KR102484953B1 - Film-coated tablet for gastrointestinal disorder comprising famotidine, magnesium hydroxide, and precipitated calcium-carbonate as active ingredient - Google Patents

Abstract

The present invention relates to a film-coated tablet for treating gastrointestinal diseases, comprising famotidine, magnesium hydroxide, and precipitated calcium carbonate as active ingredients, and more particularly, famotidine, magnesium hydroxide, and precipitated calcium carbonate as active ingredients. It relates to a film-coated tablet for treating gastrointestinal diseases, wherein the active ingredient forms granules using starch as a binder, and the granules are mixed with sugar. Unlike conventional chewable tablets, the present invention does not need to be chewed, so there is no concern about inhibition or avoidance due to bitter taste, and it solves the problem of dissolution, which has been a problem in the meantime, and exhibits excellent dissolution rate and bioavailability. It also shows excellent effects on hardness, which can be a problem during storage or handling.

Description

Film-coated tablet for the treatment of gastrointestinal diseases containing famotidine, magnesium hydroxide, and precipitated calcium carbonate as active ingredients

The present invention relates to a film-coated tablet for treating gastrointestinal diseases containing famotidine, magnesium hydroxide, and precipitated calcium carbonate as active ingredients.

Famotidine has excellent gastric acid secretion inhibitory action based on histamine H ₂ receptor antagonism, and is used as a treatment for gastric ulcer, duodenal ulcer, and other digestive system diseases [Reference: Merck Index, Thirteen edition, page 696], as an oral agent or It is a component that is widely used as an injection, and magnesium hydroxide or calcium carbonate is a component that is widely used as an antacid that neutralizes stomach acid due to its basic nature. .

Currently, complex formulations in the form of a combination of these ingredients are sold in Korea (Pamocompu™ Chewable Tablets (GL Pharma), Combined Famoside Tablets (Korea Kolmar)), taking shape This is because chewable tablets are chewed and taken orally, so faster and more reliable drug effects can be secured.

However, since the chewable tablet disintegrates in the mouth, there is a problem in that a residual feeling is left in the mouth and a bitter taste must be shielded. Although methods of enhancing sweetness or adding flavor are mainly used to mask bitterness, there is a fundamental limit to masking bitterness by increasing sugar content or adding flavor. In other words, no matter how much sugar or flavor is added, the taste or flavor that cannot be masked cannot be masked.

In particular, in the case of chewable chewable tablets, famotidine itself has a bitter taste, and in addition, magnesium hydroxide and precipitated calcium carbonate components further double the bitter taste as alkaline components, so the degree of addition of sugar or flavor components to mask bitterness does not completely remove the strong bitter taste, and as a result, has a fundamental problem of giving severe reluctance when taken orally.

Therefore, in order to fundamentally mask the bitter taste of these ingredients, it is desirable to develop tablets in the form of swallowing them with water without remaining in the mouth.

However, in the case of a tablet in the form of swallowing with water, it is difficult to express the immediate effect due to delayed disintegration, and there is a problem that the bioavailability is also reduced. Min medicine, even if the disintegration degree is increased to improve this, the hardness of the tablet is lowered and the friability is increased, which may cause other problems in that the defect greatly increases during mass production or storage.

In addition, in the case of a tablet in the form of swallowing with water, since the size of the tablet is required to be small for smooth swallowing, there is also a problem that components other than the active main component such as excipients and disintegrants cannot be used in excess.

That is, in the famotidine, magnesium hydroxide, and calcium carbonate complex formulation, the total content of the active active ingredient alone is burdensome enough to be passed over at once, so if an excipient is added to this, it is convenient to take due to the size of the tablet. may be significantly reduced.

For example, a commercially available combination formulation of famotidine, magnesium hydroxide, and calcium carbonate in the form of chewable tablets has a total active ingredient content of 975 mg (famotidine 10 mg, magnesium hydroxide 165 mg, precipitated calcium carbonate 800 mg). ), the content of the active active ingredient is almost 1000 mg, so it is not easy to make a tablet that is easy to swallow. In the case of a chewable tablet, the tablet size may not be an important issue through chewing in the mouth, but in the case of a tablet to be swallowed with water, the tablet size can be an important issue directly related to the convenience of taking.

