KR100822180B1 - Method of stabilizing marginal tablets - Google Patents

Abstract

The present invention relates to a method for stabilizing marginal-containing tablets. Tablets prepared according to the present invention can stabilize the margin stone, an active ingredient, compared to the margin stone tablets prepared by a general pharmaceutical method, superior in hygroscopicity, and does not show a decrease in dissolution rate, thereby improving formulation stability. have.

In addition, the coated marginal stone particles prepared according to the present invention are excellent in fluidity, and thus tablets may be prepared by any of a direct method, a dry method, and a wet method.

Description

METHOOD OF THE STABILIZATION OF MAZINDOL CONTAINING THE PHAMACEUTICAL EXPIENTS}

1 is a view showing a change in the content of Examples 1, 2 and Comparative Example 1 of the present invention.

2 is a SEM photograph for confirming the crystal of Mazindol.

3 is a SEM photograph for confirming the crystal of glyceryl behenate.

Figure 4 is a SEM photograph for identifying the marginal particles coated with glyceryl behenate in Example 1 of the present invention.

5 is the main peak and margin material peak of the margin stone in the HPLC content test after 90 days under the accelerated conditions (40 ℃, 75% RH) of Example 2 according to the present invention.

6 is the main peak of the marginal stones of the initial experiment in the HPLC content experiment of Comparative Example 1.

Figure 7 is the main peak and margin material peak of the margin stone in the HPLC content test after 90 days under the accelerated conditions (40 ℃, 75% RH) of Comparative Example 1.

The present invention relates to a method for stabilizing marginal-containing tablets.

Margindol; 5- (4-chlorophenyl) -2,5-dihydro-3H-imidazo [2,1-a] isoindol-5-ol or 5- (4-chlorophenyl) -2,3-dihydro- 5-hydroxy-5H-imidazo [2,1-a] isoindole] is an imidazo-isoindole-based drug that was approved by the US FDA in 1973. Marginol is a sympathetic excitatory amine (catecholamines), similar to amphetamine, and its action is anorexic or anorexigenic drug with an initial body mass index (BMI) of 30 Kg / m2 or more, or 27 Kg / m2. If abnormal, obesity patients with other risk factors (e.g. hypertension, hyperlipidemia, diabetes) are used as obesity treatments for a short period (weeks) as an adjuvant therapy for weight loss treatment.

Marginol, on the other hand, increases heart rate and blood pressure, which can cause arrhythmia and angina deterioration in people with poor heart conditions.Anticholine drugs are used to stimulate the central nervous system (CNS) such as nerves and brain. It is known to have side effects such as dry mouth, constipation, stomach discomfort and sleep disorders that are thought to be caused by the action.

Mazindol is well soluble in ethanol and methanol but insoluble in water (see Merck Index). However, the solubility varies depending on the pH of the water, especially at low pH.

Also it has been reported indicating that mazindol are stable under different acid solution (acidic solution), and its example is carrying hydrochloric acid, nitric acid, phosphoric acid solution. (Analyst, 2001, 126, 1963-1968)

Margin stone is a fine powder, and when the particles are checked by SEM, it has a needle-like small crystal structure, which is difficult to handle due to its low fluidity, and stability of the raw material alone is secured. (Lactose, microcrystalline cellulose, starch gelatinized starch, mannitol, starch, white sugar, etc.) and a simple mixing or mixing (or granules) after the tableting is characterized by poor stability.

Therefore, since the stability of the pharmaceutical composition containing margin stones is greatly changed depending on the components (additives) and the preparation method, the preparation containing margin stones requires various preparation methods to improve formulation stability.

U. S. Patent No. 6,555, 669 describes formulations using biocompatible, biodegradable microcapsules in which the drug can be slowly released over a broad period of 1 to 100 days in an aqueous physiological environment, wherein the microcapsules contain It consists of a bioactive material encapsulated in a matrix of core or other poly (lactide / glycolide) [poly (lactide / glycolide)] copolymers.

Among the above-mentioned pharmaceutical additives, lipids widely used as carriers in pharmaceutical preparations have been mainly used in sustained-release preparations or lubricants, and are not suitable for preparation of fast-release preparations due to problems of dissolution rate. come.

It is not known that the margin stones are coated with a lipid layer alone or a mixed layer of lipid and inert semi-solid waxy material.

