KR20150115334A - Granule comprising silodosin, and pharmaceutical composition and formulation comprising the same - Google Patents

Abstract

The present invention relates to a granule comprising silodosin; alkaline inorganic salt as a stabilizer; and a pharmaceutically acceptable additive. The present invention shows that the silodosin can improve stability because the granules are produced by mixing silodosin with a certain stabilizer and improve stability decreased by unwanted reaction of silodosin with other diluting agents. Thus, the granule comprising silodosin of the present invention can be used for developing a composition or formulation with a variety of dissolution characteristics, without any influence to the stability of silodosin. In addition, due to the decreased side effects caused by degradation products of silodosin, it can be utilized as a safer therapeutic agent for prostatic hypertrophy.

Description

TECHNICAL FIELD The present invention relates to granules containing gum tragacanth, and to pharmaceutical compositions and dosage forms containing the same. BACKGROUND OF THE INVENTION [0002]

The present invention relates to granules containing gum tragacanth, and to pharmaceutical compositions and formulations comprising them, and more particularly to granules comprising gum tragene, which exhibit good storage stability using certain stabilizers, ≪ / RTI >

Prostate hyperplasia is a common disease in older men, and 70% of men in their 60s suffer from the disease. As the aging process is accelerated, the number of patients with hyperplasia of the prostate is increasing rapidly, and there is a growing interest in its therapeutic treatment. The main treatment methods for prostatic hyperplasia are drug therapy and surgery. The surgical treatment is known as laparotomy, pancreatic prostatectomy (TUR-P), high temperature treatment, laser therapy, stenting, etc. The drug therapy is known as α1 adrenergic receptor blocker, antiandrogens, and herbal medicine .

In particular, silodosin, which is one of the? 1 adrenergic receptor antagonists, is a compound of formula ( I ) which is 1- (3-hydroxypropyl) -5 - [(2R) -2- (2- [ - trifluoroethoxy) phenoxy] ethylamino) propyl] -2,3-dihydro-1H-indole-7-carboxamide as an active ingredient, It is very useful for lowering the pressure in the urethra without affecting it and also acting selectively on the? 1 adrenergic receptor subtype to treat urinary disorders accompanied by enlargement of the prostate gland and the like.

[Chemical Formula 1]

Indeed dosin it is currently around the world are being sold in a variety of trade names such as glass F. (Urief ^®), true path (Thrupas ^®), Rapa flow (Rapaflo ^®), indeed Dix (Silodyx ^®).

However, it has been known that styrenaldehyde easily reacts with various excipients in pharmaceutical formulations to produce various soft materials, and in particular, reacts with lactose to lower the elution characteristics. Specifically, Patent No. 10-1072909 discloses that sorghum is reacted with various pharmaceutical excipients including lactose to produce a suppository, and D-mannitol as an excipient that can be used to improve such stability degradation Lt; / RTI > However, even when D-mannitol is used, generation of some degradation products can not be avoided, and development of a new composition for improving the stability of the ginseng is required.

The inventors of the present invention completed the present invention by confirming that the storage stability, dissolution rate and bioavailability of the saccharose can be improved by preparing granules using specific stabilizers while studying for improving the stability of saccharin.

Korean Patent No. 10-1072909

Accordingly, an object of the present invention is to provide a new formulation which is indeed improved in stability.

In one embodiment, the present invention provides a composition comprising: (a) (b) alkali inorganic salts as stabilizers; And (c) a pharmaceutically acceptable excipient.

In another embodiment, the invention provides a pharmaceutical composition comprising said granulate and a pharmaceutically acceptable additive.

In another embodiment, the present invention provides a pharmaceutical formulation prepared using the granule or the pharmaceutical composition.

The present invention shows that by combining granules with a specific stabilizer, the stability of granules can be improved by improving the stability of the granules, and the decrease in stability due to the reaction of granules with other granules can be improved, The granules containing gum arabic can be used to develop compositions or formulations having various elution properties regardless of the stability of the gum, and it is possible to reduce the side effects of the gum decomposition substances in the treatment of the patients, It can be used as a treatment for benign prostatic hyperplasia.

