KR100798672B1 - Immediate efficacious dry granules and tablets containing nizatidine and preparing method thereof - Google Patents

Abstract

The present invention relates to a dry granule comprising nizatidine, a fast-acting tablet thereof, and a method for preparing the same, and more particularly, to nizati useful as a therapeutic agent for gastric and duodenal ulcers and reflux esophagitis. It relates to a dry granule comprising a dean and oral fast-acting tablets formulated thereof and a method for preparing the same,

According to the present invention, a fast-acting granule having dry granulated nizatidine and gelatinized starch at a weight ratio of 6: 1 to 10: 1, and a fast-acting nizatidine tablet containing the same, and the above granules There is also provided a method for producing fast-acting nizatidine tablets prepared by granulation by roller compacting or crushing by dry granulation, and then making them into fast-acting tablets.

 Nizatidine tablets according to the present invention can significantly increase the disintegration and dissolution rate to increase the bioavailability of the drug and to enable fast-acting expression of pharmacological action, while the manufacturing process is simple and the manufacturing time can be shortened, economical and process efficiency Is also high.

Fast-acting nizatidine tablets

Description

Dry granules containing nizatidine, fast-acting tablets, and preparation method thereof {IMMEDIATE EFFICACIOUS DRY GRANULES AND TABLETS CONTAINING NIZATIDINE AND PREPARING METHOD THEREOF}

FIG. 1 is a graph showing nizatidine dissolution rate according to Axid (registered trademark), which is a fast-acting tablet containing nizatidine and a conventional capsule.

FIG. 2 is a graph showing changes in nizatidine content over time under severe conditions of a fast-acting tablet containing nizatidine and a conventional capsule Axid®. FIG.

The present invention relates to a dry granule comprising nizatidine, a fast-acting tablet thereof, and a method for preparing the same, and more particularly, to nizati useful as a therapeutic agent for gastric and duodenal ulcers and reflux esophagitis. The present invention relates to a dry granule comprising dine, an oral fast-acting tablet formulated therein, and a preparation method thereof.

Nizatidine included in the fast-acting tablet of the present invention is a compound represented by the following Structural Formula 1, wherein the scientific name is N-2-[(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethyl-N'-methyl 2-nitro-1,1-ethenediamine.

[Formula 1]

Nizatidine has a molecular formula of C ₁₂ H ₂₁ N ₅ O ₂ S ₂ and has a molecular weight of 331.45. Light yellow powder, hardly soluble in benzene or octanol (0.5 mg / ml or less), slightly soluble in isopropanol (3.5-5.0 mg / ml), relatively well soluble in water or buffer (10-33.3 mg / ml) Soluble in chloroform and methanol (50mg / ml or more). In addition, pharmacologically, it is known to be useful for the treatment of gastric ulcer, duodenal ulcer and reflux esophagitis by competitively and reversibly inhibiting the binding of histamine to histamine H ₂ -receptor of gastric acid secreting cells.

Nizatidine is conventionally marketed as a capsule of 150 mg and 300 mg units. However, in the case of such a conventional capsule, the disintegration and dissolution rate in accordance with its characteristics depends on the degree of dissolution of the gelatin constituting the capsule, the disintegration and the effect of external environmental factors such as moisture or temperature during storage The dissolution rate may be further delayed or the pattern may be changed. In addition, in the case of capsules, the water content of gelatin itself is about 13%, and nizatidine, which is a main drug, has moisture-sensitive properties, and thus there is a problem such as deterioration of long-term stability of the preparation.

In contrast, tablets have a relatively low production cost among oral preparations, are simple and easy to scale up, and are more chemical and mechanical than other solid preparations such as capsules. And, the microbial stability is excellent, the content of the main medicine in the solid formulation is the most constant, easy to take and carry, as well as the oxidation, taste, smell of the main drug which is a disadvantage of uncoated tablets by treatment such as surface coating The back can be effectively concealed and various modifications of the appearance are possible. In addition, unlike the release of the contents at the time of melting the gelatin capsules, the capsule has the advantage of controlling the release rate and the dissolution pattern according to the change of the composition or the tableting method.

However, since it has been known that the tablet of nizatidine has a significant problem in fastness compared to a capsule, there has been little attempt to develop a nizatidine tablet having excellent fastness.

The present inventors mixed the nizatidine compound with gelatinized starch at a specific ratio to prepare a composition of dry granules using roller compacting or smashing in the disintegration and dissolution pattern of nizatidine. As a result of discovering the unexpected and surprising effect, based on this, the result has been to develop the fast-acting nizatidine tablet of the present invention.

