KR920006901B1 - Stable tablet containing alkylcystein or its salt - Google Patents

Abstract

No content.

Description

Stable tablet containing alkylcysteine or acid addition salts thereof

The present invention relates to a nucleated tablet containing a stable tablet containing alkylcysteine or an acid addition salt thereof and a tablet coated with an enteric coating thereon.

Alkylcysteines or acid addition salts thereof (hereinafter referred to as alkylcysteines), in particular methylcysteine hydrochloride and L-ethyl cysteine hydrochloride, are used as eukaryotic expectorants, but these compounds are hygroscopic and are prone to change in combination with additives for various formulations. In addition, there is a problem that, due to the change in formulation, an intense other odor such as sulfur or mercaptan caused by alkyl cysteine is generated.

Therefore, conventionally, for the purpose of preventing these changes due to hygroscopicity, the tablet made by the conventional method is waterproof and the prevention of the occurrence of other odors and nausea in the stomach derived from alkylcysteine caused by the tablet disintegrating in the stomach. The method which coat | covers the target enteric film, forms a sugar-coated layer, and is made into sugar-coated medicine was taken.

In general medicine, unlike medical medicine, tablets containing various active ingredients have been provided. Alkyl cysteine is also considered to be used as a general-purpose drug, but the formulation is required to be used in combination with other active ingredients for its efficacy. It is difficult to technically formulate a sugar-coated tablet by coating various types of active ingredients with an enteric tablet containing an alkyl cysteine, and a problem arises that the shape of the finished tablet becomes larger than necessary.

When a tablet containing an alkyl cysteine coated with an enteric coating as described above and coated with other active ingredients therein is formulated into a tablet, a method of making a nucleated tablet is generally considered.

However, in the prior art, it is difficult to make a nucleated tablet that is stable and does not generate other odors. Therefore, it has been necessary to newly develop a method of formulating an inner nuclear tablet containing stable alkyl cysteine to make a nucleated tablet.

Accordingly, an object of the present invention is to provide an inner core tablet of alkyl cysteine that is stable and free of other odors and a nucleated tablet containing the same.

In view of such circumstances, the inventors of the present invention have conducted extensive studies on the preparation of an enteric inner core tablet containing a stable alkyl cysteine or an acid addition salt thereof and a stable nucleated tablet containing the same as a nucleus. In a binder solution obtained by dissolving a selected binder or coating agent which does not give rise to a liquid containing a selected solvent as a main component, a stable tablet is obtained by coatingly granulating only alkyl cysteine or acid addition salt thereof, and further adding a selected lubricant to form a tablet. The tablets can be made into a stable and small dragee which can be used as a medicine, or the tablets coated with an enteric coating on the stable tablets can be obtained as a nucleus tablet to produce stable and free of other odors. Figured out that you can, The completion of the person.

That is, the present invention provides a stable tablet containing (1) an alkylcysteine granulated with a binder solution or an acid addition salt thereof, and containing an alkylcysteine or an acid addition salt thereof formed by compression molding, and (2) the above-mentioned enteric coating ( 1) A nucleated tablet formed by using a tablet as a nucleus tablet is a main constitution, and an object thereof is provided.

The alkyl cysteine used in the present invention means hygroscopic medicines such as methyl cysteine and L-ethyl cysteine, and acid addition salts thereof include hydrochloride, sulfate, phosphate and the like. In particular, methyl cysteine hydrochloride and L-ethyl cysteine hydrochloride are mentioned.

The present invention reduces the destabilization factor caused by the additives by making the inner core tablet using only the minimum additives that do not cause the formulation change with the alkyl cysteine even without mixing the weighting agent, disintegrating agent, etc. required for the conventional tablet formulation. It is characterized by the fact that it produced stable inner core tablets that are unlikely to generate other odors, and that the inner core tablets were made into stable nucleated tablets without the occurrence of other odors containing various active ingredients in the outer layer. In addition, since it is a nucleated tablet, it is necessary to make an inner core tablet containing alkyl cysteine into a compact tablet having a high concentration in practical use. to be. It is not said that if it is the range according to the objective of this invention, a tablet formulation may be added by adding disintegrant weight agent etc. as needed.

The reason for coatingly granulating the alkyl cysteine using a binder solution is that the tablet contains a high concentration of the alkyl cysteine, thereby preventing the adhesion of the tablet to the pestle in the tablet formulation due to the characteristics of the alkyl cysteine, and This is to stabilize the product by excluding the adverse effect on the stability of alkyl cysteine from the outside.

