WO2015108392A1

WO2015108392A1 - Small pharmaceutical tablet containing esomeprazole

Info

Publication number: WO2015108392A1
Application number: PCT/KR2015/000549
Authority: WO
Inventors: 신용관; 이승언; 이지은; 송세현; 손세일; 이홍우
Original assignee: 대원제약주식회사
Priority date: 2014-01-20
Filing date: 2015-01-20
Publication date: 2015-07-23
Also published as: KR101658275B1; KR20150086653A

Abstract

The present invention relates to a small pharmaceutical tablet containing esomeprazole and having improved ease of preparation, convenience of dosing, and patient compliance. The small esomeprazole pharmaceutical tablet according to the present invention is easily prepared and has a significantly miniaturized formulation size compared with the conventional formulation, while exhibiting biological equivalence to the commercial esomeprazole pharmaceutical formulation prepared by core granules, and thus has effects of improving the convenience of dosing and the patient compliance.

Description

Small Pharmaceutical Tablets with Someprazole

The present invention relates to small pharmaceutical tablets containing esomeprazole with improved ease of manufacture, ease of taking and patient compliance. In addition, the present invention relates to a small pharmaceutical tablet containing esomeprazole in the same amount as a conventional pharmaceutical formulation, but having a reduced size (volume) of the final tablet. The present invention also relates to a pharmaceutical tablet in which the stability is increased by maximizing the degradation of esomeprazole while constituting the formulation as a small tablet.

Eomeprazole is (S) -5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl] -3H-benzoimidazole, which is a peptic ulcer, gastric or esophagus Proton pump inhibitors used in reflux disease and the like.

Recently, as a drug capable of strongly inhibiting gastric acid secretion by inhibiting H ⁺ -K ⁺ ATPase activity, esomeprazole has been applied for the treatment of peptic ulcer. It is emerging as a new treatment for peptic ulcers instead of blockers.

It is well known in the art that esomeprazole is susceptible to degradation or modification in acidic and neutral media, and more particularly, it is known that the degradation half-life of esomeprazole in aqueous solutions with a pH value of 3 or less is less than 10 minutes. Decomposition of esomeprazole is facilitated by acidic compounds and is affected by moisture, heat and organic solvents and light. Therefore, there has been a lot of demands for stable esomeprazole formulations, and to overcome these problems, capsules containing conventional enteric skin pellet formulations have been developed.

However, these capsules are not only bulky, but also increase in unit cost due to a large number of steps in the preparation, and have disadvantages of having various excipients.

In order to make up for the shortcomings of the capsules, Korean Patent Publication No. 10-1996-0704532 discloses an oral pharmaceutical multi-unit of omeprazole comprising individually enteric-laminated unit pellets and tablet excipients of a core material coated with one or more layers. Tablet formulations are disclosed. However, when manufacturing omeprazole tablets according to the patent, the manufacturing cost increases and coating success rate is very low because special equipment is used to prepare the individual enteric-laminated unit pellets of the core material coated with one or more layers of omeprazole. In particular, there is a problem that the size of the finished tablet is very large.

In addition, Korean Patent Publication No. 10-1996-0003605 discloses a method for producing an omeprazole core composition prepared by using omeprazole as an active ingredient and adding and mixing beta-cyclodextrin and sodium hydroxide as a stabilizing component to prepare a solid dispersion. However, the invention described in the patent has a problem of using sodium hydroxide, which is harmful to the human body, and as in the case of Patent Publication No. 10-1996-0704532, since the core composition is manufactured, it does not overcome the problem of an increase in manufacturing cost and an increase in formulation size. It was. In addition, the process of preparing a solid dispersion includes the process of dissolving omeprazole as a main component in a solvent, and thus requires a special stabilizer such as sodium hydroxide to stabilize the omeprazole.

Therefore, it is easy to manufacture while showing the same effect as the existing formulations using eomeprazole core granules, it is possible to reduce the production cost, and the sugar for the drug for esomeprazole pharmaceutical tablets, which is convenient to take and improved patient compliance by reducing the size of the tablet There was a lot of demand from the industry.

Accordingly, the inventors of the present invention have completed the present invention regarding a small pharmaceutical tablet that can be prepared through an easy manufacturing process and shows biological equivalence with a conventional formulation, after studying to improve the problems of the prior art.

SUMMARY OF THE INVENTION An object of the present invention is to provide a small pharmaceutical tablet containing esomeprazole with improved ease of manufacture, ease of use, and patient compliance, despite the reduced size, it is possible to ensure the safety of the active ingredient, existing commercial products and bioavailability It is to provide this equivalent pharmaceutical tablet.

In order to achieve the above object, the present invention provides a small pharmaceutical tablet with a total volume of 0.4 mL or less as a small tablet containing eomeprazole as an active ingredient.