Accordingly, the first object of the present invention is to increase the bioavailability of nizatidine by dramatically increasing the dissolution rate, which is the rate step in the disintegration and absorption of nizatidine, an effective therapeutic agent such as gastroduodenal ulcer and reflux esophagitis. It is to provide an oral dry granule that allows for the rapid expression of pharmacological action.

The second object of the present invention is to provide a fast-acting nizatidine tablet containing the dry granules according to the first object, which maximizes the advantages of the tablet formulation and at the same time improves the productivity and dramatically increases the dissolution rate. It is.

A third object of the present invention is to provide a method for preparing fast-acting dry granules and tablets according to the first and second objects described above.

Hereinafter, the present invention will be described in more detail.

The nizatidine dry granules according to the invention comprise gelatinized starch and can have a much greater influence on the disintegration and dissolution rate of nizatidine tablets than any other conventionally pharmaceutically acceptable excipients, in particular After the dry granules are prepared by using a specific ratio of jatidine and gelatinized starch, when the tablets are prepared using the same, the disintegration rate and dissolution pattern are excellent.

The ratio of nizatidine to pharmaceutically acceptable gelatinized starch is in a weight ratio of ratio ranging from 6: 1 to 10: 1, preferably in ratio of 7: 1 to 8: 1. If the ratio is less than 6: 1, the disintegration and dissolution rate of nizatidine may be remarkably delayed. If the ratio is more than 10: 1, the disintegration rate is increased but the dissolution rate may be lowered. It is also undesirable. The mixture in which the ratio of nizatidine and gelatinized starch is mixed at the above-mentioned specific ratio is prepared in the form of granules by compacting or crushing using a roller compactor by dry granulation, followed by disintegration and dissolution. The granules with increased speed are formulated in conventional tablet forms.

The fast-acting nizatidine dry granules and tablets according to the present invention have a simple manufacturing process, shorten the manufacturing time, and are economically industrially, and the disintegration and dissolution rate are dramatically increased, thereby increasing the bioavailability of the nizatidine and pharmacological action. Fast-acting expression of is possible.

In general, in the manufacture of tablets, all additives other than the pharmaceutical agent are collectively referred to as additives or excipients, and in more detail, they may be divided into excipients, binders, disintegrants, lubricants and the like.

Among them, excipients are selected in consideration of tablet experience, cost, compatibility with prescription ingredients, etc., and are usually used for the purpose of giving a constant volume to tablets and improving tabletability. Examples of suitable excipients include lactose, raolin, mannitol, starch, powdered white sugar, calcium phosphate, microcrystalline cellulose, colloidal silica, and the like, and other types of additives may be used as excipients. It also plays a role. Particularly preferred excipients include colloidal silica capable of improving the flowability of the powder and the compression moldability due to the peculiar small particles and the large surface area. In the present invention, at least one of the aforementioned excipients can be used in an amount of 1 to 5% by weight.

In addition to improving adhesion between the granules, the binder acts to maintain the shape of the tablet after being compressed. The amount of the binder is determined according to the experience of the person to be added, the nature of the other ingredients, etc. If the amount is too small, the binding capacity is insufficient, if too large it will become too hard to slow down the disintegration and dissolution rate of the tablet. Referring to the type and amount of preferred binder, 10 to 20% by weight corn starch suspension, 25 to 50% by weight glucose solution, maltose, natural gum (arabian gum), cellulose derivatives (methylcellulose, carboxymethyl Cellulose, microcrystalline cellulose), gelatin, povidone, and the like, and the most preferred binder is microcrystalline cellulose. In the present invention, at least one of the above binders may be used in a proportion of 10-30%, preferably 20-30% by weight, and most preferably 23% by weight, based on the total tablet content.

Glidants have effects such as improved flow from the hopper to the die, prevention of sticking to punches or dies, reduced resistance when taking tablets out of the tablet press, glossing of the tablets, and the like. Examples of preferred lubricants include talc, magnesium stearate, stearic acid, calcium stearate, fumed silicon dioxide, and the like. Particularly preferred glidants are magnesium stearate, which is most suitable. If the amount of the glidant is too high, the disintegration and dissolution of the tablets are delayed. In the present invention, at least one of the glidants is 0.1 to 5 based on the total tablet content. It is preferable to use it in the ratio of weight%.

