KR20210090975A - Pharmaceutical Composition Comprising R-Thioctic Acid, Oil and Dispersing Agent - Google Patents

Abstract

A pharmaceutical composition of the present invention is characterized by containing R-thioctic acid or a pharmaceutically acceptable salt thereof as an active component, and additionally including oil and a dispersion aid. In the pharmaceutical composition of the present invention, the oil forms a protective layer surrounding the active component to protect the active component against exposure to an acidic environment, thereby preventing the degradation of the active component while the dispersion aid improves dispersibility in a dissolution liquid, and allowing the active component to exhibit a high dissolution rate even in a low pH environment.

Description

Pharmaceutical composition comprising R-thioctic acid or a pharmaceutically acceptable salt thereof, oil and a dispersing agent {Pharmaceutical Composition Comprising R-Thioctic Acid, Oil and Dispersing Agent}

The present invention relates to a pharmaceutical composition comprising R-thioctic acid or a salt thereof as an active ingredient and an oil for improving the bioavailability of the active ingredient and a dispersing aid.

Thiocic acid (thioctic acid) is an organic compound containing sulfur derived from octanoic acid, also called alpha-lipoic acid. Thioctic acid is one of the powerful antioxidants, and it removes lipophilic free radicals and reduces oxidative stress in tissues in diabetic patients, through which it suppresses hepatocellular damage and inflammation caused by diabetic neuropathy, diabetes, insulin resistance, cataracts, neuropathy, and It is known to have a pharmacological effect to improve symptoms such as diabetic complications such as kidney disease. Thioctic acid is classified as an enantiomer and divided into R-type and S-type. Among them, the R-type is the active form in the human body.

As shown in the figure below, thioctic acid has a disulfide bond in a pentagonal ring structure in its molecular structure. The disulfide bond is an unstable bond and is easily broken by heat to form free radicals. In addition, the pentagonal ring structure is also a three-dimensionally unstable structure and exhibits energy instability. As a result, the bond is easily broken by heat and moisture to form a water-insoluble polymer. The degree of instability of R-thioctic acid, which has been extracted only R-type from existing thioctic acid, is further increased, and for this reason, when mixed with water, the solubility is very poor due to ring opening and formation of a polymerized gel.

In order to improve the low stability of R-thioctic acid, in Korean Patent Application Laid-Open No. 10-2007-0025426 (Patent Document 1), R-thioctic acid and tromethamine are combined in a 1:1 ratio. methamine salts are presented. According to Patent Document 1, the solubility and absorption rate of R-thioctic acid were increased compared to the conventional formulation, and the stability according to temperature was also improved. Also, a formulation using it is currently on the market (Bukwang Pharmaceutical's Dexid Tablet). However, the formulation of Patent Document 1 also did not sufficiently solve the instability that appears in acidic conditions, and this causes denaturation such as polymerization and resulting gel formation, resulting in poor disintegration or insufficient dissolution of the active ingredient, resulting in a low dissolution rate. show the phenomenon

Meanwhile, Korean Patent Application Laid-Open No. 10-2006-0100117 (Patent Document 2) proposes a formulation in the form of a soft capsule with improved stability including thioctic acid. Patent Document 2, as a soft capsule formulation, proposes a method for improving the stability of the soft capsule formulation, such as improving the mixing phenomenon that occurs when the liquid inside the soft capsule is transferred to the film.

However, despite the fact that studies to improve the stability as in Patent Documents 1 and 2 are continuously being made, the technology for maintaining the stability of the active ingredient during dissolution in the body, especially in acidic conditions, still needs improvement. am. In addition, since the study of the dissolution pattern according to the viscosity and dispersing power characteristics of the additive for improving the bioavailability has not been conducted, it has not yet been confirmed whether smooth dissolution actually appears, furthermore, whether significant bioavailability is improved in vivo. there is no bar

Korean Patent Publication No. 10-2007-0025426 Korean Patent Publication No. 10-2006-0100117

In the pharmaceutical formulation containing thioctic acid, the present invention improves the problem of the conventional formulation in which the active ingredient is polymerized and denatured into a gel form when exposed to an acidic environment, thereby reducing the bioavailability, and further improving the dispersibility of the pharmaceutical formulation containing thioctic acid. An object of the present invention is to provide a pharmaceutical composition that maintains a high absorption rate in the body and is rapidly dispersed in the gastrointestinal tract.

