KR20170076494A - Improved stability double-coated tablet Composition including S-omeprazole and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a dual coated tablet comprising S-omeprazole and a process for preparing the same, wherein the double coated tablets comprising S-omeprazole comprise an active ingredient, a nail core comprising S-omeprazole or a pharmaceutically acceptable salt thereof and an alkalizing agent, A first coating layer surrounding the core and comprising a water soluble polymer and a second coating layer disposed on the first coating layer and comprising an enteric polymer to facilitate formulation of S-omeprazole The stability can be improved.

Description

[0001] The present invention relates to an improved omeprazole-containing double coated tablet composition having improved stability and an improved stable double-coated tablet composition including S-omeprazole and a manufacturing method thereof.

The present invention relates to a double coated tablet comprising S-omeprazole with increased stability and a process for its preparation.

S-omeprazole and its alkaline salt are proton pump inhibitors developed by AstraZeneca. They are effective inhibitors of gastric acid secretion and are thus useful in the prevention and treatment of gastric acid-related disorders and inflammatory gastrointestinal diseases (e.g. gastric ulcer, duodenal ulcer, reflux esophagitis and gastritis).

U.S. Patent No. 5,693,818 and U.S. Patent No. 5,948,78 disclose a method for preparing S-omeprazole, and U.S. Patent No. 5,714,504 and European Patent No. 124,495 disclose a process for preparing S- ) ≪ / RTI > isomers. International Publication No. WO94 / 27988 discloses that the (S) -isomer of the isomer of omeprazole has a pharmacologically excellent therapeutic effect.

However, S-omeprazole is rapidly degraded in acidic and neutral environments, causing the product to fade and the content of S-omeprazole to decrease over time. In addition, the S-omeprazole free base has a melting point as low as about 45 캜. Therefore, formulation is very difficult, and there is a disadvantage that it is difficult to store for a long period of time because the amount of the flexible substance increases under accelerated-harsh storage conditions.

To overcome this, U.S. Patent No. 6,162,816 discloses a partially crystalline form A and an essentially crystalline form B for S-omeprazole. In addition, International Patent Publication Nos. WO02 / 98423 and 2006-0247277 disclose trihydrate of S-omeprazole but still have a disadvantage that stability and ease of formulation are limited. Thus, there is a disadvantage in that the pharmacokinetic parameters including the dissolution rate at the time of preparation in tablets are below the conventional tablets level.

Therefore, there is an urgent need to develop a pharmaceutical composition containing S-omeprazole that is easy to formulate and has improved stability.

Disclosure of the Invention The present invention has been conceived to solve the above problems, and it is an object of the present invention to provide a double coated tablet containing S-omeprazole exhibiting desired pharmacokinetic parameters including a dissolution rate and a method for producing the same, as the formulation is easy and the stability is improved It has its purpose .

The present invention provides dual coated tablets containing S-omeprazole exhibiting the desired pharmacokinetic parameters, including dissolution rate, as they are easy to formulate and improve stability. A first core layer surrounding said core and comprising a polyvinyl alcohol; and a first coating layer disposed around said core and comprising a polyvinyl alcohol, and a second coating layer disposed around said core and comprising a polyvinyl alcohol, And a second coating layer comprising an acrylic acid methacrylate copolymer.

Wherein the alkalizing agent is L-arginine, and the mass ratio of the S-omeprazole or a pharmaceutically acceptable salt thereof to the L-arginine may be 1: 5 to 1:10.

Also, when the double coated tablet is rotated for 15 minutes at 900 rpm in a pH 6.8 dissolution test liquid at a rotation speed of 100 rpm, the dissolution rate of S-omeprazole may be 5.0 to 20.0% by weight.

Another aspect of the invention provides a method of making a dual coating definition. The method comprises the steps of forming a nail core comprising S-omeprazole or a pharmaceutically acceptable salt thereof and an alkalizing agent as an active ingredient, forming a first coating layer comprising polyvinyl alcohol on the nail core surface, And forming a second coating layer comprising an acrylic acid methacrylate copolymer on the first coating layer.