The inventor of the present invention, while studying a method for preparing a formulation having excellent stability, fluidity, and non-hygroscopicity compared to a conventionally known marginal-containing formulation, is a glyceryl fatty acid ester layer alone or a glyceryl fatty acid ester and an inert semi-solid waxy substance. The present invention has been found to be excellent in formulation stability without inhibiting dissolution rate in formulations containing marginal particles coated with a mixed layer of inert semi-solid waxy material.

An object of the present invention is to provide a method for stabilizing a marginal-containing tablet having excellent formulation stability without inhibiting dissolution rate.

In order to achieve the above object, the present invention is a margin coated with a lipid-based glyceryl fatty acid esters alone or a mixed layer of glyceryl fatty acid esters and inert semi-solid waxy material (inert semi-solid waxy material) The inclusion of stone particles in the formulation provides a method for stabilizing marginal tablets.

Margindol according to the present invention is preferably contained 0.1 to 5 parts by weight based on the total weight of the tablet, the marginal tablet is coated with 5 to 100 parts by weight of glyceryl fatty acid esters alone with respect to 1 part by weight of margin stones or 5 to 100 parts by weight of glyceryl fatty acid esters and 10 to 200 parts by weight of an inert semi-solid waxy material are preferably coated with 1 part by weight of marginal stone.

In the present invention, the lipid coating the lipid is at least one selected from glyceryl fatty acid esters, glyceryl fatty acid esters are glyceryl palmitostearate, glyceryl behenate, glyceryl behenate It may be selected from glyceryl stearate, glyceryl oleate, and glyceryl myristate.

In addition, the present invention may use lauroyl macrogolglycerides as an inert semi-solid waxy material used as a coating base of margin stones.

In the present invention, glyceryl palmitostearate and glyceryl behenate are used alone in the glyceryl fatty acid esters, or lauroyl macrogol glycerides, each of which is an inert semi-solid waxy material. It is most preferable to mix and use.

The amount of margin stones included in the pharmaceutical composition comprising the margin stones of the present invention is suitably about 0.1 to 5 parts by weight based on the total weight of the composition.

In addition, the present invention may further contain additives such as conventional additives (excipients, binders, disintegrants, glidants) and the like, which are used pharmaceutically as necessary without preparation constraints.

For example, excipients can be lactose, white sugar, starch, mannitol, sorbitol, glucose, microcrystalline cellulose, calcium dihydrogen phosphate, calcium hydrogen phosphate anhydrous, calcium carbonate, dextrate, lactitol, rudipress, etc. Methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose Cellulose derivatives such as; Starch, gelatin, povidone, copovidone, gum arabic and the like, and the disintegrant may be starch; Starch derivatives such as sodium starch glycolate; Carboxymethyl cellulose derivatives such as carboxymethyl cellulose calcium and crosslinked carboxymethyl cellulose; Microcrystalline cellulose, crosslinked povidone, sodium lauryl sulfate, and the like. Glidants also include the lipids mentioned above, and may be stearic acid and its pharmaceutically acceptable alkali metal salts or amine salts, colloidal silicon oxides, silicates, talc and the like.

In general, the nature of the marginal stones should be formulated in consideration of the moisture and the pH of the tablet, and the hygroscopic additives should not be used, the tablet according to the present invention stabilization treatment by the lipid layer itself as the main ingredient marginol By doing so, even if a variety of additives can be selected during formulation design, formulation design is possible.

As shown in FIG. 2, the marginal stone itself has a needle-like particle shape, and its flowability is poor, and the powder has a powdery shape, and thus, a surface having a relatively large area in contact with an excipient has a mouth shape, but the present invention has a margin. The stone itself may be coated and granulated with a layer of glyceryl fatty acid ester to improve the poor fluidity due to the crystal bed peculiar to margin stones. That is, the present invention is a glyceryl behenate which is one of the lipid excipients shown in Figure 3 and the glyceryl behenate and the excipient as shown in Figure 4 by stirring for a predetermined time at a temperature 2 ~ 5 ℃ lower than the melting temperature As the core, the main components are repeatedly laminated and coated to form a spherical shape, which improves the flowability and improves the physical properties when tableting, and reduces the surface area in contact with excipients. By reducing the content of the main component by the surface, the surface is coated with lipid excipients can have a double effect of protection. In addition, it can be visually confirmed that the eluent penetrates into the space of the laminated layer to reduce the inhibition of solubility.

In addition, the margin stone is a material having a high hygroscopicity, there is a problem in that the stability is lowered by changing the pH during formulation or storage, the present invention is also excellent in non-hygroscopicity by coating granulated margin stone itself with a glyceryl fatty acid ester layer.