The pharmaceutical composition of the present invention contains R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient, and contains 100 to 300% by weight of oil and 150 to 350% by weight of a dispersing aid based on the total weight of the active ingredient characterized.

In this case, the pharmaceutical composition may have a total weight of 600 to 1500 mg, preferably 800 to 1200 mg. The active ingredient may be included in 5 to 25% by weight based on the total weight of the pharmaceutical composition in order to exhibit pharmacological activity. When the content of the active ingredient is less than 5% by weight based on the total weight of the pharmaceutical composition, the pharmacological activity does not appear sufficiently, and when it exceeds 25% by weight, the ratio of the main ingredient in the formulation is excessively high, and incomplete encapsulation and dissolution of the pharmaceutical composition in the oil during the dissolution test It may exhibit pharmaceutical inappropriate functions, such as insufficient dispersing power.

In particular, even when the pharmaceutical composition contains R-thioctic acid free base as an active ingredient, it suppresses the denaturation of the active ingredient in the body to form a gel, and thus exhibits high bioavailability.

The oil is propylene glycol monocaprylate Type I, propylene glycol monocaprylate Type II, glycerol / glyceryl monolinoleic acid, medium chain triglycerides, propylene glycol monolaurate, propylene glycol dicaprylate, from the group consisting of castor oil It may be one selected or a mixture of two or more, and serves to prevent denaturation of the active ingredient by encapsulating the active ingredient in oil.

The dispersing aid is an amphiphilic excipient, and one or two or more selected from the group consisting of linoleoyl, caprylocaproyl macrogol glyceride, polysorbate 20, and polysorbate 80 may be used. In particular, when an amphiphilic excipient having a relatively high viscosity is included as a surfactant, and an amphiphilic excipient having a relatively low viscosity is included as an auxiliary surfactant, an excellent effect was obtained. At this time, the surfactant included in the dispersing aid and When the auxiliary surfactant is mixed in a weight ratio of 1:1.1 to 1:2, the most excellent effect was obtained.

In addition, the difference between the hydrophilicity-lipophilicity balance (HLB) value of the oil and the dispersing aid may be preferably 4 or more, more preferably 7 or more. At this time, when the difference in the hydrophilicity-lipophilic balance (HLB) value is less than 4, the active ingredient is not sufficiently encapsulated in the oil, and a significant amount of the active ingredient is mixed in the dispersion aid, and may be exposed to an external acid and denatured.

The pharmaceutical composition of the present invention may be prepared in the form of a soft capsule or tablet, and in the case of a tablet, an adsorbent may be further included to improve tabletting performance.

In this case, the adsorbent may be included in an amount of 60 to 200% by weight based on the combined weight of the oil and the dispersing aid. In this case, when the content of the adsorbent is less than 60% by weight based on the combined weight of the oil and the dispersing aid, the tabletting property is low, and defects may occur during tablet manufacture. On the other hand, when contained in excess of 200% by weight, there is no significant tabletting improvement effect, and only the size of the formulation is unnecessarily large, which is not preferable because the convenience of taking it may decrease.

The adsorbent may be a silicon-based compound, and preferably, may be one or a mixture of two or more selected from the group consisting of calcium silicate, magnesium metasilicate, and colloidal silicon dioxide.

The pharmaceutical composition according to the present invention is characterized in that it is self-emulsifying in the body. That is, since it is emulsified so as not to be exposed to an acidic environment during oral administration, active ingredients that are easily denatured by acid are not easily exposed, and thus bioavailability is high.

The present invention is to improve the dissolution rate reduction that occurs when the active ingredient is polymerized in an acidic environment to form a gel in a pharmaceutical composition containing R-thioctic acid as an active ingredient. The pharmaceutical composition of the present invention forms a protective layer in which the oil contained together with the active ingredient in the soft capsule surrounds the active ingredient, and the internal solution is smoothly dispersed into the eluate through the dispersion aid containing the surfactant and the auxiliary surfactant, It has the effect of suppressing the polymerization of the active ingredient and smoothly releasing the drug in the eluate to improve the dissolution rate and increase the bioavailability.

