing free carboxyl groups. Therefore, omeprazole is preferably not directly coated with an enteric layer, but is finally coated with an enteric layer after protection with an intermediate coating layer. Specifically, after mixing an alkali salt and omeprazole as a binder, it is coated on the core, protected by coating an intermediate coating layer thereon, and then coated with a final enteric coating layer.

In this case, the intermediate coating layer is preferably low-viscosity HPMC. Specifically, HPMC having a viscosity of less than 7.2 cps in a 2% aqueous solution is preferable. A prescription example reflecting the above is exemplified.

The core material is prepared with omeprazole, mannitol, hydroxypropylcellulose, microcrystalline cellulose, lactose anhydride, disodium hydrogen phosphate, sodium lauryl sulfate and water. The prepared core material is intermediately coated with 6cps of hydroxypropylmethylcellulose and water to form an isolation layer. An additional layer is formed by further coating an enteric coating layer thereon with a methacrylic acid copolymer, polyethylene glycol and water.

[S-omeprazole formulation packaging paper]

Even if S-omeprazole is coated, it can react sensitively to the external environment. Therefore, in the past, special packaging materials such as ptp packaging are used. PTP has the advantage of being able to block moisture and heat and being safe from external impact. However, PTP special packaging increases the final production cost, which is undesirable in terms of economy.

Republic of Korea Patent Publication No. 10-0540720 Republic of Korea Patent Publication No. 10-0540721 Republic of Korea Patent Publication No. 10-1658275

Existing tablets still have limitations in improving stability, so special packaging is required, which is not economical in terms of production cost. The present invention is to develop a tablet that can secure sufficient stability only with a general packaging that is cheaper than a HDPE container.

The characteristic configuration of the present invention is as follows.

1. A pharmaceutical composition suitable for oral administration, comprising 0.1 to 5 parts by weight of lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose, containing S-omeprazole as an active ingredient.

2. The pharmaceutical composition according to 1 above, characterized in that it contains HPMC as the primary coating base.

3. The pharmaceutical composition according to 1 or 2, wherein the composition comprises 50 to 70% by weight of the diluent based on the total weight of the composition.

4. In 3 above, the diluent is preferably a cellulose derivative, sugar alcohol, lactose, or starch, and the cellulose derivative is microcrystalline cellulose, silicified microcrystalline cellulose, low-substituted hydroxypropyl-cellulose, hydroxypropyl cellulose, and hydroxycellulose. A pharmaceutical composition, characterized in that at least one selected from the group consisting of hydroxypropylmethylcellulose.

5. The pharmaceutical composition according to any one of 1 to 4, wherein the pharmaceutical composition comprises 3 to 5% by weight of copovidone based on the total weight of the composition.

6. A pharmaceutical product containing S-omeprazole as an active ingredient, characterized in that the container and packaging is a capsule packaging or bottle packaging, and the capsule packaging is a packaging made of PTP, AI, PVDC or PVC material. .

7. The pharmaceutical product according to the above 6, characterized in that the container and packaging is a bottle packaging.

In the present invention, the generation amount of related substances of S-omeprazole was further reduced than that of the conventional formulation, and property stability was improved. Specifically, the stability was further improved without including arginine, which is emphasized in Korean Patent Publication No. 10-1658275 and the like.

Unlike conventional formulations, the present invention is not the world's first high-cost PTP special packaging, but also general bottle packaging with low unit cost, such as HDPE.

In the present invention, the total weight is reduced and the size is smaller than that of the existing formulation, so that the convenience of taking the drug is increased.

1 is a view showing a change in the properties of Example 2. The left image is the initial appearance, and the right image is the image after 30 days.
2 is a view showing a change in the properties of Example 13. The left image is the initial appearance, and the right image is the image after 30 days.
3 is a view showing a change in the properties of Comparative Example 3. The left image is the initial appearance, and the right image is the image after 30 days.
4 is a view showing a change in the properties of Comparative Example 4. The left image is the initial appearance, and the right image is the image after 30 days.
5 is a view showing a change in the properties of Comparative Example 5. The left image is the initial appearance, and the right image is the image after 30 days.
6 is a view showing the PTP packaging.
7 is a view showing the HDPE packaging.
8 is a diagram comparing the difference in frontal size between the prior art Korean Patent Publication No. 10-1658275 and the present invention. The left side is the prior art, and the right side is the present invention.
9 is a diagram comparing the size difference of the side of the present invention with that of the prior art, Republic of Korea Patent Publication No. 10-1658275. The left side is the prior art, and the right side is the present invention.