Esomeprazole small pharmaceutical tablet according to the present invention is easy to manufacture, while showing bioequivalence with commercially available esomeprazole pharmaceutical tablets prepared as core granules, the size of the preparation is significantly smaller than that of conventional formulations to improve the convenience and patient compliance It is effective.

1 is a diagram showing the results of a bioequivalence test of esomeprazole small pharmaceutical tablet of the present invention.

Figure 2 is a diagram comparing the size of Nexium tablets commercially available tablets and small tablets of esomeprazole of the present invention.

Figure 3 is a comparison of the size of esomeprazole small pharmaceutical tablets of the present invention and capsules commercially available is 40mg.

Hereinafter, the present invention will be described in detail.

The present invention provides a small pharmaceutical tablet containing esomeprazole as an active ingredient. In the present invention, esomeprazole is a concept including all of esomeprazole or a pharmaceutically acceptable salt thereof or a hydrate thereof.

As used herein, the term "small" refers to a concept compared to the size of tablets made from existing esomeprazole capsules or core granules, which means that the size is small compared to conventionally known pharmaceutical products. The volume of the pharmaceutical tablet is 0.4mL or less, and when converted to weight, it corresponds to 0.35g to 0.45g. In the present invention, the volume 0.4mL defined as the small pharmaceutical tablet may be a value rounded off to two decimal places. Accordingly, pharmaceutical agents corresponding to the range of 0.35 ml to 0.45 mL are also included in the scope of the present invention.

According to a preferred embodiment of the present invention, the volume of the small pharmaceutical tablet is 0.4 mL or less. When the volume of the pharmaceutical tablets exceeds 0.4mL, the size of the tablets is increased, and thus, especially when the elderly or children take the pharmaceutical tablets, they may cause swallowing or vomiting.

In addition, when the total weight of the pharmaceutical tablets exceeds 0.4mL there is a fear that patient compliance due to the reduced ease of taking. Eomeprazole is a proton pump inhibitor. It is a prescription frequently used in chronic patients such as gastric ulcer, duodenal ulcer and gastritis. As the patient compliance decreases, the treatment efficiency of the disease may be significantly reduced.

According to one embodiment of the present invention, when the total volume of the pharmaceutical tablet exceeds 0.4mL it can be seen that the ease of taking and patient compliance is significantly reduced. (See Experimental Examples 4 and 5)

The small pharmaceutical tablet of the present invention contains a certain amount of magnesium oxide (MgO). The magnesium oxide is preferably 0.1 to 1 parts by weight per 1 part by weight of omeprazole. Excessive use of magnesium oxide can cause diarrhea side effects. The inventors found that tablets containing esomeprazole and magnesium oxide did not affect safety and bioavailability even when the tablet volume was less than 0.4 mL. This is considered that, in the case of tableting by simply increasing the pressure while maintaining the existing prescription to simply reduce the size of the tablet, it adversely affects the safety of the final manufactured drug, or affects dissolution and lowers bioavailability. It is a new knowledge.

That is, according to an example of the present invention, if the magnesium oxide is not included in the size of 0.4mL or less, the problem of increasing the decomposition rate of the active ingredient occurs. (See Experimental Example 1)

The small pharmaceutical agent of the present invention may further include an excipient. The excipient is microcrystalline cellulose, povidone, povidone, crospovidone, L-arginine, sodium stearyl fumarate, polyvinyl alcohol, polymethacryl It may be at least one selected from the group consisting of methacrylate (Polymethacrylate).

Small pharmaceutical agents of the present invention may further comprise a diluent, binder, disintegrant or glidant generally used in the art.

The diluent may be at least one selected from the group consisting of lactose, sucrose, crystalline cellulose, cellulose, powdered, and siliconized microcrystalline cellulose.

The binder may be at least one selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium zein, and starch. have.

The disintegrant is Carboxymethyl cellulose (calcium), Croscarmellose sodium, Starch, Sodium starch glycolate, Low-substituted hydroxypropyl cellulose (Hydroxypropyl cellulose, low) -substituted) may be one or more selected from the group consisting of.

The lubricant may be one or more selected from the group consisting of talc, magnesium stearate, silicon dioxide, stearic acid, and hydrogenated oil.

The small pharmaceutical tablet of the present invention may include an enteric coating layer. The coating base used in the enteric coating layer is at least one selected from the group consisting of phthalic hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and polymethacrylate. This is preferred.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited by the examples.

Example

Example 1.