Binders or coating agents used in the present invention include methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, carboxy methylethyl cellulose and methacrylic acid 1 or more types chosen from a copolymer are mentioned, The addition amount of these is the range of 0.5 to 20 weight% with respect to an alkyl cysteine. It is difficult to obtain sufficient coating effect at 0.5 wt% or less with respect to alkyl cysteine, and at 20 wt% or more, the binder solution concentration becomes high and it is difficult to provide practically. In addition, more than necessary additions are meaningless. In addition, it is not preferable to use the binder or coating agent other than those listed in the present formulation because color change or the like may occur due to mixing with alkyl cysteine. However, it is free to mix oil wax-like substances, such as stearic acid, paraffin, hydrogenated vegetable oil, used as a coating additive with a binder or a coating agent.

As a solvent provided for dissolving the binder or the coating agent, those which do not impair the stability of the alkyl cysteine are preferable, and methanol, ethanol, isopropyl alcohol, ethyl acetate, methylene chloride, dichloroethane, trichloroethylene, cyclohexane, n-hexane are mentioned. Can be. In addition, it is best to use a solvent having one or two or more kinds thereof as a main component so that the binder or coating agent dissolves and the alkyl cysteine does not dissolve as much as possible. For example, in the case of hydroxypropylmethyl cellulose, a mixture of 10: 0 to 5: 5 dose ratio of methylene chloride and ethanol; For hydroxypropyl cellulose, a solvent containing at least 50% methylene chloride; In the case of ethyl cellulose, a solvent containing 50% or more of ethyl acetate, methylene chloride or the like or a mixture of n-hexane and ethanol in a volume ratio of 8: 2 to 5: 5; Also for carboxymethylethylcellulose. A mixture of a same volume mixture of methylene chloride and cyclohexane and a volume ratio of 9: 1 to 5: 5 of ethanol is used. Among the solvents used in the present invention, solvents which hardly dissolve alkylcysteine are ethyl acetate, methylene chloride, dichloroethane, trichloroethane, cyclohexane, n-hexane, and dissolving alkylcysteines to some extent is methanol, ethanol and iso Propyl alcohol. In addition, since water dissolves the alkyl cysteine very well and decomposes the alkyl cysteine, it is not preferable to granulate only with water even if about 30% by weight of solvent is mixed.

The granules may be used as a granulator such as a kneader, a stirred granulator, or a fluidized bed granulator. However, when using granulators other than the fluidized bed granulator, it is essential to use a solvent which is difficult to dissolve alkylcysteine. This is because it is necessary to prevent the alkyl cysteine from dissolving at the time of granulation to be exposed to the grain surface. In addition, in the case of a granulator belonging to the fluidized bed, it is not necessary to select a solvent in this case because the granulator is attached to the surface of the alkyl cysteine by granulation, so it is not necessary to select a solvent, for example, methyl cellulose is methanol and methylene. Contemplated are those used by dissolving in a mixture of chloride or water in a 9: 1 to 7: 3 volume ratio.

In any case, it is suitable for the purpose of the present invention as long as it can be tableted by adding the following lubricants using the alkyl cysteine particles granulated by the binder, coating agent and solvent used in the present invention.

The lubricant used in the present invention is not necessarily selected because the binder or coating agent is added to the granulated surface of the alkyl cysteine by coating the granules, but there is no change in blending with the alkyl cysteine in the sense of making the tablet more stable. It is preferable. Examples of such lubricants include magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, acid treated talc, light silicic anhydride, and the like, or a mixture of two or more thereof. The amount of the lubricant to be blended also varies depending on the type of lubricant, but in principle, the range of 0.1% to 20% of the alkyl cysteine granulation powder is preferable.

The tablet obtained in this way can be used as a stable pharmaceutical product by making it into the usual dragee. In addition, an ordinary enteric coating may be coated to form a nucleated tablet containing the inner core. In the case of a nucleated tablet, there is no restriction regarding the prescription of the tablet to be the outer layer, and various prescriptions can be made. It can also be made by combining only the ineffective thing, and can also make what contains many active ingredients. In particular, when formulating general-purpose medicines containing a variety of active ingredients containing alkylcysteine, a stable formulation is obtained by making an inner core of the coating of an enteric coating on the alkylcysteine tablet as an inner core and a nucleated tablet containing other components as an outer layer. useful.

The content per tablet of the alkyl cysteine contained in the inner core tablet provided by the present invention is preferably 25 mg to 100 mg in consideration of its daily dose. In addition, the weight ratio of the inner layer tablet to the inner core tablet is preferably 3 or more for the inner core 1 in consideration of the moldability of the nucleated tablet.

