WO2003075919A1

WO2003075919A1 - Tablet containing pilsicainide hydrochloride (dry)

Info

Publication number: WO2003075919A1
Application number: PCT/JP2003/002975
Authority: WO
Inventors: Atsushi Kato
Original assignee: Daiichi Suntory Pharma Co.,Ltd.
Priority date: 2002-03-14
Filing date: 2003-03-13
Publication date: 2003-09-18
Also published as: JPWO2003075919A1; AU2003213338A1; KR20040091135A

Abstract

Tablets containing pilsicainide hydrochloride that are orally administered pharmaceuticals superior to injections from the viewpoint of deep regard to direction for use and dosage and ensuring of compliance and that not only ensure easier administration than in the use of capsules but also exhibit desirable tablet hardness and rapid disintegration. In particular, there are provided a process for producing pilsicainide-hydrochloride-containing tablets characterized by containing pilsicainide hydrochloride in a proportion of 5 to 99.5 wt.%, being formed by either effecting compression molding of granules obtained by a dry granulation technique or directly performing compression molding of a powder mixture, having a tablet hardness of 2.5 kg or more free from aging drop, and exhibiting rapid disintegration property; and tablets containing pilsicainide hydrochloride, produced by the process.

Description

Pildicainide hydrochloride-containing tablets (dry)

TECHNICAL FIELD The present invention relates to a preparation containing pillgicide hydrochloride which is a therapeutic agent for arrhythmia. Specifically, it has a desired tablet hardness, suppresses a decrease in tablet hardness over time, disintegrates quickly after oral administration, and exhibits an effect. The present invention relates to a tablet containing pilsicainide hydrochloride which has a short time, is easy to handle, and is easy to take. Background art

Pildicainide hydrochloride [JAN; INN: Chemical name: N— (2,6-dimethylphenyl) -18-pyrrolidinyl acetamide hydrochloride 1/2 hydrate] is the basic part of lidocaine. Is an 8-substituted pyrrolitidine derivative in which is substituted with a more basic pyrrolitidine skeleton, and is a compound having a strong antiarrhythmic action and a medicinal effect such as a local anesthetic action (Japanese Patent Publication No. 4 246 956) . Pildicainide hydrochloride is being developed as a therapeutic agent for arrhythmias. Injectables (brand name: Sunrhythm ® Capsule) and capsules (brand name: Sunrhythm ® Capsule 25 mg; Brand name: Sunrhythm ® Capsule) 50 mg) is already on the market.

By the way, when arrhythmia, which is a disease of the circulatory system, develops, its treatment is extremely urgent. Therefore, when designing pharmaceuticals for therapeutic agents in this field, it is necessary to focus particularly on rapid onset of drug efficacy. Pildicainide hydrochloride is also a formulation that takes into account rapid onset of drug efficacy. However, injections are administered directly into the blood, so that the time to onset of action is short, but they are painful at the time of administration, making them unsuitable for continuous administration.

On the other hand, capsules are easier to administer than injections, and adhere to dosages.

> Excellent in securing or portability. But arrhythmia treatment Considering the field of drug efficacy, it is necessary to be aware of the more rapid onset of drug efficacy when designing capsules. In addition, since the main site of absorption of pilsicainide hydrochloride in the gastrointestinal tract is in the upper small intestine, capsules filled with mere non-granulated mixed powder have been developed with a view to rapid disintegration in the stomach. Was. In addition to the design philosophy described above, due to the high dissolution rate caused by the high solubility of pilgicide hydrochloride (0.89 g Zml, 20 ° C, purified water), the capsules of pilgicide hydrochloride have a rapid The onset of drug efficacy has been achieved.

However, in general, capsules may be difficult to take due to sticking to the larynx or esophagus after swallowing, and patients, especially those with reduced swallowing power, or young children or the elderly, tend to be shunned. is there. Another problem is that the manufacturing cost of the capsule itself is relatively high.

On the other hand, there is a tablet as a dosage form that is extremely excellent in handleability. It has the same ease of handling as capsules, is easier to take than capsules, and has the advantage of lower manufacturing costs than capsules. However, with regard to the formulation of pilsicainide hydrochloride, dosage forms other than injections and capsules, especially tableting, have not yet been sufficiently studied.

In particular, as a condition required for a tablet containing pilsicainide hydrochloride, it is necessary to maintain a desired tablet hardness, but it must satisfy fast disintegration for obtaining a rapid effect after taking the tablet. It is difficult to formulate tablets with the contradictory properties of securing hardness and ensuring quick disintegration, and at present, no active studies have been made so far.

Therefore, in view of the above-mentioned circumstances, the present invention is an oral preparation superior to an injection in terms of compliance with dosage and ensuring compliance, is easier to take than a forcepsel, and has a desired tablet hardness and An object of the present invention is to provide a tablet containing pilsicainide hydrochloride having rapid disintegration.