FIG. 1 is a graph showing the stability (yield of the flexible substance I) of siloxane according to the type of stabilizer.
Fig. 2 is a graph showing the stability (total amount of the generated flexible substances) of silane modified with the type of stabilizer.
FIG. 3 is a graph showing the stability (the amount of produced flexible substance I) of siloxane according to the content of the stabilizer.
FIG. 4 is a graph showing the stability (total amount of generated flexible substances) of siloxane according to the content of the stabilizer.
FIG. 5 is a graph showing the dissolution rate of siloxane according to the content of the stabilizer.
FIG. 6 is a graph showing the stability (production of the flexible substance I) of silododosin according to the combination of various excipients and stabilizers.
FIG. 7 is a graph showing the stability (total amount of produced flexible substances) of siloxane according to the combination of various excipients and stabilizers.
8 is a graph showing the dissolution rate of scintillation according to the type of excipient.
FIG. 9 is a graph showing the dissolution rate of scintillation according to the difference in the production method.
FIG. 10 is a graph showing a pharmacokinetic comparison of Spodoptera littoralis according to the manufacturing method difference.

The present invention relates to a composition comprising (a) a polysaccharide; (b) alkali inorganic salts as stabilizers; And (c) a pharmaceutically acceptable excipient.

The present invention is characterized in that the stability of the siloxane is improved by preparing granules using alkali inorganic salts as stabilizers. The present invention also features that granular materials are prepared using alkali inorganic salts as stabilizers to minimize the interaction between the various pharmaceutical excipients used in the manufacture of granules and siloxane.

The gadodensin used as the active ingredient in the granulate according to the present invention is 1- (3-hydroxypropyl) -5 - [(2R) -2- (2- [2- - trifluoroethoxy) phenoxy] ethylamino) propyl] -2,3-dihydro-1H-indole-7-carboxamide as an active ingredient, It is very useful for lowering the pressure in the urethra without affecting it and also acting selectively on the? 1 adrenergic receptor subtype to treat urinary disorders accompanied by enlargement of the prostate gland and the like.

The daily dose of cilostazol can be administered in an amount of 1 to 16 mg per day on an adult basis in an amount of 1 mg, 2 mg, 4 mg, 8 mg or 16 mg per day.

The alkali inorganic salts used as stabilizers in the granulate according to the invention are selected from the group consisting of oxides, hydroxides, carbonates and phosphates of sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum or lithium . In one embodiment, the alkali inorganic salts may be selected from the group consisting of oxides, hydroxides, carbonates and phosphates of alkali or alkaline earth metals. In other embodiments, the alkaline inorganic salt may be a calcium carbonate (CaCO _3), magnesium carbonate (MgCO _3), sodium bicarbonate (NaHCO ₃₎ or mixtures thereof.

In view of safety, the stabilizer may be used in an amount of 0.05 to 33 parts by weight, preferably 0.1 to 10 parts by weight, relative to 1 part by weight of rosin. If the stabilizer is less than the above-mentioned lower limit range, it is not possible to achieve the stability effect of the target thread, and if the stabilizer is out of the above-mentioned upper limit range, there is a problem that the elution rate of the raw material is lowered.

The stabilizer may be an antioxidant known to improve the stability of conventional drugs (for example, butylated hydroxyanisol (BHA) or butylated hydroxytoluene (BHT)) or other stabilizing agents (e.g., meglumine It is possible to remarkably improve the stability of the film.

The excipients which may be used in the granules according to the invention may be, for example, at least one selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, plasticizers and glidants.

The diluent may be selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, But the present invention is not limited thereto. The diluent may be used in an amount of 1 to 99% by weight, preferably 5 to 95% by weight, based on the total weight of the granules.

The disintegrant may be a component exhibiting stable disintegration selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropylcellulose, starch, alginic acid or its sodium salt, and mixtures thereof , But is not limited thereto. The disintegrant may be used in an amount of from 1 to 70% by weight, preferably from 2 to 50% by weight, based on the total weight of the granules.

The plasticizers may be selected from the group consisting of polyoxyalkylene (e.g. BASF Pluronics, UCC Carboxaxes, PEGs), ether-capped polyoxyalkylene such as polyoxyethylene laauryl ether, ester-capped polyoxyalkylene such as polyoxyethylene stearate (C ₆ -C ₁₀ ) sulfate salts, and the like, and the like, as well as organic solvents such as, for example, alginic acid, alginic acid, sorbitan stearate, phosphatide, alkylamine, glycerin, polyethylene oxide, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium lauryl sulfate, But is not limited thereto. The plasticizer may be used in an amount of 0.01 to 10% by weight based on the total weight of the granules.

