KR102146724B1 - Pharmaceutical formulation comprising benzimidazole and preparation method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing a benzimidazole-based compound and a method for preparing the same, and since an organic solvent is not used when preparing granules, the organic solvent remaining in the tablet is removed, and when taken together with other drugs, an excessive amount of ethanol The risk of ingestion can be prevented in advance, the stability of the drug can be improved through the selection of a specific excipient and mixing in a specific ratio, and the process changes and process conditions of mixing after separating and manufacturing the granules can be specified. Through this, it is easy to formulate and has an excellent effect of improving processability.

Description

Pharmaceutical formulation comprising benzimidazole and preparation method thereof TECHNICAL FIELD

The present invention relates to a composition for simultaneously improving the stability and safety of a benzimidazole formulation having poor stability at low pH, and a method for preparing the same.

Benzimidazole-based compounds (e.g., rabeprazole, omeprazole, lansoprazole, etc.) are H+/K+ATPase inhibitors and are used for the purpose of treatment or prevention of gastric ulcer, duodenal ulcer, gastritis or duodenitis. However, since benzimidazole-based compounds show very unstable properties under acidic and neutral conditions and are rapidly decomposed, various methods for improving stability are known.

Specifically, Korean Patent Application Laid-Open No. 10-2007-0092439 is a technology for stabilizing sodium rabeprazole, which is unstable in acid, by mixing sodium silicoaluminate as a stabilizer with sodium rabeprazole to maintain the surrounding environment at a pH of 8 to 13. , Korean Patent No. 10-0761041 uses metal stearate and magnesium oxide as stabilizers to stabilize benzimidazole-based compounds.

On the other hand, the highest daily intake of solvent by the Food and Drug Administration is 50mg (5000ppm) or less, and in the case of commercial products, it is recognized without safety data, since it is about 500ppm in uncoated tablets. Has a harmful problem. In this respect, since the prior art uses a large amount of organic solvent instead of purified water to block moisture during granulation, an operator can inhale the organic solvent to harm health and adversely affect the patient when administering the formulation. As there are concerns, there is a need for improvement of a formulation for oral administration and a method of manufacturing the formulation having both stability and safety of the formulation.

As a result of continuous efforts to develop a pharmaceutical composition with improved stability as well as easy formulation without using an organic solvent, the present inventors significantly improved storage stability by changing the type of excipient, mixing ratio, and the manufacturing process of the formulation. The present invention was completed by confirming the composition.

It is an object of the present invention to provide a pharmaceutical composition containing benzimidazole that can be easily formulated without the use of an organic solvent, and can significantly improve stability and safety at the same time.

Another object of the present invention is to provide a method for preparing the pharmaceutical composition containing benzimidazole.

According to an embodiment of the present invention for achieving the above object, the following invention is provided.

1) A pharmaceutical composition comprising benzimidazole or a salt thereof and one or more pharmaceutical excipients as an active ingredient and no organic solvent.

2) The pharmaceutical excipient is one or more pharmaceutical compositions selected from the group consisting of calcium carbonate, hydroxypropyl cellulose, calcium hydroxide, sodium hydroxide, croscarmellose sodium, and lubricants.

3) The calcium carbonate is a pharmaceutical composition containing 25 to 65% by weight of the total weight of the composition.

4) In the dissolution test of the pharmaceutical composition (a) when the pH of the buffer solution is 1.2, less than 10% of the total weight of benzimidazole is eluted 15 minutes after the start of the test, and (b) the pH of the buffer solution is 6.8 days. In this case, more than 85% of the total weight of benzimidazole is eluted 15 minutes after the start of the test, and (c) the total amount of related substances is less than 3% when stored for 4 weeks at an accelerated condition of 40 and 75% RH. Composition.

5) 10 to 45 parts by weight of benzimidazole, 25 to 65 parts by weight of calcium carbonate, 4 to 5 parts by weight of low-value hydroxypropyl cellulose, 1 to 2 parts by weight of calcium hydroxide, 0.1 to 2 parts by weight of sodium hydroxide, hydride A pharmaceutical composition comprising 0.5 to 1 parts by weight of oxypropylcellulose and 2 to 3 parts by weight of croscarmellose sodium.

