WO2003075918A1

WO2003075918A1 - Tablet containing pilsicainide hydrochloride (wet)

Info

Publication number: WO2003075918A1
Application number: PCT/JP2003/002974
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: KR20050002856A; JPWO2003075918A1; AU2003213337A1

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 95 wt.%, being formed by compression molding of granules obtained by a wet granulation technique, having a tablet hardness of 2.5 kg or more and exhibiting rapid disintegration property; and tablets containing pilsicainide hydrochloride, produced by the process.

Description

Piljikaied hydrochloride-containing tablets (wet)

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, disintegrates quickly after oral administration, has a short onset time of action, and has good handling. The present invention relates to a tablet containing pilsicainide hydrochloride which is easy to take. Background art

Pilsicainide hydrochloride [JAN; 1! ^: Chemical name:

-(2,6-Dimethylphenyl) -18-pyrrolidinidinylacetamide hydrochloride monohydrate] is an 8-substitution in which the basic part of lidocaine is replaced by a more basic pyrrolitidine skeleton. It is a pyrrolidine derivative and a compound having a strong antiarrhythmic action and a pharmacological effect such as local anesthetic action (Japanese Patent Publication No. 4-24956). Pildicainide hydrochloride is being developed as a therapeutic agent for arrhythmia. Injectables (trade name: Sunrhythm®) and capsules (trade name: Sunrhythm® Capsule 25 mg; Sales 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 above design concept, the rapid solubility of Pilsicainide hydrochloride due to the high dissolution rate caused by the high solubility of Pilsicaede hydrochloride (0. SS g Zml, 20 ° C, purified water) gives rapid 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 pilsicainide hydrochloride preparations, 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 properties for obtaining a rapid onset of effect after taking the drug. It is difficult to formulate tablets that have the opposite properties of ensuring hardness and rapid disintegration, and at present there has been no active study.

Therefore, in view of the above situation, the present invention is an oral preparation which is superior to an injection in terms of compliance with dosages and ensuring compliance, is easier to take than a capsule, and has a desired tablet hardness and promptness. An object of the present invention is to provide a tablet containing pilsicainide hydrochloride having excellent disintegration properties.

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 view of this point, the tablet targeted by the present invention is required to have a rapid disintegration property of the tablet because it is a therapeutic agent for arrhythmia containing pilsicainide hydrochloride as an active ingredient. The release from tablets must be very good. Therefore, the disintegration of the tablet is reduced, and the delay of the dissolution (release) of the active ingredient from the preparation must be avoided as much as possible.

Therefore, the present inventor has proposed that, in the production of tablets of pilsicainide hydrochloride, a desired tablet hardness can be maintained without using a binder which causes a decrease in disintegration or by reducing as much as possible. In addition, we conducted intensive research with an emphasis on developing technologies that can develop tablets with good disintegration properties.

The inventor first noted the high solubility of pilsicainide hydrochloride in water. Pilsicainide hydrochloride has a solubility of 0.89 g Zm 1 (37 ° C, purified water), which is the most soluble lactose (0.17 g / (m 1, 20 ° C, purified water; DMV-200, DMV company).

Then, the present inventor evaluated the viscosity and dissolution rate of the aqueous solution having each concentration of pilsicainide hydrochloride and lactose. As a result, the viscosity of the solution of pilsidide hydrochloride at a concentration close to the saturation solubility is higher than that of lactose, and is comparable to the viscosity of the binder solution used in the usual pharmaceutical manufacturing process. Was found. Furthermore, it was found that the dissolution rate of pilsicainide hydrochloride in water was extremely fast.

Thus, the present inventor has reported that when pilzikaied hydrochloride is brought into contact with a small amount of water, a partially high concentration aqueous solution of pilgicide hydrochloride is obtained, and the same granulating action as that of the binder solution can be exhibited. Inspired. Based on this, the present inventor has found that the formability of tablets can be improved by subjecting pilsidide hydrochloride to a formulation step of bringing it into contact with water, particularly a wet granulation step. In addition, by setting the blending ratio of pilsicainide hydrochloride, which is the main drug in the tablet composition, to 5 to 95% by weight, preferably 10 to 90% by weight, a binder causing a reduction in the friability of the tablet is obtained. The present inventors have found that it is possible to secure the strength of a tablet after compression molding without using or reducing the amount of use, and have completed the present invention. Disclosure of the invention