KR 10-0553019 B1 (2006. 02. 09.)

The present invention is to provide a tablet with improved bioavailability or slow disintegration, which is a problem of the prior art.

In addition, an object of the present invention is to provide a tablet that is smaller in size than conventional chewable tablets and has excellent swallowability.

Furthermore, it is intended to provide a tablet that is easy to mass-produce, store, and handle because the strength of the tablet itself is not brittle even if it shows excellent dissolution characteristics.

The present invention has been made to solve the above-mentioned problems of the prior art,

A film-coated tablet for treating gastrointestinal diseases containing famotidine, magnesium hydroxide, and precipitated calcium carbonate as active ingredients,

The active ingredient forms granules with the first lactose diluent and starch binder,

The granules are in the form of post-mixing with an additional second lactose diluent,

The additional second lactose diluent provides a film-coated tablet for treating gastrointestinal diseases, characterized in that in granular form.

In the present invention, the ratio of the additional second lactose diluent to the first lactose diluent provides a film-coated tablet for treating gastrointestinal diseases, characterized in that the weight ratio is 0.2 to 0.6.

In the present invention, the total content ratio of the first and second lactose diluents to the content of the active ingredient is 0.1 to 0.2 to provide a film-coated tablet for treating gastrointestinal diseases, characterized in that the weight ratio.

In the present invention, the starch binder provides a film-coated tablet for treating gastrointestinal diseases, characterized in that at least one of corn starch, potato starch, wheat starch, rice starch, and pregelatinized starch.

In the present invention, the lactose diluent provides a film-coated tablet for treating gastrointestinal diseases, characterized in that anhydrous lactose, lactose hydrate, or a combination thereof.

In the present invention, the starch binder provides a film-coated tablet for treating gastrointestinal diseases, characterized in that corn starch.

In the present invention, the lactose diluent provides a film-coated tablet for treating gastrointestinal diseases, characterized in that the lactose hydrate.

In the present invention, it further comprises a disintegrant, and the disintegrant provides a film-coated tablet for treating gastrointestinal diseases, characterized in that the low-substituted hydroxypropyl cellulose.

In the present invention, the active ingredient is a film-coated tablet for treating gastrointestinal diseases, characterized in that it contains 5 to 20 mg of famotidine, 100 to 200 mg of magnesium hydroxide, and 600 to 1000 mg of precipitated calcium carbonate in a single dose. to provide.

In the present invention, the starch binder is 10 ~ 100mg, and the lactose diluent provides a film-coated tablet for treating gastrointestinal diseases, characterized in that it contains 60 ~ 200mg.

In the present invention, there is provided a film-coated tablet for treating gastrointestinal diseases, characterized in that the total weight of a single administration of the tablet is 1300 mg or less.

In the present invention, the hardness of the tablet provides a film-coated tablet for the treatment of gastrointestinal diseases, characterized in that at least 10kP or more.

Unlike conventional chewable tablets, the present invention does not need to be chewed, so there is no concern about inhibition or avoidance due to bitter taste, and it solves the problem of disintegration rate that has been a problem so far, showing rapid disintegration and bioavailability, It also shows excellent effects on hardness, which can be a problem during storage or handling of tablets.

1 is a photograph comparing the tablet sizes of Comparative Examples and Examples of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention,

A film-coated tablet for treating gastrointestinal diseases containing famotidine, magnesium hydroxide, and precipitated calcium carbonate as active ingredients,

The active ingredient forms granules with the first lactose diluent and starch binder,

The granules are in the form of post-mixing with an additional second lactose diluent,

The additional second lactose diluent is a film-coated tablet for treating gastrointestinal diseases, characterized in that it is granular.