The lubricant includes, but is not limited to, stearic acid, magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, silicon dioxide (SiO ₂ ), and the like. The glidant may be used in an amount of 0.01 to 10% by weight based on the total weight of the granulate.

The granulate according to the present invention can be prepared by a granulation process widely known in the pharmaceutical field, for example, a dry granulation process or a wet granulation process.

Preferably, the granulate according to the present invention is produced by a wet granulation process using a mixed granulator or a fluidized bed granulator. Although it is generally known in the pharmaceutical field that wet granulation processes are more vulnerable to drug stability than dry granulation processes, the granulates according to the present invention, despite being produced by a wet granulation process, And exhibits excellent drug stability, dissolution rate and bioavailability.

The present invention also provides a pharmaceutical composition comprising the granules described above and a pharmaceutically acceptable additive. The additive may be a diluent, a disintegrant, a wetting agent, a binder or a lubricant. The wetting agent is selected from the group consisting of polyoxyalkylene (e.g., BASF Pluronics, UCC Carboxaxes, PEGs), ether-capped polyoxyalkylene such as polyoxyethylene laauryl ether, ester Capped polyoxyalkylene such as polyoxyethylene stearate, sorbitan stearate, phosphatide, alkylamine, glycerin, polyethylene oxide, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium lauryl sulfate , Aryl (C ₆ -C ₁₀ ) sulfate salts, and the like. The wetting agent may be used in an amount of 0.01 to 10% by weight based on the total weight of the composition. The binder may also be a silicate derivative such as hydroxypropylcellulose, hydromellose, polyvinylpyrrolidone, copovidone, macrogol, light anhydrous silicic acid, synthetic aluminum silicate calcium silicate or magnesium metasilicate aluminate (magnesium aluminum silicate) , Phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and mixtures thereof, but are not limited thereto. The binder may be used in an amount of 0.3 to 30% by weight, preferably 1 to 20% by weight, based on the total weight of the composition.

Furthermore, the present invention provides pharmaceutical formulations prepared using the above-described granules or the aforementioned pharmaceutical compositions. The pharmaceutical formulations of the present invention may be formulations for oral administration such as tablets or capsules.

For example, in the case of tablets, the above-described granules or the pharmaceutical composition can be prepared by tableting using a conventional rotary tablet machine or the like, preferably by a light-shielding coating process, have.

In the case of capsules, the capsules may be prepared by filling the capsules with the above-described granules or the pharmaceutical composition using a conventional capsule filling machine. The capsule is preferably a hard capsule made of HPMC, gelatin or the like.

In the case of the above-mentioned capsules, the dissolution-lowering effect of various excipients disclosed in Modern Pharmics, 1989, 470 pages general designation of the Hard Gelatin Capsule Formulation, that is, magnesium stearate as a lubricant and magnesium stearate, (For example, sodium lauryl sulfate (SLS)) may be used.

On the other hand, the present invention provides a method for producing the above-mentioned granules, which comprises the following steps:

(a) preparing granules by a dry granulation process or a wet granulation process by mixing ginsenosides, alkaline inorganic salts as stabilizers, and pharmaceutically acceptable excipients.

The invention also provides a method of making a pharmaceutical composition or pharmaceutical formulation comprising the steps of:

 (a) preparing a granulate by dry granulation or a wet granulation process by mixing ginsenosides, alkaline inorganic salts as stabilizers, and pharmaceutically acceptable excipients; And

(b) adding a pharmaceutically acceptable additive to the granulate of step (a) to formulate.

EXAMPLES Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

EXAMPLES 1 to 3: Preparation of a rosuvastatin dosage form containing a stabilizer

According to the composition shown in the following Table 1, granules containing gum arabicin were prepared by a wet granulation method and then filled into capsules to prepare capsule formulations.