Accordingly, the present invention provides (1) compression-molding granules obtained by a wet granulation method, comprising 5 to 95% by weight of pilsicainide hydrochloride as a main drug, and a tablet hardness of 2.5 kg or more; A method for producing tablets containing pilsicainide hydrochloride characterized by having rapid disintegration properties, and (2) extrusion granulation, stirring granulation, kneading granulation, rolling granulation, and wet granulation. The method for producing a tablet containing pilsicaide hydrochloride according to the above 1, which is a fluidized bed granulation method, a tumbling fluidized bed granulation method, or a spray granulation method, (3) The method according to the above 1 or 2, wherein a bitterness suppressing substance is added. (4) The method for producing a tablet containing pilgicide hydrochloride according to the above (3), wherein the amount of the bitterness-inhibiting substance added is 1 to 90% by weight, (5) a bitterness-inhibiting component. But white sugar, glucose, lactose, D-mannitol, aspartame, The method for producing a tablet containing pilsicaide hydrochloride according to the above item 4, which is any one of xylitol, sodium hydrogen carbonate, magnesium carbonate, sodium carbonate, ascorbic acid, sodium chloride, starch, partially pregelatinized starch and crystalline cellulose, (6 ) The method for producing a tablet containing pilsicainide hydrochloride according to the above 1 or 2, which further covers the coating layer. (8) The method for producing a tablet containing pilzikaied hydrochloride according to any one of the above (1) to (7), wherein the content of the active drug per tablet is 12.5 mg, 25 mg, or 50 mg. Further, the present invention relates to (9) Pildica hydrochloride obtained by the production method described in 1 above. 2974

Nide-containing tablet, (10) a pirgicinide hydrochloride-containing tablet obtained by the production method according to any one of the above 2 to 8, (11) a hydrochloric acid according to the above 9 or 10, which is a gastrodisintegrable tablet A tablet containing 20 to 80% by weight of pilsicainide hydrochloride, crystalline cellulose or cornstarch as the active ingredient, and a binder containing up to 3% by weight of a binder; Granulation is performed by a wet granulation method comprising a fluidized-bed granulation method, and the obtained granules are compression-molded into uncoated tablets, and then 100 parts of the uncoated tablets are based on hydroxypropyl methylcellulose. A method for producing a gastric disintegrating and rapidly disintegrating pyrdicainide hydrochloride-containing tablet, which comprises coating 2 to 4 parts of the film to be formed, (13) the method described in (12) above. Containing pilsicainide hydrochloride obtained in It is an agent. BEST MODE FOR CARRYING OUT THE INVENTION

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. In the tablet provided by the present invention, which contains such a pilsicainide hydrochloride as an active ingredient, the desired tablet hardness depends on the diameter and shape of the tablet. It should have a hardness of 5 kg or more, more preferably 3 kg or more. In order to obtain a tablet having such a desired tablet hardness, it is preferable that the blending ratio of pilsicainide hydrochloride as an active ingredient is 5 to 95% by weight. Among them, considering the ease of tablet production, it is desirable that the content be in the range of 10 to 90% by weight.

On the other hand, the particle size of the active ingredient, pilsidide hydrochloride, is not particularly limited, as long as it does not affect the ensuring of 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. Depending on the tablet manufacturing method and the blending ratio of pilsicainide hydrochloride, for example, when tablets are manufactured by granulation by fluidized bed granulation and compression molding to produce tablets, content uniformity in granulated granules for tableting The particle size of pilsicainide hydrochloride is 75-500 Is preferably distributed in the range of 50% or more.

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. Also, the size of the tablet is not particularly limited, but in consideration of ease of taking and handling, in the case of a round tablet, the diameter is preferably about 5 to 14 mm, particularly for elderly people. It is desirable to have a size of about 6 to 1 O mm, which is easy 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.

The present invention provides tablets having appropriate tablet hardness, rapid disintegration, and excellent release of the active ingredient, and further, if necessary, generally required pharmaceutical requirements. Various additives can be appropriately selected and blended in order to ensure stability and absorbability or to improve the production process.

Such additives include (1) excipients such as lactose, starch, partially alpha starch, crystalline cellulose, D-mannitol, dextrose, calcium carbonate and phosphoric acid, (2) starch, Disintegrators such as croscarmellose sodium, and (3) lubricants such as magnesium stearate, sucrose fatty acid ester, talc, and hydrated silicon dioxide. Further, if necessary, a stabilizer, a flavoring agent, a coloring agent and the like can be added. 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 order to ensure the desired tablet hardness and rapid disintegration, the tablets containing the active ingredient pilsicainide hydrochloride provided by the present invention must not contain a binder commonly used in pharmaceuticals, or One of the features is that the compounding amount of the agent is reduced as much as possible. Therefore, when compounding a binder, tablets 03 02974

The type is appropriately selected within a range that does not impair the rapid disintegration of the product. Examples of such a binder include hydroxypropyl cellulose, starch, polyvinylpyrrolidone, carboxymethyl cellulose and the like.