Margindol-containing tablets according to the present invention exhibits a dissolution rate suitable for USP standards despite the use of glyceryl fatty acid esters used in sustained-release formulations as a coating material, glyceryl fatty acid esters and inert semi-solid waxy substances ( 1 to 5 parts by weight of inert semi-solid waxy material is mixed with 5 to 100 parts by weight of glyceryl fatty acid ester and 10 to 200 parts by weight of inert semi-solid waxy material. By supplementing the disadvantages of the glyceryl fatty acid esters while maintaining the main component protection effect, the solubilization properties of the inert semi-solid waxy material is synergistic, showing a more smooth dissolution rate.

The present invention provides a method for producing marginal coating particles contained in marginal tablets.

The present invention comprises the steps of adding 5 to 100 parts by weight of glyceryl fatty acid esters to 1 part by weight of marginal stones to prepare a mixture;

Preparing a melt by mixing the mixture at a temperature lower than 2 to 5 ° C. below the melting point of glyceryl fatty acid esters; And

Cooling the lysate to form a marginal stone particles coated in the doldol tablets comprising the step of forming a marginal stone particles coated with glyceryl fatty acid esters.

In the present invention, when using glyceryl fatty acid esters alone as the coating base of the margin stones, 5 to 100 parts by weight of glyceryl fatty acid esters are added to 1 part by weight of the margin stones to prepare a mixture. If the ratio of glyceryl fatty acid esters in the mixture is too low than the above ratio, the coating may not be completed. If the ratio of glyceryl fatty acid esters is too higher than the above ratio, it will affect the dissolution of the drug.

In the present invention, the melt is a margin on the surface of the glyceryl fatty acid ester by melting the surface of the glyceryl fatty acid ester by mixing the mixture for 10 minutes to 120 minutes while maintaining the temperature 2 ~ 5 ℃ lower than the melting point of the glyceryl fatty acid esters Prepare the lysate to which the stone is adsorbed. At this time, since the molten glyceryl fatty acid esters are continuously stirred, the surface of the marginal stone is recoated to protect the main component, so that the film is thin and does not inhibit elution. In addition, the glyceryl fatty acid esters used in the production method of the present invention generally fall in the range of 40 ~ 90 ℃. For example, when glyceryl palmitostearate is used, a temperature of about 50 ° C. is slightly lower than 53 to 57 ° C., which is the melting point of glyceryl palmitostearate.

In the present invention, the coated margin stone particles are rapidly cured by cooling the melt through cooling water, and thus, a small amount of granule particles are formed due to the formation of small granule particles.

In another aspect, the present invention provides another method for producing the marginal coating particles contained in the marginal tablets.

In the present invention, another method for preparing a tablet containing margin stones is 5 to 100 weight of glyceryl fatty acid esters based on 1 part by weight of glyceryl fatty acid esters and inert semi-solid waxy material. Preparing a mixture by mixing 10 parts by weight to 200 parts by weight of the inert semi-solid waxy material and the inert semi-solid waxy material;

Dissolving the mixture at a temperature above the melting point of glyceryl fatty acid esters, and then mixing the mixture with marginal stones at a temperature higher than the melting point of the glyceryl fatty acid esters to prepare a molten mixture; And

Cooling the molten mixture may include preparing the coated margin stone particles, thereby preparing margin stone coated particles contained in the margin stone tablets.

In the present invention, the coating base is 5 to 100 parts by weight of glyceryl fatty acid esters and inert semi-solid waxy resin based on 1 part by weight of glyceryl fatty acid esters and inert semi-solid waxy materials. 10 to 200 parts by weight of the inert semi-solid waxy material may be mixed, and the ratio of glyceryl fatty acid esters to the inert semi-solid waxy material may be 1: 0.5 to 1: 5. Most preferred. If the ratio of glyceryl fatty acid ester in the mixture is too lower than the above ratio, the coated margin stone becomes sticky due to the physical properties of the inert semi-solid waxy material, and thus the workability is not good. If the ratio of reyl fatty acid esters is too high than the above ratio, it will adversely affect the dissolution of the drug.

In the present invention, the molten mixture is melted in advance at a temperature of 5 to 8 ° C. above the melting point of the glyceryl fatty acid esters, preferably mixed sufficiently, and the mixture is mainly composed of the main components, such as margin stones and glyceryl fatty acid esters, and inert semi-solid wax properties. A melt mixture is prepared by mixing an inert semi-solid waxy material mixture for 20 to 120 minutes at a temperature of 5 to 8 ° C. higher than the melting point of glyceryl fatty acid esters.

