JP2003517432A - Pravastatin sodium-containing drug composition - Google Patents

Abstract

  (57) [Summary]   The present invention relates to a pharmaceutical composition containing pravastatin sodium (pravastatin sodium), and more specifically, contains pravastatin sodium as an active ingredient and β-cyclodextrin as a stabilizer to increase the temperature and temperature. The present invention relates to a pharmaceutical composition capable of contributing to stability of pravastatin sodium which is unstable under conditions of humidity.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing pravastatin sodium, more particularly, pravastatin sodium as an active ingredient and β-cyclodextrin as a stabilizer to increase the temperature and The present invention relates to a pharmaceutical composition containing pravastatin sodium, which can contribute to the stability of pravastatin sodium which is unstable under the condition of humidity.

[0002]

[Prior art]

Hyperlipidemia is a condition in which the concentration of plasma lipids (cholesterol, neutral lipids, phospholipids, free fatty acids, etc.) is increased beyond the normal range, but clinically it is arteriosclerosis. It causes hypertension, ischemic heart disease and pancreatitis. Therefore, the development of drugs capable of lowering cholesterol is in progress, but in the case of pravastatin sodium represented by the following chemical formula among these drugs, hydroxymethylglutaryl Co-A enzyme is involved in the process of cholesterol biosynthesis. It is well known that it is useful for the treatment of hyperlipidemia because it has an excellent ability to inhibit the production of cholesterol by inhibiting the action of. Pravastatin sodium forms various isomers with its own lactone under the conditions of high temperature and humidity.

[0003]

[Chemical 1]

When a drug composition containing pravastatin sodium represented by the above chemical formula as a main component is formulated, existing lactose, silicon dioxide, croscarmellose sodium, microcrystalline cellulose, polyvinylpyrrolidone, etc. Pharmaceutical compositions have been formulated using only the above excipients. For example, pravastatin sodium, lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate have been adopted as general pharmaceutical compositions (VIDAL, p.568 (1997), ELISOR; VIDAL, p.1750. -1751 (1997), VASTEN
20 mg; ROTE LISTE 58 038 (1996), PRAVASIN 5 mg / 10 mg / 20 mg). However, a pharmaceutical composition using only such an excipient has a problem that decomposition rapidly occurs in a high temperature and high humidity environment.

[0005]

[Problems to be Solved by the Invention]

As part of such research, the present inventor has completed the present invention by discovering that β-cyclodextrin has a property of including a low-molecular substance and blocking the surrounding environment.

Accordingly, the present invention comprises formulating a pharmaceutical composition comprising pravastatin sodium, an excipient, a binder, a disintegrant, a lubricant and β-cyclodextrin,
Unstable pravastatin sodium (pravastatin s) under high temperature and humidity conditions
Its purpose is to provide a pharmaceutical composition comprising pravastatin sodium, which can contribute to the stability of odium).

[0007]

[Means for Solving the Problems]

The present invention uses pravastatin sodium as an active ingredient, and in a pharmaceutical composition containing an excipient, a binder, a disintegrating agent, and a lubricant, β-cyclodextrin as a stabilizer of pravastatin sodium which is the above-mentioned active ingredient. Is contained in the pharmaceutical composition.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail as follows. In order to prevent decomposition that occurs rapidly in a high temperature and high humidity environment, a low molecular weight substance β-is used in the formulation of a pharmaceutical composition containing pravastatin sodium as a main component.
It is intended to provide a pharmaceutical composition having excellent stability against temperature and humidity by utilizing the property of enclosing with cyclodextrin to block the surrounding environment.

The pharmaceutical composition of the present invention comprises pravastatin sodium as an active ingredient, β-cyclodextrin as a stabilizer, and one or more excipients selected from lactose, starch, microcrystalline cellulose and the like, hydroxypropyl. Cellulose, microcrystalline cellulose,
One or more binders selected from hydroxypropylmethyl cellulose and dextrin, one or more disintegrants selected from low-substituted hydroxypropyl cellulose and croscarmellose sodium, magnesium stearate,
It contains one or more lubricants selected from talc, stearic acid and the like.

The pravastatin sodium contained as a useful ingredient in these ingredients is contained in an amount of 2 to 50% by weight, preferably 2 to 30% by weight, based on the whole pharmaceutical composition. Pravastatin sodium inhibits the action of hydroxymethylglutaryl Co-A enzyme in the process of cholesterol biosynthesis and suppresses the production of cholesterol. If the content of pravastatin sodium is less than 2% by weight, the increase in the weight of the tablet reduces the adaptability to patient administration. However, if it exceeds 50% by weight, there is a problem that it is difficult for each patient to control the dose.

Since pravastatin sodium forms various isomers with its own lactone under the condition of high temperature and humidity, β-cyclodextrin is added as a stabilizer of the active ingredient in the present invention to prevent this. . In the past, when a pharmaceutical composition was formulated, rapid degradation occurred by formulating only a conventional excipient.
On the other hand, in the present invention, by adding β-cyclodextrin as a stabilizer, it is possible to obtain a pharmaceutical composition which is stable even under the above environmental conditions. The β-cyclodextrin comprises 50-5,000 parts by weight, preferably 100-3,000 parts by weight, based on 100 parts by weight of pravastatin sodium. When the content of β-cyclodextrin is less than 50 parts by weight, pravastatin sodium is not sufficiently stabilized, so that decomposition may occur under temperature and humidity conditions. On the other hand, if it exceeds 5,000 parts by weight, there is a problem that formulation becomes difficult.

In the pharmaceutical composition of the present invention, in addition to pravastatin sodium which is the above-mentioned active ingredient and β-cyclodextrin which is a stabilizer, excipients, binders and disintegrators which are commonly used in pharmaceutical compositions are provided. Agents and lubricants are included.

As the excipient, 1 selected from corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, microcrystalline cellulose, dextrin, or methylcellulose is used. More than a seed,
5-90% by weight based on the total pharmaceutical composition.

The binder is selected from methylcellulose, microcrystalline cellulose, hydroxycellulose, glycerin, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, or polyvinyl alcohol.
More than one species, 25-35% by weight of the total pharmaceutical composition.

The disintegrant is one or more selected from hydroxypropylmethylcellulose, hydroxypropylstarch, polyvinylpyrrolidone, methylcellulose, and low-substituted hydroxypropylcellulose, and the total disintegrant composition is 0.5-10% by weight is included.

The lubricant is one or more selected from stearic acid, magnesium stearate, talc, liquid paraffin, or hard silicic acid anhydride, and is used in an amount of 0.25-5% by weight based on the whole pharmaceutical composition. %included.

The pharmaceutical composition of the present invention having such a composition is produced by the following method. First, pravastatin sodium and β-cyclodextrin are ground in an appropriate container for several tens of minutes. Subsequently, one or more kinds of excipients are added depending on the purpose, and a solution of one or more kinds of binders in a solvent (water, isopropanol, dichloromethane) is wet granulated and dried, or one or more kinds of lubricants are added. After the agent and one or more binders have been added, dry granulation is carried out with a pressing roller.

After carrying out the above process, one or more disintegrants, lubricants, or binders are optionally selected and included to prepare the pharmaceutical composition of the present invention.

A pharmaceutical composition containing pravastatin sodium, which is the active ingredient of the present invention, and β-cyclodextrin, which is a stabilizer, prepared by the above-mentioned method,
It can be compounded with an ordinary pharmaceutically acceptable carrier, and can be formulated as an oral administration preparation such as tablets, capsules, powders, granules, pills and the like, which is a usual preparation in the pharmaceutical field.