In addition, the mixing ratio of the binder within a range that does not impair good disintegration varies depending on the type, grade, and addition method of the binder selected as appropriate, and also on the content of the active ingredient pildikinide hydrochloride, It cannot be limited unconditionally. For example, in the case of starch and the like, it is added as an excipient and exhibits properties as a binder. In short, when a binder is added, a range that does not impair the quick disintegration of the tablet is selected.

In the tablet provided by the present invention, in the tablet manufacturing process, the tablet formability is improved and the hardness is improved by passing the active ingredient pilsicainide hydrochloride into contact with water. There was found. Therefore, as a method for producing the tablet provided by the present invention, a method of compression-molding granulated granules obtained by a granulation method using water is preferable. That is, it is desirable to employ wet granulation to produce granules for compression molding.

Examples of such wet granulation include extrusion granulation, stirring granulation, kneading granulation, tumbling granulation, fluidized bed granulation, tumbling fluidized bed granulation, or spray drying. Granulation method can be used. The wet granulation method is an excellent production method that is less affected by the powder characteristics of the main drug and excipients, and can easily ensure uniform content as compared with the dry granulation method.

A lubricant is mixed with the wet granulated granules obtained by such a wet granulation method, and 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 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 tablet provided by the present invention, the active ingredient pirgicide hydrochloride is characterized in that it has a bitter taste and a local anesthetic action, 0302974

In the formulation, it is also necessary to reduce such unpleasant bitterness to improve compliance of the recipient.

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 anesthesia in the oral cavity or esophagus due to the local anesthetic effect of pilsicide 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 is suppressed and the amount in the stomach is reduced. Can be appropriately set 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), oid rug h®E (aminoalkyl methacrylate copolymer E), A gastric-soluble film using a gastric-soluble coating base such as AEA (polyvinyl acetate or rucetylaminoacetate), or one that dissolves in the stomach, such as sugar coating, is desirable. In addition, enteric coatings using hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit®-L, LD, S (methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S), etc. Sustained-release coatings made of cellulose or Eudragit b®-RS (aminoalkyl methacrylate copolymer RS), even if they have a composition or amount that can dissolve or disintegrate in the stomach to release the drug For example, it can be used as a film component for the tablet of the present invention.

Among them, hydroxypropyl methylcellulose is characterized by being able to suppress bitterness with a small amount of film, being water-soluble, being easy to prepare a film solution, and having a short time required for a coating process. It is particularly preferable to coat about 2 to 4 parts of a film based on (HP MC) based on 100 parts of the uncoated tablet as the tablet of the present invention. There is no particular limitation on the coating method for applying a film to the tablet. JP03 / 02974

9 can be performed using a

Further, for the purpose of suppressing bitterness in the oral cavity, a bitterness-suppressing additive can be incorporated into the tablet composition. Such bitterness-suppressing additives include sweeteners and sweeteners such as sucrose, glucose, lactose, D-manni! -Yl, aspartame, and xylitol; sodium hydrogen carbonate, magnesium carbonate, sodium carbonate, ascorbic acid, and chloride. Buffers such as sodium or PH regulators; and excipients capable of reducing 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, pyridicanide hydrochloride, but is preferably about 1 to 90% by weight in view of the effect of suppressing bitterness.

Among them, corn starch, which has an excellent bitterness-inhibiting effect and an improved soil disintegration property and is effective in ensuring the strength of tablet edges, and a good bitterness-inhibiting action, and has excellent moldability and disintegration properties Crystalline cellulose having a characteristic of not impairing 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, It is also desirable to add about 10 to 60% by weight.

In the tablet provided by the present invention, the content of the active ingredient, pilgicide 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. Is preferably 12.5 mg, 25 mg or 5 O mg.Therefore, based on such a content of pilzikaied hydrochloride, the above-described specific structure of the present invention is appropriately combined, and Thus, a tablet containing pilsidide hydrochloride that is effective in treating arrhythmias 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, “part” and “%” are each unless otherwise specified.

"Parts by weight" and "% by weight" are indicated. Test Example 1: Viscosity of various solutions of pilsidide hydrochloride

In order to ascertain the characteristics of the aqueous solution of pilgicanide hydrochloride, aqueous solutions of various concentrations were prepared and their viscosities were measured. In addition, the time required for dissolution when preparing an aqueous solution for viscosity measurement was evaluated.