By the way, some tablets are used to prevent chipping and cracking of tablets during the packaging process and transportation, or to withstand the coating process that is performed as necessary. Strength (tablet hardness) is required. Generally, in order to ensure tablet strength, it is performed by compounding a binder into the compounding formulation. However, although the addition of a binder is effective in ensuring tablet strength, on the other hand, the disintegration of the tablet is reduced, and the dissolution (release) of the active ingredient from the preparation is delayed.

In particular, the tablet targeted by the present invention is required to have rapid disintegration of the tablet because it is a therapeutic agent for arrhythmia containing pilsicainide hydrochloride as an active ingredient. For this purpose, a disintegrant may be added, but the addition of a disintegrant tends to gradually decrease the hardness of the tablet during storage.

Accordingly, the present inventor relates to the production of tablets of pilzikaied hydrochloride, even if a disintegrant is used, while having the desired tablet hardness, the tablet hardness does not decrease over time during storage, and disintegration We conducted intensive research with an emphasis on developing technologies that could develop good tablets.

Many disintegrants used to impart tablet disintegration have hygroscopicity. For tablets containing many of these, it is generally difficult to ensure the physical and chemical stability of tablets during the manufacturing process and during storage. On the other hand, in the tablet of the present invention intended for quick disintegration, it is necessary that the amount and type of disintegrant to be added can be selected widely. Therefore, the present inventor selected a production method in which contact with water was avoided as much as possible, and studied a production technique capable of reducing the binder in the production method.

As a result, the present inventor surprisingly found that, when tablets were formed without going through a formulation step of contacting water with pilsicainide hydrochloride, 5% or more, preferably 10%, of the main drug, pilsicainide hydrochloride, was obtained. It has been found that by blending at least 30%, the strength of the tablet after compression molding can be ensured, and a decrease in tablet hardness over time can be suppressed.

Furthermore, when the tablet is formed without going through a formulation step of contacting with water, an additive that tends to decrease the tablet hardness during storage, such as a disintegrant added to obtain a desired disintegration property, is used. However, they have found that they can be freely added irrespective of their type and amount, and have completed the present invention. Disclosure of the invention

The present invention provides (1) compression-molding of granules obtained by dry granulation containing 5 to 99.5% by weight of pilsicainide hydrochloride as a main drug or direct compression-molding of a mixed powder. 2. It is not less than 5 kg, its decline over time is suppressed, and it has rapid crushing properties. (2) The method for producing a tablet containing pirudikaidide hydrochloride according to the above (1), which contains 10 to 95% by weight of pilsicainide hydrochloride; (3) The pirjikai hydrochloride according to the above (1), to which a bitterness suppressing substance is added. The method for producing a tablet containing nide, (4) the method for producing a tablet containing pilsicainide hydrochloride according to the above item 3, wherein the amount of the bitter suppressing substance added is 1 to 80% by weight, and (5) the bitter taste suppressing substance is sucrose or glucose. The hydrochloric acid according to the above 4, which is any of lactose, lactose, D-mannitol, aspartame, xylitol, sodium bicarbonate, magnesium carbonate, sodium carbonate, ascorbic acid, sodium chloride, starch, partially alpha starch and crystalline cellulose. A method for producing a pillgicide-containing tablet, (6) further containing a pilgicide hydrochloride according to 1 above, which coats a coating layer. (7) the method for producing a tablet containing pilsicainide hydrochloride according to the above (6), wherein the coating layer is a film that dissolves or disintegrates in the stomach; (8) the active drug content per tablet is 12.5 mg, 25 mg or 8. The method for producing a tablet containing pilsidide hydrochloride according to the above 1 to 7, which is 50 mg.

Further, the present invention provides (9) a tablet containing pilsicainide hydrochloride obtained by the production method described in 1 above, (10) a tablet containing pilsicainide hydrochloride obtained by the production method described in any of 2 to 8 above, 11) The tablet containing pilsicainide hydrochloride according to 9 or 10 above, which is a tablet disintegrating in the stomach. More specifically, (12) 20 to 80% by weight of pilsicainide hydrochloride as the main drug, crystalline cellulose and The mixture containing the starch and the disintegrant is directly compression-molded into uncoated tablets, or the granulated product obtained by dry granulation is compression-molded to form a tablet. A tablet, and 100 parts of the uncoated tablet is coated with 2 to 4 parts of a gastrosoluble film based on hydroxypropylmethylcellulose. The present invention relates to a method for producing a rapidly disintegrating tablet containing pilsicaidide hydrochloride, and (13) a tablet containing pilsicaidide hydrochloride obtained by the method described in the above (12). BEST MODE FOR CARRYING OUT THE INVENTION

The tablets containing pilsidide hydrochloride provided by the present invention are basically characterized in that they are tablets obtained without going through a formulation step of bringing them into contact with water.

By the way, tablet manufacturing methods include: 1) wet granulation compression method in which granulated granules obtained by wet granulation method are compressed and molded; 2) dry granulation compression method in which granulated granules obtained by dry granulation method are compression molded. , And ③ It is roughly divided into the direct powder compression method of directly compressing and molding the mixed powder. Among them, the dry granule compression method or the direct powder compression method, which has no manufacturing process that comes in contact with water, is used when the drug to be contained is unstable to water or when additives that absorb moisture are used. This is an effective method for producing a disintegrant.