Examples of the carrier used according to the present invention include carriers commonly used in the pharmaceutical field, such as binders, lubricants, disintegrants, excipients, stabilizers, and garments. Can be mentioned. In addition, in order to prevent the drug from being decomposed by gastric acid during oral administration, an antacid may be used in combination, or it may be formulated and administered as a formulation in which tablets, granules and the like are coated with viscera.

According to the present invention, oral administration in tablet form is in principle the preferred route of administration (
ABPI Compendium of Data Sheets, VIDAL, ROTE, LISTE, Physicians' Desk Re
conference).

The human body dose of the active ingredient according to the present invention is appropriate in consideration of the degree of absorption, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, the serious condition of the disease to be treated and the like. However, in general, 10-40 mg / day is administered to adults before bedtime (ABPI C
ompendium of Data Sheets, p.1780-1782 (1995-1996), LIPOSTAT TABLETS)
, Or 10-20 mg / day as the initial dose. As a general dose, 10-40 mg / day for adults and 20 mg or less for the elderly are administered daily (Physicians' Desk R
eference, p.732-735 (1995), PRAVACHOL). Also, once as an initial dose 10
40mg / day, maximum dose 40mg in the evening (VIDAL, P.568 (1997), ELISOR:
p.1750-1751 (1997) VASTEN), or 5-10 mg / day as initial dose and 40 mg as maximum dose (ROTE LISTE, 58 038 (1996), PRAVASIN 5 mg / 10 mg / 20 mg)
) Do. Therefore, in the present invention, it is preferable to administer 5-10 mg / day once in the evening or before going to bed based on the above-mentioned literature.

[0023] As described above, a pharmaceutical composition containing pravastatin sodium of the present invention as an active ingredient and β-cyclodextrin as a stabilizer is formulated, and β is included in order to enclose the active ingredient of the pharmaceutical composition. Physical force was applied after mixing cyclodextrin and pravastatin sodium. As a result, when β-cyclodextrin was contained, it was confirmed that the stability against temperature and humidity was remarkably excellent (FIGS. 1 to 29). When comparing the stability of the drug of the present invention shown in FIGS. 1 to 20 and FIGS. 26 to 29 with β-cyclodextrin or the stability of A tablet, the drug of the present invention is the conventional drug. It is recognized that the stability was superior to temperature as compared with. Further, as shown in FIGS. 21 to 25, it can be seen that the drug of the present invention was more stable against humidity. Furthermore, in the process of formulating the pharmaceutical composition of the present invention, existing machines such as a rolling compactor can be applied even in the case of mass production, so that the cost of additional production equipment can be improved. Can be satisfied with the physical aspects.

[0024]

【Example】

The present invention will be described in more detail based on the following examples, but the present invention is not limited thereto. Example 1 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Hydroxypropylcellulose 5 mg Low-substituted hydroxypropylcellulose 13.5 mg Lactose 48.51 mg Magnesium stearate 0.9 mg Pravastatin sodium and β-cyclodextrin were mixed well in a suitable container. Crushed for 20 minutes. Lactose was added to this and mixed thoroughly, granulated with an aqueous binder solution (hydroxypropyl cellulose), and dried in an oven maintained in the range of 30-40 ° C. The dried product was sized with a No. 20 sieve, low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well, and then tableted.

Example 2 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Hydroxypropylcellulose 5 mg Low-substituted hydroxypropylcellulose 13.5 mg Lactose 30.0 mg Corn starch 18.51 mg Magnesium stearate 0.9 mg Pravastatin sodium and β-cyclodextrin are well Mix and grind for 20 minutes in a suitable container. Lactose and starch were added to this and mixed thoroughly to obtain a binder aqueous solution (
Hydroxypropyl cellulose) and granulated in an oven maintained in the range of 30-40 ° C. The dried product was sized with a No. 20 sieve, low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well, and then tableted.

Example 3 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Hard silicic acid anhydride 1.75 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 30.0 mg Magnesium stearate 1.6 mg Pravastatin sodium and β-cyclodextrin are well mixed and suitable. It was crushed for 20 minutes in a different container. Hard silicic acid anhydride, lactose and magnesium stearate
(1/2 amount) was added and mixed thoroughly, and dry granules were produced with a compression roller. Granules with low-substituted hydroxypropyl cellulose and magnesium stearate (1/2
(Amount) was added and mixed well before tableting.

Example 4 Pravastatin sodium 5 mg β-Cyclodextrin 127.09 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 20.07 mg Corn starch 28.0 mg Dextrin 7.8 mg Red pigment # 3 0.12 mg Blue pigment # 1 Aluminum lake 0.12 mg Stearic acid Magnesium 1.6 mg Pravastatin sodium and β-cyclodextrin were thoroughly mixed and ground in a suitable container for 20 minutes. Lactose and corn starch (1/2 volume) were added to this and mixed well to dissolve the dye (red dye # 3, blue dye # 1 aluminum lake) in the binder solution (
Dextrin) was added to produce granules. After thoroughly drying in an oven maintained in the range of 30-40 ° C, the remaining corn starch (1/2 volume), low substituted hydroxypropyl cellulose and magnesium stearate were added to the granulate and mixed well. Tableted from.

Example 5 Pravastatin sodium 5 mg β-Cyclodextrin 127.09 mg Lactose 30.31 mg Potato starch 30.0 mg Polyvinyl alcohol 7.8 mg Magnesium stearate 1.9 mg Pravastatin sodium and β-cyclodextrin are mixed well and in a suitable container for 20 minutes. Crushed. Lactose and potato starch were added thereto and mixed well, and a binder which was an aqueous solution of polyvinyl alcohol was added to produce granules. Granules 30-
After drying well in an oven maintained in the range of 40 ° C., magnesium stearate was added to and mixed with the granules, and then tableted.

Comparative Example 1 Pravastatin sodium 5 mg Hydroxypropyl cellulose 5 mg Low-substituted hydroxypropyl cellulose 10.0 mg Lactose 175.6 mg Magnesium stearate 0.9 mg Pravastatin sodium and lactose were thoroughly mixed to form a binder aqueous solution (hydroxypropyl cellulose aqueous solution). Granulated in and dried in an oven maintained in the range of 30-40 ° C. The dried product was sized with a No. 20 sieve, and low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well, and then tableted.

Comparative Example 2 Pravastatin sodium 5 mg Hydroxypropylcellulose 5 mg Low-substituted hydroxypropylcellulose 13.5 mg Lactose 157.09 mg Corn starch 18.51 mg Magnesium stearate 0.9 mg Pravastatin sodium, lactose and corn starch were thoroughly mixed and binders It was granulated with an aqueous solution (hydroxypropyl cellulose aqueous solution) and dried in an oven maintained in the range of 30-40 ° C. The dried product was sized with a No. 20 sieve, and low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well, and then tableted.

Comparative Example 3 Pravastatin sodium 5 mg Hard anhydrous silicic acid 1.75 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 181.65 mg Magnesium stearate 1.6 mg Pravastatin sodium, hard anhydrous silicic acid and magnesium stearate (1 /
(2 volumes) were thoroughly mixed, and dry granules were produced by a pressing roller. Low-substituted hydroxypropylcellulose and magnesium stearate (1/2 amount) were added to the dried product and mixed well, and then tableted.

Comparative Example 4 Pravastatin sodium 5 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 120.27 mg Corn starch 55.09 mg Dextrin 7.8 mg Red pigment # 3 0.12 mg Blue pigment # 1 Aluminum lake 0.12 mg Magnesium stearate 1.6 mg Pravastatin sodium, A binder solution (dextrin) in which lactose and corn starch are mixed well and dyes (red dye # 3, blue dye # 1 aluminum lake) are dissolved
Was added to produce granules. After thoroughly drying in an oven maintained in the range of 30-40 ° C, the remaining corn starch (1/2 volume), low substituted hydroxypropyl cellulose and magnesium stearate were added to the granulate and mixed well. Tableted from.