According to the present invention, formulation of nucleated tablets is achieved without the occurrence of other odors having excellent stability of alkylcysteine, especially moisture resistance. It can be said that stable nucleated tablets obtained by nucleating the alkylcysteine are coated with a binder or a coating without impairing the stability, and the direct or indirect influences outside the alkylcysteine are excluded.

Hereinafter, the present invention will be described with reference to experimental examples.

Example 1

(1) Take 100 g of L-ethyl cysteine hydrochloride or methyl cysteine hydrochloride and wet using a solution obtained by dissolving each of commonly used binders, coating agents and oily waxy substances in a concentration of 10 w / v% in the solvents shown in Table 1. Granules were dried and passed through a 24 mesh screen. Next, a mixture of 1.5 g of magnesium stearate, the most commonly used lubricant for tablets, was used to prepare a tablet in a 5 mm 5.5 R paste to make 50 mg of L-ethyl cysteine hydrochloride or methyl cysteine hydrochloride per tablet. It was. The amount of the solution added at the time of wet granulation was 35 ml for the mixing ratio (capacity ratio) of methylene chloride and ethanol of 9 to 1 and 3 to 7 and 15 ml of water only (I to I and V in Table 1). To).

(2) Magnesium stearate 1.5g was mixed with 100 g of L-ethyl cysteine hydrochloride, and a tablet of 5 mm diameter 5.5R was prepared at a weight of 50.75 mg per tablet (iii in Table 1).

(3) Magnesium stearate and 1.5 g of magnesium stearate were mixed with 100 g of methyl cysteine hydrochloride to form a tablet with a weight of 50.75 mg per tablet in a 5.5 R diameter pestle. (XIV in Table 1).

The tablet thus produced was stored for 2 weeks in an exposed state at 40 ° C. in a relative humidity of 75%, and the appearance change was observed. The results as shown in Table 1 were obtained. In addition, the following became clear from this result.

1. The solvent used for wet granulation is high in methylene chloride. This is because the alkyl cysteine hydrochloride hardly dissolves in methylene chloride, and thus, the binder, coating agent, and the like are granulated in a form in which the alkyl cysteine hydrochloride is coated, and the influence from the outside is eliminated. In addition, it can be seen that the granulated particles having a high content of methylene chloride float in water and a binder, a coating agent, and the like are coated around the alkyl cysteine hydrochloride.

2. Even in a mixed solvent of ethanol and methylene chloride in a 7 to 3 volume ratio, some stabilizing effect is obtained, but it is not sufficient. This is considered to be because alkylcysteine hydrochloride dissolves in ethanol during wet granulation and is exposed to the particle surface.

3. As can be seen from X and XVI, tablets prepared by mixing magnesium stearate in the same state without granulating L-ethyl cysteine hydrochloride and methyl cysteine hydrochloride tend to be colored. It can be seen that the associative treatment in a solvent containing as a main component is stabilized.

4. In this Experimental Example, the compound which does not cause a change in blending even when directly mixed with alkali hydrochloric acid hydrochloride is methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose Low phthalate, carboxymethylethylcellulose, methacrylic acid copolymer, stearic acid, paraffin and hydrogenated vegetable oil.

[Table 1 (Appearance change after storage for 2 weeks at 40 ℃, 75%)]

Note 1) Details of binders or coatings used are as follows. It is left blank because it has not been tested for insoluble in water.

I) hydroxypropylmethyl cellulose II) carboxymethyl ethyl cellulose

Ⅲ) hydroxypropylmethylcellulose phthalate

Ⅳ) Copolymer of Methacrylic Acid and Methyl Methacrylic Acid

Ⅴ) Hydroxypropyl cellulose VI) Polyvinylpyrrolidone

I) polyvinyl acetal diethylamino acetate i) polyvinyl alcohol

Iii) No addition Ⅹ) Methyl cellulose

XII) Ethylcellulose XII) Stearic Acid

ⅩⅢ) Solid paraffin ⅩⅣ) Hydrogenated vegetable oil (Libra wax) ⅩⅤ) Cornstarch ⅩⅥ) Free

Note 2) (-) shows little change, white, and (±) is slightly yellowish.

(+) Is yellow, (+ +) is dark yellow or brown,

(S) shows dissolution, which was completely white at the time of manufacture.