The double coated tablet containing S-omeprazole according to the present invention and its preparation method can facilitate the formulation of S-omeprazole and improve the stability, so that there is an effect showing the desired pharmacokinetic parameters including the dissolution rate .

1 is a graph showing the dissolution test results of Comparative Production Example 2 and Production Example 1 of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Like reference numerals designate like elements throughout the specification.

A method for preparing a double coating definition comprising S-omeprazole according to one embodiment of the present invention comprises the steps of forming a nail core comprising S-omeprazole or a pharmaceutically acceptable salt thereof and an alkalizing agent as an active ingredient, Forming a first coating layer containing a water-soluble polymer on the first coating layer, and forming a second coating layer containing the enteric polymer on the first coating layer.

In the step of forming the nipping core, the S-omeprazole or a pharmaceutically acceptable salt thereof includes all of the omeprazole free base or its metal salt or its metal salt hydrate, and there is no particular limitation on its selection. Here, the metal salt refers to a salt of omeprazole and an alkali metal or an alkaline earth metal. Specifically, sodium salt, potassium salt, magnesium salt and the like may be included. The metal salt hydrate of omeprazole refers to a metal salt of omeprazole produced by hydration of water. The method for preparing a metal salt or a metal salt hydrate corresponds to a well-known method well known in the art and can be modified within a known method limit.

The alkalizing agent prevents the degradation of S-omeprazole under an acidic or neutral atmosphere. The mass ratio of the S-omeprazole or a pharmaceutically acceptable salt thereof to the alkalizing agent may be 1: 5 to 1:10. When the mass ratio of S-omeprazole or a pharmaceutically acceptable salt thereof and the alkalizing agent is less than 1: 5, the probability that S-omeprazole is decomposed under an acidic or neutral atmosphere may increase, and there may be a change in properties due to moisture penetration have. When the mass ratio of S-omeprazole or a pharmaceutically acceptable salt thereof and the above alkalizing agent is more than 1:10, the solubility of S-omeprazole is drastically lowered as the pH of S-omeprazole increases, and there may be a problem in bioavailability have.

The alkalizing agent may include at least one of L-arginine and magnesium oxide. Particularly, when the alkalizing agent includes L-arginine and magnesium oxide, it is possible to prevent moisture from being changed due to a moisture permeation blocking effect, There is an effect that can have.

The nipping core may further comprise a binder. The binding agent can improve the binding force of the first coating layer and the second coating layer, which will be described later, disposed on the nipping core.

The binder includes at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, dextrin, gelatin, methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, polyvinyl alcohol, paste, and gum arabic can do.

The core may further comprise colloidal silicon dioxide. The colloidal silicon dioxide can prevent a lump phenomenon from occurring in the production of the core.

In addition, it may further comprise additives such as conventional disintegrants, excipients, flavoring agents, coloring agents, lubricants and fillers for preparing tablets.

The core is prepared by laminating the active ingredient on a seed material using a conventional technique or a centrifugal granulator / roto granulator, from a seed material, such as a non-pareils ™, Can be manufactured. The active ingredient and the alkalizing agent may be homogenized and then extruded and spheronized, or they may be manufactured by a compression method, but not limited thereto, and may be manufactured by a method of manufacturing core materials known in the art have.

Next, a first coating layer containing a water-soluble polymer is formed on the surface of the nailing core. Since the first coating layer includes a water-soluble polymer, it elicits the elution of the active ingredient from the core when it comes into contact with the effluent.

The water-soluble polymer may include at least one selected from the group consisting of saccharides, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives and carboxyvinyl polymers

Wherein the water soluble polymer is selected from the group consisting of sugars selected from dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinozaylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin ; Hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, and hydroxyethylmethylcellulose. Selected cellulose derivatives; Guar gum, locust bean gum, tragacanth, carrageenan, acacia gum, gum arabic and gellan gum; Proteins selected from gelatin, casein and zein; Polyvinyl derivatives selected from polyvinyl alcohol, polyvinylpyrrolidone and polyvinyl acetal diethylaminoacetate; A copolymer of poly (methacrylic acid, methyl methacrylate) and poly (methacrylic acid, ethyl acrylate) copolymer, poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) A polymethacrylate copolymer selected from a copolymer; Polyethylene < / RTI > glycol and polyethylene oxide; And a carboxyvinyl polymer as a carboxyvinyl polymer.