6) (a) dissolving a stabilizer or a binder in a solvent to prepare a binding solution, (b) mixing benzimidazole and a pharmaceutical excipient as an active ingredient, and then adding the binding solution prepared in step (a) to the mixture A method for producing a pharmaceutical composition comprising the step of preparing granules, (c) drying the granules and then sizing.

7) A method for preparing a pharmaceutical composition in which the weight ratio of purified water as a solvent and sodium hydroxide as a stabilizer is 3:1 to 1:1 when preparing the binding solution in step (a).

8) A method of preparing a pharmaceutical composition for preparing granules by separating them into two times when preparing the granules in step (b).

9) The step (c) is to prepare a sized product by sizing the granule to 14 to 20 mesh, but the Hausner ratio of the sized product is 1.45 or less, and a method for producing a pharmaceutical composition that does not cause tabletting disorder.

10) 10 to 45 parts by weight of benzimidazole, 25 to 65 parts by weight of calcium carbonate, 4 to 5 parts by weight of low-value hydroxypropyl cellulose, 1 to 2 parts by weight of calcium hydroxide, 0.1 to 2 parts by weight of sodium hydroxide, hydride A pharmaceutical composition comprising 0.5 to 1 parts by weight of oxypropylcellulose and 2 to 3 parts by weight of croscarmellose sodium.

Since the pharmaceutical composition according to the present invention does not use an organic solvent when preparing granules, the organic solvent remaining in the tablet is removed, so that when taken together with other drugs, the risk of ingesting excessive ethanol can be prevented in advance. have.

In addition, even if an organic solvent is not used when manufacturing granules, the stability of the drug can be improved by selecting a specific excipient and mixing in a specific ratio, and through the process change and process conditions of mixing after separating and preparing the granules. It is easy to formulate and has an excellent effect of improving processability.

The present invention provides a pharmaceutical composition comprising benzimidazole or a salt thereof and at least one pharmaceutical excipient as an active ingredient, but not an organic solvent.

In the present invention, the pharmaceutical excipient may be one or more selected from the group consisting of calcium carbonate, hydroxypropyl cellulose, calcium hydroxide, sodium hydroxide, D-mannitol, sodium croscarmellose, and a lubricant, but is not limited thereto.

In the present invention, the calcium carbonate may be contained in an amount of 25% to 65% by weight of the total weight of the composition. In the present invention, the calcium carbonate is used as a stabilizer, and when the content of calcium carbonate is less than 25% by weight, there may be a problem of poor stability, and when it exceeds 65% by weight, tableting disorder may occur.

The pharmaceutical composition of the present invention is suitable for oral administration. Bioavailability is important for pharmaceutical compositions suitable for oral administration. Bioavailability is the relative amount by which a drug reaches the systemic circulation in an unchanged form with respect to the administered dose, and is important in determining the therapeutically active concentration at the site of action. Since both drug release from the formulation and the stability of the formulation will affect bioavailability, it is important that the drug formulation releases virtually all active drug.

In the dissolution test of the pharmaceutical composition of the present invention, (a) when the pH of the buffer solution is 1.2, 10% or less of the total weight of benzimidazole is eluted 15 minutes after the start of the test, and (b) the pH of the buffer solution is 6.8 days. In this case, at least 85% of the total weight of benzimidazole is eluted 15 minutes after the start of the test.

The pharmaceutical composition of the present invention may also exhibit storage stability of less than 3% of the total amount of related substances when stored for 4 weeks at a temperature of 40 and an accelerated condition of 75% RH.

The present invention also provides 10 to 45 parts by weight of benzimidazole, 25 to 65 parts by weight of calcium carbonate, 4 to 5 parts by weight of low-value hydroxypropyl cellulose, 1 to 2 parts by weight of calcium hydroxide, 0.1 to 2 parts by weight of sodium hydroxide It provides a pharmaceutical composition comprising 0.5 to 1 parts by weight of hydroxypropyl cellulose, 2 to 3 parts by weight of croscarmellose sodium.