'S-omeprazole' referred to in the present specification includes all of the main components substantially containing S-omeprazole as an active ingredient (API), such as S-omeprazole and pharmaceutically acceptable salts thereof. Examples of the salt of S-omeprazole include, but are not limited to, magnesium salt, sodium salt, potassium salt or strontium salt.

[Formulation]

The present invention can be prepared by preparing pellets or granules, tableting the raw tablet, and coating an enteric coating layer thereon. For the enteric layer, any conventionally known coating base may be used. If necessary, in the present invention, a protective layer may be additionally coated before the enteric coating layer to prevent discoloration of S-omeprazole.

Specifically, the pellets can be prepared by first coating the core with a coating solution containing S-omeprazole, a diluent, a stabilizer and a binder. Granules can be prepared by mixing S-omeprazole, a diluent, a stabilizer and a binder, adding a binder solution, kneading, drying, and sizing.

After forming pellets or granules, a lubricant is added and mixed, followed by tableting to prepare uncoated tablets.

Uncoated tablets may be additionally coated with an intermediate protective layer before the enteric coating, and the preferred intermediate coating layer coating base will be described by changing the paragraph.

[Stabilization method]

Since S-omeprazole is sensitive to acid, it is known that it is desirable to mix with an alkalizing agent to adjust the pH environment.

Korean Patent No. 10-0540721 discloses, as preferred stabilizers, sodium, potassium, calcium, magnesium, aluminum salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminum hydroxide/sodium bicarbonate mixture; antacids such as aluminum hydroxide, calcium hydroxide, and magnesium hydroxide; magnesium oxide; Organic pH buffers, basic amino acids, similar pharmaceutically acceptable pH buffers, etc. are comprehensively listed, and disodium hydrogen phosphate is used in specific examples.

In Korea Patent Publication No. 10-1658275, magnesium oxide is used, and in particular, when combined with the diluent L-arginine, it is introduced that it is effective in reducing the final tablet size while ensuring the stability of S-omeprazole.

However, the present inventors have confirmed that when combining arginine and magnesium oxide, there is a property that arginine expands after moisture, so there is a problem in property stability. That is, according to the prior Korean Patent Publication No. 10-1658275, the stability of S-omeprazole can be guaranteed under the condition that the property is maintained, but there is a limit that the property can be changed and destroyed under other conditions, so PTP packaging with high unit price It came to the realization that special packaging, etc. would be required.

The present invention began by excluding arginine as a diluent. The present inventors have experimented with various diluent combinations, and as a result, when L-HPC and lactose are adjusted and mixed in a specific ratio, the stability of S-omeprazole, stability of properties, and reduction of the final tablet size can all be achieved. Confirmed.

In particular, the present invention is of special technical significance that it is the world's first tablet that has secured property stability to the extent that HDPE general packaging is possible.

The present invention is characterized in that it essentially contains L-HPC and lactose as diluents. Preferably, it is characterized in that it contains 0.1 to 5 parts by weight of lactose hydrate based on 1 part by weight of L-HPC. When the above content conditions are satisfied, the amount of related substances generated by S-omeprazole can be reduced, and at the same time, the water stability and property stability of the final tablet are excellent. In addition, it can be realized as small as the final tablet size.

Meanwhile, the present invention may further include D-mannitol, microcrystalline cellulose, or starch as a diluent if necessary. In this case, the total diluent content is preferably 50 to 70% by weight based on the total weight of the composition including the coating agent to reduce the final tablet size. The present invention was able to sufficiently secure the stability of S-omeprazole even with a small diluent content by essentially blending L-HPC and lactose.

The present invention includes known stabilizers in a content range that can be adopted by a person skilled in the art. There is no particular limitation on the component of the stabilizer, and preferably, magnesium oxide has a slightly better interaction with L-HPC and lactose.