1 is a graph showing the results of a dissolution test for commercially available R-thioctate tromethamine salt tablets (Bugwang Pharmaceutical 'Dexid Tablets') under pH 1.2 dissolution conditions.
Figure 2 is a schematic diagram of the denaturation phenomenon of commercially available R-thioctate tromethamine salt tablets (Bukwang Pharmaceutical 'Dexid Tablets') as they are eluted under pH 1.2 eluent conditions and photos of the actually denatured properties.
3 is a comparison of the dispersion state before and after stirring through a vortexing machine when 1 mL of the oil and dispersing aid prepared in Preparation Examples 19 to 27 is added to 10 mL of a pH 1.2 solution.
4 is a graph showing the dissolution test results of the formulations of Examples 1 to 5 and Comparative Example 1 under pH 1.2 dissolution conditions.
5 is a photograph of the state of the dissolution solution after the dissolution test in the dissolution condition of pH 1.2 for the formulations of Examples 1 to 5.
FIG. 6 schematically shows whether or not a polymerization phenomenon occurs when the R-thioctic acid active ingredient is encapsulated by oil and when not encapsulated.
7 shows the dissolution profiles of Example 3, Comparative Example 1, and the reference drug (Bugwang Pharmaceutical 'Dexid Tablet') formulations compared and dissolution profiles under each dissolution condition.
8 shows a comparative dissolution graph between the R-thioctic acid tablet prepared in Example 9 and Comparative Example 2 and the reference drug (Bugwang Pharmaceutical 'Dexid Tablet').

In order to achieve the above object, the present invention provides an oral formulation having improved stability and dissolution rate compared to conventional formulations, and containing R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

Specifically, the pharmaceutical composition of the present invention includes R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient, an oil for blocking the active ingredient from an acidic environment, and a dispersing aid for improving dispersibility.

In the present invention, 'dispersion aid' refers to a pharmaceutically acceptable excipient used to increase dispersibility in an acidic environment when the R-thioctic acid active ingredient is eluted from the body. Specifically, the dispersing aid comprises a specific surfactant suitable for increasing the dispersibility of R-thioctic acid and an additional auxiliary surfactant.

Hereinafter, the present invention will be described in detail.

According to the research results known so far, the bioavailability of thioctic acid when orally administered as an active ingredient appears to be about 30%. There are three main reasons for the low bioavailability of thioctic acid. The first is denaturation such as polymerization due to low stability, the second is a fast intrahepatic metabolic rate, and the third is low solubility in acidic conditions. Except for the metabolic rate in the liver, which is the second of the above causes, the pharmaceutical improvement is expected to be effective in improving the bioavailability. It is found that this bioavailability has a significant effect on degradation.

As a result of the dissolution test under acidic conditions of the pH 1.2 eluate for the commercially available R-thioctate tromethamine salt control drug (Bukwang Pharmaceutical's Dexid Tablet), the surface of the tablet was denatured under acidic conditions, resulting in a highly viscous polymer gel ( polymer gel), and this polymer gel acts as a barrier to prevent the eluate from penetrating into the tablet, and as a result, it was found that disintegration and dissolution inside the tablet did not occur smoothly. This phenomenon continued during the dissolution test, and it was confirmed that the final dissolution rate of the tablet was about 20% or less even when the dissolution test was performed for 2 hours or more. The dissolution graph for the corresponding experiment, the appearance of the tablet after completion of dissolution in acidic conditions, and a schematic diagram of the tablet state according to the dissolution conditions are shown in FIGS. 1 and 2, respectively.

In order to improve the low dissolution rate of these conventional formulations, the pharmaceutical composition of the present invention prevents the formation of a polymer gel under acidic conditions by first encapsulating R-thioctic acid in oil. In addition, by improving the dispersibility of the active ingredient by using a dispersing aid comprising a surfactant and an auxiliary surfactant, the dissolution rate in acidic conditions was remarkably improved compared to the conventional formulation. Accordingly, the pharmaceutical composition of the present invention was able to significantly increase the dissolution rate and dissolution rate under acidic conditions in the stomach at the beginning of oral administration compared to the existing commercial formulations, and furthermore, through reduction of the liver first-pass effect in vivo (receptor saturation) An additional effect of increasing bioavailability can also be expected.