In the present invention, an additive such as a disintegrating agent having hygroscopicity can be freely selected, and a dry granule compression method or a direct powder compression method, which has no production step of contacting with water, is suitably used.

In the tablet provided by the present invention, pilsidide hydrochloride contained as an active ingredient is an antiarrhythmic drug described in Japanese Patent Publication No. Hei 4-46969. According to the tablet provided by the present invention, which contains such a pilgikaied hydrochloride as an active ingredient, the desired tablet hardness depends on the diameter and shape of the tablet, but is easy to handle in a coating step and a packaging step. It should have a hardness of not less than 2.5 kg, more preferably not less than 3 kg. In addition, in order to prevent cracking and chipping during transportation or when taking out of the package before taking it, it is necessary to maintain favorable hardness even after storage. In order to obtain a tablet having such a desired tablet hardness, it is preferable that the compounding ratio of pilsicainide hydrochloride, which is an active ingredient, be 5 to 99.5% by weight. Among them, in the case where a disintegrating agent and the like are blended, it is within the range of 10 to 90% by weight in consideration of suppressing the time-dependent decrease in tablet hardness during storage. desirable. On the other hand, the particle size of the active ingredient, pilsicainide hydrochloride, is not particularly limited, as long as it does not affect the uniformity of the content of the preparation. If necessary, the particle size of pilsicainide hydrochloride can be controlled by adding a pulverizing step or a sizing step. It depends on the tablet manufacturing method and the blending ratio of pilsicainide hydrochloride.For example, when manufacturing tablets by the direct powder compression method, take into account the securing of uniformity of the content in the powder mixture for tableting, and consider the use of pilsicainide hydrochloride. Preferably, the particle size is 50% or more in the range of 75 to 50 O ^ m.

The shape of the tablet provided by the present invention and containing pilsicainide hydrochloride as an active ingredient is not particularly limited, and may be any of a round flat tablet, a round face tablet, and a shaped tablet. In addition, the size of the tablet is not particularly limited, and considering the ease of taking and handling, the diameter of a round tablet is preferably about 5 to 14 mm. It is desirable that the size is about 6 to 1 O mm, which is easy for even the elderly to take.

The weight of the tablet depends on the content of the active ingredient, pilsicainide hydrochloride, and the shape of the tablet.In consideration of ease of administration and ease of handling, for example, the tablet weight is 50 to 50%. Omg is preferred, and especially about 70 to 20 Omg, which is easy for elderly people to take.

According to the present invention, a tablet having an appropriate tablet hardness, having a rapid disintegration property, and excellent in releasing the active ingredient is provided. Various additives can be appropriately selected and blended to ensure the required stability and absorbency or to improve the production process.

Such additives include (1) excipients such as lactose, starch, partially alpha starch, crystalline cellulose, D-mannitol, glucose, calcium carbonate and phosphoric acid, (2) hydroxypropyl cellulose, Binders such as starch, polyvinylpyrrolidone, carboxymethylcellulose, crystalline cellulose, and (3) lubricants such as magnesium stearate, sucrose fatty acid ester, talc, and hydrous silicon dioxide. Also, if necessary, stabilizers, flavoring Agents, coloring agents and the like. The types and mixing ratios of these additives can be appropriately selected and set in consideration of the properties required for the tablets provided by the present invention.

In the tablet containing the active ingredient pilsicainide hydrochloride provided by the present invention, a disintegrant may be added in order to ensure the desired tablet hardness and rapid disintegration. The addition of a disintegrant tends to cause the tablet hardness to decrease over time during storage of the tablet.However, in the case of the tablet containing pilsicainide hydrochloride obtained by the production method of the present invention, the tablet at the time of such storage is used. One feature is that the decrease in hardness over time is suppressed. Therefore, when a disintegrating agent is blended, the amount of the disintegrating agent is appropriately selected within a range in which the tablet hardness during storage does not decrease over time. The disintegrant referred to in the present invention refers to all additives that improve the disintegration of tablets, in addition to additives classified as disintegrants in the official regulations and the like.

Examples of such disintegrants include starch, partially alpha starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, carmellose calcium, carboxymethyl starch sodium, and the like.

The mixing ratio of the disintegrant within a range that does not cause a decrease in tablet hardness during storage over time and does not impair good disintegration varies depending on the shape, size, manufacturing method, and composition of other components of the tablet. For example, it is about 0.1 to 80% by weight.

The tablets provided by the present invention are prepared without going through the step of bringing the active ingredient, pilsicainide hydrochloride, into contact with water in the tablet manufacturing process, thereby ensuring the physical and chemical stability of the active ingredient In addition, it was found that rapid disintegration and hardness of the tablet were ensured, and that the tablet hardness during storage was prevented from decreasing over time. Therefore, the tablet manufacturing method provided by the present invention includes a dry granulation compression method of compression-molding granules obtained by a dry granulation method such as a crushing granulation method, and a direct compression molding of a mixed powder directly. It is preferable to produce by a powder compression method.