The present invention is also unique in the selection of binders.

Korean Patent Publication No. 10-0540721 discloses, as examples of binders, cellulose (hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, microcrystalline-cellulose, carboxymethyl-cellulose sodium), polyvinylpyrrolidone, sugar, starch and all other cohesive pharmaceutically acceptable materials, hydroxypropylcellulose is employed in the examples.

Korean Patent Publication No. 10-1658275 uses povidone as a binder.

However, according to the experimental results of the present inventor, hydroxypropyl cellulose or povidone, which are binders of the prior art, has a limit in sufficiently securing the stability of S-omeprazole in the additive combination environment of the present invention using L-HPC and lactose as essential diluents. there was. That is, there was a difference in the amount of related substances generated depending on the binder component.

The present invention is characterized in that preferably copovidone is used as binder. The content of the binder can be appropriately selected by a person skilled in the art.

In addition, the lubricant and other pharmaceutical additives included in the present invention are not particularly limited. A conventionally known appropriate component may be formulated in an appropriately selectable amount, and detailed description thereof will be omitted.

[Coating base]

In the present invention, an intermediate coating may be performed in the concept of a protective layer before the final enteric coating. At this time, the intermediate coating layer coating base is not particularly limited, but HPMC is preferable as an example.

Korean Patent No. 10-2006777 discloses that PVA is more preferable than HPMC for intermediate coating as a protective layer concept for blocking contact between S-omeprazole and an enteric coating base.

However, according to the experimental results of the present inventors, when HPMC rather than PVA was used as the primary coating base, it was more effective in stability of S-omeprazole. When HPMC coating base was used rather than PVA coating base, the amount of related substances was further reduced.

[tablet size]

Korean Patent Publication No. 10-1658275 describes that when arginine is adopted as a diluent, the final tablet size can be reduced to 0.28 to 0.4 mL, and the size can be reduced to improve the convenience of taking.

However, the present invention implemented a smaller tablet size than the prior art, except for arginine.

For example, referring to Example 1 of Korean Patent Publication No. 10-1658275, the weight of the prepared raw tablet is about 283.8 mg, but the weight of the raw tablet prepared in Example 1 of the present invention is 250 mg, which is sufficient even with a smaller additive amount. It can be compared that the stability has been secured.

In addition, as shown in FIGS. 8 and 9 , even when comparing 'S1 AMP Tablet 40mg' implemented according to Korean Patent Publication No. 10-1658275 and the final coated tablet prepared according to an embodiment of the present invention, the front and side In both dimensions, the present invention is smaller. 8 and 9 are results of comparison with an enteric-coated tablet corresponding to 40 mg of S-omeprazole active ingredient.

[packaging]

Packaging methods for solid pharmaceuticals for oral administration, such as tablets, are divided into capsule packaging and bottle packaging.

Single-use packaging refers to single-use or PTP or FOIL packaging, and PTP, AI, PVDC, or PVC materials are used a lot, and it is also called small pharmaceutical packaging. Although bulk packaging usually costs more to manufacture than bottle packaging, however, for pharmaceuticals that may be exposed to air when the package is opened, which may cause stability problems, the single packaging method is selected.

S-omeprazole is known as an active ingredient with very poor stability, so all conventional packaging methods are package packaging. For example, if you look at Nexium Tablet, the representative drug of S-omeprazole, it is packaged in PTP.

However, the present invention is the first S-omeprazole drug, which is characterized in that the container and packaging is not a package packaging but a bottle packaging is also possible.

Hereinafter, the present invention will be described in more detail by way of Examples. However, the following examples are merely illustrative of one embodiment of the present invention, and the scope of the present invention is not limited thereto.

1. Low-substituted hydroxypropyl cellulose: Stability test according to the weight ratio of lactose hydrate

Esomeprazole magnesium hydrate and low-substituted hydroxypropyl cellulose and lactose hydrate according to Comparative Examples 1-2 and Examples 1-12 were added according to weight ratio, and mannitol, copovidone, and magnesium oxide were mixed in a high-speed stirring mixer at 80 rpm with agitator, Mix under the condition of chopper 2000rpm. Ethanol, which is a binding solution, is added and kneaded in a high-speed stirrer under the conditions of agitator 80rpm and chopper 2000rpm. After placing in a dryer and drying the tray, granules having an LOD of 1.5% or less were formed, and the dried granules were used to form a sized product using a sizing machine. A final mixture was obtained by lubrication by adding sodium stearyl fumarate to the sized product. The final mixture was compressed using a rotary tablet press to prepare tablets.