Pill dicainide hydrochloride is added to the water-filled glass, magnetic stirrer

(Yamato Kagaku, MA G-MIX ER m-41) and a stirrer (Φ 8 mm X 6 O mm) to obtain 50 O ml of a solution of pyridikai hydrochloride in various concentrations. The number of revolutions of the magnetic stirrer was adjusted as appropriate while observing the progress of melting. The time required for the dissolution operation was measured. The viscosity of the obtained aqueous solution was measured using a B-type viscometer (manufactured by Tokyo Keiki).

As controls, lactose, a commonly used excipient, and hydroxypropylcellulose, a binder, were similarly tested.

Table 1 shows the results.

TJP03 / 02974

11 Table 1: Viscosity of various aqueous solutions

Solution number Component name Concentration (w / v) Viscosity (CPS) Dissolution time *

1 Pildicainide hydrochloride 9% 5.8 1 minute

2 Pilsicainide hydrochloride 12% 6.8 1 min

3 Pilsicainide hydrochloride 45% 9.6 1 min

4 Pildicainide hydrochloride 60% 16.2 3 minutes

5 Lactose (DMV-200) 9% 5.3 2 minutes

6 Lactose (DMV-200) 12% 6.5 30 minutes

7 Hydroxy ropircell mouth (HPL-C) 2% 18.3 40 minutes

*: Using Stara (YAMATO SCIENCE, MAG-MIXER M-41) and stirrer (Φ8 （60 thigh)

The time required for dissolution was measured. As can be seen from the results shown in the table, the viscosity of the aqueous solution of pyrdicaide hydrochloride increased as the concentration increased to 9 to 60% (w / v). In addition, when compared with an aqueous solution of lactose, the viscosity was slightly higher than that of a solution of the same concentration in pill dicainide hydrochloride [concentration 9% (w / v) or 12% (w / v), solution No. 1, 2, 5, 6].

On the other hand, comparing the solutions (Solution No. 4 and Solution No. 6) adjusted to a concentration of about 70% with respect to the saturated solution, the viscosity (16.2 cps) of the pilsidide hydrochloride solution (Solution No. 4) was It was higher than the viscosity (6.5 cps) of lactose (Solution No. 6). The viscosity value of this solution of Pildica Hydrochloride (Solution No. 4) is determined by the viscosity (18.3 cps) of hydroxypropylcellulose (HPC-L) as a binder at a commonly used concentration (2%). It was almost equivalent. Therefore, it was found that the solution of pyrdicaide hydrochloride was highly viscous, especially at a high concentration.

Regarding the dissolution rate, pirgicinide hydrochloride was dissolved within 3 minutes at any concentration [9 to 60% (w / v)]. On the other hand, lactose took as long as 30 minutes in a 12% (w / v) solution (concentration of about 70% of saturation solubility). In the test on the required dissolution time, it cannot be said that the average particle diameters of the respective powders are necessarily the same, and a strict comparison cannot be made because the rotational speed of the stirrer was adjusted appropriately to accelerate dissolution. However, at least, pilsidide hydrochloride is a saturated solution It was found that the substance was rapidly dissolved even at a concentration close to the resolution.

From the above, it was found that when the powder of pilsicaide hydrochloride was brought into contact with a small amount of water, a high-concentration pilsicainide hydrochloride solution having a certain viscosity was partially obtained promptly, and the effect of a binder can be expected. did. Test Example 2: Tests with various ratios of pilsicainide hydrochloride (Part 1)

The effect of the blending ratio of pilsicainide hydrochloride contained in the tablets on the formulation properties (disintegration and hardness) was determined by compression molding using granules obtained by wet granulation (extrusion granulation). It examined using the tablet obtained by doing.

According to the formulation shown in Table 2 below, a composition containing pircadide hydrochloride (hereinafter sometimes referred to as “compound 1”) in various proportions was granulated by wet granulation, and tablets were formed by compression molding. Obtained.

That is, about 200 g of a mixed powder of components excluding magnesium stearate and hydroxypropylcellulose (HPC-L) was placed in a mortar, and an HPC-L solution (samples 1 and 2) and an appropriate amount of purified water (sample 18) were added. ) And kneaded with a pestle. The obtained kneaded product was extruded and granulated with a screen having a pore diameter of 0.8 mm, dried on a shelf, and sized with a No. 15 sieve (100 m) to obtain granulated granules. After mixing the granulated granules with magnesium stearate, the mixture was tableted using a rotary tableting machine.