Disintegrants swell when in contact with water and disrupt the tablets in the gastrointestinal tract. Examples of preferred disintegrants include starch derivatives (corn starch, potato starch, sodium starch glycolate, croscarmellose), cellulose derivatives (carboxy) Sodium methyl cellulose, polyvinylpyrrolidone), crospovidone, cation exchange resins, and the like. Particularly preferred disintegrants include sodium starch glyconate, which rapidly absorbs water and swells. In the present invention, it is preferable to use at least one of the above-mentioned disintegrants in a weight ratio of 2 to 8% based on the total tablet content.

Particularly important excipients in the nizatidine dry granules and tablets of the present invention are microcrystalline cellulose and gelatinized starch.

Microcrystalline cellulose is a pharmaceutically widely used excipient and is commonly used as a binder or excipient in tablets and capsules. However, depending on the content, it also shows the ability of a lubricant or disintegrant, and in general, when used as a binder or excipient in tablets, the amount of addition is 20 to 90% by weight, and when used as a disintegrant, 5 Although it is a ratio of -15 weight%, and when used as a lubricant, it is used in the quantity of 5-20 weight%, but this addition amount is not absolute and is combined suitably in consideration of mutual relationship with other excipients, etc. Additions for the purpose of binders may in some cases act as disintegrants by interaction with other excipients and vice versa.

Therefore, the present invention considers the interrelationship with other excipients, in particular gelatinized starch, and shows the optimal result at a content of about 23% by weight, which can be faithfully exhibited as a fast-acting tablet, and the possible amount of use is limited. Although not necessarily, as mentioned above, it is the range of 10-30 weight%, Preferably it is the range of about 20-30 weight%.

In addition, gelatinized starch is derived from starch, and is used as a binder or excipient in oral capsules and tablets for the purpose of further improving the fluidity of the powder and increasing the tableting capacity compared to starch. As described above, about 1 to 11% by weight is used.

In addition, magnesium stearate of a certain amount or more has been reported to increase the strength of the tablet when used in combination with gelatinized starch, and to lower the dissolution, and is not generally used in combination. However, in the present invention, when used in combination at a specific ratio, it has been found to increase disintegration or dissolution rate, and when granulated by dry granulation within a specific ratio of main medicine and gelatinized starch, gelatinized starch is used as a disintegrant. Acting results in a noticeable increase in disintegration and dissolution rate.

Therefore, the nizatidine tablet in the present invention contains 50 to 70% by weight of nizatidine-gelatinized starch dry granules and 15 to 30% by weight of microcrystalline cellulose, and 1 to 11 weight of gelatinized starch as other optional ingredients. %, 2 to 8% by weight of disintegrant such as sodium starch glycolate, 1 to 5% by weight of excipient such as colloidal silica, and 0.1 to 5% by weight of lubricant such as magnesium stearate.

The content of nizatidine in the nizatidine tablet according to the present invention may be preferably formulated, for example, 150 mg or 300 mg, but this is not limitative and optional for the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, which are intended to illustrate the present invention but do not limit the present invention.                     

(Example)

Example 1 and Comparative Examples 1-3: Preparation of dry granules of nizatidine-gelatinized starch

First, nizatidine and gelatinized starch were high speed at a weight ratio of 15: 1 (Comparative Example 1), 7.5: 1 (Example 1), 5: 1 (Comparative Example 2), and 3.75: 1 (Comparative Example 3). Mix homogeneously using a mixer. Subsequently, the mixture was prepared into granules using a roller compactor by dry granulation. The granules were pulverized and then apples were sieved in a 25mesh sieve to prepare the final nizatidine-gelatinized starch dry granules, which were compared with Comparative Example 1 (weight ratio 15: 1) and Example 1 (weight ratio 7.5: 1), respectively. It was set as Example 2 (weight ratio 5: 1), and the comparative example 3 (weight ratio 3.75: 1).

Example 2 and Comparative Examples 4-6: Preparation of uncoated tablet

To nizatidine-gelatinized starch dry granules prepared in Examples 1 and 3, microcrystalline cellulose, gelatinized starch, sodium starch glyconate, colloidal silica, and magnesium stearate as lubricants After mixing to the following weight was compressed into tablets to prepare a uncoated tablet, these were set as Example 2 and Comparative Examples 4-6, respectively.