Experimental Example 2

Take 1 g each of L-ethyl cysteine hydrochloride or methyl cysteine hydrochloride, and combine all of the two in each of 100 mg of magnesium stearate, calcium stearate, stearic acid, talc, acid treated talc, light silicic anhydride and hydrogenated vegetable oil. For the mixture, the mixture was preserved at 40 ° C. and 75% RH for 2 weeks to investigate the appearance change.

As a result, those which did not discolor at all are stearic acid, acid treated talc, hard silicic anhydride; Slightly yellow with magnesium stearate, calcium stearate; What was yellow was talc.

Therefore, it was found that it is safe not to use talc in the conventionally used tablet type lubricant.

EXAMPLE

Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited at all to these Examples. "Part" in an Example shows a weight part.

Example 1

(1) 900 g of 1-ethyl cysteine hydrochloride was added to a microspeed mixer, and 18 g of carboxymethylethyl cellulose was dissolved in a mixture of 340 ml of methylene chloride and 400 ml of ethanol, followed by wet association and drying. After drying, a 24 mesh screen was passed through it, and 18 g of calcium stearate and 18 g of stearic acid were mixed and purified to a weight of 53 mg per tablet using a 5 mm diameter 5R pestle.

(2) Next, the tablets were sprayed with a film coating solution containing 50 parts of carboxymethylethyl cellulose, 10 parts of stearic acid and 7.5 parts of castor oil in a mixture of 660 parts of methylene chloride and 400 parts of ethyl alcohol. Enteric enteric coating and inner core.

(3) Separately, 225 g of pendizoic acid croperastin, 13.5 g of d-maleic acid chlorophenylamine, 150 g of dl-methyl ephedrine hydrochloride, 300 g of anhydrous caffeine, 1050 g of carboxymethylcellulose and 1260 g of microcrystalline cellulose were added to a speed mixer, The whole amount of the liquid which melt | dissolved 25.5 g of methylcellulose (SM-25) in 900 g of water was added here, and it combined and dried. After drying, 24 mesh screens were passed through which 1200 g of dilactose, 1467 g of calcium citrate, 165 g of talc and 30 g of magnesium stearate were mixed. What was produced here was made into the nucleus tablet whose weight per tablet was 390 mg, using the 9.5 mm 2-stage R pestle made into the inner core as what was produced in (2).

(4) The nucleated tablets made in this way were preserved at 60 ° C. for 1 month in an exposed atmosphere at 40 ° C. and 75% relative temperature, and then kept at 60 ° C. for 1 month to observe stability. A stable formulation was obtained as shown in the table.

[Table 2]

(5) By applying sugar to the tablet obtained in the above (2) by the usual method, a stable small sugar tablet without other odors was obtained.

Example 2

(1) 900 g of L-ethyl cysteine hydrochloride was added to a kneader, and 40.5 g of hydroxypropylmethylcellulose was added to 370 ml of a mixed solution of 7: 2.5: 0.5 volume of methylene chloride, ethyl acetate and ethanol. United. After drying, 13.5 g of magnesium stearate was mixed by passing through a 24 mesh screen, and the tablets were formulated at a weight of 53 mg per tablet using a 5.5 mm diameter pestle.

(2) Next, spray using a film coating solution of 45 parts of hydroxypropylmethylcellulose phthalate, 1.2 parts of stearic acid, 9 parts of talc, and 4.8 parts of dibutyl phthalate in a mixture of 660 parts of methylene chloride and 400 parts of ethanol. The enteric coating of 10 mg per tablet was coated by the method, and this was used as the inner core tablet.

(3) Separately, 810 g of potassium sulfonate, 180 g of pendizoic acid croferastin, 90 g of noscapine, 90 g of d-maleic acid, chlorophenylamine, 13.5 g of anhydrous caffeine, 300 g of carboxymethylcellulose and 795 g of microcrystalline cellulose were speeded up. It put in the mixer, and it combined and dried by adding the whole quantity of the liquid which melt | dissolved 25.5g of hydroxypropylmethylcellulose in 900g of water. After drying, 1247 g of dilactose, 400 g of calcium hydrogen phosphate, 45 g of calcium stearate, and 180 g of talc were mixed with each other by passing through a 24-mesh screen. What was produced here was made into the outer layer powder, and what was produced in (2) was made into the inner core, and it made into the nucleated tablet which is 340 mg weight per tablet using the 9-mm 2-stage R pestle.

(4) The nucleated tablets made in this way were preserved at 60 ° C. for 1 month in an exposed condition at 40 ° C. and 75% relative humidity, and then kept at 60 ° C. for 1 month in a sealed state. As shown in Table 3, a stable formulation was obtained.