Comparative Example 1

A tablet having a ratio of 0 lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 1

A tablet having a ratio of 0.1 lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 2

A tablet having a ratio of 0.5 lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 3

A tablet having a ratio of 0.7 lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 4

A tablet having a ratio of 1 lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 5

A tablet having a ratio of lactose hydrate of 1.5 based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 6

A tablet having a ratio of lactose hydrate of 2 based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 7

A tablet having a ratio of 2.5 lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 8

A tablet having a ratio of lactose hydrate of 3 based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 9

A tablet having a ratio of 3.5 lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 10

A tablet having a ratio of lactose hydrate of 4 based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 11

A tablet having a ratio of lactose hydrate of 4.5 based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Example 12

A tablet having a ratio of 5 parts by weight of lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose was prepared.

Comparative Example 2

A tablet having a ratio of lactose hydrate of 1 based on 0 parts by weight of low-substituted hydroxypropyl cellulose was prepared.

Raw material name Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 weight
(mg) weight
(mg) weight
(mg) weight
(mg) weight
(mg) weight
(mg) weight
(mg) esomeprazole magnesium hydrate 44.5 44.5 44.5 44.5 44.5 44.5 44.5 Low-substituted hydroxypropyl cellulose 64.0 58.2 42.7 37.0 32.0 25.6 21.3 lactose hydrate 0.0 5.8 21.3 27.0 32.0 38.4 42.7 mannitol 108.5 108.5 108.5 108.5 108.5 108.5 108.5 copovidone 10.0 10.0 10.0 10.0 10.0 10.0 10.0 magnesium oxide 16.0 16.0 16.0 16.0 16.0 16.0 16.0 Sodium Stearyl Fumarate 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Sum 250.0 250.0 250.0 250.0 250.0 250.0 250.0

Raw material name Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Comparative Example 2 weight
(mg) weight
(mg) weight
(mg) weight
(mg) weight
(mg) weight
(mg) weight
(mg) esomeprazole magnesium hydrate 44.5 44.5 44.5 44.5 44.5 44.5 44.5 Low-substituted hydroxypropyl cellulose 18.3 16.0 14.2 12.8 11.6 10.7 0.0 lactose hydrate 45.7 48.0 49.8 51.2 52.4 53.3 64.0 mannitol 108.5 108.5 108.5 108.5 108.5 108.5 108.5 copovidone 10.0 10.0 10.0 10.0 10.0 10.0 10.0 magnesium oxide 16.0 16.0 16.0 16.0 16.0 16.0 16.0 Sodium Stearyl Fumarate 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Sum 250.0 250.0 250.0 250.0 250.0 250.0 250.0

Stability test

Storage conditions: 60℃, RH80%, 1 week storage

operating conditions

- Detector: UV absorbance spectrometer (measurement wavelength: 302 nm)

- Column: A column filled with 3 μm octadecylsilyl silica gel for liquid chromatography in a stainless steel tube with an inner diameter of about 4.6 mm and a length of about 10 cm.

- Flow rate: 1.0 mL/min

- Injection volume: 20 μL

- Diluent: After mixing 1.0M monobasic sodium phosphate buffer 5.2mL and 0.5M dibasic sodium phosphate buffer 5.2mL, diluted to 1000mL with water, pH7.6 phosphate buffer

- Lee Sang Sang

Mobile phase A) Acetonitrile · Diluent · Water = 100 : 100 : 800

Mobile phase B) Acetonitrile · Diluent · Water = 800 : 10 : 190

hours (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 10 80 20 30 0 100 31 100 0 45 100 0

A related substance produced by decomposition from esomeprazole magnesium is related substance A.