Lactose is widely used as a general excipient, but in the present invention, lactose is specially selected as a diluent for forming granules or a post-mixing component for tableting.

That is, lactose has excellent compressibility and compression hardness compared to other diluents and can be useful in preventing brittleness of tablets, so it can be specially selected. For example, compared to other diluents such as hydroxypropyl cellulose or mannitol, not only the hardness increase effect is high compared to the amount added, but also compact tablets can be manufactured with good compressibility. A detailed understanding of this will be made through an embodiment to be described later.

In addition, here, lactose is added by dividing a first lactose diluent forming granules together with active ingredients and an additional second lactose diluent post-mixed together with the granules.

This is because it was found that, rather than simply adding lactose, adding the first lactose diluent and the second lactose diluent separately can improve the hardness and disintegration of the tablet more effectively, even if the same total amount of lactose diluent is included. to be.

Even when lactose is added as a main excipient (diluent, disintegrant, lubricant, etc., the most included excipient component other than active ingredients), if the content is too small, the desired physical properties cannot be met. When the content is increased, the size of the tablet inevitably increases, greatly impairing the convenience of taking.

Accordingly, it is very important to minimize the content of the diluent in terms of tablet size and to exhibit hardness suitable for mass production of tablets.

In particular, the ratio of the additional second lactose diluent to the first lactose diluent is preferably in the range of 0.2 to 0.6, more preferably in the range of 0.3 to 0.5, and even more preferably in the range of 0.35 to 0.45.

Since the first lactose diluent forms granules with a binder, it is preferably milled lactose.

The particle size distribution of the first lactose diluent is 50 to 65% (m) below 45 μm, 90 to 100% (m) below 100 μm, 96 to 100% (m) below 150 μm, and 99 to 100% below 250 μm. (m) can be used, 45 μm or less 58 ± 5% (m), 100 μm or less 95 ± 5% (m), 150 μm or less 100% (m), 250 μm or less 100% (m) more preferable

The second lactose diluent is preferably provided in the form of granules in terms of tablet disintegration and tablet hardness, and is mixed with the granules granulated with the first lactose diluent and binder and tableted immediately. can Depending on whether the lactose to be mixed is ground or granular, the physical properties of the tablet can be greatly affected. A more detailed understanding of this will be able to be done through examples to be described later.

The particle size distribution of the second lactose diluent was 75 μm or less 10-30% (m), 150 μm or less 40-70% (m), 355 μm or less 90-100% (m), 500 μm or less 100% (m) ) can be used, and 75 μm or less 20 ± 5% (m), 150 μm or less 60 ± 5% (m), 355 μm or less 97 ± 3% (m), 500 μm or less 100% (m) more preferable

In the present invention, the total content ratio of the first and second lactose diluents to the content of the active ingredient may be 0.1 to 0.2 weight ratio. If less than 0.1 is included, it may be insufficient to match the hardness of the tablet, and if it exceeds 0.2, the size of the tablet becomes large by that much, which may impair the convenience of taking and adversely affect the disintegration degree.

The starch binder may use one or more of corn starch, potato starch, wheat starch, rice starch, and pregelatinized starch, among which corn starch is preferred. Corn starch is advantageous in terms of changes over time due to moisture, and has the advantage of compliance with the human body when taken.

The lactose diluent may be anhydrous lactose, lactose hydrate, or a combination thereof, but lactose hydrate is preferred. Lactose hydrate is advantageous in terms of processability when mass-producing tablets and has the advantage of increasing hardness. However, although anhydrous lactose has the effect of increasing the hardness of tablets, it is more hygroscopic than lactose hydrate, so there is a relatively high possibility of causing problems during manufacture or storage of tablets due to moisture absorption. There may be a possibility of exhibiting somewhat unstable characteristics such as occurrence of deviation.

The disintegrant is preferably low-substituted hydroxypropyl cellulose, and a detailed understanding thereof will be made through the examples to be described later.