The pharmaceutical technology mainly used in the present invention is the self-emulsifying drug delivery system (SEDDS), in which the drug encapsulated in oil obtains sufficient dispersing power by a dispersing agent including surfactants and auxiliary surfactants to achieve homogeneity with body fluids under in vivo conditions. It is a formulation method that induces an emulsion state of one type. By self-emulsification, an emulsion is formed even with relatively mild agitation such as gastrointestinal movement, ensuring the complete dissolution of poorly soluble preparations or drugs that are unstable under certain conditions, and facilitates rapid release of drugs, gastrointestinal permeation and absorption in vivo when taken. .

Hereinafter, Examples and Comparative Example 1 of the present invention will be described in more detail through comparative tests with reference drugs. The following examples are for explaining the present invention in more detail, and the scope of the present invention is not limited by these examples.

<Preparation Examples 1 to 11: R-thioctic acid solubility screening test according to oil>

The oil excipients of the components listed in Table 1 below are added to 100 mg of R-thioctic acid in a weight ratio of 1:1, mixed uniformly, and the drug is dissolved in oil for a sufficient time using a sonicator to prepare a solution. The prepared solution was filtered with a 0.45 μm filter, diluted 1:100 in ethanol, and then the peak value of the diluted solution was checked using HPLC, so that the solubility of R-thioctic acid according to the oil type of each preparation example was confirmed.

Classification ingredient Solubility
(Unit: μg/ml) remark Preparation Example 1 R-thioctic acid Glycerol/Glyceryl Monolinoleic Acid 438.13 Maisine 35-1 Preparation 2 soybean oil 350.20 Preparation 3 mineral oil 117.28 Preparation 4 olive oil 272.83 Preparation 5 medium chain triglycerides 493.82 Labrafac lipophile WL 1349 Preparation 6 Propylene glycol dicaprylate 455.54 Labrafac PG Preparation 7 Propylene glycol monolaurate 562.86 Capmul PG-12 Preparation 8 Propylene glycol monocaprylate Type I 642.53 Capryol PGMC Preparation 9 Propylene glycol monocaprylate Type II 673.52 Capryol 90 Preparation 10 castor oil 415.78 Preparation 11 sunflower oil 178.25

As a result of the test, it was confirmed that the greatest amount of R-thioctic acid could be dissolved when propylene glycol monocaprylate Type II of Preparation Example 9 was used as an oil. In addition, the oils of Preparation Examples 1, 5, 6, 7, 8 and 10 having a solubility of 400 μg/ml or more are also considered suitable.

In addition, in the case of propylene glycol monocaprylate Type II, its viscosity is also relatively low among oil bases, so it is expected that problems due to viscosity that may appear in the preparation and dissolution of the soft capsule solution will be significantly improved. . In particular, since R-thioctic acid has a high drug dose for effect expression, it is preferable to use an oil with high solubility in order to minimize the weight of the formulation.

<Preparation Examples 12 to 18: R-thioctic acid solubility screening test for selection of dispersion aids including surfactants and auxiliary surfactants>

The amphiphilic excipients of the components listed in Table 2 below were added 1:1:1 with R-thioctic acid and propylene glycol monocaprylate Type II oil having an HLB value of 5 and uniformly mixed with an ultrasonic dispersing device (sonicator) Disperse for a sufficient time using to prepare a mixture. The mixture was filtered with a 0.45 μm filter, diluted 1:100 in ethanol, and the peak value of the diluted solution was checked using HPLC to confirm the solubility of each oil in R-thioctic acid. . In addition, the mixture was administered to a pH 1.2 solution to determine whether the mixture formed polymer gel formation.

Classification Dispersion adjuvant candidates HLB value of dispersing aid HLB difference with oil (propylene glycol monocaprylate Type II) polymer gel
Formation Preparation 12 Linoleoyl Macrogol
Glyceride M 2125 9 4 X Preparation 13 Linoleoyl Macrogol
Glyceride M1944 9 4 X 14 in manufacturing Caprylocaproyl Macrogol Glyceride 12 7 X Preparation 15 Transcutol 4 One O Preparation 16 Polysorbate 20 17 12 X Preparation 17 Polysorbate 80 15 10 X Preparation 18 Diethylene glycol monolaurate 6 One O

As a result of the test, as in Preparation Example 15, it was confirmed that R-thioctic acid showed the highest solubility in a mixture of propylene glycol monocaprylate Type II oil (HLB value 5) and transcutol 1:1 as a dispersing aid.