At this time, the method of forming the first coating layer may be a well-known method well known in the art, and may be modified within a known method limit. For example, the first coating layer may be formed through a spray process using a spray gun after rapidly dispersing a mixed solution containing the first coating material and the proper solvent, but the present invention is not limited thereto. In addition, the mass of the first coating layer may be 10 wt% to 25 wt% of the mass of the core. If the above range is not satisfied, the release properties of the active material of the tablet may be deteriorated.

Next, a second coating layer containing an enteric polymer is formed on the first coating layer. As the second coating layer contains the enteric polymer, the elution of esomeprazole contained in the nipping core is controlled. Accordingly, the second coating layer is formed on the first coating layer to exhibit an appropriate dissolution rate. The enteric polymer may include a copolymer of a carboxylic acid monomer and an ester monomer, and the copolymer may include an acrylic acid-methacrylate copolymer .

At this time, the method of forming the second coating layer may be the same as the first coating layer, but it is possible to use a process of forming a coating layer on the non-magnetic core known in the art. In addition, for example, the second coating layer forming material and the solvent may be dispersed at a high speed and mixed, followed by a dispersion process using a spray gun. In addition, the mass of the second coating layer may be 10 wt% to 20 wt% of the mass of the core. If the above range is not satisfied, the release properties of the active material of the tablet may be deteriorated.

The thus prepared double coating tablet comprising S-omeprazole is provided with an emulsion core comprising S-omeprazole or a pharmaceutically acceptable salt thereof and an alkalizing agent as an active ingredient, a first coating layer disposed around the emulsion core and comprising a water-soluble polymer And a second coating layer disposed on the first coating layer and including an enteric polymer. At this time, as the nipping core contains an alkalizing agent, it has excellent stability under an acidic or neutral atmosphere, has low water permeability and excellent stability, and has elution characteristics within a desired range. In addition, the inclusion of the first coating layer and the second coating layer can lower the permeation rate of water to further improve the stability and control the dissolution rate to a desired level. In addition, the description of the nipping core, the first coating layer, and the second coating layer will be described in the foregoing.

Specifically, when the double coated tablet is rotated for 15 minutes at a rotation speed of 100 rpm in 900 ml of a pH 6.8 dissolution test liquid, the dissolution rate of S-omeprazole may be 5.0 to 20.0% by weight.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[ Example ]

Example : S-omeprazole  Included Nail core  Produce

Example  One

Mixed with a solution prepared by dissolving 43.38 mg of S-omeprazole magnesium dihydrate (40 mg of S-omeprazole), 25 mg of magnesium oxide and 360.12 mg of microcrystalline cellulose 101, and then 30 mg of povidone dissolved in 60 mg of ethanol, followed by drying and mixing the dried product with 20 mg of crospovidone, 102 mg of colloidal silicon dioxide, 5 mg of colloidal silicon dioxide and 9 mg of sodium stearyl fumarate were mixed and kneaded to prepare an untreated core having 500.5 mg.

Example  2 to 6

And the amount of L-arginine was adjusted as shown in Table 1 below to prepare a core having the same amount as in Example 1.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 S-omeprazole magnesium dihydrate (mg) 43.38 43.38 43.38 43.38 43.38 43.38 Magnesium oxide (mg) 25 25 25 25 25 25 L-arginine (mg) - 50.12 100.12 200.12 275.12 300.12 Microcrystalline cellulose 101 (mg) 360.12 310 260 160 85 60 Povidone (mg) 30 30 30 30 30 30 Crospovidone (mg) 20 20 20 20 20 20 Microcrystalline cellulose 102 (mg) 8 8 8 8 8 8 Colloidal silicon dioxide (mg) 5 5 5 5 5 5 Sodium stearyl fumarate (mg) 9 9 9 9 9 9 Total (mg) 500.5 500.5 500.5 500.5 500.5 500.5