The tableting conditions were as follows: tablet weight: 100 mg, tablet diameter: 6.0 mm, curved surface diameter: 8.0 mm, and tableting pressure: 100 kgf. However, for Sample 8, the charge amount was 10 g, and an autograph (manufactured by Shimadzu Corporation) was used as a tableting machine. The hardness and disintegration of the eight tablets obtained were evaluated. The hardness was measured using a tablet hardness tester (Schleuniger). For the evaluation of disintegration, the disintegration time was measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd., 10 times up and down, Z minutes, amplitude 55 mm, purified water 90 OmL, 37 ° C). Among the measurement conditions, the upper and lower counts were set to 10 times, which is a condition under which the degree of crushing property can be strictly determined.

These results are summarized in Table 2. 2974

13 Table 2: Formulation characteristics of tablets by wet granulation compression method

Sample No. 1 2 3 4 5 6 7 8 Ingredient ratio (%) 3.0 3.0 0.0 3.0 5.0 10.0 60.0 95.0 Ingredient name Ingredient amount per tablet (mg

Main compound 1 3.0 3.0 0.0 3.0 5.0 10.0 60.0 95.0 Binder HP C-L 10.0 3.5 0.0 0.0 0.0 0.0 0.0 0.0 Excipient Lactose 52.5 59.0 65.5 62.5 60.5 55.5 5.5 0.0 Excipient Maize 7 30.0 30.0 30.0 30.0 30.0 30.0 30.0 0.5 Excipient Crystal cell mouth 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Lubricant Mac stearate nesium 0.5 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 Tablet hardness (kg) 3.6 3.5 1.9 1.8 3.4 3.5 4.0 3.2 Disintegration time (min) 5.5 4.3 1.0 1.5 1.2 1.8 2.0 1.9 Evaluation of bitterness * (Test 6) 〇〇〇〇 Δ XXX

*: Time until bitterness is felt; X10 seconds or less, 10-30 seconds, 〇30 seconds or more As can be seen from the results shown in the table, hydroxypropyl cellulose (HPC-L )) (Samples 1 and 2) were tablets of sufficient strength, each having a value (2.5 kg) or more, which is a measure of tablet hardness for tablets of this size. However, its disintegration decreased depending on the amount of HPC-L binder. That is, the addition of the binder tended to reduce the disintegration.

On the other hand, in the case of the sample containing no hydroxypropylcellulose (HPC-L) as a binder (samples 3-8), the disintegration time of each formulation is within 2 minutes, It showed disintegration. Regarding the tablet hardness, tablets with a compounding ratio of compound 1 of 3% or less (samples 3 and 4) had an insufficient hardness of 1.8 to 1.9 kg, but the compounding ratio of compound 1 was 5%. The tablet hardness of the present invention (samples 5 to 8), which is 9090%, was 3.2 to 4.0 O kg, and sufficient strength was obtained. From the above results, the tablet of the present invention, which was formed by compression molding using granulated granules prepared by extrusion granulation, which is a type of wet granulation, containing 5% or more of pilsicainide hydrochloride, was mixed with a binder. Even without it, it was confirmed that it had both sufficient tablet hardness and rapid disintegration. Test Example 3: Tests with various formulations of pilsicainide hydrochloride (Part 2)

The effect of the amount of pilsicainide hydrochloride in the tablets on the formulation properties (disintegration, hardness and friability) of the tablets was investigated using granules obtained by wet granulation (fluid bed granulation). It examined using the tablet obtained by compression molding.

Based on the formulation shown in Table 3 below, tablets containing various ratios of Compound 1 were prepared. That is, a mixed powder of components excluding magnesium stearate and hydroxypropylcellulose (HPC-L) (however, half of HP C_L was added as a powder in sample 9, and half of polyvinylpyrrolidone was added as a powder in sample 16) 200 g was charged into a fluid bed granulator (Nummarmerizer NQ-LABO; manufactured by Fuji Padal) and mixed for 2 minutes. Spray the aqueous solution of HPC-L (samples 9 and 10) or purified water (samples 11 to 15) or polyvinylpyrrolidone aqueous solution (sample 16) at a rate of 1.4 to 1.7 mLZ while spraying 50 to 1 Granulated for 10 minutes (product temperature: 24 ° (:, intake temperature: 30 to 70 ° C) After that, dried for 5 minutes using the same device (product temperature: 24 to 30 ° (:, intake temperature: 40 to 65) ° C) The obtained granules were taken out and sized with a No. 15 sieve (1000 zm) to obtain granulated granules. Tableting was performed using a single tableting machine.

The tableting conditions were as follows: tablet weight was 100 mg, tablet diameter was 6.0 mm, curved surface diameter was 8.0 mm, and tableting pressure was 1000 kgf.