In the present invention, the marginal coating particles are coated with a mixture of the glyceryl fatty acid esters and the inert semi-solid waxy material, and the glyceryl fatty acid esters cooled by cooling them. And the inert semi-solid waxy material mixture is prepared with the main component of marginal stone coated with a mixture of fine granular glyceryl fatty acid esters and inert semi-solid waxy material. do. The coating film is cured rapidly by cooling the mixed melt of the glyceryl fatty acid esters and the inert semi-solid waxy material through a cooling water, and glyceryl fatty acid due to the formation of small granular particles due to this phenomenon. The main ingredient of the marginal stone is coated with a thin film of a mixture of esters and inert semi-solid waxy materials.

The main ingredient of Marginol coated with a mixture of glyceryl fatty acid esters and inert semi-solid waxy material prepared in this way protects the main ingredient from moisture and ensures stability. Due to the properties of the inert semi-solid waxy material, it does not inhibit dissolution but rather helps dissolve the drug.

In addition, a certain amount of disintegrants generally known in the pharmaceutical field is used to prepare a marginal main ingredient coated with a mixture of glyceryl fatty acid esters and an inert semi-solid waxy material, thereby improving the effect. The disintegrant used at this time may preferably be carboxymethyl cellulose calcium or the like, and the ratio of the main component and the disintegrant is preferably 1: 0.4 to 1: 8.

Glyceryl fatty acid esters used in the production method of the present invention, the melting point is generally in the range of 40 ~ 90 ℃. The glyceryl fatty acid esters used here are preferably glyceryl palmitostearate and lauroyl macrogol glyceride as an inert semi-solid waxy material.

The above two raw materials Glyceryl palmitostearate and lauroyl macrogol glyceride have a melting point of 44 ~ 57 ℃, so the temperature difference is not so large that it is suitable for use as excipient of hot melt granulation, which is a pharmaceutical granulation method. The physical properties are also complementary, so there are many advantages that can be obtained when two excipients are used together.

Margindol-containing tablets in the present invention may be prepared in various ways according to the tablet manufacturing method generally known in the pharmaceutical art.

The coated margin stone particles obtained in the present invention may use wet granule compression method because the glyceryl fatty acid esters used surround the drug particles to prevent the penetration of moisture, and thus the range of use may be more versatile.

In the present invention, the production method by the direct compression method is an anhydrous lactose, spray-dried lactose, microcrystalline cellulose, calcium dihydrogen phosphate, rudipures, pregelatinized starch, mannitol and the like, as known in the pharmaceutical field. Compressed powders are compression molded directly using other excipients.

In the present invention, when using the dry granulation method (dry granulation method) of the granulated powder using a low-speed tableting machine or a crusher to produce a slug (slug) and then to crush the granules obtained by crushing again or a roller compactor And compression molding of the granules obtained.

In the present invention, the wet granulation method of the wet granulation method (wet granulation method) is a compression molding of the granules obtained by associating the mixed powder using a binder and then granulating and drying the granulated powder.

As described above, the manufacturing method of the present invention gives a wider selection range of the tablet manufacturing method than the conventional manufacturing method, which is sensitive to moisture and pH inside the tablet and is restricted in the manufacturing method, so that an appropriate method can be selected as necessary. It can increase the convenience and efficiency of the preparation of stone-containing tablets.

Hereinafter, preferred preparation examples are provided to aid the understanding of the present invention. However, the following Preparation Examples and Examples are provided to facilitate the use of the present invention is not limited to the contents of the present invention by the Preparation Examples and Examples.

<Manufacture example 1> Preparation of Abrasive Stone Coating Particles (Coating Base: Glyceryl Behenate)

Apples Margdol 67g and Glyceryl Behenate 33g in No. 20 sieve and mixed them into a mixer, and after mixing the temperature control speed mixer to a temperature of about 65 ℃, add the mixture and stirred for about 30 minutes at 50rpm The coating was progressed and cooled using cooling water to prepare marginal coated particles as fine granules.

<Manufacture example 2> Preparation of Abrasive Stone Coating Particles (Coating Base: Glyceryl Behenate)

Apples Marginol 77g and Glyceryl Behenate 23g with No. 20 sieve and mixed them into a mixer, and after mixing the temperature control speed mixer to a temperature of about 65 ℃, add the mixture and stirred for 30 minutes at 50rpm The coating was progressed and cooled using a cooling water to prepare marginal coated particles as fine granules.