Experimental Example

(One) S-omeprazole  Stability evaluation

(Weight%) at 60 DEG C / 75% RH was measured. Specifically, the nails of Examples 1 to 6 were each placed on a flat plastic container and stored for 3 months under the condition of 60/75% RH. Thereafter, in order to compare the moisture permeability of the tablets, the weight change and the property change of each tablets were observed, and the results are shown in Table 2 below.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Weight increase rate (% by weight) 5.28 4.56 4.17 3.69 2.94 2.93 Constellation change +++++ +++++ +++++ +++ + + Evaluation Criteria: + Good, +++ Moderate, +++++ Bad

As can be seen from the above Table 2, it was found that the moisture permeation blocking effect was more effective than that of the other Examples in the Examples 5 and 6, and the change in the nail properties was also small.

Manufacturing example  One: Double coating definition  Produce

The nonwoven core prepared in Example 5 was prepared. Thereafter, polyvinyl alcohol, polyethylene glycol, talc, and titanium oxide were added to 400 ml of purified water, and the mixture was dispersed at a high speed using a homogenizer to prepare a first coating layer forming composition. Then, the first coating layer-forming composition was sprayed onto the nipping core prepared in Example 5 with a spray gun to form a water-soluble coating film so as to have a weight of 5% by weight.

Thereafter, sodium hydrogencarbonate, sodium lauryl sulfate, and triethyl citrate were dissolved in 500 mL of purified water, followed by dispersing Eudragit L100-55. Then, talc and titanium oxide were added thereto and dispersed at a high speed using a homogenizer to obtain an enteric film coating solution . Thereafter, the second coating layer-forming composition prepared in Example 5 was sprayed with a spray gun to form an enteric coating film so as to have an amount of 15% by weight based on the weight of the nonwoven base.

The specific contents of the first coating layer-forming composition and the second coating layer-forming composition are shown in Table 3 below.

Comparative Manufacturing Example  One

A double coated tablet was prepared in the same manner as in Preparation Example 1 except that the first coating layer was not formed.

Comparative Manufacturing Example  2

40 mg of Nexium tablets (Lot No 60012217, AstraZeneca), a commercially available drug, was purchased and used as Comparative Preparation Example 2.

Configuration ingredient Example 7 Example 8 The first coating layer Polyvinyl alcohol (mg) 10 Polyethylene glycol (mg) 5 Talc (mg) 3.8 Titanium oxide (mg) 6.2 The second coating layer Sodium hydrogencarbonate (mg) 0.7 0.7 Sodium lauryl sulfate (mg) 0.3 0.3 Eudragit L100-55 (mg) 44.9 44.9 Talc (mg) 12.6 12.6 Titanium oxide (mg) 9.5 9.5 Triethyl citrate (mg) 7.0 7.0 Coating Coating Layer Weight (mg) 75.0 100 Film coating rate (wt% based on loam weight) 15% 20%

(2) Under the condition of 60 DEG C / 75% RH By coating composition  Weight increase rate (weight % )

The double coated tablets of Preparation Example 1 and Comparative Preparation Example 1 were each placed on a flat plastic container and stored at 60 ° C / 75% RH for 3 months. Thereafter, the weight change of each tablet was observed in order to compare the moisture permeability of the tablets, and the results are shown in Table 4 below.

Comparative Preparation Example 1 Production Example 1 Weight increase rate (% by weight) 1.52 0.02

As can be seen from the above Table 4, the production example 1 of the present invention is superior to the comparative preparation example 1 in the moisture permeation blocking effect.

(3) 60 ° C / RH 75%  Conditional Flexible material  Confirm creation

The double-coated tablets of Examples 1 to 6, the double coated tablets of Preparation Example 1, and the double coated tablets of Comparative Production Example 1 were stored at 60 ° C / RH 75% for 3 months, And the change amount of the flexible material is shown in Table 5 below.