However, when administered to a pH 1.2 solution in Preparation Example 15, a phenomenon in which a polymer gel was formed was observed. This phenomenon is considered to be caused by the difference in HLB value between the amphiphilic excipient, a dispersing aid, and propylene glycol monocaprylate Type II oil. When the HLB value of the oil excipient used as a surfactant such as Transcutol and the amphipathic excipient used as a dispersing aid is similar, the encapsulation effect of R-thioctic acid encapsulated in the oil is weakened by the amphiphilic excipient, and the pH 1.2 It is easily exposed to the solution to form a polymer gel, and it is judged that the dispersion in the solution is poor. However, if the HLB values of the oil excipient and the amphiphilic excipient show a difference of more than a certain level, the state of R-thioctic acid encapsulated in the oil is maintained, so that it is not directly exposed to a pH 1.2 solution. Dispersion was confirmed.

Specifically, in the case of Preparation Example 15 and Preparation Example 18 in which the difference in HLB value is less than 4, it was found that a polymer gel was formed, but in the case of the remaining Preparation Examples in which the difference in HLB value was 4 or more. No polymer gel was formed. Therefore, it has been shown that the oil and the dispersing aid are preferably prevented from forming a polymer gel when there is a difference in HLB values of 4 or more, more preferably 7 or more.

As a result of testing for the dispersing aid candidate substances in Table 2 with respect to propylene glycol monocaprylate Type II oil, the one with the highest solubility of R-thioctic acid was Preparation Example 14, followed by Preparation Example 17. appear. Therefore, caprylocaproyl macrogol glyceride and polysorbate 80 used in Preparation Examples 14 and 17 were selected as auxiliary surfactants and surfactants for the final formulation, respectively. However, linoleoyl macrogol glyceride M 2125, linoleoyl macrogol glyceride M1944, which did not form a polymer gel in the above experiment. When polysorbate 20 was also included as a dispersing aid, it was expected that the solubility-increasing effect would appear.

<Preparation Examples 19 to 27: Screening test for selecting the optimal ratio of self-emulsifying drug delivery system base between oil, auxiliary surfactant, and surfactant>

In order to select the optimal ratio of the base for realizing the self-emulsifying drug delivery system (SEDDS) between oil, auxiliary surfactant, and surfactant to be used in R-thioctic acid soft capsule contents, each component was mixed in the ratio shown in Table 3 below. After that, 1 mL of the mixture was added to 10 mL of a pH 1.2 solution, and the dispersion state before and after stirring through a vortexing machine was visually compared. The test results are shown in FIG. 3 .

ingredient Preparation 19 Preparation 20 Preparation 21 Preparation 22 Preparation 23 Preparation 24 Preparation 25 Preparation 26 Preparation 27 Propylene glycol monocaprylate Type II 500.0 500.0 500.0 500.0 500.0 550.0 600.0 650.0 700.0 Caprylocaproyl Macrogol Glyceride 250.0 300.0 350.0 400.0 450.0 400.0 400.0 400.0 400.0 Polysorbate 80 450.0 400.0 350.0 300.0 250.0 300.0 300.0 300.0 300.0

As a result of the test, it was confirmed that a homogeneously dispersed emulsion was formed when a pH 1.2 solution was added in Preparation Examples 19 to 27 and then physically mixed by stirring using a vortexing machine. However, in the state in which the pH 1.2 solution was added and not stirred, the state was different according to each preparation example, and it was confirmed that a significant difference appeared.

First, comparing Preparation Examples 19 to 22, it can be seen that as the ratio of caprylocaproyl macrogol glyceride is gradually increased, it is rapidly mixed with the pH 1.2 solution even before stirring. This is considered to be due to the difference in viscosity between polysorbate 80 and caprylocaproyl macrogol glyceride. As this decreases, the difference in the dispersing speed becomes larger.