In the present invention, the present invention further comprises the steps of (a) dissolving a stabilizer or a binder in a solvent to prepare a binding solution, (b) mixing benzimidazole and a pharmaceutical excipient as an active ingredient, and then mixing the mixture with the binding solution prepared in step (a). It provides a method for preparing a pharmaceutical composition comprising the step of preparing granules by putting them and (c) drying the granules and then sizing them.

In the manufacturing method of the present invention, it is preferable that the weight ratio of purified water as a solvent and sodium hydroxide as a stabilizer is 3:1 to 1:1 when preparing the binding solution in step (a). When the ratio of sodium hydroxide is low, the stability is not improved, and when the ratio is increased to a high ratio outside the above range, the stability of the tablet may be degraded due to strong moisture absorption.

In the manufacturing method of the present invention, when the granules in step (b) are prepared, the granules can be prepared as single granules or separated into two, and the stability can be greatly improved by increasing the surface area where the active ingredient and the stabilizer meet. It is more preferable to prepare the granules by separating them in two times.

Hereinafter, the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not construed as being limited by these examples.

Comparative Examples and Examples 1 to 5: Preparation of separated granules

Comparative Examples and Examples 1 to 5 were prepared according to the following procedure according to the components and contents of the following [Table 1].

1) A binding solution (1) was prepared by dissolving sodium hydroxide (stabilizer) in purified water, and a binding solution (2) was prepared by dissolving hydroxypropyl cellulose (binder) in purified water.

2) Precipitated calcium carbonate (excipient), low-substituted hydroxypropyl cellulose (disintegrant), and calcium hydroxide (stabilizer) are mixed with benzimidazole-based drugs (active ingredient), and then the binder solution of step 1) (1) The mixture was prepared and dried, and then sieved with 14 to 20 mesh to prepare granules (1).

3) After mixing D-mannitol (soluble excipient) and croscarmellose (disintegrant) in the benzimidazole-based drug (active ingredient) in order, add the binding solution (2) of step 1) to the mixture to prepare the combined product. After preparing and drying, it was sieved with 14-20 mesh to prepare granules (2).

4) The granules (1), granules (2), and magnesium stearate (lubricating agent) were mixed, followed by post-mixing and lubricating processes.

5) The granules that went through the lubricating process were tableted.

6) After dissolving the first coating base in ethanol, the tablet was coated on the uncoated tablet that had undergone the tableting process of step 5).

7) After dissolving the second coating base in ethanol, it was coated on the first coated tablet of step 6) to complete the oral formulation.

Ingredient (Unit: wt%) Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5








Najeong Primary granules chief ingredient Benzimidazole drugs 11.90 11.90 11.90 11.90 47.62 35.71 Excipient Precipitated calcium carbonate (hard coal) - 25.00 63.69 63.69 27.98 27.98 Disintegrant Low-substituted hydroxypropyl cellulose 4.11 4.11 4.11 4.11 4.11 4.11 stabilizator Calcium hydroxide
- 1.79 1.79 1.79 1.79 1.79 Primary granule binding liquid stabilizator Sodium hydroxide
- 1.79 1.79 1.79 1.79 1.79 Secondary granule binding solution Binder Hydroxypropylcellulose 0.89 0.89 0.89 0.89 0.89 0.89 Secondary
Granules Excipient D-mannitol 67.26 38.69 - - - - Disintegrant Croscarmellose Sodium
2.98 2.98 2.98 2.98 2.98 2.98 after
mix Lubricant Magnesium stearate 1.79 1.79 1.79 1.79 1.79 1.79
1st coating Gelatinizer Ethyl cellulose 1.79 0.60 0.60 0.60 0.60 0.60 stabilizator Calcium hydroxide - 1.19 1.19 1.19 1.19 1.19


Secondary coating
(Enteric coating) Gelatinizer Hypromellosephthalate 7.26 7.26 7.26 7.26 7.26 7.26 Gelatinizer Glycerin fatty acid ester 0.71 0.71 0.71 0.71 0.71 0.71 Gelatinizer Talc 0.71 0.71 0.71 0.71 0.71 0.71 Gelatinizer Titanium oxide 0.36 0.36 0.36 0.36 0.36 0.36 Gelatinizer Yellow No. 4 Aluminum Lake 0.24 0.24 0.24 0.24 0.24 0.24 Sum(%) 100 100 100 100 100 100

Comparative Example 2: Preparation of single granules

An oral dosage form was prepared in the same composition and method as in Example 1, except that it was prepared as a single granule, and specifically prepared in the following order.