In addition, the ingredients obtained by excluding the active ingredient pilsicainide hydrochloride are obtained by wet granulation. It can also be produced by a semi-dry granule compression method, in which pilsicainide hydrochloride is mixed with the obtained granules and compression-molded.

After mixing a lubricant with the granulated granules or mixed powder obtained by the dry granulation method, the mixture is subjected to compression molding using a rotary tableting machine or the like to obtain the tablet of the present invention. . The tableting pressure can be set as appropriate within a range that does not impair the rapid collapse. Although it depends on the size and weight of the tablet, it is preferably in the range of 500 kgf to 300 kgf, for example, in consideration of the influence on the chemical stability of the active ingredient and the ease of production. The obtained tablets may be further provided with a coating film as needed.

In the tablets provided by the present invention, the active ingredient, pilsidide hydrochloride, is characterized in that it has a bitter taste and a local anesthetic action. It is also necessary to improve such unpleasant bitterness.

Therefore, in the tablet provided by the present invention, measures such as adding a bitter taste modifying additive or applying a film can be taken to suppress bitterness in the oral cavity. In addition, if it is necessary to suppress irritation or local anesthetic action in the oral cavity and esophagus due to the local anesthetic action of pilsicainide hydrochloride, it is necessary to apply a film to the tablet.

When a film is applied to the tablet of the present invention for the purpose of suppressing bitterness in the oral cavity or suppressing local anesthetic action, the amount of the film is such that the bitterness in the oral cavity can be suppressed and the amount in the stomach can be reduced. It can be set appropriately within a range that does not impair the rapid disintegration of the tablet.

Examples of the type of film include a water-soluble film using a water-soluble base such as hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC), Eudragit® E (aminoalkyl methacrylate copolymer E), and AEA ( It is desirable to use a film using a gastrosoluble coating base such as polyvinyl acetal (ethyl acetylaminoacetate), or a film that dissolves in the stomach such as sugar coating. In addition, hydroxypropyl methylcellulose acetate succinate (HPMCAS) Hydragit ®-enteric coating using L, LD, S (methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S), etc., ethylcellulose or Eudragit @ I RS (aminoalkylmethacrylic) (Rate copolymer (RS)) can also be used as a coating component for the tablet of the present invention as long as the composition or amount can dissolve or disintegrate in the stomach to release the drug. it can.

Among them, hydroxypropyl methylcellulose (HPMC), which has the characteristics of being able to suppress bitterness with a small amount of film, being water-soluble, being easy to prepare film liquid, and having a short coating process time. It is particularly preferable to coat about 2 to 4 parts of a base film of the present invention with 100 parts of the uncoated tablet of the present invention. The coating method for forming a film on the tablet is not particularly limited, and it can be performed using a usual coating machine.

Further, for the purpose of suppressing bitterness in the oral cavity, a bitterness-suppressing additive can be incorporated into the tablet composition. Examples of such bitterness-suppressing additives include sweeteners and sweeteners such as sucrose, glucose, lactose, D-mannitol, aspartame and xylitol; sodium hydrogencarbonate, magnesium carbonate, sodium carbonate, ascorbic acid, sodium chloride, etc. Buffers or pH regulators; and excipients that can alleviate bitterness, such as lactose, starch, partially alpha starch, crystalline cellulose, D-mannitol, and glucose. The proportion of these additions depends on the proportion of the active ingredient, pilsicainide hydrochloride, but is preferably about 1 to 80% by weight in view of the effect of suppressing bitterness.

Among them, corn starch, which has an excellent bitterness-suppressing action and an improvement in disintegration and is effective in securing the strength of tablet edges; and a good moldability in addition to good bitterness-inhibiting action, impairs disintegration Crystalline cellulose, which has the characteristic of not being present, is particularly preferred. The proportion of corn starch ゃ microcrystalline cellulose depends on the proportion of the active ingredient, pilsicainide hydrochloride, and the type and amount of other ingredients, but considering the bitterness-suppressing effect and the tablet disintegration and friability, Also 10 to 60 It is desirable to add about%.

In the tablet provided by the present invention, the content of the active ingredient, pilsicainide hydrochloride, can be variously changed depending on the daily effective dose as a therapeutic agent for arrhythmia and the number of times of administration. However, in view of the fact that the currently marketed pilsicainide hydrochloride capsules are capsules containing 25 mg or 5 O mg, and that there is a need for a low-content formulation, the tablets provided by the present invention provide pirgicide hydrochloride in the tablets provided by the present invention. The content of indide is preferably 12.5 mg, 25 mg or 5 O mg. Therefore, based on such a content of pilsicainide hydrochloride, the above-described specific structure of the present invention may be appropriately combined. Thus, a tablet containing pilsicaide hydrochloride which is effective for the actual treatment of arrhythmia will be provided. Example

Hereinafter, the present invention will be described more specifically by various tableting studies instead of the examples. However, these examples do not limit the scope of the present invention. In the following description, “parts” and “%” indicate “parts by weight” and “% by weight”, respectively, unless otherwise specified. Test example 1: Tests with various formulations of pilsicainide hydrochloride (Part 1)

The effect of the blending ratio of pilsicainide hydrochloride contained in the tablets on the change over time in tablet hardness was examined.