Related substance A

Omeprazole Sulfone
(CAS no. 88546-55-8)

Related Substance Results

- Early

Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Related Substance A (%) 0 0.05 0.05 0 0 0 Other Most Flexible Substances (%) 0.05 0 0 0 0.05 0.05 Total related substances (%) 0.05 0.05 0.05 0 0.05 0.05

Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Comparative Example 2 0 0 0 0 0 0.05 0 0.05 0.05 0.05 0 0 0.05 0 0.05 0.08 0.05 0.05 0 0 0.05 0.05 0.05 0.15

- 1 week harsh

Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Related Substance A (%) 0.1 0.06 0.07 0 0 0 Other Most Flexible Substances (%) 0.57 0.09 0.07 0.15 0.08 0.09 Total related substances (%) 0.78 0.21 0.19 0.17 0.21 0.14

Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Comparative Example 2 0.05 0.05 0 0.05 0 0.08 0.05 0.15 0.09 0.07 0.09 0.08 0.09 0.15 0.18 0.43 0.26 0.24 0.40 0.36 0.42 0.70 0.82 1.26

(Based on related substances: 0.5% or less of related substances A, 0.2% or less of other related substances, 2.0% or less of total related substances)

As shown in the table, the initial amount of related substances in Comparative Example 1 and Examples 1 to 12 showed similar results, and Comparative Example 2 was the highest at 0.15%. When the amount of related substances increased under the harsh conditions for one week, in Comparative Example 1, the total amount of related substances increased significantly from 0.05% to 0.78%, and in Comparative Example 2, 0.15% to 1.26%, exceeding the standard value.

2. Stability test according to the primary coating base

Based on the composition of Example 2, a coated tablet was prepared by changing the primary coating base.

operating conditions

Supply air temperature: 50 - 55℃

Exhaust temperature: 35 - 40℃

Atomizing Air Pressure : 1.0 Bar

Pattern Air Pressure : 1.3 Bar

Fan speed: 10 rpm

/시간Air Flow: 10

/hour

Related Substance Results

Storage conditions: 60℃, RH80%, storage for 7 days

Early 1 week harsh Stability test Example 13 Comparative Example 3 Example 13 Comparative Example 3 Primary coating base Opadry
(HPMC) Opadry
(PVA) Opadry
(HPMC) Opadry
(PVA) Related Substance A (%) 0.05 0.09 0.09 0.12 Other related substances (%) 0.00 0.08 0.09 0.22 Total related substances (%) 0.05 0.16 0.21 0.83

(Based on related substances: 0.5% or less of related substances A, 0.2% or less of other related substances, 2.0% or less of total related substances)

As shown in the table, when stored under severe conditions, the total related substances of the coated tablet of Example 13 using the HPMC base as the primary coating base increased from 0.05% to 0.21%. In the coated tablet of Comparative Example 3 using the PVA base, the total amount of related substances was 0.16% to 0.83%, and more related substances were generated than the HPMC base.

3. Stability evaluation according to the binder

In Comparative Example 4, esomeprazole magnesium hydrate was stored in a vial, and in Examples 14 and 5 to 6, the indicated binder was mixed with esomeprazole magnesium hydrate in a 1:1 ratio, put in a light-shielding glass vial, and closed with a lid for 4 weeks kept. Tablets of Example 2 and Comparative Examples 7-8 were prepared by applying the binder used in Example 14 and Comparative Examples 4-5.

Comparative Example 4

Store esomeprazole magnesium hydrate alone.

Example 14

Esomeprazole magnesium hydrate and copovidone are combined.

Comparative Example 5

Mix esomeprazole magnesium hydrate and hydroxypropyl cellulose.

Comparative Example 6

Esomeprazole magnesium hydrate and povidone are combined.

Comparative Example 7

Esomeprazole magnesium hydrate, low-substituted hydroxypropyl cellulose, lactose hydrate, mannitol, hydroxypropyl cellulose, and magnesium oxide were mixed, and ethanol was added to knead the mixture. After drying, sodium stearyl fumarate was mixed and tableted to prepare tablets.

Comparative Example 8

Esomeprazole magnesium hydrate, low-substituted hydroxypropyl cellulose, lactose hydrate, mannitol, povidone, and magnesium oxide were mixed, and ethanol was added to knead the mixture. After drying, sodium stearyl fumarate was mixed and tableted to prepare tablets.