The disintegration and hardness of the obtained eight tablets were evaluated by the methods described in Test Example 2. Table 3 summarizes these results. TJP03 / 02974

15 Table 3

Sample number 9 10 11 12 13 14 15 16 Ingredient ratio (%) 3.0 3.0 3.0 5.0 10.0 30.0 60.0 3.0 Ingredient name Ingredient amount per tablet 11

Fl U Binder HPC-L 10 0 U 0.0 0.0 0.0 nnu 0 0 0 0 Binder Polyvinylpyrrolidone 0.0 0.0 0.0 0.0 0.0 0.0 0.0 10.0 Excipient Lactose 48.5 53.5 58.5 56.5 51.5 31.5 1.5 48.5 Excipient Maize 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 Excipient Crystalline cellulose 8.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 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 Tablet hardness (kg) 4.0 3.7 0.5 3.6 3.5 3.0 3.6 4.2 Disintegration time (min) 12.0 11.7 0.6 1.5 1.9 1.2 1.9 17.0 Hydroxypropyl cellulose as binder In the samples based on the formulation containing (HPC-L) (Samples 9 and 10), the tablet hardness (3.7 4. O kg) showed a good value, but the disintegration time was 10 minutes or more. Disintegration deteriorated depending on the amount of the agent Polyvinylpyrrolidone as a binder The sample (Sample 16) to which 10% (wXw) was added also had good hardness but poor disintegration, while hydroxypropylcellulose (HPC-L) as a binder was not added ( Samples 1 1 15) showed good disintegration with a disintegration time of less than 2 minutes, and tablets with 3% compound 1 (Sample 11) had insufficient tablet hardness. However, the tablet of the present invention (Sample 1215) in which the compounding ratio of Compound 1 was 5% or more showed sufficient tablet hardness.

As described above, the tablet of the present invention obtained by compression-molding granulated granules obtained by fluidized-bed granulation, which is a type of wet granulation, in which pillicainide hydrochloride is blended by 5% or more, is combined with a binder. It was confirmed that the tablet had characteristics that had both sufficient tablet hardness and rapid disintegration.

The disintegrant containing pilsicainide hydrochloride provided by the present invention does not contain a binder, Alternatively, even if the amount used is reduced, the strength of the tablet after compression molding can be ensured, and the tablet has rapid crushing properties.

That point was examined by the following test. Test example 4: Test with a formulation containing a binder

Based on the formulation shown in Table 4 below, hydroxypropylcellulose (HPC-L) was used as a binder, and the composition in which the blending ratio was changed was granulated by a stirring granulation method. The granules thus obtained were compression molded to prepare tablets.

That is, about 250 g of the mixed powder of the components excluding the lubricant is put into a stirring granulator (High Speed Mixer LFS-GS-2J; manufactured by Fukae Industries Co., Ltd.) and mixed for 1 minute (stirring blade: 800 rpm Z minute) , Chopper: 4000 revolutions Z minutes). An appropriate amount of purified water was added thereto, and the mixture was stirred for 2 minutes (stirring blade: 800 rotations Z minutes, chopper: 4000 rotations / minute). The obtained kneaded product was dried with a fluidized bed granulating dryer (Floco Ichiichi FLO-1; manufactured by Baurek) for 20 minutes and sized (710 II m) to obtain granulated granules. After the lubricant was mixed with the granulated granules, the mixture was tableted using a single tableting machine. The tableting conditions were as follows: tablet weight was 100 mg, tablet diameter was 6.0 mm, curved surface diameter was 8.0 mm, and tableting pressure was lOOOkgi. The obtained tablets (samples 17 to 20) were evaluated for disintegration and hardness by the method described in Example 1.

The results are shown in Table 4.

Table 4

Sample No. 17 18 19 20

Ingredient ratio (%) 5.0 5.0 5.0 5.0

Ingredient name Amount per tablet (mg)

Active compound 1 5.0 5.0 5.0 5.0

Binder HPC-L 0.0 1.0 2.0 3.0

Excipient Lactose 80.1 79.1 78.1 77.1

Excipient Crystalline cellulose 14.4 14.4 14.4 14.4

Lubricant Magnesium stearate 0.5 0.5 0.5 0.5

Total 100.0 100.0 100.0 100.0

Tablet hardness (kg) 3.0 3.1 3.5 3.8

Disintegration time (min) 2.5 2.6 2.8 2.9 Tablets of the present invention obtained by compression-molding granulated granules obtained by the agitation granulation method do not contain any binder (HP CL) (Sample 17), or 1 to 3. 3% (samples 18 to 20) all showed good formulation characteristics. That is, in the tablet of the present invention, depending on the blending ratio of the active ingredient, pilzikaied hydrochloride, and the types and blending ratios of other components, it is possible to add a reduced amount of a binder within a range that does not impair the disintegration property. It turns out that it can be done. Test Example 5: Examination of the effect of tablet weight and Z size

Tablets were prepared with the same composition but with varying tablet weight and Z size for tablets containing pilsicainide hydrochloride as the active ingredient, and the effects on tablet hardness and disintegration were examined.