According to the formulation shown in Table 1 below, a composition containing various ratios of pyridicanide hydrochloride (hereinafter, also referred to as “compound 1”) in various proportions was compression-molded by a direct powder compression method to obtain tablets. . The charge amount was 10 g, and an autograph (manufactured by Shimadzu Corporation) was used as a tableting machine. The tableting conditions were as follows: tablet weight was 10 Omg, tablet diameter was 6.0 Omm, curved surface diameter was 8.0 mm, and tableting pressure was 100 kgf.

The tablet hardness and disintegration of the obtained eight types of tablets (samples 1 to 8) were evaluated. Hardness was measured using a tablet hardness tester (Schleuniger). Disintegrating For evaluation, the disintegration time was measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd., 30 times in the vertical direction, amplitude 55 mm, purified water 900 mL, 37 ° C).

In addition, these tablets were stored in a glass bottle (opened) under the conditions of 25 ° C. and 60% RH for 2 weeks, and the tablet hardness of the stored tablets was measured in the same manner.

These results are summarized in Table 1. Sample number 1 2 3 4 5 6 7 8 Ingredient ratio of active drug (%) 0.0 3.0 5.0 10.0 30.0 50.0 70.0 99.5 Component name Amount per tablet (mg)

Drug compound 1 0.0 3.0 5.0 10.0 30.0 50.0 70.0 99.5 Excipient Lactose 70.0 67.0 65.0 60.0 40.0 20.0 0.0 0.0 Binder Crystal cell mouth 29.5 29.5 29.5 29.5 29.5 29.5 29.5 0.0 Lubricant Magnesium stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Disintegration time (min) 3.0 3.1 3.8 3.6 3.6 4.4 4.0 2.9 Tablet hardness Before storage 6.9 7.2 6.7 6.6 5.2 5.8 4.8 3.7

(kg) After storage 2.4 2.6 3.8 4.6 4.2 4.9 4.0 3.6 Difference in hardness 4.5 4.6 2.9 2.0 1.0 0.9 0.8 0.1 Evaluation of bitterness * (Test Example 6) 〇〇 Δ X X X X X

*: Time until bitterness is felt; X within 10 seconds, △ 10 'to 30 seconds., 〇30 seconds or more As can be seen from the results in the table, the disintegration time of tablets of each sample 1 to 8 is all

2. It was in the range of 9 to 4.4 minutes, showing good disintegration.

Regarding tablet hardness, tablets (Samples 1 and 2) containing 3% or less of compound: 1 had good tablet hardness of 6.9 to 7.2 kg before storage, but stored. After that, the tablet hardness was greatly reduced to 2.4 to 2.6 kg. In other words, the difference in tablet hardness between before and after storage was as large as 4.5 to 4.6 kg, indicating a tendency for the hardness to decrease upon storage.

On the other hand, in the tablets of the present invention (samples 3 to 8), the tablet hardness was both before and after storage. Weighed 3.6 to 6.7 kg, reaching the target value (2.5 kg or more). The difference in tablet hardness between these tablets before and after storage was 2.9 kg or less, and the degree of decrease in hardness due to storage was small compared to Samples 1 and 2. In particular, when the compounding ratio of the main drug, pilsicainide hydrochloride, was 10% or more (samples 4 to 8), the difference in tablet hardness before and after storage was 2.0 kg or less, which was particularly good. From the above results, the tablet of the present invention containing 5% or more of pilsicainide hydrochloride has good disintegration, suppresses a decrease in tablet hardness during storage, and provides sufficient strength after storage. Was confirmed. Test example 2: Tests with various formulations of Piljikaied hydrochloride (Part 2)

The effect of the mixing ratio of pilsicainide hydrochloride contained in the tablets on the change over time in tablet hardness was examined by using a formulation containing a disintegrant.

According to the formulation shown in Table 2 below, tablets containing pilsidide hydrochloride were prepared by a direct powder compression method. Approximately 200 g of mixed powder of various formulations was tableted with a rotary tableting machine. The tablet weight was 100 mg, the tablet diameter was 6.0 mm, the curved surface diameter was 8.0 mm, and the tableting pressure was 1000 kg: f. The storage conditions of the tablets were the same as in Test Example 1, and the disintegration and hardness of each disintegrant before and after storage were measured by the methods described in Test Example 1.

Table 2 summarizes these results.