Concretely, calcium lactate (CaCO ₃ ), magnesium carbonate (MgCO ₃ ) or hydrogen carbonate (MgCO ₃ ) were added as an active ingredient to be used as the active ingredient (Dongwoo Sinnec Co., Ltd.), lactose as an excipient, Sodium (NaHCO ₃ ) was mixed with a high speed mixer (Sejong, Korea; Agitator 126 ± 10 rpm, Chopper 3000 ± 300 rpm, combined time 2 ± 1 min). The mixture was dried to a moisture content of 2.0 ± 0.5% using a fluid bed drier (air temperature 50 ± 10 ° C.), and then sodium stearyl fumarate (pruv ^® ) and sodium lauryl sulfate (SLS ) Was added, followed by post-mixing with a Column Blender to obtain granules. The gelatin-containing granules were then filled in No. 3 gelatin capsules using a capsule filling machine (SF-100, Bosch, Germany) to prepare capsule formulations.

COMPARATIVE EXAMPLES 1 to 4: Preparation of fibrillated formulations with different stabilizers

(BHA) or butylated hydroxytoluene (BHT), which is an antioxidant, or meglumine, which is a stabilizer, is used instead of the stabilizer used in Example 1 , The process of Example 1 was repeated to prepare the capsule formulations of Comparative Examples 1 to 3. On the other hand, in Comparative Example 4, a capsule formulation was prepared without using a stabilizer or an antioxidant.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Indeed 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Lactose 130.0 130.0 130.0 130.0 130.0 130.0 130.0 Pregelatinized starch 36.0 36.0 36.0 36.0 36.0 36.0 36.0 Calcium carbonate 2.0 - - - - - - Magnesium carbonate - 2.0 - - - - - Sodium hydrogencarbonate - - 2.0 - - - - BHA - - - 2.0 - - - BHT - - - - 2.0 - - Meglumine - - - - - 2.0 - Pruv 1.8 1.8 1.8 1.8 1.8 1.8 1.8 SLS 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Total amount (mg) 174.0 174.0 174.0 174.0 174.0 174.0 174.0

Experimental Example  One: Stabilizer  Storage stability of formulations according to type

The formulations of Examples 1 to 3 and Comparative Examples 1 to 4 were sealed in an HDPE bottle and stored under the conditions of 60 占 폚, respectively. Then, at 1, 2 and 4 weeks, the amount of the resulting flexible substance was measured as follows.

<Analysis method>

Approximately 50 mg of the standard product was added to a 100-mL volumetric flask and adjusted to the indicated value with methanol. Take exactly 1 mL of this solution, adjust the final volume to 100 mL with methanol, and filter through a 0.45 μm membrane filter to make the standard solution. Separately, 50 mg of the contents were taken from the capsules of Examples 1 to 3 and Comparative Examples 1 to 4, and the final volume was adjusted to 100 mL with methanol. The resulting solution was filtered through a 0.45 μm membrane filter to prepare a sample solution .

10 占 L of the standard solution and the test solution were tested according to the liquid chromatographic method under the following conditions.

&Lt; HPLC Measurement Condition >

- Detector: ultraviolet absorption spectrophotometer (measuring wavelength: 225 nm)

- Column: column packed with octadecylsilylated silica gel (25 cm x 4.6 mm, 5 um) or similar column

- Flow rate: Adjust the peak hold time to about 12-15 minutes

- Column temperature: 40 ° C

- mobile phase: A: 3.9 g of sodium dihydrogen phosphate dihydrate (NaH ₂ PO ₄ .2H ₂ O) was dissolved in 1000 mL of DW and adjusted to pH 3.4 with diluted phosphoric acid (1 → 10); B: acetonitrile

- Mobile condition

The amounts of the flexible substances (the flexible substances I and the total flexible substances) produced from the formulations of Examples 1 to 3 and Comparative Examples 1 to 4 are shown in the following Table 2 and FIGS.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Flexible Substance I Early 0 0 0 0 0.02 0.03 0.02 1 week 0.08 0.11 0.23 0.24 0.52 0.31 0.53 2 weeks 0.18 0.32 0.35 0.41 0.8 0.58 0.76 4 weeks 0.69 0.89 0.90 1.32 1.93 1.52 2.4 Total flexible material Early 0 0 0 0 0.02 0.03 0.03 1 week 0.1 0.19 0.28 0.9 0.83 0.44 1.21 2 weeks 0.21 0.33 0.46 1.2 1.76 0.73 1.82 4 weeks 0.88 0.98 0.98 2.07 2.44 1.92 3.07