Comparative Example 5 Pravastatin sodium 5 mg Lactose 130.31 mg Potato starch 57.09 mg Polyvinyl alcohol 5.7 mg Magnesium stearate 1.9 mg Pravastatin sodium, lactose and potato starch were mixed well and a binder which was an aqueous polyvinyl alcohol solution was added to form granules. Manufactured. After the granules were well dried in an oven maintained in the range of 30-40 ° C, magnesium stearate was added to and mixed with the granules before tableting.

Experimental Example 1 In order to prove the effect of the present invention, the final formulation was subjected to severe temperature conditions (40 ° C.).
, 50 ° C., 60 ° C., 70 ° C.), and changes in the content and degradation products were observed using the following equipment. The results are shown in the following Table 1-5 and FIG. 1-20. And high performance liquid chromatography (HPLC): Waters (R) 510 Detector: Ultraviolet absorptiometer system (238 nm) Column: Kosumojiru (Cosmosil) C ₁₈ move like: methanol, H ₂ O, TEA-glacial acetic acid (500 : 500: 1: 1) Flow rate: 1.5 ml / min Injection volume: 5 μl ・ Autosamler: Waters (registered trademark) 717 ・ Integrator: Waters (registered trademark) 740 ・ Detector: Waters (registered trademark) 186 ・ Oven: SUN YOUNG, SY-IN.G (40 ° C) Space Chemical Corporation, VO-C-2 (50 ° C) Space Chemical Corporation, VO-C-2 (60 ° C) EYELA. NDO-600-ND (70 ℃) ・ Life tester (autosamler): JEIO TECH. Co., Ltd. TH-10

[0035]

[Table 1]

[0036]

[Table 2]

[0037]

[Table 3]

[0038]

[Table 4]

[0039]

[Table 5]

Experimental Example 2 In order to prove the effect of the present invention, the final preparation was subjected to accelerated conditions (40 ° C./70% R
.H.) Was observed for changes in content and degradation products. The results are shown in Table 6 below and FIG. 21-2.
5 shows.

[0041]

[Table 6]

Experimental Example 3 In order to prove the effect of the present invention, the final formulation (Example 1) and the existing A tablet (registered trademark) of Company H marketed in Japan were subjected to severe temperature conditions. (40 ℃, 50 ℃, 60 ℃
, 70 ° C) and the change in content and degradation products were observed. The results are shown in the following Table 7 and FIG.
It shows in -29.

[0043]

[Table 7]

[0044]

【The invention's effect】

As described above, a pharmaceutical composition containing pravastatin sodium formulated according to the present invention as an active ingredient and β-cyclodextrin as a stabilizer has a high temperature and a higher temperature than conventional pharmaceutical compositions. By having excellent stability even under high humidity conditions, not only can rapid decomposition be prevented in high temperature and high humidity environments, but also existing machines can be applied during mass production, The effect is that there is no financial burden such as additional production equipment.

[Brief description of drawings]

FIG. 1 is a graph comparing the stability of drugs prepared from Example 1 and Comparative Example 1 at 40 ° C.

FIG. 2 is a graph comparing the stability of drugs prepared from Example 1 and Comparative Example 1 at 50 ° C.

FIG. 3 is a graph comparing the stability of drugs prepared from Example 1 and Comparative Example 1 at 60 ° C.

FIG. 4 is a graph comparing the stability of drugs prepared from Example 1 and Comparative Example 1 at 70 ° C.

FIG. 5 is a graph comparing the stability of the agents prepared from Example 2 and Comparative Example 2 at 40 ° C.

FIG. 6 is a graph comparing the stability of drugs prepared from Example 2 and Comparative Example 2 at 50 ° C.

FIG. 7 is a graph comparing the stability of the agents prepared from Example 2 and Comparative Example 2 at 60 ° C.

FIG. 8 is a graph comparing the stability of the agents prepared from Example 2 and Comparative Example 2 at 70 ° C.

FIG. 9 is a graph comparing the stability of drugs prepared from Example 3 and Comparative Example 3 at 40 ° C.

FIG. 10 is a graph comparing the stability of drugs prepared from Example 3 and Comparative Example 3 at 50 ° C.

FIG. 11 is a graph comparing the stability of drugs prepared from Example 3 and Comparative Example 3 at 60 ° C.

FIG. 12 is a graph comparing the stability of the agents prepared from Example 3 and Comparative Example 3 at 70 ° C.

FIG. 13 is a graph comparing the stability of drugs prepared from Example 4 and Comparative Example 4 at 40 ° C.

FIG. 14 is a graph comparing the stability of drugs prepared from Example 4 and Comparative Example 4 at 50 ° C.

FIG. 15 is a graph comparing the stability of the agents prepared from Example 4 and Comparative Example 4 at 60 ° C.

FIG. 16 is a graph comparing the stability of the agents prepared from Example 4 and Comparative Example 4 at 70 ° C.

FIG. 17 is a graph comparing the stability of the agents prepared from Example 5 and Comparative Example 5 at 40 ° C.

FIG. 18 is a graph comparing the stability of the agents prepared from Example 5 and Comparative Example 5 at 50 ° C.

FIG. 19 is a graph comparing the stability of drugs prepared from Example 5 and Comparative Example 5 at 60 ° C.

FIG. 20 is a graph comparing the stability of the agents prepared from Example 5 and Comparative Example 5 at 70 ° C.

FIG. 21 is a graph comparing the stability of drugs prepared from Example 1 and Comparative Example 1 under accelerated conditions of 40 ° C. and 75% RH.

FIG. 22 is a graph comparing the stability of drugs prepared from Example 2 and Comparative Example 2 under accelerated conditions of 40 ° C. and 75% RH.

FIG. 23 is a graph comparing the stability of drugs prepared from Example 3 and Comparative Example 3 under accelerated conditions of 40 ° C. and 75% RH.

FIG. 24 is a graph comparing the stability of drugs prepared from Example 4 and Comparative Example 4 under accelerated conditions of 40 ° C. and 75% RH.

FIG. 25 is a graph comparing the stability of the agents prepared from Example 5 and Comparative Example 5 under accelerated conditions of 40 ° C. and 75% RH.

FIG. 26 is a graph comparing the stability of the drug prepared from Example 1 and tablet A under the condition of 40 ° C.

FIG. 27 is a graph comparing the stability of the drug prepared from Example 1 and tablet A under the condition of 50 ° C.

FIG. 28 is a graph comparing the stability of the drug prepared from Example 1 and tablet A under the condition of 60 ° C.

FIG. 29 is a graph comparing the stability of the drug prepared from Example 1 and tablet A under the condition of 70 ° C.

[Procedure amendment]

[Submission date] October 2, 2000 (2000.10.2)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Contents of correction]

Title: Pharmaceutical composition containing pravastatin sodium

[Claims]

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing pravastatin sodium, more specifically, pravastatin sodium as an active ingredient, and β-cyclodextrin as a stabilizer. The present invention relates to a pharmaceutical composition containing pravastatin sodium, which can contribute to the stability of unstable pravastatin sodium under the condition of high temperature and humidity.

[0002]

2. Description of the Related Art Hyperlipidemia is a condition in which the concentration of plasma lipids (cholesterol, neutral lipids, phospholipids, free fatty acids, etc.) is increased beyond the normal range, and It causes arteriosclerosis, hypertension, ischemic heart disease and pancreatitis. Therefore, the development of drugs capable of lowering cholesterol is in progress, but in the case of pravastatin sodium represented by the following chemical formula among these drugs, hydroxymethylglutaryl Co-A enzyme is involved in the process of cholesterol biosynthesis. It is well known that it is useful for the treatment of hyperlipidemia because it has an excellent ability to inhibit the production of cholesterol by inhibiting the action of. Pravastatin sodium forms various isomers with its own lactone under the conditions of high temperature and humidity.