Tablet formulation example

Nizatidine-gelatinized starch dry                     

         871.3 g of granules (Examples 1 and 3)

Microcrystalline cellulose 358.8 g

102.5 g of gelatinized starch

102.5 g of starch sodium glyconate

51.3g colloidal silica

Magnesium Stearate 51.3g

Example 3 and Comparative Examples 7-9: Preparation of film-coated tablets

On the surface of the uncoated tablets prepared in Examples 2 and Comparative Examples 4 to 6, hydroxypropylmethylcellulose as a film coating agent, titanium oxide as a light shielding agent, propylethylene glycol 6000 as a plasticizer and iron sulfate as a coloring agent were used at the following weights. Coated tablets were prepared, and were shown in Example 3 and Comparative Examples 7 to 9, respectively. The thickness of the film coating layer was 100 micrometers.

-Film coating layer formulation example-

Hydroxypropyl Methyl Cellulose 61.5g

Titanium oxide 7.7g

Propylethylene glycol 6000 10.2 g

1 g of iron sulfate

Test Example 1: Measurement of Disintegration Rate

Uncoated tablets prepared in Examples 2 and Comparative Examples 4-6, film-coated tablets prepared in Examples 3 and 7 and 9, and capsules of the same capacity as conventional (Axid (registered trademark), Korean Lily, hereinafter, Disintegration time of 'Axid (abbreviated trademark)' was measured, and the disintegration test was performed according to the disintegration test method of the general test method of the Korean Pharmacopoeia, and water was used as the test solution. The results are shown in Table 1 below, each of which was randomly selected and measured, and then the measured values were averaged. In Table 1, the measured values were arranged in order from small to large for easy contrast.

 Comparison of Disintegration Rates of Nizatidine Uncoated Tablets, Film-Coated Tablets, and Axid®, a Conventional Capsule Uncoated tablet of nizatidine-geratized starch Film coated tablets of nizatidine-geratized starch Capsule Axid (registered trademark) Comparative Example 4 Example 2 Comparative Example 5 Comparative Example 6 Comparative Example 7 Example 3 Comparative Example 8 Comparative Example 9 Comparative Example 10 3 minutes 53 seconds 4 minutes 11 seconds 4 minutes 19 seconds 5 minutes 43 seconds 6 minutes 56 seconds 7 minutes 02 seconds 30 seconds 45 seconds 55 seconds 1 minute 05 seconds 1 minute 13 seconds 1 minute 20 seconds 18 minutes 34 seconds 18 minutes 43 seconds 20 minutes 13 seconds 20 minutes 25 seconds 20 minutes 52 seconds 21 minutes 41 seconds 18 minute 38 seconds 19 minute 41 seconds 20 minutes 56 seconds 21 minutes 28 seconds 22 minutes 18 seconds 23 minutes 24 seconds 9 minutes 12 seconds 10 minutes 18 seconds 10 minutes 36 seconds 12 minutes 25 seconds 13 minutes 38 seconds 15 minutes 13 seconds 2 minutes 24 seconds 2 minutes 37 seconds 2 minutes 55 seconds 3 minutes 15 seconds 3 minutes 38 seconds 4 minutes 02 seconds 23 min 37 sec 23 min 52 sec 24 min 48 sec 26 min 07 sec 26 min 19 sec 26 min 56 sec 24 min 21 sec 25 min 34 sec 26 min 13 sec 28 min 35 sec 28 min 42 sec 29 min 15 sec 10 minutes 52 seconds 12 minutes 41 seconds 13 minutes 17 seconds 15 minutes 07 seconds 15 minutes 25 seconds 17 minutes 13 seconds Average 5 minutes 21 seconds 58 seconds on average Average 20 minutes 05 seconds Average 21 minute 04 seconds Average 11 minute, 54 seconds Average 3 minutes 09 seconds Average 25 minute 07 seconds Average 27 minute 07 seconds Average 14 minutes 10 seconds

As can be seen from Table 1 above, the uncoated tablet of Example 2 and the coated tablet of Example 3 prepared by dry granulating nizatidine and gelatinized starch at a weight ratio of 7.5: 1 to a remarkable degree compared to the formulation of other formulations It shows an amazing disintegration rate.

Test Example 2: Dissolution Rate Measurement

The dissolution test was performed for the coated tablets prepared in Example 3, Comparative Examples 7-9, and Axid (registered trademark), which is a conventional capsuling agent. The dissolution test was carried out using the dissolution test method and the second method (paddle method) of the general test method of the Korean Pharmacopoeia, water was used as the eluent, and maintained at 37 ℃, 5, 10, After 15, 30, 45, and 60 minutes, 1 ml of the sample was collected and filtered, and the filtrate was analyzed using high performance liquid chromatography (HPLC). The results are shown in Table 2 below, and the results are graphed in FIG. 1. Marked as.