On the other hand, comparing Preparation Examples 22 to 23, the dispersion rate of Preparation Example 22 was faster, which is thought to be because the dispersing power of polysorbate 80 is stronger than that of caprylocaproyl macrogol glyceride. That is, when the relative ratio of polysorbate 80, which has a greater dispersibility than caprylocaproyl macrogol glyceride, is reduced below a certain level, it has a significant effect on the decrease in the dispersibility of the entire mixture, and the results appear to have appeared.

That is, considering the relationship between the viscosity and the dispersing power between caprylocaproyl macrogol glyceride and polysorbate 80, it can be determined that the optimum dispersing power is exhibited when added in the same ratio as in Preparation Example 22.

In addition, comparing Preparation Examples 22 and 24-27, it can be seen that the mixing speed is slowed as the ratio of propylene glycol monocaprylate Type II is gradually increased. In the self-emulsifying drug delivery system, as the specific gravity of the oil increases, the amount of oil to be dispersed by the surfactant and auxiliary surfactant increases, and as a result, dispersion at a high speed cannot be achieved. That is, when the ratio of propylene glycol monocaprylate Type II increases above a certain level, the dispersing power of the mixture is insufficient and complete emulsification is not expected before physically mixing with a pH 1.2 solution. However, as the ratio of the oil serving to encapsulate the R-thioctic acid increases, the amount of R-thioctic acid that can be added increases. Therefore, it is necessary to input the oil in the highest ratio as possible. That is, Preparation 25 containing the highest ratio of propylene glycol monocaprylate Type II among the completely emulsified preparations was selected as the optimal ratio of the self-emulsifying drug delivery system base.

<Examples 1 to 5 and Comparative Example 1: Preparation of R-thioctic acid soft capsules with improved dissolution rate in acidic conditions>

According to the components and contents shown in Table 4 below, the components included in the internal solution and the capsule base were separately and uniformly mixed to prepare the internal solution and the capsule base solution, respectively. The prepared mixture was prepared into soft capsules using a capsule base and a rotary soft capsule molding machine.

Classification ingredient
(Unit: mg) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 remark active ingredient R-thioctic acid 100.0 125.0 150.0 175.0 200.0 150.0 oil propylene glycol
Monocaprylate Type II 270.0 270.0 270.0 270.0 270.0 595.0 Capryol 90 auxiliary surfactant caprylocaproyl
macrogol glycerides 180.0 180.0 180.0 180.0 180.0 - Labrasol interface
activator Polysorbate 80 135.0 135.0 135.0 135.0 135.0 - capsule base gelatin 125.0 125.0 125.0 125.0 125.0 125.0 capsule base concentrated glycerin 45.0 45.0 45.0 45.0 45.0 45.0 capsule base D-Sorbitol 18.0 18.0 18.0 18.0 18.0 18.0 Total (mg/capsule) 873.0 898.0 923.0 948.0 973.0 933.0

<Test Example 1>

For the R-thioctic acid soft capsules prepared in Examples 1 to 5, a comparative dissolution test was performed for 1 hour to confirm the dissolution pattern in acidic conditions according to the content of R-thioctic acid added in the capsule. As the test conditions, 900 mL of the dissolution test method 1 (pH 1.2) of the 11th revision of the Korean Pharmacopoeia was used as the dissolution solution, and the rotating sample barrel method at 100 revolutions per minute (the 11th revision of the Korean Pharmacopoeia, the dissolution test method 1 method) was applied. The test results are shown in FIG. 4 .

As a result of the test, it was confirmed that the dissolution rate and final dissolution rate of R-thioctic acid in acidic conditions and the final dissolution rate were different depending on the content of R-thioctic acid included in the Examples. In particular, in the case of Examples 4 and 5, it was confirmed that the dissolution rate and the final dissolution rate decreased to a significant level. When the content of R-thioctic acid increased during the preparation of the internal solution during the preparation process of each Example, the viscosity of the internal solution increased. It was confirmed that the dispersion of the contents did not appear smoothly.