[0003]

[Chemical 1]

When a drug composition containing pravastatin sodium represented by the above chemical formula as a main component is formulated, existing lactose, silicon dioxide, croscarmellose sodium, microcrystalline cellulose, polyvinylpyrrolidone, etc. Pharmaceutical compositions have been formulated using only the above excipients. For example, pravastatin sodium, lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate have been adopted as general pharmaceutical compositions (VIDAL, p.568 (1997), ELISOR; VIDAL, p.1750. -1
751 (1997), VASTEN 20mg; ROTE LISTE 58 038 (1996), PRAVASIN 5mg / 10mg / 20m
g). However, a pharmaceutical composition using only such an excipient has a problem that decomposition rapidly occurs in a high temperature and high humidity environment.

[0005]

As part of such research, the present inventor has found that β-cyclodextrin has a property of including a low-molecular substance and blocking the surrounding environment, and completed the present invention. did. Accordingly, the present invention provides a pharmaceutical composition comprising pravastatin sodium, an excipient, a binder, a disintegrant, a lubricant and β-cyclodextrin, which comprises:
Unstable pravastatin sodium (pravastatin s) under high temperature and humidity conditions
Its purpose is to provide a pharmaceutical composition comprising pravastatin sodium, which can contribute to the stability of odium).

[0006]

Means for Solving the Problems The present invention provides pravastatin sodium as an active ingredient, and in a pharmaceutical composition containing an excipient, a binder, a disintegrant, and a lubricant, pravastatin sodium as the above-mentioned active ingredient. Β-Cyclodextrin is contained as a stabilizer for the pharmaceutical composition.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail as follows. In order to prevent decomposition that occurs rapidly in a high temperature and high humidity environment, a low molecular weight substance is added to β-
It is intended to provide a pharmaceutical composition having excellent stability against temperature and humidity by utilizing the property of enclosing with cyclodextrin to block the surrounding environment. The pharmaceutical composition of the present invention comprises pravastatin sodium as an active ingredient, β-cyclodextrin as a stabilizer, and one or more excipients selected from lactose, starch, microcrystalline cellulose, hydroxypropyl cellulose, Crystalline cellulose,
One or more binders selected from hydroxypropylmethyl cellulose and dextrin, one or more disintegrants selected from low-substituted hydroxypropyl cellulose and croscarmellose sodium, magnesium stearate,
It contains one or more lubricants selected from talc, stearic acid and the like. The pravastatin sodium contained as a useful ingredient in these ingredients is contained in an amount of 2 to 50% by weight, preferably 2 to 30% by weight, based on the whole pharmaceutical composition. Pravastatin sodium inhibits the action of hydroxymethylglutaryl Co-A enzyme in the process of cholesterol biosynthesis and suppresses the production of cholesterol. If the content of pravastatin sodium is less than 2% by weight, the increase in the weight of the tablet reduces the adaptability to patient administration. However, if it exceeds 50% by weight, there is a problem that it is difficult for each patient to control the dose. Since pravastatin sodium forms various isomers with its own lactone under the condition of high temperature and humidity, β-cyclodextrin is added as a stabilizer of the active ingredient in the present invention to prevent this. In the past, when a pharmaceutical composition was formulated, rapid degradation occurred by formulating only a conventional excipient.
On the other hand, in the present invention, by adding β-cyclodextrin as a stabilizer, it is possible to obtain a more stable pharmaceutical composition at high temperature and humidity. According to the present invention, β-cyclodextrin comprises 50-5,000 parts by weight, preferably 100-3,000 parts by weight, based on 100 parts by weight of pravastatin sodium. β-
When the content of cyclodextrin is less than 50 parts by weight, pravastatin sodium is not sufficiently stabilized, so that decomposition may occur under temperature and humidity conditions. On the other hand, if it exceeds 5,000 parts by weight, there is a problem that formulation becomes difficult. In addition to pravastatin sodium, which is the above-mentioned active ingredient, and β-cyclodextrin, which is a stabilizer, the pharmaceutical composition of the present invention contains excipients, binders, disintegrating agents, and lubricants that are commonly used in pharmaceutical compositions. Includes drugs and the like. Excipients include corn starch, potato starch, wheat starch, lactose, sucrose,
Glucose, fructose, D-mannitol, precipitated calcium carbonate, microcrystalline cellulose,
It is one or more selected from dextrin and methylcellulose, and is contained in an amount of 5-90% by weight based on the total drug composition. The binder is selected from methylcellulose, amorphous cellulose, hydroxycellulose, glycerin, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, or polyvinyl alcohol 1
More than one species, 25-35% by weight of the total pharmaceutical composition. The disintegrant is one or more selected from hydroxypropylmethyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, ethyl cellulose, and low-substituted hydroxypropyl cellulose, and the amount of the disintegrant is the same in the entire pharmaceutical composition. In contrast, 0.5-10% by weight is contained. The lubricant is one or more selected from stearic acid, magnesium stearate, talc, liquid paraffin, or hard silicic acid anhydride, and is contained in an amount of 0.25-5% by weight based on the whole pharmaceutical composition. . The pharmaceutical composition of the present invention having such a composition is produced by the following method. First, pravastatin sodium and β-cyclodextrin are ground in an appropriate container for several tens of minutes. Subsequently, one or more kinds of excipients are added depending on the purpose, and a solution of one or more kinds of binders in a solvent (water, isopropanol, dichloromethane) is wet granulated and dried, or one or more kinds of lubricants are added. After the agent and one or more binders have been added, dry granulation is carried out with a pressing roller. After carrying out the above process, one or more disintegrants, lubricants, or binders are optionally included to prepare the pharmaceutical composition of the present invention. A pharmaceutical composition containing pravastatin sodium, which is the active ingredient of the present invention, and β-cyclodextrin, which is a stabilizer, produced by the method as described above,
It can be compounded with an ordinary pharmaceutically acceptable carrier, and can be formulated as an oral administration preparation such as tablets, capsules, powders, granules, pills and the like, which is a usual preparation in the pharmaceutical field. Examples of the carrier used according to the present invention include carriers commonly used in the pharmaceutical field, such as binders, lubricants, disintegrants, excipients, stabilizers, and garments. In addition, in order to prevent the drug from being decomposed by gastric acid during oral administration, an antacid may be used in combination, or it may be formulated and administered as a formulation in which tablets, granules and the like are coated with viscera. The preferred route of administration is oral administration in tablet form (AB
PI Compendium of Data Sheets, VIDAL, ROTE, LISTE, Physicians' Desk Refe
rence). According to the present invention, the dose of the active ingredient in the human body is appropriately determined in consideration of the degree of absorption of the active ingredient in the body, inactivation rate and excretion rate, age, sex and condition of the patient, serious condition of the disease to be treated and the like. Adjust. Ingestion of the pharmaceutical composition is recommended as follows: a)
Generally, adults are given 10-40 mg / day before bedtime (ABPI Compendium of Dat
a Sheets, p. 1780-1782 (1995-1996), LIPOSTAT TABLETS). The usual dose is 10-40 mg / day for adults and 20 mg or less for the elderly (Physicians'
Desk Reference, p.732-735 (1995), PRAVACHOL). Also, the initial dose is 1
Take 10 mg once a day, 40 mg as the maximum dose in the evening (VIDAL, P.568 (1997),
ELISOR: p. 1750-1751 (1997) VASTEN), or as an initial dose, 5-10 mg / 1
40 mg given daily as maximum dose (ROTE LISTE, 58 038 (1996), PRAVASIN 5 mg / 1
0mg / 20mg). Therefore, it is desirable to administer 5-40 mg / day once in the evening or before going to bed based on the above literature. As described above, a pharmaceutical composition containing pravastatin sodium of the present invention as an active ingredient and β-cyclodextrin as a stabilizer is formulated, and β-cyclodextrin for inclusion of the active ingredient of the pharmaceutical composition is prepared. After mixing with pravastatin sodium, physical force was applied. As a result, when β-cyclodextrin was contained, it was confirmed that the stability against temperature and humidity was remarkably excellent (FIGS. 1 to 29). When comparing the stability of the drug of the present invention shown in FIGS. 1 to 20 and FIGS. 26 to 29 with β-cyclodextrin or the stability of A tablet, the drug of the present invention is the conventional drug. It is recognized that the stability was superior to temperature as compared with. Further, as shown in FIGS. 21 to 25, it can be seen that the drug of the present invention was more stable against humidity. Furthermore, in the process of formulating the pharmaceutical composition of the present invention, existing machines such as a rolling compactor can be applied even in the case of mass production, so that the cost of additional production equipment can be improved. Can be satisfied with the physical aspects.