43.38 mg of eomeprazole magnesium hydrate (40 mg as esmeprazole), 75 mg of L-arginine, 4 mg of magnesium oxide, 124.42 mg of microcrystalline cellulose, 15 mg of povidone and 15 mg of crospovidone, followed by 7 mg of sodium stearyl fumarate Uncoated tablets were prepared. The volume of the uncoated tablet prepared was 0.28 mL. (Volume measurement was performed by placing a tablet in a measuring cylinder containing water, and then monitoring the amount of water increased.)

Example 2.

Uncoated tablet was prepared in the same manner as in Example 1 except that the magnesium oxide content was mixed at 8 mg. The volume of the uncoated tablet prepared was 0.29 mL.

Example 3.

Uncoated tablets were prepared in the same manner as in Example 1, except that the magnesium oxide content was 20 mg. The volume of the prepared uncoated tablet was 0.30 mL.

Example 4.

Uncoated tablets were prepared in the same manner as in Example 1 except that the magnesium oxide content was 40 mg. The volume of the uncoated tablet prepared was 0.32 mL.

Example 5.

S.omeprazole magnesium magnesium hydrate 43.38 mg, microcrystalline cellulose 124.42 mg, magnesium oxide 15 mg, L-arginine 75 mg as diluent, povidone 15 mg as binder, crospovidone 15 mg as disintegrant, 7 mg stearic acid fumarate as lubricant, through wet granulation process The uncoated tablet made by tableting was coated with polyvinyl alcohol, triethyl citrate and polymethacrylate to prepare enteric coated tablets. The final tablet weight was about 370 mg and volume was about 0.37 mL.

Comparative Example 1.

Uncoated tablets were prepared in the same manner as in Example 1, except for magnesium oxide. The volume of the uncoated tablet prepared was 0.27 mL.

Comparative Example 2.

Uncoated tablets were prepared in the same manner as in Example 1, except that 20 mg of calcium hydroxide was mixed instead of magnesium oxide. The volume of the prepared uncoated tablet was 0.30 mL.

Comparative Example 3.

Uncoated tablets were prepared in the same manner as in Example 1 except that 20 mg of sodium hydrogen phosphate was mixed instead of magnesium oxide. The volume of the prepared uncoated tablet was 0.30 mL.

Comparative Example 4.

Uncoated tablets were prepared in the same manner as in Example 1, except that 20 mg of calcium carbonate was mixed instead of magnesium oxide. The volume of the prepared uncoated tablet was 0.30 mL.

Comparative Example 5.

Uncoated tablets were prepared in the same manner as in Example 1, except that 20 mg of potassium hydrogen carbonate was mixed in place of magnesium oxide. The volume of the prepared uncoated tablet was 0.30 mL.

Comparative Example 6.

Comparative Example 6 was prepared by referring to Korean Unexamined Patent Publication No. 10-2009-0033000. Add a solution of povidone (40 mg) and NaOH (1.8 mg) in an appropriate amount of ethanol, mix well, add Esmeprazole Magnesium Hydrate (43.38 mg) to dissolve completely, and add some magnesium oxide (50 mg) to the solution. . The solution was sprayed onto colloidal silicon dioxide (12.5 mg) and magnesium oxide (50 mg) in a fluidized bed to prepare granules. The granulated tablets were mixed with microcrystalline cellulose (265.7 mg), crospovidone (25.0 mg) and magnesium stearate (5.0 mg) to prepare uncoated uncoated tablets. Thereafter, using a tablet coater to coat the HPMC prepared above to make a separation layer, and to prepare a tablet by enteric coating with HPMC P (HP-50) thereon. The final tablet weighed 564 mg and had a volume of 0.56 ml.

Experimental Example 1-Comparison of Drug Degradation Rates of Examples and Comparative Examples

In the pH 6.5 biological solution (solution made by adding 3.4 g of sodium dihydrogen phosphate in 1 liter and 6.2 g of sodium chloride), the pharmacologic elution test 2 method was carried out with pure eomeprazole magnesium hydrate, Examples 1-4, and Comparative Examples 1-5. The amount of decomposition per unit time of esomeprazole magnesium hydrate was measured.

The ratio of the decomposition amount per unit time of the undisassembled, ie stable, esmeprazole magnesium hydrate of each Example and the comparative example to the unit amount decomposition time of the pure esomeprazole magnesium hydrate was calculated as follows.

A: Degradation amount per unit of pure esomeprazole magnesium hydrate (mg / hr)

B: Degradation amount per mg of omeprazole magnesium hydrate in each Example or Comparative Example (mg / hr)

C: stable omeprazole magnesium hydrate (%)

Table 1

	Stable Eomeprazole Magnesium Hydrate (%)		Stable Eomeprazole Magnesium Hydrate (%)
Example 1	3.8	Comparative Example 1	0.1
Example 2	7.5	Comparative Example 2	0.2
Example 3	19.9	Comparative Example 3	0.3
Example 4	39.3	Comparative Example 4	0.2
		Comparative Example 5	0.4

As shown in Table 1, Examples 1 to 4 of the small pharmaceutical tablet according to the present invention can be seen that the decomposition rate is significantly reduced compared to Comparative Examples 1 to 5 are formulated into a stable someprazole formulation.