The active ingredient may include 5 to 20 mg of famotidine, 100 to 200 mg of magnesium hydroxide, and 600 to 1000 mg of precipitated calcium carbonate in a single dose.

Accordingly, the starch binder may be 10 to 100 mg and the lactose diluent may be 60 to 200 mg.

The total weight of the tablet per administration may be 1300 mg or less, preferably 1200 mg or less. This is because the smaller the tablet size, the better the swallowing effect.

The hardness of the tablet may be at least 10 kP or more, preferably, 12 kP or more, more preferably, 14 kP or more, and most preferably, 15 kP or more. In order to reduce the defect rate of the purification process and mass-produce stable tablets, it should be at least 10 kP, preferably 14 kP or more.

In addition, the disintegration of the tablet will be within 5 minutes, more preferably within 4 minutes, still more preferably within 3 minutes, and most preferably within 2 minutes, in terms of rapid effect.

Hereinafter, examples of the present invention will be described in more detail. It is clear that the following examples are only for detailed description of the invention, and are not intended to limit the scope of rights thereby.

Example

In the mixing ratio shown in Table 1, the active ingredient and the diluent were mixed, and after sieving them, the binder, corn starch, was gelatinized in purified water of 90 ° C. or higher to prepare a binder solution.

Thereafter, the mixture and the binder solution were combined, dried and sized (sifted) to prepare granules, and after mixing the granules with excipients such as additional diluents, disintegrants, and lubricants, film coating and tableting were performed.

Blending purpose raw material name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 amount amount amount amount amount amount amount amount active ingredient famotidine 10 10 10 10 10 10 10 10 magnesium hydroxide 165 165 165 165 165 165 165 165 Precipitated Calcium Carbonate 800 800 800 800 800 800 800 800 diluent
(granular) ground lactose monohydrate 100 85 75 0 85 38 83 - D-mannitol - - - - - - - 78 povidone - - - - - - - 15 HPC-L - - - - - 10 15 - binder corn starch 30 - - - 15 - - - Starch 1500 - 30 50 90 50 - - - disintegrant Croscarmellose Sodium - - - - - 25 25 30 L-HPC 40 - - - - - - - diluent
(post-mixing) granular lactose monohydrate 40 75 75 - 65 102 42 47 colloidal silicon dioxide 5 5 5 5 5 - - - glidant Magnesium Stearate 10 10 10 10 5 2 2 2

Blending purpose raw material name Example 9 Example 10 Example 11 Example 12 Example 13 amount amount amount amount amount active ingredient famotidine 10 10 10 10 10 magnesium hydroxide 165 165 165 165 165 Precipitated Calcium Carbonate 800 800 800 800 800 diluent
(granular) ground lactose monohydrate 140 - 70 140 100 D-mannitol - - - - - povidone - - - - - HPC-L - - - - - binder corn starch 30 30 30 30 30 Starch 1500 - - - - - disintegrant Croscarmellose Sodium - - - - - L-HPC 40 40 40 40 40 diluent
(post-mixing) granular lactose monohydrate - 140 70 70 - ground lactose monohydrate - - - - 40 colloidal silicon dioxide 5 5 5 5 5 glidant Magnesium Stearate 10 10 10 10 10

Here, Pharmatose® 200M (DFE pharma) was used for pulverized lactose hydrate, and SuperTab® 30GR, granulated (DFE pharma) was used for granulated lactose hydrate.

comparative example

Commercially available Pepcid® Complete (Manufacturer: Jhonson&Johnson consumer INC.)

Measurement of physical properties and storage stability

- Hardness measurement: tested using Erweka TBH125TD (country of manufacture: Germany).

- Measurement of disintegration: Tested with water solution for disintegration test in the general test method of the 12th edition of the Korean Pharmacopoeia.

The experimental measurement results were shown in Tables 3 to 6 below.