Raw material name Comparative Example 7 Comparative Example 8 Weight (mg) Weight (mg) esomeprazole magnesium hydrate 44.5 44.5 Low-substituted hydroxypropyl cellulose 35.0 35.0 lactose hydrate 35.0 35.0 mannitol 102.5 102.5 Hydroxypropyl Cellulose 10.0 - povidone - 10.0 magnesium oxide 16.0 16.0 Sodium Stearyl Fumarate 7.0 7.0 Sum 250.0 250.0

Related Substance Results

Storage conditions: 40℃, RH75%, 4 weeks storage

Early accelerated 1 month Stability test Example 14 Comparative Example 4 Comparative Example 5 Comparative Example 6 Example 14 Comparative Example 4 Comparative Example 5 Comparative Example 6 Related Substance A (%) 0.00 0.06 0.00 0.00 0.00 0.19 0.09 0.23 Other related substances (%) 0.03 0.16 0.17 0.13 0.07 0.13 0.27 0.98 Total related substances (%) 0.12 0.23 0.17 0.20 0.28 0.32 0.65 3.91

(Based on related substances: 0.5% or less of related substances A, 0.2% or less of other related substances, 2.0% or less of total related substances)

When esomeprazole magnesium hydrate and binder were mixed and stored for 1 month under accelerated conditions, the increase in related substances was the highest in Comparative Example 6, from 0.20% to 3.91%. In the case of Example 14 containing copovidone, the increase in related substances was the most stable from 0.12% to 0.28%. The binder used in Example 14 and Comparative Examples 5 - 6 was added to prepare uncoated tablets, and then stability was confirmed.

Storage conditions: 60℃, RH80%, storage for 7 days

Early 1 week harsh Stability test Example 2 Comparative Example 7 Comparative Example 8 Example 2 Comparative Example 7 Comparative Example 8 Related Substance A (%) 0.05 0.04 0.00 0.07 0.05 0.00 Other related substances (%) 0 0.05 0.26 0.07 0.24 1.14 Total related substances (%) 0.05 0.09 0.26 0.19 0.38 3.45

(Based on related substances: 0.5% or less of related substances A, 0.2% or less of other related substances, 2.0% or less of total related substances)

In the case of Comparative Example 8, which is a tablet tableted using povidone as a binder, it exhibited the largest increase in related substances from 0.26% of the initial related substances to 3.45% when stored under severe conditions for 1 week, exceeding the standard, and copovidone was used under the same conditions. In the case of Example 2, the amount of related substances increased the least from 0.05% to 0.19% and was stable.

4. Property Stability

In order to confirm the stability of the tablets to which low-substituted hydroxypropyl cellulose and lactose hydrate were added, the properties of the coated tablets of Control Examples 1 to 4 were compared.

Control Example 1

A prototype commercial product using L-arginine and microcrystalline cellulose was used.

Control Example 2

A prototype commercial product using L-arginine and microcrystalline cellulose was used.

Control Example 3

A rectangular commercial product using L-arginine and microcrystalline cellulose was used.

Control Example 4

A prototype commercial product using L-arginine and microcrystalline cellulose was used.

Raw material name Example 13 Control Example 1 Control Example 2 Control Example 3 Control Example 4 esomeprazole magnesium hydrate O O O O O Low-substituted hydroxypropyl cellulose O lactose hydrate O L-Arginine O O O O Microcrystalline Cellulose O O O O mannitol O copovidone O povidone O O O crospovidone O O O Croscarmellose Sodium O magnesium oxide O O O O O Sodium Stearyl Fumarate O O O O Light anhydrous silicic acid O

Character check result

Example 13 and the coated tablets of Control Examples 1 - 4 were placed in a weighing plate and stored under each storage condition in an open state to confirm the change in properties.