[Table 3]

Example 3

(1) 900 g of methyl cysteine hydrochloride was placed in a fluidized bed granulator, and fluidized bed granulation was performed by adding a liquid in which 45 g of methyl cellulose (SM-25) was dissolved in a mixed solution of 615 g of methanol and 135 g of water. After drying, the mixture was passed through a 24 mesh screen, and 9 g of magnesium stearate and 4.5 g of hard silicic anhydride were mixed and tableted to a weight of 106.5 mg per tablet in a pestle having a diameter of 6.5 mm and 7 R.

Next, 15.5 mg of enteric solution per tablet was sprayed using a film coating solution in which 50 parts of carboxymethylethyl cellulose, 10 parts of stearic acid and 7.5 parts of dibutyl phthalate were dissolved in a mixture of 660 parts of methylene chloride and 400 parts of methanol. It coated and it was set as internal nuclear tablet.

(2) mix 90 g of dihydrocodein phosphate, 750 g of fenifene, 180 g of noscapine, 225 g of dl-methyl-ephedrine hydrochloride, 800 g of microcrystalline cellulose, and 200 g of low-substituted hydroxypropyl cellulose; The liquid which dissolved 7 g of cellulose in 800 g of water was added, and it combined and dried. After drying, a 24 mesh screen was passed through which 466 g of dilactose, 50 g of talc and 14 g of magnesium stearate were mixed. What was produced here was made into the outer layer powder, and what was produced in (1) was made into the inner core, and it made into the nucleated tablet which is 440 mg weight per tablet using the 10-mm 2-stage R pestle.

(3) The resulting nucleated tablets were preserved at 60 ° C for 1 month in an exposed atmosphere at 40 ° C and 75% relative humidity, and then kept at 60 ° C for 1 month in a sealed state. Stable tablets were obtained as shown in the table.

[Table 4]

Example 4

200 g of L-ethyl cysteine hydrochloric acid was put into a kneader, and the liquid which melt | dissolved 12 g of carboxymethyl ethyl cellulose in 4.5 volume part of cyclohexane, 4.5 volume part of methylene chlorides, and 1 volume part of ethanol was added, and it combined.

After drying, the mixture was passed through a 24 mesh screen, 4 g of magnesium stearate was mixed, and a tablet of 54 mg per tablet was weighed using a pestle having a diameter of 5 mm 5.5.

While this tablet was coated with an enteric coating by the method of Example 1 (2) as the inner core, and made by the method of Example 1 (3) as the powder for the outer layer, 1 using a 9.5 mm two-stage R pestle was used. It was made with a nucleus tablet of 391 mg per party. The nucleated tablets thus produced had the same stability as the tablets shown in Table 2.

Example 5

200 g of L-ethyl cysteine hydrochloric acid was put into a kneader, and the liquid which melt | dissolved 8 g of ethyl cellulose in 90 ml of mixtures of 5 volume parts of n-hexane and 5 volume parts of ethyl acetate was added and it combined. After drying, through a 24 mesh screen, 48 g of calcium hydrogen phosphate, 45 g of low-substituted hydroxypropyl cellulose, 3 g of calcium stearate, and 8 g of acid treated talc were mixed, using a 5 mm diameter 5.5R pestle. Tablets were formulated at a weight of 52 mg per tablet.

This tablet was coated with an enteric coating by the method of Example 2 (2) as an inner core, and made with the method of Example 2 (3) as an outer layer powder, and a 9.5 mm two-stage R pestle was used. 339 mg of nucleated tablets were made per tablet. The nucleated tablets thus produced had the same stability as the tablets shown in Table 3.

Claims (4)

Methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose and methacrylic acid copolymers Alkylcysteine or acid addition salt thereof granulated in a solution in which at least one binder or coating agent is dissolved in a solvent containing one or two or more mixtures selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, and methylene chloride as a main component Alkyl cysteine or acid addition salts obtained by mixing one or two or more lubricants selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, acid treated talc and light silicic anhydride, and compression molding Stable tablet containing. A nucleated tablet comprising the tablet according to claim 1 coated with an enteric coating by a spray method. The tablet according to claim 1, wherein the alkylcysteine or acid addition salt thereof is methylcysteine hydrochloride or L-ethylcysteine hydrochloride. The nucleated tablet according to claim 2, wherein the alkyl cysteine or acid addition salt thereof is methyl cysteine hydrochloride or L-ethyl cysteine hydrochloride.