1) A binding solution was prepared by dissolving hydroxypropyl cellulose and calcium hydroxide in purified water.

2) Precipitated calcium carbonate (excipient), low-substituted hydroxypropyl cellulose (disintegrant), and calcium hydroxide (stabilizer) are mixed with benzimidazole-based drugs (active ingredient), and then the binding solution of step 1) is added to the mixture. Water was prepared, dried, and then sieved through 14-20 mesh to prepare granules.

3) D-mannitol for direct compression (soluble excipient) and croscarmellose sodium (disintegrant) were added to the granules sieved in step 2) and mixed.

4) The mixture of step 3) was lubricated in the same manner as in Example 1, followed by tableting and coating to complete an oral formulation.

Experimental Example 1. Evaluation of dissolution of Examples and Comparative Examples

According to the second method (paddle method) of the general test methods of the Korean Pharmacopoeia for Examples 1 to 5 and Comparative Examples 1 and 2, the eluate was performed at pH 1.2 and pH 6.8. Test solution pH1.2 was eluted with a paddle rotation speed of 50 rpm in 900 mL of the elution test solution, and the test solution pH 6.8 was eluted with a paddle rotation speed of 100 rpm in 900 mL of the dissolution test solution, and the results of the elution of benzimidazole-based drugs were obtained. It was confirmed, and the results are shown in [Table 2].

Dissolution test Comparative example
One Comparative example
2 Example
One Example
2 Example
3 Example
4 Example
5 Test condition 1
(pH 1.2) Dissolution rate (%) 0 0 0 0 0 0 0 Judgment fitness fitness fitness fitness fitness fitness fitness Test condition 2
(pH 6.8) Dissolution rate (%) 92.5 93.7 91.6 91.6 91.5 87.5 93.2 Judgment fitness fitness fitness fitness fitness fitness fitness

(Test condition 1): Dissolution of pH 1.2 dissolution test solution 900mL at a rotational speed of 50rpm, Criteria: If the drug dissolution rate is 10% or less, it is judged as suitable

(Test condition 2): pH 6.8 dissolution test solution 900mL Dissolution at a rotational speed of 100rpm, Criteria: If the drug dissolution rate is 85% or more, it is judged as suitable

Experimental Example 2. Stability confirmation of the benzimidazole tablet of the present invention

In order to check the stability of benzimidazole tablets according to Examples and Comparative Examples, each coated tablet was stored in an open state under accelerated conditions (40, 75% RH) for 4 weeks, and then the content of related substances was evaluated under the following conditions. And shown in the following [Table 3]. If the total content of related substances is less than 3%, it was determined to be suitable.

<Liquid chromatography analysis conditions>

Detector: Ultraviolet absorption photometer (measurement wavelength 290 nm)

Column: octadecylylated column C18, 5 µm. 150mm long, 4.6mm inner diameter or similar column

Column temperature: 30°C

Flow rate: 0.7 ml/min

Mobile phase: Methanol: 0.05 mol/L phosphate buffer (pH 7.0) mixed solution (300: 200. V/V)

stability
exam Comparative example
One Comparative example
2 Example
One Example
2 Example
3 Example
4 Example
5 Total related substances (%) 12.3 2.9 1.5 1.5 1.2 1.2 1.2 Judgment incongruity fitness fitness fitness fitness fitness fitness

As shown in [Table 3], it can be seen that the tablets of Examples 1 to 5 of the present invention have remarkably excellent stability compared to Comparative Examples, as the related material generation rate is 1.5% or less even under accelerated conditions.