Based on the formulation shown in Table 5 below, tablets having the same composition and varying tablet weight and size were prepared. That is, using the granules of Sample 14 obtained in Test Example 3, a tablet with a tablet weight of 50 mg and a tablet diameter of 5.0 mm (Sample 21), a tablet weight of 100 mg and a tablet weight of 6. Omm The tablet (Sample 22) and the tablet weight of 50 OmgZ The tablet with a tablet diameter of 11.1 Omm (Sample 23) were compressed using an autograph. Force was adjusted at 1000 kgf. The disintegration and tablet hardness of each of the obtained tablets were evaluated. The evaluation items and evaluation method conformed to Test Example 2.

The results are shown in Table 5.

Table 5:

Sample No. 21 22 23

Tablet size (mg) 50.0 100.0 500.0 Die and die diameter (mm) 5.0 6.0 11.0 Incorporation ratio of active drug (%) 30.0 30.0 30.0

Ingredient name Amount per tablet: (mg)

Compound 1 15.0 30.0 150.0 Excipient Lactose 15.75 31.5 157.5 Excipient Maize 15.0 30.0 150.0 Excipient Microcrystalline cellulose 4.0 8.0 40.0 Lubricant Mac stearate Nesidum 0.25 0.5 2.5

Total 50.0 100.0 500.0 Tablet hardness (kg) 4.9 3.1 3.0 Disintegration time (min) 2.9 1.8 0.7 As a result, any of the tablets provided by the present invention showed good hardness and rapid disintegration. Therefore, it has been found that tablets of various weights Z size can be provided by the present invention.

Test Example 6: Influence 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 compounding ratio of the drug, Pilkaikaied hydrochloride, on the degree of bitterness was evaluated using the tablets (samples 1 to 8) obtained in Test Example 2.

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. Evaluation should be taken when taking tablets Considering the time that the drug stays in the oral cavity, the time to feel bitterness is less than 10 seconds (X mark), 10 to 30 seconds (△ mark), and 30 seconds or more (〇 mark) Was determined.

The results are shown in Table 2 above.

As can be seen from the results in the table, as the proportion of the main drug, pilsicainide hydrochloride, was increased, the time until bitterness was felt became faster. Therefore, when the blending ratio of the active ingredient is high, it can be said that the tablet of the present invention should be considered to be subjected to a treatment for suppressing bitterness in some cases. Test Example 7: Bitter taste suppression test with bitterness suppressing additive

As one of means for suppressing bitterness, there is a method in which a bitterness-suppressing additive such as a flavoring agent Z sweetener, a buffering agent ZpH regulator, and a bitterness-reducing excipient is incorporated into the formulation. For these substances, the effect of suppressing the bitterness of the tablet of the present invention was examined.

Assuming that the compounding ratio of the main drug, Pilzikaied hydrochloride, was 7.5%, the preparations were prepared according to the various compounding formulations shown in Table 6 below. The method for preparing tablets was in accordance with the method described in Test Example 2. However, the charging amount was 10 g, and an autograph was used as a tableting machine. The evaluation of bitterness was based on the criteria described in Test Example 6.

The results are shown in Table 6.

Table 6

Sample No. 24 25 26 27 28 29 30 Ingredient ratio (%) 7.5 7.5 7.5 7.5 7.5 7.5 7.5 Component name Amount per tablet (mg)

Compound 1 7.5 7.5 7.5 7.5 7.5 7.5 7.5 Binder HPC-L 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Excipient Calcium hydrogen phosphate 90.0 89.0 0.0 0.0 0.0 0.0 0.0 Flavor Aspartame 1.0

Flavor D-Manni! Le 90.0

Buffer sodium bicarbonate 90.0

Excipient Lactose 90.0

Excipient Corn corn. 90.0 Excipient Microcrystalline cellulose 90.0 Lubricant Magnesium stearate 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 〇〇

*: Time until bitterness is felt; X10 seconds or less, Δ10 to 30 seconds, 〇30 seconds or more The tablet using a tasteless excipient (calcium hydrogen phosphate) (Sample 24) suffered from disintegrant. On the other hand, tablets (Sample 25) containing a sweetener Ζ flavoring agent (aspartame, D-mannitol), a buffer ΖρΗ regulator (sodium bicarbonate), or an excipient that reduces bitterness (lactose, corn starch, crystalline cellulose) In ~ 30), 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 regulator, or an excipient that alleviates bitterness is added to the tablet derived from the active ingredient pill dicaiedo hydrochloride. It turned out that it has the effect of suppressing bitterness.