In light of these results, when the viscosity is higher than a certain level, it is difficult to disperse the solution according to stirring in the dissolution test, and it can be interpreted that the dissolution rate and final dissolution rate are also low. In addition, in the case of Example 5, some polymerization occurred during the dissolution test. As the ratio of R-thioctic acid to oil increased, drug encapsulation in oil was not completely completed, and R-thioctic acid was exposed to a pH 1.2 solution. It is considered that polymerization has occurred. The state of the eluate after the test and a schematic diagram of the relationship between drug encapsulation and polymerization in oil, which is the cause of the phenomenon, is shown in FIG. 5 . As a result of the test, it was found that Example 3 was a preferred R-thioctic acid soft capsule pharmaceutical composition containing the largest amount of active ingredient and dissolution of all drugs in 1 hour.

<Test Example 2>

A comparative dissolution test was performed with the R-thioctic acid soft capsule prepared in Example 3 and Comparative Example 1 with 'Dexid Tablet' of Bukwang Pharmaceutical, a currently commercially available product. The test was conducted for 1 hour with four dissolutions using 900 mL of water, pH 1.2 solution, pH 4.0 solution, and pH 6.8 solution as the eluent, and the paddle method at 75 revolutions per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2 method) ) was applied. The preparation method of each eluate is as follows.

pH 1.2 Dissolution solution: Use the 1st solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.

pH 4.0 Eluent: 0.05 mol/L sodium acetate buffer [0.05 mol/L acetic acid, 0.05 mol/L sodium acetate mixture (82 : 18)] is used.

pH 6.8 solution: Use the second solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.

The test results are graphically shown in FIG. 7 .

In the case of Example 3, each dissolution solution showed a fast dissolution rate and a final dissolution rate of 90% or more, whereas the control drug showed a dissolution rate of less than 20% in a dissolution test in a pH 1.2 solution, and as a result of visual observation, it was confirmed that there was a denatured gel. . That is, it can be seen that Example 3 has excellent stability and dissolution rate in acidic conditions compared to the reference drug. On the other hand, in Comparative Example 1, although polymerization did not occur under acidic conditions, it can be confirmed that the final dissolution rate of all four dissolutions was 50% or less. This is considered to be because Comparative Example 1, unlike Example 3, was not sufficiently miscible with the eluate because it did not contain an appropriate ratio of surfactant and auxiliary surfactant capable of dispersing oil.

<Examples 6 to 9 and Comparative Example 2: Preparation of R-thioctic acid tablets with improved dissolution rate in acidic conditions>

According to the components and contents shown in Table 5 below, the components except for the adsorbent, disintegrant, and lubricant were added and uniformly mixed to make a solution, and then the prepared solution was adsorbed using an adsorbent and then dried sufficiently. Thereafter, the dried powder, disintegrant, and lubricant were uniformly mixed, and then tablets were prepared using a rotary tablet press.

Classification ingredient
(Unit: mg) Example 6 Example 7 Example 8 Example 9 Comparative Example 2 remark active ingredient R-thioctic acid 100.0 100.0 100.0 100.0 100.0 oil propylene glycol
Monocaprylate Type II 180.0 180.0 180.0 180.0 390.0 Capryol 90 auxiliary surfactant caprylocaproyl
macrogol glycerides 120.0 120.0 120.0 120.0 - Labrasol interface
activator Polysorbate 80 90.0 90.0 90.0 90.0 - absorbent calcium silicate 100.0 150.0 200.0 250.0 250.0 excipient Microcrystalline Cellulose 102 200.0 200.0 200.0 200.0 200.0 disintegrant Low-substituted hydroxypropyl cellulose 70.0 70.0 70.0 70.0 70.0 disintegrant Croscarmellose Sodium 60.0 60.0 60.0 60.0 60.0 lubricant colloidal silicon dioxide 30.0 30.0 30.0 30.0 30.0 Total (mg/tablet) 1000.0 1050.0 1100.0 1150.0 1150.0

In the case of Examples 6 to 8, the amount of calcium silicate, which is an adsorbent, was insufficient, so that some tablets were not sufficiently adsorbed. Accordingly, it was confirmed that a sticking phenomenon appeared in some tablets in the tableting process during the manufacturing process. did. On the other hand, in the case of Example 9 and Comparative Example 2, there was no problem at all during tableting.