Experimental Example 2-Comparison of properties of small pharmaceutical tablets and commercial formulations according to the present invention

The size of the enteric-coated tablet of Example 5 and 40 mg of Nexium tablet (Korea AstraZeneca), which is a commercially available esomeprazole tablet, and 40 mg of Esomer capsule (esque chemical) were separately observed. The volume of the Nexium tablet was 0.52 ml (weight 570 mg) and the volume of the enteric coated tablet according to Example 5 was 0.37 ml (weight was 370 mg).

As a result, the small pharmaceutical tablet according to the present invention was found to be a significantly smaller form than the commercial formulation. (See Figures 2 and 3)

Experimental Example 3-Bioequivalence Test of Small Pharmaceutical Tablets According to the Present Invention

A biological equivalence test was performed on Example 5 and Nexium tablet 40 mg (AstraZeneca Korea) on 60 healthy adult volunteers according to the 2 × 2 cross-test.

As a result, the small pharmaceutical tablet according to the present invention was found to be biologically equivalent to a commercial tablet. (See Figure 1)

Experimental Example 4-Comparison of Ease of Consumption with Small Pharmaceutical Tablets and Commercially Available Preparations According to the Present Invention

Dose convenience tests were conducted in 30 patients on Example 5 prepared in accordance with the present invention and on commercially available formulations (Nexium tablet 40 mg, Esomemed capsule 40 mg). Patients were randomly assigned to one group of 10 people, and each group was to receive the formulation of Example 5, Nexium tablets, and capsules of Esomed. Dose convenience was calculated by grading the degree of ease of throbbing when the tablet was swallowed by 1: very hard / 2: hard / 3: normal / 4: easy / 5: very easy scoring. The test results are shown in the table below.

TABLE 2

	Example 5	Commercial formulation
		Nexium Tablets 40mg	Esomed Capsule 40mg
Convenience	4.7	2.5	1.8

As shown in Table 2, the score for the convenience of taking the pharmaceutical tablet of Example 5 according to the present invention was found to be the highest. This is because Example 5 is smaller in size than commercially available tablets, and it is determined that the capsules, which are disadvantages of commercially available capsules, adhere to the esophagus to remove unpleasant elements.

Experimental Example 5-Comparison of Patient Preference with Small Pharmaceutical Tablets and Commercially Available Preparations According to the Present Invention

In Example 5 prepared according to the present invention and commercially available formulations (Nexium tablet 40 mg, Esomed capsule 40 mg), 30 patients were asked to select a preferred dosage form. The test results are shown in the table below.

TABLE 3

	Example 5	Commercial formulation
		Nexium Tablets 40mg	Esomed Capsule 40mg
Patient preference	25	3	2

Claims

A small pharmaceutical tablet containing Someprazole as an active ingredient and having a total volume of 0.4 mL or less.
2. The small pharmaceutical tablet of claim 1, wherein the pharmaceutical tablet comprises magnesium oxide.
The small pharmaceutical according to claim 2, wherein the magnesium oxide is included in an amount of 0.1 to 1 parts by weight based on 1 part by weight of omeprazole.
The small pharmaceutical tablet of claim 1, wherein the small pharmaceutical tablet comprises an enteric coating layer.
The method of claim 4, wherein the enteric coating layer is characterized in that it comprises at least one coating base selected from the group consisting of hydroxypropyl methyl cellulose, polymethacrylate, hydroxypropyl methyl cellulose acetate succinate. Small Pharmaceutical Tablets.
The small pharmaceutical according to claim 1, wherein the small pharmaceutical further comprises a diluent, a binder, a disintegrant and a lubricant.
The small pharmaceutical according to claim 6, wherein the diluent is at least one selected from the group consisting of microcrystalline cellulose, L-arginine, lactose, white sugar, crystalline cellulose, cellulose, and siliconized microcrystalline cellulose.
The method of claim 6, wherein the binder is povidone, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium is a small pharmaceutical, characterized in that at least one selected from the group consisting of starch.
7. The disintegrant according to claim 6, wherein the disintegrant is at least one selected from the group consisting of crospovidone, carboxymethyl cellulose calcium, croscarmellose sodium, starch, sodium starch glycolate, and low-substituted hydroxypropyl cellulose. Small Pharmaceutical Tablets.
The small pharmaceutical agent according to claim 6, wherein the lubricant is at least one selected from the group consisting of sodium stearyl fumarate, talc, magnesium stearate, silicon dioxide, stearic acid, and hydrogenated oil.