Test example 8: Bitterness suppression test by coating film

As one of means for suppressing bitterness when taking tablets, there is a means for coating tablets with a coating film. Therefore, the bitterness of the tablet of the present invention is It was investigated whether tablets could be obtained that could be suppressed by a membrane and ensure rapid disintegration.

Coating tablets were prepared using tablets (uncoated tablets: sample 7) with a poor taste evaluation obtained so far. That is, a water-soluble film was coated with the composition shown in Table 7 below. The amount of the coating was 3 parts per 100 parts of uncoated tablets. The coating machine used was Hiko Yuichi Mini (Freund; 15 rpm, exhaust temperature approx. 45 ° C), and the amount charged was 200 g with the addition of colored placebo tablets.

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 7:

Component name Amount (mg) Uncoated tablet 100.0

Base: Human ', Pixif. 13 Pyrmethylcell base (HPMC) 2.7

Plasticizer e. Ethylene glycol 6000 0.3

The coated tablets (Sample 31) obtained in total 103.0 were evaluated for tablet hardness and disintegration by the method described in Test Example 2, and evaluated for the presence or absence of bitterness by the evaluation method described in Test Example 6.

Table 8 shows the results.

Table 8:

Sample No. 7 31 Tablet hardness (kg) 4.0 4.2 Disintegration time (min) 2.0 2.1 Evaluation of bitterness * X 〇

*: Time until bitterness is felt; X within 10 seconds, A10 to 30 seconds, 〇30 seconds or more Coating tablets (sample 31) containing the active ingredient of the present invention, pilsicainide hydrochloride, must be coated. As a result, the bitterness observed in the uncoated tablet (Sample 7) before coating was suppressed. The formulation characteristics of coated tablets are It had the same good formulation characteristics as the uncoated tablet (Sample 7).

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

As described above, according to the present invention, in the case of a tablet of pilzikaied hydrochloride which is a therapeutic agent for arrhythmia, which has not been specifically studied for tableting at all, rapid onset of the effect essential for arrhythmia treatment is achieved. And a tablet having the desired tablet hardness.

The tablet containing pilzikaied 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 forcepsels. It can be safely taken by patients with reduced swallowing power, or by young children and the elderly.

In addition, by applying the technology of the present invention, the content of pilsicainide hydrochloride was variously changed.

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. Tablets containing 2.5 to 95% by weight of pilsicainide hydrochloride as the main drug and compression-molding granules obtained by wet granulation, tablet hardness of 2.5 kg or more, and rapid disintegration A method for producing a tablet containing pilsicaid hydrochloride, characterized by comprising:

2. Wet granulation method is extrusion granulation method, stirring granulation method, kneading granulation method, tumbling granulation method, fluidized bed granulation method, tumbling fluidized bed granulation method, or spray granulation method. 3. The method for producing a tablet containing pilsicainide hydrochloride according to claim 1.

3. The method for producing a pillgicinide hydrochloride-containing tablet according to claim 1 or 2, further comprising a bitterness suppressing substance.

4. The method for producing a pyrdicainide hydrochloride-containing tablet according to claim 3, wherein the amount of the bitterness suppressing substance added is 1 to 90% by weight.

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

6. The method for producing a pilsicainide hydrochloride-containing tablet according to claim 1 or 2, further comprising coating a coating layer.

7. The method according to claim 5, wherein the coating layer is a film that dissolves or disintegrates in the stomach.

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

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

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

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

12. A mixture containing 20 to 80% by weight of pilzikaied hydrochloride, crystalline cellulose or corn starch as a main ingredient, and further containing up to 3% by weight of a binder, is prepared by stirring granulation or fluidized bed granulation. The granulated product is granulated by a wet granulation method, and the obtained granulated material is compression-molded to form an uncoated tablet. A method for producing a tablet containing pilsicainide hydrochloride, which is disintegrating in the stomach and is rapidly disintegrating, characterized by coating four parts.

13. A tablet containing pilsicainide hydrochloride obtained by the method according to claim 12.