As can be seen from Table 2 and FIGS. 1 and 2, when the peaks of the flexible material appearing in the RRT (relative peak retention time) 1.34 relative to the peak area of the main component are observed in the order of the initial, 1, 2 and 4 weeks, In the case of the formulations of Examples 1 to 3 using alkali inorganic salts such as magnesium carbonate or sodium hydrogen carbonate as the stabilizer, the amount of the flexible substance was significantly smaller than that of Comparative Example 4 in which no stabilizer or antioxidant was used at all. In addition, the formulations of Examples 1 to 3 were significantly lower in the amount of the flexible substance than the formulations of Comparative Examples 1 to 3 using BHA, BHT, or meglumine. The results show that the stability of scyllo-toxins can be improved by using alkaline inorganic salts (such as calcium carbonate, magnesium carbonate or sodium bicarbonate) as stabilizers. Particularly, among the alkali inorganic salts, calcium carbonate is the most preferable as the stabilizer.

Example  4 to 9: different amounts of stabilizer Indeed  Manufacturing of formulations

In order to compare the stability according to the content of the stabilizer, a capsule formulation containing various contents of calcium carbonate was prepared according to the composition shown in Table 3 below. The capsules were prepared according to the methods described in Examples 1 to 3.

Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Indeed 4.0 4.0 4.0 4.0 4.0 4.0 Lactose 131.9 131.6 122.0 92.0 52.0 0.0 Pregelatinized starch 36.0 36.0 36.0 36.0 36.0 36.0 Calcium carbonate 0.1 0.4 10.0 40.0 80.0 132.0 Pruv 1.8 1.8 1.8 1.8 1.8 1.8 SLS 0.2 0.2 0.2 0.2 0.2 0.2 Total amount (mg) 174.0 174.0 174.0 174.0 174.0 174.0 The content of stabilizer relative to 1 part by weight
(Parts by weight) 0.025 0.1 2.5 10 20 33

Experimental Example  2 : Stabilizer  Storage stability of formulation according to content

The amounts of the resulting soft materials were measured in the same manner as in Experimental Example 1 on the capsule formulations of Examples 4 to 9. The above results are shown in Table 4 and Figs. 3 and 4.

Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Flexible Substance I Early 0 0 0 0 0 0 1 week 0.45 0.09 0.08 0.05 0.03 0.02 2 weeks 0.68 0.18 0.17 0.16 0.14 0.09 4 weeks 1.56 0.72 0.59 0.57 0.49 0.38 Total flexible material Early 0.02 0 0 0 0 0 1 week 1.09 0.13 0.1 0.06 0.05 0.03 2 weeks 1.57 0.28 0.2 0.11 0.23 0.18 4 weeks 2.74 0.92 0.79 0.73 0.65 0.46

Comparing the results of Table 4 and FIGS. 3 and 4 with the results of Experimental Example 1, it can be seen that the capsule formulations (Examples 4 to 9) of the present invention containing alkali inorganic salts as stabilizers, It was confirmed that the storage stability was very excellent as compared with the formulations (Comparative Examples 1 to 4).

In particular, it has been shown that as the content of the stabilizer increases, the amount of the flexible substance decreases, indicating that the use of a sufficient amount of the stabilizer is desirable from the standpoint of stability of the product.

However, in the case of the formulation of Example 4 containing the stabilizer in an amount of 0.025 parts by weight based on 1 part by weight of the stabilizer, the generation of the flexible substance was higher than those of Examples 5 to 9 in which the stabilizer was contained in an amount of 0.1 part by weight or more . It is preferable to use 0.1 part by weight or more of the stabilizer per 1 part by weight of the stabilizer in order to maximize the stability effect of the formulation containing gum tragacanth.

Experimental Example  3: Stabilizer  Depending on the content Indeed  Dissolution test

For the capsule formulations of Examples 4 to 9, a dissolution test was performed in a USP paddle using a sinker in 900 mL of 0.1 N hydrochloric acid solution at 50 rpm. The results are shown in Table 5 and FIG.