EXAMPLES The present invention will be described in more detail based on the following examples, but the present invention is not limited thereto. Example 1 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Hydroxypropylcellulose 5 mg Low-substituted hydroxypropylcellulose 13.5 mg Lactose 48.51 mg Magnesium stearate 0.9 mg Pravastatin sodium and β-cyclodextrin were mixed well in a suitable container. Crushed for 20 minutes. Lactose was added to this and mixed thoroughly, and lumped with an aqueous binder solution (hydroxypropylcellulose solution). The solution was dried in an oven maintained in the range of 30-40 ° C, and the dried product was sized by a No. 20 sieve. Low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well before tableting. Example 2 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Hydroxypropylcellulose 5 mg Low-substituted hydroxypropylcellulose 13.5 mg Lactose 30.0 mg Corn starch 18.51 mg Magnesium stearate 0.9 mg Pravastatin sodium and β-cyclodextrin are well mixed and suitable. It was crushed for 20 minutes in a different container. Lactose and corn starch were added to this and the reaction solution was mixed well, and agglomerated with an aqueous binder solution (hydroxypropyl cellulose solution). The solution was dried in an oven maintained in the 30-40 ° C range. The dried product was sized with a No. 20 sieve, low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well, and then tableted. Example 3 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Hard anhydrous silicic acid 1.75 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 30.0 mg Magnesium stearate 1.6 mg Pravastatin sodium and β-cyclodextrin are mixed well in a suitable container. Grind for 20 minutes, then add hard anhydrous silicic acid, lactose and magnesium stearate (0
.8 mg) was added and mixed thoroughly to produce dry granules with a compression roller. Low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well before tableting. Example 4 Pravastatin sodium 5 mg β-Cyclodextrin 127.09 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 20.07 mg Corn starch 28.0 mg Dextrin 7.8 mg Red pigment # 3 0.12 mg Blue pigment # 1 Aluminum lake 0.12 mg Magnesium stearate 1.6 mg Pravastatin Sodium and β-cyclodextrin were mixed well and ground in a suitable container for 20 minutes. Lactose and corn starch (14.0 mg) were added to this, and the reaction solution was mixed well, and a binder solution (dextrin) containing a dye (red dye # 3, blue dye # 1 aluminum lake) was added and agglomerated. Dry completely in oven at -40 ° C. The remaining corn starch (14.0 mg), low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well before tableting. Example 5 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Lactose 30.31 mg Potato starch 30.0 mg Polyvinyl alcohol 7.8 mg Magnesium stearate 1.9 mg Pravastatin sodium and β-cyclodextrin were well mixed and ground in a suitable container for 20 minutes. Lactose and potato starch were added to this, the reaction solution was mixed well, the binder aqueous solution (polyvinyl alcohol) was added to agglomerate, and it was well dried in an oven at 30-40 ° C. After adding magnesium stearate, the mixture was mixed well and then tableted. Comparative Example 1 Pravastatin sodium 5 mg Hydroxypropylcellulose 5 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 175.6 mg Magnesium stearate 0.9 mg Completely mix pravastatin sodium and lactose and granulate with a binder aqueous solution (hydroxypropylcellulose aqueous solution) And dried in an oven maintained in the range of 30-40 ° C. The dried product was sieved through a No. 20 sieve. Low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well, and then tableted. Comparative Example 2 Pravastatin sodium 5 mg Hydroxypropyl cellulose 5 mg Low-substituted hydroxypropyl cellulose 13.5 mg Lactose 157.09 mg Corn starch 18.51 mg Magnesium stearate 0.9 mg Pravastatin sodium, lactose and corn starch were thoroughly mixed to prepare an aqueous binder solution (hydroxypropyl cellulose). ), And dried in an oven at 30-40 ° C. The dried product was sized with a No. 20 sieve, low-substituted hydroxypropyl cellulose and magnesium stearate were added, mixed well, and tabletted. Comparative Example 3 Pravastatin sodium 5 mg Hard anhydrous silicic acid 1.75 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 181.65 mg Magnesium stearate 1.6 mg Pravastatin sodium, hard anhydrous silicic acid and magnesium stearate (0.
8 mg) were thoroughly mixed and dry granules were produced with a rolling roller. Low-substituted hydroxypropyl cellulose and magnesium stearate (0.8 mg) were added, mixed well, and compressed into tablets. Comparative Example 4 Pravastatin sodium 5 mg Low-substituted hydroxypropyl celluloe 10.0 mg Lactose 120.27 mg Corn starch 55.09 mg Dextrin 7.8 mg Red pigment # 3 0.12 mg Blue pigment # 1 Aluminum lake 0.12 mg Magnesium stearate 1.6 mg Pravastatin sodium, lactose and corn starch ( 1/2 volume),
Mix the reaction solution well, add the binder aqueous solution (dextrin) in which the dyes (red dye # 3, blue dye # 1 aluminum lake) are dissolved to agglomerate, and completely dry in an oven at 30-40 ° C. It was The remaining cornstarch, low-substituted hydroxypropylcellulose and magnesium stearate were added to the granulate, mixed well and compressed into tablets. Comparative Example 5 Pravastatin sodium 5 mg Lactose 130.31 mg Potato starch 57.09 mg Polyvinyl alcohol 5.7 mg Magnesium stearate 1.9 mg Pravastatin sodium, lactose and potato starch were mixed well, and a binder aqueous solution (polyvinyl alcohol) was added to agglomerate the mixture. After drying well in an oven at -40 ° C, magnesium stearate was added to and mixed with the granules, and then tableted. Experimental Example 1 To prove the effect of the present invention, the final formulation was subjected to severe temperature conditions (40 ° C).
, 50 ° C., 60 ° C., 70 ° C.), and changes in the content and degradation products were observed using the following equipment. The results are shown in the following Table 1-5 and FIG. 1-20. 1) High performance liquid chromatography: Waters 510 Detector: Ultraviolet absorptiometry (238 nm) Column: Cosmosil C ₁₈ Mobile: Methanol / H ₂ O / TEA / acetic acid (500: 500: 1: 1) Flow rate: 1.5 ml / min Injection volume: 5 μl 2) Automatic sampler (autosamler): Waters 717 3) Integrator: Waters 740 4) Detector: Waters 186 5) Oven SY-IN.G (SUN YOUNG, Korea), at 40 ℃ VO-C-2 (Space Chemistry, Korea), at 50 and 60 ℃ NDO-600-ND (EYELA, Korea), at 70 ℃ 6) Life tester: JEIO TECH. Co., Ltd. TH-10

[0008]

[Table 1] (Note) ^* The residual amount of pravastatin sodium in the pharmaceutical composition.

[0009]

[Table 2] (Note) ^* The residual amount of pravastatin sodium in the pharmaceutical composition.