Experimental Example 3. Confirmation of residual organic solvent in benzimidazole tablets of the present invention

The results of analyzing the residual ethanol solvent in the uncoated tablet by the residual solvent analysis method described in the Korean Pharmacopoeia are shown in Table 4 below. In Comparative Example 1, after preparing granules using an organic solvent, after removing the organic solvent by various drying methods, the amount of residual organic solvent was checked. As a result, ethanol was the highest in the case of plate drying with the lowest process cost, and In the case, the organic solvent was the lowest, but it is difficult to apply to the industry because of the high process cost. Accordingly, in Comparative Examples 2 and 1 to 5, the amount of residual organic solvent was confirmed after drying by a plate drying method with low process cost, and it was confirmed that no residual organic solvent remained as shown in the following [Table 4]. .

Comparative example
One Comparative example
2 Example 1 Example
2 Example
3 Example
4 Example
5 Residual organic
menstruum
(ppm) Plate drying Vacuum drying Fluidized bed Plate drying Plate drying Plate drying Plate drying Plate drying Plate drying 611.6 204.8 415.2 0 0 0 0 0 0

Claims (10)

First granules comprising benzimidazole or a salt thereof as an active ingredient, calcium carbonate as an excipient, low-substituted hydroxypropylcellulose as a first disintegrant, sodium hydroxide as a first stabilizer, and calcium hydroxide as a second stabilizer; And
As a pharmaceutical composition containing croscarmellose sodium as a second disintegrant and second granules containing hydroxypropyl cellulose as a binder, and not containing an organic solvent,
10 to 45 parts by weight of the benzimidazole or salt thereof based on 100 parts by weight of the pharmaceutical composition; 25 to 65 parts by weight of the calcium carbonate; 4 to 5 parts by weight of the low-substituted hydroxypropyl cellulose; 0.1 to 2 parts by weight of the sodium hydroxide; 1 to 2.98 parts by weight of the calcium hydroxide; 2 to 3 parts by weight of the croscarmellose sodium; And 0.5 to 1 part by weight of the hydroxypropyl cellulose,
When stored for 4 weeks at a temperature of 40° C. and an accelerated condition of 75% RH in the stability test, the sum of the total related substances is 1.5% or less.
delete delete The method of claim 1,
The pharmaceutical composition is in the dissolution test
(a) When the pH of the buffer solution is 1.2, 10% or less of the total weight of benzimidazole elutes 15 minutes after the start of the test,
(b) When the pH of the buffer solution is 6.8, at least 85% of the total weight of benzimidazole is eluted 15 minutes after the start of the test.
delete delete (a) After dissolving sodium hydroxide as a first stabilizer in a first solvent to prepare a first binding solution, benzimidazole or a salt thereof as an active ingredient, calcium carbonate as an excipient, and low-substituted hydroxy as a first disintegrant Preparing first granules by adding the prepared first binding liquid to a mixture of propyl cellulose and calcium hydroxide as a second stabilizer;
(b) dissolving hydroxypropyl cellulose as a binder in a second solvent to prepare a second binder solution, and then adding the prepared second binder solution to croscarmellose sodium as a second disintegrant to prepare second granules. step; And
(c) A method for preparing a pharmaceutical composition comprising the step of post-mixing the first granules prepared in step (a) and the second granules prepared in step (b), but without using an organic solvent,
10 to 45 parts by weight of the benzimidazole or salt thereof based on 100 parts by weight of the pharmaceutical composition; 25 to 65 parts by weight of the calcium carbonate; 4 to 5 parts by weight of the low-substituted hydroxypropyl cellulose; 0.1 to 2 parts by weight of the sodium hydroxide, 1 to 2.98 parts by weight of the calcium hydroxide; 2 to 3 parts by weight of the croscarmellose sodium; And 0.5 to 1 part by weight of the hydroxypropyl cellulose,
When stored for 4 weeks at a temperature of 40° C. and an accelerated condition of 75% RH in the stability test, the total amount of related substances is 1.5% or less.
The method of claim 7,
When preparing the first binding solution in step (a), the weight ratio of the first solvent and sodium hydroxide is 3:1 to 1:1.
delete The method of claim 7,
(d) a method for producing a pharmaceutical composition, further comprising the step of coating with a coating base containing calcium hydroxide as a third stabilizer.