<Manufacture example 3> Preparation of Abrasive Stone Coating Particles (Coating Base: Glyceryl Palmitostearate)

Apple 77g Marginol and 23g Glyceryl Palmitostearate were mixed with No. 20 sieve and mixed in a mixer.Then, the temperature control speed mixer was heated to a temperature of about 50 ℃, then the mixture was added and stirred at 50 rpm for about 30 minutes. The coating of the margin stones was carried out and cooled using a cooling water to prepare the fine granules of the coated granules.

<Manufacture example 4> Preparation of Abrasive Stone Coating Particles (Coating Base: Glyceryl Palmitostearate and Lauroyl Macrogol Glyceride)

17.39 g of marginal stones and 69.56 g of carboxymethyl cellulose calcium are apples with No. 20 sieve and mixed in a mixer. Separately, 8.70 g of lauroyl macrogol glyceride and 4.35 g of glyceryl palmitostearate prepared from apples in 20 are prepared. After the temperature control speed mixer is heated to a temperature of about 65 ° C., the above mixture of marginal stone, carboxymethyl cellulose calcium, glyceryl palmitostearate and lauroyl macrogol glyceride is added, and the mixture is stirred at 50 rpm for about 30 minutes. The coating of the stone was progressed and cooled using a cooling water to prepare the fine granules as a marginal coated particles.

<Example 1> Preparation of margin stone tablet of the present invention by the direct hit method 1

10g of the marginal coating particles prepared in Preparation Example 2, 465.4g of microcrystalline cellulose, 384.6g of Ludipress, 30.8g of copovidone, 69.2g of crospovidone, and 1.5g of colloidal silicon dioxide were mixed in a V-type mixer for 10 minutes. 38.5 g of glycerol dibehenate was added to the mixture, followed by further mixing for 5 minutes, and then, using a rotary tablet press, 130 mg per tablet weight and hardness of 5 kp or more were prepared.

<Example 2> Preparation of margin stone tablet of the present invention by the direct hit method 2

44.2 g of the marginal coated particles prepared in Preparation Example 4, 431.2 g of microcrystalline cellulose, 384.6 g of Ludipress, 30.8 g of copovidone, 69.2 g of crospovidone, and 1.5 g of colloidal silicon dioxide were mixed in a V-type mixer for 10 minutes. 38.5 g of glycerol dibehenate was added to the mixture, followed by further mixing for 5 minutes, and then, using a rotary tablet press, 130 mg per tablet weight and hardness of 5 kp or more were prepared.

Comparative Example 1 Preparation of margin stone tablets by general direct hit method

Apples were measured with 1 g of marginal stones, 106.2 g of rudipress, 10 g of povidone, and 10 g of carboxymethyl cellulose calcium. The apples were put in a mixer and mixed for 20 minutes. 1.3 g of talc and 1.5 g of magnesium stearate were added to the mixture, followed by further mixing for 5 minutes, thereby preparing a tablet with a tablet weight of 130 mg per tablet using a tableting machine.

<Comparative Example 2> Preparation of tablets by the direct blow method of marginal stones coated by melt granulation method

Apple 50g and glyceryl behenate 50g in a No. 20 sieve, put it in a mixer and mix the temperature control speed mixer temperature adjustable to about 75 ℃, add the mixture and stirred for about 30 minutes at 50rpm The coating proceeded and cooled with cooling water to form granules.

The coated raw material 2g, Rudipress 106.5g, povidone 10g, carboxymethyl cellulose calcium 10g apples the raw material measured by No. 20 sieve and put the apples into a mixer and mixed for 20 minutes. 1.5 g of magnesium stearate was added to the mixture, followed by further mixing for 5 minutes, thereby preparing a tablet with a tablet weight of 130 mg per tablet using a tableting machine.

Experimental Example 1 Stability Test of Marginol Tablet

1 week (7 days), 2 weeks (14) while storing the marginal tablets prepared in Example 1, Example 2 and Comparative Example 1 in a sealed state in a polyethylene container at 40 ℃, 75% RH At the time of 1), 1 month (30 days), 2 months (60 days) and 3 months (90 days), the content of the main ingredient drug in the tablet was measured by high performance liquid chromatography. In the measurement of the content, the results of three experiments were measured at each time point, and the results are shown in comparison with FIGS. 1 and 1.