Sample No. 9 10 11 12 13 Proportion of main drug (%) 0.0 3.0 5.0 10.0 50.0

Ingredient name Combination per tablet Parent t (mg) Drug compound 1 0.0 3.0 5.0 10.0 50.0 Excipient Lactose 50.0 47.0 45.0 40.0 0.0 Binder Crystal cell opening 29.5 29.5 29.5 29.5 29.5 Disintegrant Partially pregelatinized 20.0 20.0 20.0 20.0 Lubricant Magnesium stearate 0.5 0.5 0.5 0.5 0.5

Total 100.0 100.0 100.0 100.0 100.0 Decay time Before storage 1.3 0.9 0.6 1.6 2.9

(Min) After storage 1.2 1.1 0.9 2.5 2.8 Tablet hardness Before storage 8.0 7.9 6.3 6.1 6.2

(kg) After storage 1.9 2.0 3.5 4.1 5.4

Difference in hardness 6.1 5.9 2.8 2.0 0.8 The disintegration of tablets was extremely fast in all samples (samples 9 to 13) before and after storage. The disintegration properties of these tablets were generally better than the tablets containing no disintegrant (Test Example 1; Samples 1 to 8).

Regarding hardness, the difference in tablet hardness before and after storage for tablets with a compounding ratio of Compound 1 of 3% or less (samples 9 and 10) was as large as about 6 kg, and the formulation without disintegrant (Test Example 1, sample The degree of hardness decrease was greater than in cases 1 and 2).

On the other hand, the tablets (samples 11 to 13) of the present invention had sufficient hardness (2.5 kg or more) both before and after storage. Furthermore, the difference in tablet hardness before and after storage was 2.8 kg or less, and the degree of decrease in tablet hardness during storage was small. In particular, when the proportion of the main drug, pilsicainide hydrochloride, was 10% or more (samples 12 and 13), the difference in tablet hardness before and after storage was 2.0 kg or less, which was particularly good.

From the above results, the tablets of the present invention containing 5% or more of pirgicinide hydrochloride, which is an active ingredient, are hygroscopic, such as partially pregelatinized starch, and cause a decrease in hardness after storage. It was found that in formulations containing easy additives, a decrease in tablet hardness after storage was suppressed. That is, when a disintegrating agent is added in order to impart good disintegration, an additive having a hygroscopic property can be selected, so that the present invention was shown to be useful. Test example 3: Examination of the effect of tablet weight and Z size

In tablets containing pircadinide hydrochloride as the active ingredient, tablets are prepared with the same composition and with different tablet weights / sizes, and the hardness of the drug, whether there is a decrease in hardness before and after storage, and disintegration It was investigated.

Tablets of different sizes were prepared using the same composition as Sample 13 used in Test Example 2. Tablets with a tablet weight of 5 Omg / tablet diameter of 5. Omm (Sample 14), tablets with a tablet weight of 10 OmgZ tablets with a tablet diameter of 6. Omm (Sample 15), and tablet weights of 50 Omg / tablet Tablets with a diameter of 11. 1. Omm (sample 16) were prepared at a tableting pressure of 1000 kgf using an autograph. Each of the obtained tablets was evaluated for disintegration and hardness before and after storage. The storage conditions, evaluation items and evaluation method were the same as in Test Example 1.

The results are summarized in Table 3.

Table 3

14 15 a

丄 0

1 ^ ½ ½

Suspicion (mg 50.0 100.0 r n n

oUU. U rod says diameter (band) 5.0 6.0 11. U ) ίί \%) 50.0 50.0 oU. U ingredient per tablet ”

Ogaku Ketai 1 25.0 50.0 o r n

ZoU. U

Α Α 口刘幺 Mushi said ^

Mouth Says Norenoro! ^-14.8 29.5 1 1 A 7

t 0

Divider

II.

R J "

Lubricant 10.0 20.0 i u n unυn Lubricant Magnesium stearate 0.3 0.5 2.5

A trigram

□ Mouth 1 50.0 100.0 500.0 Breakdown time before storage 3.6 2.5 1.0

(Min) After storage 3.8 2.7 1.3 Tablet hardness Before storage 4.6 5.8 5.5

(kg) After storage 4.0 5.0 5.1 Hardness difference 0.6 0.8 0.4 All tested tablets (samples 14 to 16) showed good hardness and rapid crushing. Therefore, it was found that the present invention can provide tablets containing pilsicainide hydrochloride of various weights Z size. Test Example 4: Tests with formulations containing various amounts and types of disintegrants and lubricants

The tablet of the present invention was prepared by variously changing the type and amount of the disintegrant and the type and amount of the lubricant. That is, tablets were prepared by the direct powder compression method according to the formulation shown in Table 4 below. The obtained tablets were evaluated for disintegration and hardness before and after storage, respectively. The storage conditions, evaluation items and evaluation method were the same as in Test Example 1.