In vitro release 5 minutes 10 minutes 15 minutes 30 minutes Example 4 49.2% 90.0% 92.5% 97.5% Example 5 47.4% 89.2% 91.9% 96.9% Example 6 44.8% 87.5% 90.7% 95.3% Example 7 42.0% 83.5% 88.1% 90.6% Example 8 20.3% 45.1% 49.0% 50.3% Example 9 10.5% 19.5% 20.1% 21.3%

As shown in Table 5 and FIG. 5, in the case of the formulations of Examples 8 and 9, which contained 20 parts by weight and 33 parts by weight of a stabilizer per 1 part by weight of tall roast, the stabilizer was added in an amount of 10 parts by weight or less The dissolution rate was found to be lower than that of the formulation containing it. The above results show that it is preferable to use the stabilizer in an amount of 10 parts by weight or less in terms of the dissolution rate of the silane.

Example  10 to 13: Various excipients and Stabilizer  Included Indeed  Manufacturing of formulations

It is known that Shirodoshin reacts with various excipients to produce various degradation products. Therefore, in order to examine whether the stabilizer of the present invention can inhibit the reaction between Glycine and various excipients, a capsule preparation was prepared using various excipients as shown in Table 6 below. The capsules were prepared according to the methods described in Examples 1 to 3.

Comparative Example  5 to 8: Stabilizer  not included Indeed  Manufacturing of formulations

The procedures described in Examples 10 to 13 were repeated, except that the stabilizers were not used in Examples 10 to 13, according to the composition shown in Table 6 below to prepare the capsule formulations of Comparative Examples 5 to 8.

Example
10 Example
11 Example
12 Example
13 Comparative Example
5 Comparative Example
6 Comparative Example
7 Comparative Example
8 Indeed 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Calcium carbonate 2.0 2.0 2.0 2.0 - - - - D-mannitol 130.0 - - - 130.0 - - - Xylitol - 130.0 - - - 130.0 - - Sorbitol - - 130.0 - - - 130.0 - Avicel - - - 130.0 - - - 130.0 Pregelatinized starch 36.0 36.0 36.0 36.0 36.0 36.0 36.0 36.0 Pruv 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 SLS 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Total amount 174.0 174.0 174.0 174.0 172.0 1720 172.0 172.0

Experimental Example  4: Storage stability of formulations according to combination of various excipients and stabilizers

The amount of the resulting flexible material was measured in the same manner as in Experimental Example 1, using the capsule formulations of Examples 10 to 13 and Comparative Examples 5 to 8. The above results are shown in Table 7 and Figs. 6 and 7.

Example
10 Example
11 Example
12 Example
13 Comparative Example
5 Comparative Example
6 Comparative Example
7 Comparative Example
8 Flexible Substance I Early 0 0.01 0.01 0.02 0.02 0 0.01 0.03 1 week 0.07 0.13 0.13 0.2 0.21 0.28 0.036 0.99 2 weeks 0.29 0.36 0.34 0.45 0.64 0.78 0.92 2.36 4 weeks 0.83 0.89 0.81 0.92 1.23 1.83 1.79 6.7 gun
Flexible material Early 0 0.01 0.01 0.02 0.2 0 0.01 0.03 1 week 0.13 0.16 0.17 0.22 0.34 0.42 0.44 1.41 2 weeks 0.39 0.42 0.41 0.49 0.85 1.01 1.12 2.82 4 weeks 0.92 One 1.07 1.2 1.75 1.93 1.98 7.16

As shown in Table 7 and FIG. 6 and FIG. 7, there was a slight difference in the amount of generation of the flexible material depending on the type of excipient, but the formulations of Examples 10 to 13 using alkali inorganic salts as stabilizers did not use stabilizers It was confirmed that the stability was remarkably superior to the formulations of Comparative Examples 5 to 8, which were not. These results show that the stabilizer of the present invention can inhibit the reaction between ginsenosides and various excipients to improve the stability of xylose.

Experimental Example  5: Depending on the type of excipient Indeed  Dissolution test

In order to compare the dissolution rates of sprouts according to the types of excipients, the capsule formulations of Examples 10 to 13 prepared using various excipients were tested in a USP paddle using a sinker in 900 mL of 0.1N hydrochloric acid at 50 rpm A dissolution test was performed. The results are shown in Table 8 and FIG. In the case of Figure 8, the dissolution rate of Example 1 was plotted for comparison.