Comparison of Dissolution Rate of Film Coated Tablets and Axid (TM) of Nizatidine-Gelatinized Starch Over Time Hour, minute Film coated tablets of nizatidine-gelatinized starch Capsule Axid (registered trademark) Comparative Example 7 Example 3 Comparative Example 8 Comparative Example 9 Comparative Example 10 0 0 0 0 0 0 5 13.7 (± 1.7) ^* 94.9 (± 2.1) 6.4 (± 0.4) 5.1 (± 0.5) 65.2 (± 3.8) 10 58.7 (± 2.1) 95.7 (± 1.9) 10.7 (± 1.9) 9.4 (± 0.9) 83.9 (± 3.9) 15 98.3 (± 0.1) 97.1 (± 2.2) 30.0 (± 9.5) 28.5 (± 7.0) 94.4 (± 2.6) 30 101.9 (± 0.1) 98.8 (± 2.3) 100.9 (± 0.2) 85.9 (± 2.4) 98.6 (± 1.6) 45 103.0 (± 0.4) 98.0 (± 3.1) 100.5 (± 0.4) 98.5 (± 1.4) 98.0 (± 1.9) 60 102.8 (± 0.4) 98.7 (± 3.1) 100.3 (± 0.3) 101.6 (± 0.6) 98.2 (± 0.6)

* Dissolution rate (mean value ± standard deviation,%)

From the above results, it can be seen that the initial dissolution rate of Example 3, which is a coated tablet prepared by dry granulating nizatidine and gelatinized starch at a weight ratio of 7.5: 1, is significantly higher than the others, and is proportional to the disintegration rate. have.

Test Example 3: Measurement of stability over time under severe conditions

The coated tablets prepared in Example 3 and Axid (registered trademark), a conventional capsule, were evaluated by dissolution rate measurement under severe conditions. The stability test was conducted every two months using a thermo-hygrostat (Cont. Temp. Humidity Chamber, Jeio-Tech, Korea) at 40 ° C and 75% RH (relative humidity), and conducted for six months. . The results are shown in Table 3 below and FIG. 2.

Comparison of Dissolution Rates with Time of Film-Coated Tablets and Capsules of Example 3 (Axid®) Hours, months Coated Tablet of Example 3 Capsule Axid (registered trademark) 0 99.9 (± 0.23) 100.4 (± 0.22) 2 99.2 (± 0.12) 99.8 (± 0.24) 4 98.8 (± 0.13) 98.6 (± 0.18) 6 98.4 (± 0.11) 97.8 (± 0.16)

From the above results, it was confirmed that the film coated tablet prepared in Example 3 was slightly more stable than the capsule (Axid®).

As described above, the nizatidine tablet according to the present invention can dramatically increase the disintegration and dissolution rate, increase the bioavailability of the drug and enable the rapid expression of pharmacological action, and at the same time, the manufacturing process is simple and the manufacturing time can be shortened. Economical and process efficiency is also high.

Claims (6)

A fast-acting granule in which nizatidine and gelatinized starch represented by Structural Formula 1 below are dry granulated at a weight ratio of 6: 1 to 10: 1. [Formula 1]

A fast-acting nizatidine tablet containing the granule according to claim 1. The fast-acting nizatidine tablet according to claim 2, wherein the ratio of nizatidine to gelatinized starch is in the range of 7: 1 to 8: 1 by weight. The fast-acting nizatidine tablet according to claim 2 or 3, comprising 50 to 70% by weight of nizatidine-gelatinized starch dry granules and 15 to 30% by weight of microcrystalline cellulose. The fast-acting nizatidine tablet according to claim 3, further comprising 1-11 wt% of gelatinized starch, 2-8 wt% of disintegrant, 1-5 wt% of excipient, and 0.1-5 wt% of lubricant. In the manufacturing method of the film-coated tablets, nazatidine and gelatinized starch represented by the following Structural Formula 1 are mixed at a weight ratio of 6: 1 to 10: 1, and the roller compacting method or the roller compacting method by dry granulation method Dry granulation step of preparing into a granule using; And a tableting step of making the granules into fast-acting tablets.   [Formula 1]

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