As can be seen from the results of Table 1, in Example 1 and Example 2 according to the present invention can be confirmed that only three months after the content of only -4% decrease in the content of the stability is significantly increased. In addition, the tablet prepared in Example 2 is the HPLC main component peak of the content experiment 3 months elapsed under the conditions of 40 ℃, 75% RH in Figure 5 showing a good state that the degree of very small or almost no peak of the flexible material It can be confirmed that the effect of suppressing the formation of this flexible substance is excellent.

However, the marginal tablet of Comparative Example 1 prepared by the method of preparing a general tablet can be confirmed that a rapid decrease in the content of the marginal stone itself as a main component after 3 months under the influence of moisture and temperature under 40 ℃, 75% RH conditions. have. As can be seen in the accompanying FIG. 6, in Comparative Example 1, no peak was observed except for the HPLC main component peak of the content experiment, but the comparative example 1 of 3 months elapsed under the conditions of 40 ° C. and 75% RH was observed. In the HPLC main component peak of the content test in Figure 7 it can be seen that the content decreases due to the formation of a flexible material due to other excipients and moisture.

Experimental Example 2 Dissolution test of margin stone tablets

The dissolution rate of each of the tablets prepared in Example 1, Example 2, and Comparative Example 2 was measured according to the dissolution test items of the USP margin stone tablets. 500 mL of 0.01 N hydrochloric acid was used as the test solution, and the rotation speed of the paddle was 50 rpm. The test solution was collected 120 minutes after the start of the test, and the drug concentration was measured. The drug dissolution rate of each tablet is shown in Table 2.

As shown in Table 2, in Examples 1 and 2 prepared by the method of the present invention can be confirmed that there is no inhibition of dissolution rate due to the properties of glyceryl fatty acid esters, which is coated with glyceryl fatty acid esters stability It can be confirmed that the problem of inhibiting the dissolution rate, which is a problem of the technology to secure the solution, is overcome.

However, it can be seen that the tablet prepared using the marginal stone coated by the melt granulation method as in Comparative Example 2 has a problem that the release of the drug cannot be released within the dissolution time due to the dissolution rate inhibition effect of the glyceryl fatty acid esters. .

The present invention has a strong hygroscopic ability to stabilize the marginal stone is stable stability decreases the pH is changed by the moisture during formulation or storage, it is excellent in non-hygroscopicity compared to the marginal stone tablet prepared by the general pharmaceutical method, the dissolution rate There is no degradation and the formulation stability can be improved.

In addition, the marginal coating particles produced by the present invention is excellent in fluidity can be produced tablets by any method of the direct method, dry method, wet method.

Claims (6)

5 to 100 parts by weight of glyceryl fatty acid esters were added to 1 part by weight of marginal stone to prepare a mixture, and the mixture was mixed while maintaining a temperature lower than 2 to 5 ° C. below the melting point of glyceryl fatty acid esters to prepare a melt. Then, the method of stabilizing marginal tablets characterized in that it contains the marginal coating particles formed by cooling the lysate. According to claim 1, Glyceryl fatty acid esters are glyceryl palmitostearate (glyceryl palmitostearate), glyceryl behenate (glyceryl behenate), glyceryl stearate (glyceryl stearate), glyceryl oleate (glyceryl oleate), Method for stabilizing marginal tablets, characterized in that selected from glyceryl myristate (glyceryl myristate). delete 5 to 100 parts by weight of glyceryl fatty acid esters and 10 to 200 parts by weight of lauroyl macrogolglycerides, an inert semi-solid waxy material, based on 1 part by weight of margin stone. A mixture was prepared, and the mixture was dissolved at a temperature of 5 ° C. to 8 ° C. above the melting point of glyceryl fatty acid esters, and then mixed with a marginal stone at a temperature of 5 ° C. to 8 ° C. above the melting point of glyceryl fatty acid esters to melt the mixture Method of stabilization of margin stone tablets, characterized in that it contains the margin stone coating particles formed by cooling after the preparation. According to claim 4, Glyceryl fatty acid esters are glyceryl palmitostearate (glyceryl palmitostearate), glyceryl behenate (glyceryl behenate), glyceryl stearate (glyceryl stearate), glyceryl oleate (glyceryl oleate), Method for stabilizing marginal tablets, characterized in that selected from glyceryl myristate (glyceryl myristate). A margin stone tablet containing margin stone coated particles produced by the method according to claim 5.

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