[0010]

[Table 3] (Note) ^* The residual amount of pravastatin sodium in the pharmaceutical composition.

[0011]

[Table 4] (Note) ^* The residual amount of pravastatin sodium in the pharmaceutical composition.

[0012]

[Table 5] (Note) ^* The residual amount of pravastatin sodium in the pharmaceutical composition.

Experimental Example 2 In order to prove the effect of the present invention, the final formulation was subjected to accelerated conditions (40 ° C./70% R
.H.), The change in content and degradation products were observed, and the results are shown in Table 6 below and FIGS.

[0014]

[Table 6] (Note) ^* The residual amount of pravastatin sodium in the pharmaceutical composition.

Experimental Example 3 In order to prove the effect of the present invention, the final formulation (Example 1) and the existing A tablet (registered trademark) of Company H marketed in Japan were subjected to severe temperature conditions. (40 ℃, 50 ℃, 60 ℃
, 70 ° C) and the change in content and degradation products were observed. The results are shown in Table 7 below and Fig. 26-2.
Shown in 9.

[0016]

[Table 7] (Note) ^* The residual amount of pravastatin sodium in the pharmaceutical composition.

[0017]

As described above, a pharmaceutical composition containing pravastatin sodium formulated according to the present invention as an active ingredient and β-cyclodextrin as a stabilizer is a conventional pharmaceutical composition. It has excellent stability under high temperature and high humidity conditions compared to the above, so that it not only prevents rapid decomposition in high temperature and high humidity environment, but also applies existing machines during mass production. Therefore, there is an effect that there is no economical burden such as additional production equipment.

[Brief description of drawings]

FIG. 1 is a graph showing the stability of drug compositions prepared from Example 1 and Comparative Example 1 at 40 ° C.

FIG. 2 is a graph showing the stability of drug compositions prepared from Example 1 and Comparative Example 1 at 50 ° C.

FIG. 3 is a graph showing the stability of drug compositions prepared from Example 1 and Comparative Example 1 at 60 ° C.

FIG. 4 is a graph showing the stability of drug compositions prepared from Example 1 and Comparative Example 1 at 70 ° C.

FIG. 5 is a graph showing the stability of drug compositions prepared from Example 2 and Comparative Example 2 at 40 ° C.

FIG. 6 is a graph showing the stability of drug compositions prepared from Example 1 and Comparative Example 1 at 50 ° C.

FIG. 7 is a graph showing the stability of drug compositions prepared from Example 1 and Comparative Example 1 at 60 ° C.

FIG. 8 is a graph showing the stability of drug compositions prepared from Example 1 and Comparative Example 1 at 70 ° C.

FIG. 9 is a graph showing the stability of drug compositions prepared from Example 3 and Comparative Example 3 at 40 ° C.

FIG. 10 is a graph showing the stability of drug compositions prepared from Example 3 and Comparative Example 3 at 50 ° C.

FIG. 11 is a graph showing the stability of drug compositions prepared from Example 3 and Comparative Example 3 at 60 ° C.

FIG. 12 is a graph showing the stability of drug compositions prepared from Example 3 and Comparative Example 3 at 70 ° C.

FIG. 13 is a graph showing the stability of drug compositions prepared from Example 4 and Comparative Example 4 at 40 ° C.

FIG. 14 is a graph showing the stability of drug compositions prepared from Example 4 and Comparative Example 4 at 50 ° C.

FIG. 15 is a graph showing the stability of drug compositions prepared from Example 4 and Comparative Example 4 at 60 ° C.

FIG. 16 is a graph showing the stability of drug compositions prepared from Example 4 and Comparative Example 4 at 70 ° C.

FIG. 17 is a graph showing the stability of drug compositions prepared from Example 5 and Comparative Example 5 at 40 ° C.

FIG. 18 is a graph showing the stability of drug compositions prepared from Example 5 and Comparative Example 5 at 50 ° C.

FIG. 19 is a graph showing the stability of drug compositions prepared from Example 5 and Comparative Example 5 at 60 ° C.

FIG. 20 is a graph showing the stability of drug compositions prepared from Example 5 and Comparative Example 5 at 70 ° C.

FIG. 21: Example 1 and Comparative Example 1 under accelerated conditions (40 ° C./75% RH) at 40 ° C.
3 is a graph showing the stability of the pharmaceutical composition produced from.

FIG. 22 Example 2 and Comparative Example 2 under accelerated conditions (40 ° C./75% RH) at 40 ° C.
3 is a graph showing the stability of the pharmaceutical composition produced from.

FIG. 23 Example 3 and Comparative Example 3 under accelerated conditions (40 ° C./75% RH) at 40 ° C.
3 is a graph showing the stability of the pharmaceutical composition produced from.

FIG. 24 Example 4 and Comparative Example 4 under accelerated conditions (40 ° C./75% RH) at 40 ° C.
3 is a graph showing the stability of the pharmaceutical composition produced from.

FIG. 25 Example 5 and Comparative Example 5 under accelerated conditions (40 ° C./75% RH) at 40 ° C.
3 is a graph showing the stability of the pharmaceutical composition produced from.

FIG. 26 is a graph showing the stability of the pharmaceutical composition prepared from Example 1 and Tablet A (registered trademark) at 40 ° C.

FIG. 27 is a graph showing the stability of the pharmaceutical composition prepared from Example 1 and A tablet (registered trademark) at 50 ° C.

FIG. 28 is a graph showing the stability of the pharmaceutical composition prepared from Example 1 and A tablet (registered trademark) at 60 ° C.

FIG. 29 is a graph showing the stability of the pharmaceutical composition prepared from Example 1 and A tablet (registered trademark) at 70 ° C.

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[Submission date] November 21, 2000 (2000.11.21)