Therefore, when the adsorbent calcium silicate is included in an amount of 60% by weight or more based on the combined weight of the oil and the dispersing aid, the sticking phenomenon that may appear in some tablets does not appear, so the most excellent productivity can be expected. As the adsorbent, other known adsorbents other than calcium silicate may be used, and the amount may be increased up to 200% by weight to exhibit a desirable effect. However, in the case of using calcium silicate, it is more preferable to minimize the size of the dosage form because it is sufficiently effective to use 100 wt% or less.

<Test Example 3>

A comparative dissolution test was conducted with the R-thioctic acid tablet prepared in Example 9 and Comparative Example 2 with 'Dexid Tablet', a currently commercially available product, Bukwang Pharmaceutical. The test was conducted for 1 hour with four dissolutions using 900 mL of water, pH 1.2 solution, pH 4.0 solution, and pH 6.8 solution as the eluent, and the paddle method at 75 revolutions per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2 method) ) was applied. The preparation method of each solution is as follows.

pH 1.2 solution: Use the first solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.

pH 4.0 solution: 0.05 mol/L sodium acetate buffer

[0.05 mol/L acetic acid, 0.05 mol/L sodium acetate mixture (82: 18)] is used.

pH 6.8 solution: Use the second solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.

The test results are graphically shown in FIG. 8 .

As shown in FIG. 8, in the case of Example 9, all four dissolutions showed a fast dissolution rate and a final dissolution rate of 90% or more, whereas the control drug showed a dissolution rate of less than 20% in a dissolution test in a pH 1.2 solution, and the results of visual observation It was confirmed that there was a denatured gel. That is, it can be seen that Example 9 has excellent stability and dissolution rate in acidic conditions compared to the reference drug. On the other hand, in Comparative Example 2, although polymerization did not occur under acidic conditions, it can be confirmed that the final dissolution rate of all four phases of dissolution was 50% or less. This can be determined because Comparative Example 2 is not miscible with the eluate because the surfactant and auxiliary surfactant that can disperse the oil are not included in an appropriate ratio, unlike Example 9.

Claims (13)

Contains R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient,
A pharmaceutical composition comprising 100 to 300% by weight of oil and 150 to 350% by weight of a dispersing aid based on the total weight of the active ingredient.
According to claim 1,
The content of the active ingredient is a pharmaceutical composition that is 5 to 25% by weight based on the total weight of the pharmaceutical composition.
According to claim 1,
The oil is propylene glycol monocaprylate Type I, propylene glycol monocaprylate Type II, glycerol / glyceryl monolinoleic acid, medium chain triglycerides, propylene glycol monolaurate, propylene glycol dicaprylate, from the group consisting of castor oil A pharmaceutical composition that is one selected or a mixture of two or more.
According to claim 1,
The dispersing aid is one or more amphiphilic excipients selected from the group consisting of linoleoyl, caprylocaproyl macrogol glyceride, polysorbate 20, and polysorbate 80. Pharmaceutical composition.
5. The method of claim 4,
The dispersing aid is a pharmaceutical composition comprising a surfactant having a relatively high viscosity and an auxiliary surfactant having a relatively low viscosity among the amphiphilic excipients.
6. The method of claim 5,
The dispersion aid is a pharmaceutical composition comprising a surfactant and an auxiliary surfactant in a weight ratio of 1:1.1 to 1:2.
According to claim 1,
The difference between the hydrophilicity-lipophilic balance (HLB) value of the oil and the dispersing aid is 4 or more.
According to claim 1,
The pharmaceutical composition is a pharmaceutical composition, characterized in that the soft capsule formulation.
According to claim 1,
The pharmaceutical composition is a pharmaceutical composition, characterized in that the tablet formulation.
10. The method of claim 9,
The pharmaceutical composition further comprises an adsorbent in an amount of 60 to 200% by weight based on the combined weight of the oil and the dispersing aid.
11. The method of claim 10,
The pharmaceutical composition of the adsorbent is a silicon-based compound.
11. The method of claim 10,
The adsorbent is one or two or more selected from the group consisting of calcium silicate, magnesium metasilicate aluminate, and colloidal silicon dioxide.
According to claim 1,
The pharmaceutical composition is to form an emulsion in the body (Emulsifying) when administered orally.

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