Storage conditions: 25℃, room temperature, storage for 30 days

Example 13 Control Example 1 Control Example 2 Control Example 3 Control Example 4 Day 1 4.27mm 3.65mm 4.71mm 4.73mm 4.59mm Day 5 4.28mm 3.69mm 4.75mm 4.73mm 4.58mm Day 10 4.27mm 3.74mm 4.78mm 4.79mm 4.70mm Day 30 4.29mm 4.54mm 5.03mm 4.96mm 5.09mm increment 0.02mm (0.5%) 0.89mm (24.4%) 0.32mm (6.8%) 0.23mm (4.9%) 0.50mm (10.9%)

Storage conditions: 40℃, RH75%, storage for 30 days

Example 13 Control Example 1 Control Example 2 Control Example 3 Control Example 4 Day 1 4.26mm 3.65mm 4.72mm 4.68mm 4.57mm Day 5 4.39mm 3.78mm 5.09mm 5.12mm 5.03mm Day 10 4.35mm 3.94mm 5.11mm 5.22mm 5.03mm Day 30 4.35mm 5.05mm 5.13mm 5.25mm 5.11mm increment 0.09mm (2.1%) 1.40mm (38.3%) 0.41mm (8.7%) 0.57mm (12.2%) 0.54mm (11.8%)

Storage conditions: 60℃, RH80%, storage for 30 days

Example 13 Control Example 1 Control Example 2 Control Example 3 Control Example 4 Day 1 4.33mm 3.65mm 4.69mm 4.68mm 4.60mm Day 5 4.46mm 3.80mm 5.20mm (burst) 5.31mm 4.98mm Day 10 4.55mm 3.99mm 5.43mm (burst) 5.63mm 5.02mm Day 30 4.57mm 5.10mm 5.43mm (burst) 6.64mm (burst) 5.40mm increment 0.24mm (5.5%) 1.45mm (39.7%) 0.74mm (15.8%) 1.96mm (41.9%) 0.80mm (17.4%)

5. Stability evaluation according to packaging material

Esomeprazole was released in PTP (Alu/Alu) packaging, which is strong against moisture, rather than HDPE packaging, which is weak against moisture when manufactured as tablets. In order to confirm the stability improvement, tablets were prepared, and PTP (Alu/Alu) packaging and HDPE packaging were performed to evaluate stability.

Example 15

Packaging was carried out using HDPE packaging material.

Comparative Example 9

Packaging was carried out using PTP (Alu/Alu) packaging material.

Storage conditions: 40℃, RH75%, storage for 6 months

Early accelerated 1 month accelerated 3 months accelerated 6 months Stability test Example
15 comparative example
9 Example
15 comparative example
9 Example
15 comparative example
9 Example
15 comparative example
9 Related Substance A (%) 0.00 0.05 0.07 0.05 0.07 0.05 0.06 0.05 Etc
Related substances (%) 0.00 0.06 0.00 0.07 0.07 0.07 0.14 0.10 Total related substances (%) 0.00 0.11 0.07 0.15 0.18 0.12 0.46 0.42

(Based on related substances: 0.5% or less of related substances A, 0.2% or less of other related substances, 2.0% or less of total related substances)

As a result of confirming the occurrence of related substances according to the packaging material, the HDPE packaging material, which is weak to moisture, also showed an increase in related substances similar to that of PTP (Alu/Alu).

6. Tablet size

Among the tablets using esomeprazole, it has a smaller size than the small pharmaceutical tablet presented in Registration No. 10-1658275. The size of the small tablet presented in the existing patent corresponds to 0.35 g to 0.45 g in terms of weight. The size of the tablet corresponding to the present technology is a pharmaceutical tablet having a weight of less than 0.30 g, preferably 0.25 g or less, based on the raw tablet weight.

Claims (5)

S-omeprazole as an active ingredient, containing 0.1 to 5 parts by weight of lactose hydrate based on 1 part by weight of low-substituted hydroxypropyl cellulose, 3 to 5% by weight of copovidone based on the total weight of the composition, and magnesium oxide A pharmaceutical composition suitable for a solid formulation for oral administration, characterized in that The pharmaceutical composition according to claim 1, comprising HPMC as the primary coating base. The pharmaceutical composition according to claim 1, comprising 50 to 70% by weight of the diluent based on the total weight of the composition. delete A pharmaceutical comprising the pharmaceutical composition according to claim 1, wherein the container and packaging are bottle packaging.

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