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[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail as follows. The present invention, when formulating a pharmaceutical composition containing pravastatin sodium as a main component, in order to prevent decomposition that occurs rapidly in a high temperature and high humidity environment, a low molecular weight substance is clathrated with β-cyclodextrin to surround the environment. The present invention provides a pharmaceutical composition having excellent stability against temperature and humidity by utilizing the property of blocking the above. The pharmaceutical composition of the present invention comprises pravastatin sodium as an active ingredient, β-cyclodextrin as a stabilizer, and one or more kinds of excipients selected from lactose, starch, microcrystalline cellulose, hydroxypropyl cellulose, and microparticles. Crystalline cellulose,
One or more binders selected from hydroxypropylmethyl cellulose and dextrin, one or more disintegrants selected from low-substituted hydroxypropyl cellulose and croscarmellose sodium, and magnesium stearate and talc. , One or more lubricants selected from stearic acid and the like. The pravastatin sodium contained as a useful ingredient in these ingredients is contained in an amount of 2 to 50% by weight, preferably 2 to 30% by weight, based on the whole pharmaceutical composition. Pravastatin sodium inhibits the action of hydroxymethylglutaryl Co-A enzyme in the process of cholesterol biosynthesis and suppresses the production of cholesterol. If the content of pravastatin sodium is less than 2% by weight, the increase in the weight of the tablet reduces the adaptability to patient administration. However, if it exceeds 50% by weight, there is a problem that it is difficult for each patient to control the dose. Since pravastatin sodium forms various isomers with its own lactone under the condition of high temperature and humidity, β-cyclodextrin is added as a stabilizer of the active ingredient in the present invention to prevent this. In the past, when a pharmaceutical composition was formulated, rapid degradation occurred by formulating only a conventional excipient.
On the other hand, in the present invention, by adding β-cyclodextrin as a stabilizer, it is possible to obtain a more stable pharmaceutical composition at high temperature and humidity. According to the present invention, β-cyclodextrin comprises 50-5,000 parts by weight, preferably 100-3,000 parts by weight, based on 100 parts by weight of pravastatin sodium. β-
When the content of cyclodextrin is less than 50 parts by weight, pravastatin sodium is not sufficiently stabilized, so that decomposition may occur under temperature and humidity conditions. On the other hand, if it exceeds 5,000 parts by weight, there is a problem that formulation becomes difficult. In addition to pravastatin sodium, which is the above-mentioned active ingredient, and β-cyclodextrin, which is a stabilizer, the pharmaceutical composition of the present invention contains excipients, binders, disintegrating agents, and lubricants that are commonly used in pharmaceutical compositions. Includes drugs and the like. Excipients include corn starch, potato starch, wheat starch, lactose, sucrose,
Glucose, fructose, D-mannitol, precipitated calcium carbonate, microcrystalline cellulose,
It is one or more selected from dextrin and methylcellulose, and is contained in an amount of 5-90% by weight based on the total drug composition. As the binder, one selected from methylcellulose, microcrystalline cellulose, hydroxycellulose, glycerin, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, or polyvinyl alcohol 1
More than one species, 25-35% by weight of the total pharmaceutical composition. The disintegrant is one or more selected from hydroxypropylmethyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, ethyl cellulose, and low-substituted hydroxypropyl cellulose, and the amount of the disintegrant is the same in the entire pharmaceutical composition. In contrast, 0.5-10% by weight is contained. The lubricant is one or more selected from stearic acid, magnesium stearate, talc, liquid paraffin, or light anhydrous silicic acid, and is contained in an amount of 0.25-5% by weight based on the whole drug composition. . The pharmaceutical composition of the present invention having such a composition is produced by the following method. First, pravastatin sodium and β-cyclodextrin are ground in an appropriate container for several tens of minutes. Subsequently, one or more kinds of excipients are added depending on the purpose, and a solution of one or more kinds of binders in a solvent (water, isopropanol, dichloromethane) is wet granulated and dried, or one or more kinds of lubricants are added. After the agent and one or more binders have been added, dry granulation is carried out with a pressing roller. After carrying out the above process, one or more disintegrants, lubricants, or binders are optionally included to prepare the pharmaceutical composition of the present invention. A pharmaceutical composition containing pravastatin sodium, which is the active ingredient of the present invention, and β-cyclodextrin, which is a stabilizer, produced by the method as described above,
It can be compounded with an ordinary pharmaceutically acceptable carrier, and can be formulated as an oral administration preparation such as tablets, capsules, powders, granules, pills and the like, which is a usual preparation in the pharmaceutical field. Examples of the carrier used according to the present invention include carriers commonly used in the pharmaceutical field, such as binders, lubricants, disintegrants, excipients, stabilizers, and garments. In addition, in order to prevent the drug from being decomposed by gastric acid during oral administration, an antacid may be used in combination, or it may be formulated and administered as a formulation in which tablets, granules and the like are coated with viscera. The preferred route of administration is oral administration in tablet form (AB
PI Compendium of Data Sheets, VIDAL, ROTE, LISTE, Physicians' Desk Refe
rence). According to the present invention, the dose of the active ingredient in the human body is appropriately determined in consideration of the degree of absorption of the active ingredient in the body, inactivation rate and excretion rate, age, sex and condition of the patient, serious condition of the disease to be treated and the like. Adjust. Ingestion of the pharmaceutical composition is recommended as follows: a)
Generally, adults are given 10-40 mg / day before bedtime (ABPI Compendium of Dat
a Sheets, p.1780-1782 (1995-1996), LIPOSTAT TABLETS); b) 10-20 mg / day as an initial dose, and 10-40 mg / 1 for adults as a general dose.
Daily, 20 mg or less per day for the elderly and 10-20 mg per day as an initial dose once (Physicians' Desk Reference, p.732-735 (1995), PRAVACHOL); c
) Also, take 10 mg once daily as an initial dose and 40 mg as a maximum dose in the evening (VIDAL, P.568 (1997), ELISOR: p.1750-1751 (1997) VASTEN); d) or 5-10 mg once daily as initial dose, 40 mg as maximum dose (ROTE LISTE,
58 038 (1996), PRAVASIN 5mg / 10mg / 20mg). Therefore, it is desirable to administer 5-40 mg / day once in the evening or before going to bed based on the above literature. As described above, a pharmaceutical composition containing pravastatin sodium of the present invention as an active ingredient and β-cyclodextrin as a stabilizer is formulated, and β-cyclodextrin for inclusion of the active ingredient of the pharmaceutical composition is prepared. After mixing with pravastatin sodium, physical force was applied. As a result, when β-cyclodextrin was contained, it was confirmed that the stability against temperature and humidity was remarkably excellent (FIGS. 1 to 29). When comparing the stability of the drug of the present invention shown in FIGS. 1 to 20 and FIGS. 26 to 29 with β-cyclodextrin or the stability of A tablet, the drug of the present invention is the conventional drug. It is recognized that the stability was superior to temperature as compared with. Further, as shown in FIGS. 21 to 25, it can be seen that the drug of the present invention was more stable against humidity. Furthermore, in the process of formulating the pharmaceutical composition of the present invention, existing machines such as a rolling compactor can be applied even in the case of mass production, so that the cost of additional production equipment can be improved. Can be satisfied with the physical aspects.