In vitro release 5 minutes 10 minutes 15 minutes 30 minutes Example 10 40.2% 84.8% 91.9% 97.4% Example 11 43.7% 89.2% 94.2% 98.7% Example 12 49.1% 90.4% 93.5% 98.8% Example 13 44.0% 85.6% 93.9% 97.9%

As shown in Table 8 and FIG. 8, when the formulation was prepared by the wet granulation method, it was confirmed that an excellent dissolution rate could be obtained even when various excipients were used.

Comparative Example  9: By different manufacturing methods Indeed  Manufacturing of formulations

A capsule formulation was prepared according to the same composition as in Example 1 except that the mixture was directly charged into capsules without granulation, to prepare a capsule formulation.

Experimental Example  6: Depending on the manufacturing method Indeed  Dissolution test

The capsules formulations prepared in Example 1 and Comparative Example 9 were prepared by dissolving the capsules in a USP paddle using a sinker in 900 mL of 0.1 N hydrochloric acid at 50 rpm. The results are shown in Table 9 and FIG.

In vitro release 5 minutes 10 minutes 15 minutes 30 minutes Example 1 48.7% 88.2% 92.3% 97.2% Comparative Example 9 23.4% 46.2% 51.4% 55.2%

As shown in Table 9 and FIG. 9, the formulation of Example 1 containing the granules produced by the wet granulation method was found to have a much better dissolution rate than the formulation of Comparative Example 9 which was not granulated. The results show that the granules prepared by the wet granulation method are preferable in terms of dissolution rate.

Experimental Example  7: Indeed  Pharmacokinetic comparison

Male rats (Sprague-Dawley, Sprague-Dawley, USA) (n = 4) were divided into two groups, the capsules of Example 1 were administered by the double blind method to the first group, The capsules were administered. After analyzing the drug concentration in the blood, the pharmacokinetic parameter results are shown in Table 10 using the WinNonlin ^® program of Phoenix ^® using the drug concentration over time. The results are shown in Table 10 and FIG.

Indeed parameter Example 1 Comparative Example 9 AUC _{0 - 12} (ng · hr / mL) 42.7 ± 7.6 26.8 ± 8.4 C _max (ng / mL) 30.2 ± 4.1 13.7 ± 3.7 T _max (hr) 0.6 ± 0.1 0.8 ± 0.2

As shown in Table 10 and FIG. 10, the capsule of Example 1 containing granules produced by the wet granulation method had a C _max and AUC of about two times higher than that of the capsule of Comparative Example 9 which was not granulated . Therefore, it is believed that by improving the stability of gypsum by wet granulation, it is possible to maximize the drug concentration in a specific organ, thereby increasing the bioavailability of the drug, thereby maximizing the therapeutic effect of the drug.

Claims (10)

(a) Truncated; (b) alkali inorganic salts as stabilizers; And (c) a pharmaceutically acceptable excipient.
The method according to claim 1, wherein the alkali inorganic salts are at least one selected from the group consisting of oxides, hydroxides, carbonates and phosphates of sodium, calcium, potassium, magnesium, manganese, iron, copper, Characterized by granular water.
The granule according to claim 1, wherein the alkali inorganic salts are calcium carbonate (CaCO ₃ ), magnesium carbonate (MgCO ₃ ), sodium hydrogencarbonate (NaHCO ₃ ) or a mixture thereof.
The granular material according to claim 1, wherein the alkali inorganic salts are contained in an amount of 0.05 to 33 parts by weight based on 1 part by weight of gallic acid.
The granule according to claim 1, wherein the pharmaceutically acceptable excipient is at least one selected from the group consisting of a diluent, a disintegrant, a plasticizer and a glidant.
The granule of claim 1, characterized in that the granulate is produced by a wet granulation process.
A pharmaceutical composition comprising the granulate of claim 1 and a pharmaceutically acceptable additive.
8. The pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable additive is a diluent, a disintegrant, a wetting agent, a binder or a lubricant.
A pharmaceutical formulation prepared using the granulate of any one of claims 1 to 6 or the pharmaceutical composition of any one of claims 7 to 8.
10. The pharmaceutical formulation of claim 9, wherein the pharmaceutical formulation is a tablet or capsule.

Images