The results are summarized in Table 4. Table 4:

Formula B charge number 17 18 19 20 21 22 Proportion of main drug (%) 10.0 10.0 10.0 10.0 10.0 10.0

Component name Amount per tablet (lg)

Active ingredient Compound 1 10.0 10.0 10.0 10.0 10.0 10.0 Excipient Lactose 77.9 59.5 0.0 59.5 59.5 59.5 Binder Crystal cell mouth 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Disintegrant Maize 0.120.0 79.5

Croscarmellose sodium 20.0

Partially pre-gelatinized

Carmellose-calcium

Lubricants Sucrose fatty acid ester 2.0

Magnesium stearate 0.5 0.5 0.5 0.5 0.5 Total 100.0 100.0 100.0 100.0 100.0 100.0 Disintegration time (min) 3.0 2.1 0.9 0.5 1.0 1.5 Tablet hardness Before storage 3.7 3.8 3.6 3.2 5.5 4.0

(kg) After storage 3.0 3.3 3.2 2.9 4.0 3.0

Hardness difference 0.7 0.5 0.4 0.3 1.5 1.0 As can be seen from the results shown in the table, the tablets containing the pilsicainide hydrochloride of the present invention (samples 17 to 22) rapidly disintegrated both before and after storage. And good hardness. Therefore, it was confirmed that by using the production method of the present invention, it is possible to obtain a tablet having a small degree of time-dependent decrease in tablet hardness without being affected by the type of disintegrant or lubricant and the amount thereof added. . That is, it was shown that the present invention is particularly useful when various additives are blended for the purpose of improving the disintegration property and improving the production process.

Test Example 5: Effect of blending ratio of pilsicainide hydrochloride on bitterness

The tablet containing pilsicainide hydrochloride provided by the present invention has bitterness derived from the active ingredient pilsicainide hydrochloride. The effect of the proportion of pill dicainide hydrochloride, the main drug, on the degree of bitterness was evaluated using the tablets (samples 1 to 8) obtained in Test Example 1. Valued.

That is, three healthy panelists included one tablet of each of Samples 1 to 8 in the oral cavity and measured the time until bitterness was felt. Considering the time the tablet stays in the oral cavity when taking the tablet, the time to feel bitterness is less than 10 seconds (X), 10 to 30 seconds (3), 3 Judgment was made in three stages of 0 seconds or more (marked with 〇).

The results are shown in Table 1 above.

As can be seen from the results in the table, the higher the proportion of the active ingredient, pilsicainide hydrochloride, the faster the time until bitterness is felt. Therefore, when the blending ratio of the main drug is high, it may be considered that in the tablet of the present invention, it is necessary to take measures to suppress bitterness in some cases. Test Example 6: Bitter taste suppression test with bitterness suppressing additive

One of the means to suppress bitterness is to add a flavoring agent Z sweetener, a buffering agent, a pH regulator, and a bitterness-reducing excipient and a bitterness-suppressing additive to the formulation. Can be For these substances, the effect of suppressing the bitterness of the tablet of the present invention was examined.

Tablets were prepared using the various formulations shown in Table 5 below, with the blending ratio of the main drug, pilsicainide hydrochloride being 10%. In addition, crystalline cellulose (Seolas) was used as a binder. The method for preparing the tablets was in accordance with the method described in Test Example 1. The evaluation of bitterness was based on the criteria described in Test Example 5.

The results are shown in Table 5. Table 5:

g formula charge number "¾ ■ 9 Q 24 25 26-7 28 υ? Q Ingredient ratio (%) 1U.U 10.0 10.0 10.0 1U.U 1U. U Ingredient name Combination per tablet '垦 (mg)

Drug compound 1 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Binder Crystal cell mouth (Sai-Las) 9.5 9.5 9.5 9.5 9.5 9.5 9.5 Excipient Calcium hydrogen phosphate 80.0 79.0 0.0 0.0 0.0 0.0 0.0 Flavoring agent -M 1.0

Flavoring agent D-mannitol 80.0

Buffer sodium bicarbonate 80.0

Excipient Lactose 80.0

Excipient Corn corn. 80.0 Excipient Crystal Cell D-S (Avicel) 80.0 Lubricants Magnesium diphosphate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Evaluation of bitterness * X 〇 △ △ Δ Δ 〇

*: Time until bitterness is felt; X within 10 seconds, Δ10-30 seconds, 〇30 seconds or more

For tablets with a tasteless excipient (calcium hydrogen phosphate) (Sample 23), the tablets were bitter. On the other hand, tablets (samples) containing a sweetener Ζ flavoring agent (aspartame, D-mannitol), a buffer Ζρ Η regulator (sodium bicarbonate), or an excipient that reduces bitterness (lactose, corn starch, crystalline cellulose) In 24-29), bitterness was suppressed.

Therefore, in the tablet of the present invention, a bitterness-suppressing additive such as a flavoring agent Ζ a sweetener, a buffering agent ΡΗ a regulator, or an excipient that alleviates bitterness is added to a tablet derived from pill dicainide hydrochloride as an active ingredient. It turned out that it has the effect of suppressing bitterness.

Test example 7: Bitterness suppression test by coating film

As one of means for suppressing bitterness when taking tablets, there is a method for coating tablets with a coating film. Therefore, it was examined whether the tablet of the present invention can suppress bitterness by the coating film and can be a tablet that can ensure rapid disintegration. Coated tablets were prepared using the tablets obtained so far (uncoated tablets: sample 13). That is, a water-soluble film was coated with the composition shown in Table 6 below. The amount of film was 3 parts per 100 parts of uncoated tablet. As a coating machine, a high-coating mini (Freund Co., Ltd .; rotation speed: 15 rpm, exhaust temperature: about 45 ° C) was used, and the charged amount was set to 200 g by adding a colored placebo tablet.