EXAMPLES The present invention will be described in more detail based on the following examples, but the present invention is not limited thereto. Example 1 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Hydroxypropylcellulose 5 mg Low-substituted hydroxypropylcellulose 13.5 mg Lactose 48.51 mg Magnesium stearate 0.9 mg Pravastatin sodium and β-cyclodextrin were mixed well in a suitable container. Crushed for 20 minutes. Lactose was added to this and mixed thoroughly, and kneaded with an aqueous binder solution (hydroxypropyl cellulose solution). The wet mass was dried in an oven maintained in the range of 30-40 ° C, and the dried product was sized by a No. 20 sieve. Low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well before tableting. Example 2 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Hydroxypropylcellulose 5 mg Low-substituted hydroxypropylcellulose 13.5 mg Lactose 30.0 mg Corn starch 18.51 mg Magnesium stearate 0.9 mg Pravastatin sodium and β-cyclodextrin are well mixed and suitable. It was crushed for 20 minutes in a different container. Lactose and corn starch were added to this and the mixture was mixed well and kneaded with an aqueous binder solution (hydroxypropyl cellulose solution). 30 wet mass
Dried in an oven maintained in the -40 ° C range. The dried product was sized with a No. 20 sieve, low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well, and then tableted. Example 3 Pravastatin sodium 5 mg β-Cyclodextrin 127.09 mg Light anhydrous silicic acid 1.75 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 54.56 mg Magnesium stearate 1.6 mg Mix well pravastatin sodium and β-cyclodextrin in a suitable container. was ground for 20 minutes, this light quality silicic anhydride, lactose and magnesium stearate (0
.8 mg) was added and mixed thoroughly to produce dry granules with a compression roller. Low-substituted hydroxypropyl cellulose and magnesium stearate (0.8 mg) were added and mixed well before tableting. Example 4 Pravastatin sodium 5 mg β-Cyclodextrin 127.09 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 20.27 mg Corn starch 28.0 mg Dextrin 7.8 mg Red dye # 3 0.12 mg Blue dye # 1 Aluminum lake 0.12 mg Magnesium stearate 1.6 mg Pravastatin Sodium and β-cyclodextrin were mixed well and ground in a suitable container for 20 minutes. Lactose and corn starch (14.0 mg) were added to the mixture, and the mixture was mixed well, and a binder solution (dextrin) containing a dye (red dye # 3, blue dye # 1 aluminum lake) was added and kneaded at 30-40 ° C. Completely dried in an oven. The remaining corn starch (14.0 mg), low-substituted hydroxypropyl cellulose and magnesium stearate were added to the granules and mixed well before tableting. Example 5 Pravastatin sodium 5 mg β-cyclodextrin 127.09 mg Lactose 30.31 mg Potato starch 30.0 mg Polyvinyl alcohol 5.7 mg Magnesium stearate 1.9 mg Pravastatin sodium and β-cyclodextrin were well mixed and ground in a suitable container for 20 minutes. Lactose and potato starch were added to this and the mixture was mixed well, an aqueous binder solution (polyvinyl alcohol) was added, kneaded, and dried well in an oven at 30-40 ° C. After adding magnesium stearate, the mixture was mixed well and then tableted. Comparative Example 1 pravastatin sodium 5 mg hydroxypropylcellulose 5 mg low-substituted hydroxypropylcellulose 13.5 mg lactose 175.6 mg magnesium stearate 0.9 mg pravastatin sodium and lactose were thoroughly mixed and kneaded with a binder aqueous solution (hydroxypropylcellulose aqueous solution) Granulated and dried in an oven maintained in the range 30-40 ° C. The dried product was sieved through a No. 20 sieve. Low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed well, and then tableted. Comparative Example 2 Pravastatin sodium 5 mg Hydroxypropyl cellulose 5 mg Low-substituted hydroxypropyl cellulose 13.5 mg Lactose 157.09 mg Corn starch 18.51 mg Magnesium stearate 0.9 mg Pravastatin sodium, lactose and corn starch were thoroughly mixed to prepare an aqueous binder solution (hydroxypropyl cellulose). ) And dried in an oven at 30-40 ° C. The dried product was sized with a No. 20 sieve, low-substituted hydroxypropyl cellulose and magnesium stearate were added, mixed well, and tabletted. Comparative Example 3 Pravastatin sodium 5 mg Light anhydrous silicic acid 1.75 mg Low-substituted hydroxypropylcellulose 10.0 mg Lactose 181.65 mg Magnesium stearate 1.6 mg Pravastatin sodium, light anhydrous silicic acid and magnesium stearate (0.8
(mg) was thoroughly mixed, and dry granules were produced with a rolling roller. Low-substituted hydroxypropyl cellulose and magnesium stearate (0.8 mg) were added, mixed well, and compressed into tablets. Comparative Example 4 Pravastatin sodium 5 mg low substituted hydroxypropyl cell row scan 10.0 mg Lactose 120.27 mg corn starch 55.09 mg dextrin 7.8 mg red dye # 3 0.12 mg blue dye # 1 Aluminum Lake 0.12 mg Magnesium stearate 1.6 mg pravastatin sodium, lactose and corn starch (1/2 amount),
The mixture was mixed well, a binder aqueous solution (dextrin) in which dyes (red dye # 3, blue dye # 1 aluminum lake) were dissolved was added, and the mixture was kneaded and completely dried in an oven at 30-40 ° C. The remaining cornstarch, low-substituted hydroxypropylcellulose and magnesium stearate were added to the granulate, mixed well and compressed into tablets. Comparative Example 5 Pravastatin sodium 5 mg Lactose 130.31 mg Potato starch 57.09 mg Polyvinyl alcohol 5.7 mg Magnesium stearate 1.9 mg Pravastatin sodium, lactose and potato starch were mixed well, and a binder aqueous solution (polyvinyl alcohol) was added and kneaded, 30-40. After drying well in an oven at ℃, magnesium stearate was added to the granules and mixed, and then tableted. Experimental Example 1 To prove the effect of the present invention, the final formulation was subjected to severe temperature conditions (40 ° C).
, 50 ° C., 60 ° C., 70 ° C.), and changes in the content and degradation products were observed using the following equipment. The results are shown in the following Table 1-5 and FIG. 1-20. 1) High-performance liquid chromatography (HPLC): Waters 510 Detector: Ultraviolet absorptiometry (238 nm) Column: Cosmosil C ₁₈ Mobile: Methanol, H ₂ O, TEA, glacial acetic acid (500: 500: 1: 1) Flow rate: 1.5 ml / min Injection volume: 5 µl 2) Automatic sampler (autosamler): Waters 717 3) Integrator: Waters 740 4) Detector: Waters 186 5) Oven SY-IN .G (SUN YOUNG, Korea), VO-C-2 (Space Chemistry, Korea) for processing at 40 ° C, NDO-600-ND (EYELA, Korea) for processing at 50 ° C and 60 ° C, 6) Life tester: JEIO TECH. Co., Ltd. TH-10

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[Contents of correction]

FIG. 29

─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Sue, Seung, Won             Seoul 136-143, Seoul, South Korea             -Ku, Jianui-3dong, 115-25 (72) Inventor Cha, Jung, Kwon             Republic of Korea Kunk Key 435-050, Khun             Po, Geum Jeon-Dong, 849, Juco             Apartment, 109-406 (72) Inventor Lee, Jun, Min             Republic of Korea Kunk Key 435-050, Khun             Po, Keum Jeon-Dong, 764-4, Le             Home 201 (72) Inventor Kim, Jun, Joo             Republic of Korea Kunkey 431-070, Ani             Yang, Donggang, Puncheon             Hyang Chung Apartment 302-1602 (72) Inventor Kang, Tae, Suk             South Korea Seoul 151-019, Kuwanaku-             Ku, Sirim-9 Dong, 244, Kuwanakua             Part, DA 306 F-term (reference) 4C076 AA36 BB01 CC21 CC29 DD25                       DD28C DD34C DD38 DD41C                       DD67 EE06 EE31 EE32 EE38                       EE39Q FF02 FF04 FF05                       FF09 FF36                 4C206 AA01 AA02 DB28 MA02 MA03                       MA05 NA03 ZC33

Claims (11)

[Claims] 1. In a pharmaceutical composition comprising pravastatin sodium as an active ingredient and an excipient, a binder, a disintegrating agent, and a lubricant therein, β-cyclo is used as a stabilizer of pravastatin sodium as the above-mentioned active ingredient. A pharmaceutical composition comprising dextrin. 2. The above pravastatin sodium is contained in an amount of 2-50% by weight based on the total pharmaceutical composition.
The pharmaceutical composition according to claim 1, which is contained. 3. The pharmaceutical composition according to claim 1, wherein the β-cyclodextrin is contained in an amount of 50 to 5,000 parts by weight based on 100% by weight of pravastatin sodium. 4. The pharmaceutical composition according to claim 1, wherein the excipient is contained in an amount of 5-90% by weight based on the total amount of the pharmaceutical composition. 5. The above-mentioned excipient is selected from corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, microcrystalline cellulose, dextrin and methylcellulose. The pharmaceutical composition according to claim 4, characterized in that 6. The pharmaceutical composition according to claim 1, wherein the excipient is contained in an amount of 2.5 to 35% by weight based on the total amount of the pharmaceutical composition. 7. The pharmaceutical composition according to claim 1, wherein the binder is selected from methylcellulose, microcrystalline cellulose, hydroxycellulose, glycerin, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin and polyvinyl alcohol. object. 8. The pharmaceutical composition according to claim 1, wherein the disintegrant is contained in an amount of 0.5 to 10% by weight based on the total amount of the pharmaceutical composition. 9. The pharmaceutical composition according to claim 8, wherein the disintegrant is selected from hydroxypropylmethylcellulose, hydroxypropylstarch, polyvinylpyrrolidone, methylcellulose and low-substituted hydroxypropylcellulose. 10. The pharmaceutical composition according to claim 1, wherein the lubricant is contained in an amount of 0.25-5% by weight based on the total amount of the pharmaceutical composition. 11. The pharmaceutical composition according to claim 10, wherein the lubricant is selected from stearic acid, magnesium stearate, talc and liquid paraffin.