Storage period (months) Test Items Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 0 Hardness 15kp 9kp 7kp 4kp 8kp 6kp 8kp 6kp disintegration time within 2 minutes 10 minutes 10 minutes 9 minutes 7 minutes 7 minutes 7 minutes 5 minutes One Hardness 16kp 9kp 7kp 4kp 8kp 6kp 8kp 6kp disintegration time within 2 minutes 11 minutes 11 minutes 9 minutes 9 minutes 7 minutes 7 minutes 5 minutes 3 Hardness 15kp 9kp 7kp 4kp 9kp 6kp 8kp 6kp disintegration time 2-3 minutes 13 minutes 13 minutes 9 minutes 11 minutes 8 minutes 7 minutes 6 minutes

Storage period (months) Test Items Example 9 Example 10 Example 11 Example 12 Example 13 0 Hardness 9kp 5kp 9kp 17kp 9kp disintegration time 7 minutes 5 minutes 7 minutes 6 minutes 8 minutes One Hardness 9kp 6kp 9kp 17kp 9kp disintegration time 7 minutes 7 minutes 7 minutes 6 minutes 9 minutes 3 Hardness 8kp 7kp 8kp 18kp 10kp disintegration time 8 minutes 8 minutes 8 minutes 7 minutes 9 minutes

As can be seen from the comparison between Example 1 and Example 5, it was confirmed that the binder using corn starch had higher hardness and faster disintegration than Starch 1500.

In the case of the disintegrant, it was confirmed that the low-substituted hydroxypropyl cellulose was more effective in increasing the hardness and exhibiting the rapid disintegration compared to croscarmellose.

In addition, in the case of a tablet weighing more than 1 g, a hardness of 10 kp or more is required to perform the film coating process. However, when croscarmellose is used as a disintegrant, the hardness is low, resulting in low productivity.

On the other hand, lactose hydrate is advantageous in increasing the hardness of the tablet, and even if the same amount of lactose hydrate is used, it is possible to achieve high disintegration and tablet hardness at the same time by using an appropriate amount in the granulation and post-mixing process.

Example 12 was the most advantageous in terms of hardness, but there were problems in that the disintegration time was slightly longer and the tablet size was slightly larger due to the large amount of the first and second lactose diluents.

Measurement of tablet size

As shown in Figure 1, the comparative example was measured to have a diameter of 17.70 mm and a thickness of 5.65 mm, and Example 1 was measured to have a long axis of 18.30 mm, a short axis of 8.20 mm, and a thickness of 7.05 mm. They are 1390.22 mm3 and 956.19 mm3.

As a result, the tablet of Example is about 68.77% larger than the chewable tablet of Comparative Example and significantly reduced in size by 30% or more compared to the conventional chewable tablet.

In addition, even in the form of the tablet, it was made into a rectangular shape to maximize swallowing.

Claims (12)

A film-coated tablet for treating gastrointestinal diseases containing 5 to 20 mg of famotidine, 100 to 200 mg of magnesium hydroxide, and 600 to 1000 mg of precipitated calcium carbonate as active ingredients for one-time administration,
The active ingredient forms granules with the first lactose diluent and the corn starch binder,
The granules are in the form of post-mixing with an additional second lactose diluent, a low-substituted hydroxypropyl cellulose disintegrant, and a lubricant,
the additional second lactose diluent is granular;
The ratio of the additional second lactose diluent to the first lactose diluent is 0.2 to 0.6 by weight,
A film-coated tablet for treating gastrointestinal diseases, characterized in that the total weight of a single administration of the tablet is 1300 mg or less, and the hardness of the tablet is at least 10 kP or more. delete The film-coated tablet for treating gastrointestinal diseases according to claim 1, wherein the ratio of the total content of the first and second lactose diluents to the content of the active ingredient is 0.1 to 0.2 by weight. delete The film-coated tablet for treating gastrointestinal diseases according to claim 1, wherein the lactose diluent is anhydrous lactose, lactose hydrate, or a combination thereof. delete The film-coated tablet for treating gastrointestinal diseases according to claim 5, wherein the lactose diluent is lactose hydrate. delete delete delete delete delete

Images