<HPLC Conditions>

Detector: Ultraviolet absorptiometer (measuring wavelength 302 nm)

Column: Zorbax Eclipse XDB C18, 5 탆, 4.6 x 150 mm

Mobile: Gradient

      A: acetonitrile: phosphate buffer (pH 7.6): water = 1: 1: 8 (v / v%

B: acetonitrile: phosphate buffer (pH 7.3): water = 8: 1: 1.9 (v / v%

Flow rate: 1 mL / min

Injection amount: 20 μl

Flexible material Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Preparation Example 1 Production Example 1 Omeprazole N-oxide 4.8% 3.6% 3.1% 2.8% 2.6% 2.5% 3.86 0.1% Omeprazole Flexible A 17.3% 10.3% 5.4% 5.0% 4.9% 4.8% 18.64% 0.1% Individual unknown substance 5.2% 3.0% 2.4% 2.1% 1.9% 1.9% 9.33% 0.1% Total flexible material 27.3% 16.9% 10.9% 9.9% 9.4% 9.2% 37.83% 0.3%

As shown in the results of Table 5, it was confirmed that as the amount of L-arginine increases, the soft substance of S-omeprazole is inhibited. Also, as in Example 8, the water-soluble coating film layer (first coating layer) containing polyvinyl alcohol and the enteric coating film layer (second coating layer) must be formed so that the amount of generation of the flexible substance can be remarkably reduced .

(4) Elution test

The commercially available formulation of Comparative Preparation Example 2 and the double coated tablets of Preparation Example 1 were tested according to Method 2 of the dissolution test method in the General Test Methods of the Korean Pharmacopoeia 10 th Revision.

The test solution was prepared by adding 250 mL of 0.2 M potassium dihydrogen phosphate solution and 118 mL of 0.2 M sodium hydroxide solution and 1 L of pH 6.8 buffer solution.

At the start of the elution test, 1.5 mL of the eluate was sampled at 5, 10, 15 and 30 minutes, and immediately thereafter, 1.5 mL of the test liquid at 37 ± 0.5 ° C was added to the elution tank.

1.5 mL of the eluate was filtered through a 0.45 μm syringe filter and analyzed by HPLC.

The HPLC analysis conditions are as follows.

Mobile phase: acetonitrile: phosphate buffer (pH 7.3): water (35:50:15, v / v%)

      Flow rate: 1 mL / min

      Injection amount: 20 μl

      Measured wavelength: 302 nm

1 is a graph showing the dissolution test results of Comparative Production Example 2 and Production Example 1 of the present invention. Referring to FIG. 1, it can be seen that the double coated tablets of the present invention exhibit more stable dissolution characteristics .

(5) Biological equivalence test

The bioequivalence test for Comparative Preparation Example 2 and Preparation Example 1 was conducted on 60 healthy adult volunteers according to the 2 × 2 cross-over test, and the results are shown in Table 6 below.

Comparative Production Example 2 Production Example 1 Cmax 1379.7 1638.5 AUC 4069.3 4031.4

As shown in Table 6, it can be seen that the double coated tablets according to the present invention are biologically equivalent to commercially available tablets.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (4)

A tabular core comprising S-omeprazole or a pharmaceutically acceptable salt thereof and an alkalizing agent as active ingredients;
A first coating layer surrounding the nipping core and comprising polyvinyl alcohol; And
A second coating layer disposed on the first coating layer and comprising an acrylic acid methacrylate copolymer. The method according to claim 1,
Wherein the alkalizing agent is L-arginine,
Wherein the mass ratio of S-omeprazole or a pharmaceutically acceptable salt thereof to the L-arginine is from 1: 5 to 1:10. The method according to claim 1,
Wherein the double coated tablet is rotated at 900 rpm in a pH 6.8 dissolution test liquid at a rotation speed of 100 rpm for 15 minutes and a dissolution rate of S-omeprazole is 5.0 to 20.0% by weight. Forming an emulsion core comprising S-omeprazole or a pharmaceutically acceptable salt thereof and an alkalizing agent as an active ingredient;
Forming a first coating layer comprising polyvinyl alcohol on the surface of the nipping core; And
And forming a second coating layer comprising an acrylic acid methacrylate copolymer on the first coating layer.

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