During the coating process, no obstacle such as cracking or chipping of the tablet was observed, and the tablet of the present invention had good strength.

Table 6:

Ingredient name Compounding amount Wg)

100.0

Base Hidexif. Mouth pill methyl cell mouth (HPMC) 2.7

Plasticizer e. Rechilenk "Recall 6000 0.3

A total of 103.0 of the obtained coated tablets (sample 30) were evaluated for tablet hardness and disintegration by the method described in Test Example 1, and evaluated for the presence or absence of bitterness by the evaluation method described in Test Example 5.

Table 7 shows the results.

Table 7:

5 formula fee "13 30

Disintegration time Storage 刖 2.9 2.8

(Min) After storage 2.8 3.5

Tablet hardness Storage 刖 6.2 7.2

(kg) After storage 5.4 6.2

Hardness difference 0.8 1.0

Evaluation of bitterness * X 〇

*: Time until bitterness is felt; X within 10 seconds, Δ10 to 30 seconds, Ο30 seconds or more The coated tablet (pill 30) containing the active ingredient of the present invention, pilsicainide hydrochloride, suppressed the bitterness observed in the uncoated tablet (sample 13) before coating by coating. The formulation properties of the coated tablets were as good as the uncoated tablets (Sample 13) before coating.

Therefore, it has been found that the tablet provided by the present invention can suppress the bitterness of the tablet derived from pilsicainide hydrochloride, which is an active ingredient contained therein, by coating the coating layer. Industrial applicability

As described above, according to the present invention, it has been found that, with respect to a tablet of pilsicainide hydrochloride, a therapeutic agent for arrhythmia, which has not been studied at all, the effect essential for the treatment of arrhythmia has a rapid and rapid disintegration, and Provided is a tablet capable of preventing a decrease in tablet hardness and further tablet hardness due to storage.

The tablet containing pilsicainide hydrochloride provided by the present invention can avoid the pain at the time of administration observed in injections which have been developed so far and obviates the difficulty in taking it which has been observed in capsules. It can be safely taken by patients with reduced swallowing power, or by young children and the elderly.

Further, by applying the technology of the present invention, it is possible to provide tablets in which the content of pilsicainide hydrochloride is variously changed, and the manufacturing cost is lower than that of capsules. Therefore, the present invention has a great effect on the medical industry.

Claims

The scope of the claims

1. The tablet contains 5 to 99.5% by weight of pirgicide hydrochloride as the main drug, and is formed by compression molding granules obtained by dry granulation or by directly compression molding a mixed powder. A method for producing a tablet containing pilsicaidide hydrochloride, characterized in that the weight of the tablet is not less than kg, the decrease with time is suppressed, and the tablet has rapid disintegration properties.

2. The method according to claim 1, wherein the content of pilsicainide hydrochloride is 30 to 99.5% by weight.

3. The method for producing a tablet containing pilsicaide hydrochloride according to claim 1, to which a bitterness suppressing substance is added.

4. The method for producing a pyrdicainide hydrochloride-containing tablet according to claim 2, wherein the amount of the bitterness suppressing substance added is 1 to 80% by weight.

5. Bitter suppressants are sucrose, glucose, lactose, D-mannitol, aspartame, xylitol, sodium bicarbonate, magnesium carbonate, sodium carbonate, ascorbic acid, sodium chloride, starch, partially pregelatinized starch and crystalline cellulose 5. The method for producing a pillgicinide hydrochloride-containing tablet according to claim 4, which is any one of the following.

6. The method according to claim 1, wherein the tablet further comprises a coating layer.

7. The method according to claim 6, wherein the coating layer is a film that dissolves or disintegrates in the stomach.

8. The method according to claim 1, wherein the active drug content per tablet is 12.5 mg, 25 mg, or 5 Omg.

9. A tablet containing pilsicaid hydrochloride obtained by the production method according to claim 1.

10. A tablet containing pilsicainide hydrochloride obtained by the production method according to any one of claims 2 to 8.

1. The tablet containing pilsicainide hydrochloride according to claim 9 or 10, which is a gastric disintegrating tablet.

2. A mixture containing 20 to 80% by weight of pilzikaied hydrochloride, crystalline cellulose or corn starch as the main drug, and further containing a disintegrant, is directly compression-molded into uncoated tablets, or by dry granulation. The granulated product obtained by granulation is compression molded to form an uncoated tablet, and then 100 to 100 parts of the uncoated tablet is coated with 2 to 4 parts of a film based on hydroxypropylmethylcellulose. A method for producing a tablet containing pilsicaidide hydrochloride, which is disintegratable in the stomach and rapidly disintegrates.

3. Containing pilsicainide hydrochloride obtained by the production method according to claim 12.