KR20100009175A - Oral soft capsule of aceclofenac having improved stability - Google Patents

Abstract

PURPOSE: A composition of soft capsule formulation containing aceclofenac having improved stability is provided to improve release property of an active ingredient and enhance bioavailability. CONSTITUTION: A soft capsule contains aceclofenac liquid composition which is manufactured by mixing and solubilizing aceclofenac, oil, and suspension. The oil is macadamia ternifolia nut oil, hydrogenated high-erucic acid rape seed oil, olive oil, jojoba oil, hybrid sunflower oil, dog rose lips oil, peanut oil, corn oil, sesame oil, canbra oil, cottonseed oil, or palm oil. The suspension is white wax, paraffin wax or bees wax.

Description

Oral Soft Capsule of Aceclofenac Having Improved Stability}

The present invention relates to a soft capsule containing a composition for improving the stability of aceclofenac. Specifically, aceclofenac susceptible to hydrolysis is suspended in a base having an oily property by using a suspending agent to inhibit contact with water, thereby improving stability of aceclofenac, thereby improving dissolution rate and bioavailability.

Aceclofenac (2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid) is a known compound having the following structural formula, as well as chronic joint diseases of rheumatoid arthritis, osteoarthritis or ankylosing spondylitis, as well as toothache, postoperative In addition, it is a phenylacetic acid-based anti-inflammatory analgesic that shows excellent efficacy against pain after delivery. Compared to anti-inflammatory drugs such as naproxen and diclofenac, the drug is easier to penetrate drugs in inflammatory tissues such as joints and thus has an excellent therapeutic effect due to its excellent blocking effect of prostaglandin. On the other hand, normal prostaglandin production in the gastric mucosa is weak and the gastrointestinal disorders are alleviated, so it is suitable for long-term use. In particular, it inhibits the production of interleukin-1, which destroys cartilage in the joints. It promotes the production of glycans (Glycosaminoglycan) and has the advantage of preventing the exacerbation of rheumatoid arthritis and osteoarthritis.

Aceclofenac (2-[(2,6-dichlorphenyl) amino] -phenylacetoxyacetic acid) is well soluble in organic solvents and relatively insoluble in water. Aceclofenac is rapidly absorbed from the gastrointestinal tract upon oral administration and is distributed in high concentrations in the kidneys, bladder, liver, thyroid gland, and low concentrations in the eyes, brain, and adipose tissue. Aceclofenac has a time of onset of action within 30 minutes when administered orally. The time to reach peak blood concentration is about 1.5-2.5 hours, and the duration is about 12 hours. Aceclofenac is the major metabolite of 46-75% of the administered drug as aceclofenac at oral administration at the peak blood concentration (Tmax), with extensive metabolism following Tmax. It is also known to be an active drug, and it is known that 4-hydroxydiclofenac and indole derivatives are also observed as other metabolites. Aceclofenac is known to excrete about 66.8% in urine and about 18% in feces during oral administration, and the rate of excretion (half life) is about 4 hours.

The clinical features of aceclofenac are 1) suitable for rheumatoid arthritis or osteoarthritis because it blocks the production of interleukin-1, which destroys articular cartilage and promotes the production of glycosaminoglycan, a component of articular cartilage. 2) The gastrointestinal mucosa has minimal effect on the production of normal prostaglandin in gastric mucosa, and 3) the high concentration of drug penetrates into inflammation-prone areas such as joints, which is a strong blocking effect of prostaglandin production.

Various formulation means have been developed to enhance the solubilization or dissolution rate of various poorly soluble drugs in order to improve the dissolution of the soluble drug and enhance the bioavailability. For example, micronization method, micelle method, solid dispersion method, spray drying method, inclusion complex method, and solubilization method using water-soluble polymers or surfactants are used. However, there are many limitations in commercializing these means in terms of manufacturing method, commerciality and efficiency.

In addition, when a poorly soluble drug is formulated into a tablet, which is one of the pharmaceutical formulations, disintegration should be performed preferentially during oral administration, and a multi-step process in which a drug mixed with an excipient or the like is dissolved in a digestive or bodily fluid is required for absorption. Moreover, when tablets are poorly soluble in a substance such as aceclofenac, dissolution rate and dissolution rate are generally not good, so the bioavailability is low and the expression of the drug cannot be properly expressed. Therefore, in the case of tablets, the effect expression time is inevitably delayed when compared to liquid preparations or soft capsules.

The general soft gelatin capsule is composed of the capsule contents (filling) and the outer shell (gelatin), and the capsule contents are composed of one or more active ingredients and bases (excipients) with activity, and the coating is composed of gelatin, a certain amount of plasticizer and water. As the bases used in the contents, oils, water-soluble polymer bases, fatty acids, surfactants and the like can be used. Existing formulations have been used in the form of oils, fatty acids, or mixtures, emulsions or microemulsions comprising them to enhance the dissolution rate of poorly soluble aceclofenac. However, aceclofenac, which is susceptible to hydrolysis, is hydrolyzed with only a small amount of water present in the gelatinous coating, not only with a water-soluble base, to turn into diclofenac, the product of degradation of the drug. As a soft capsule formulation, there are two main methods of prescription and preparation of drug substance. First, generally known methods include oils such as vegetable oils such as soybean oil, palm oil, sunflower seed oil, sesame oil, perilla oil, olive oil and oils such as medium-chain fatty acid triglycerides. It is a method of suspending a main component drug using a suspending agent such as beeswax in a base having properties. This method may delay the dissolution of the drug and should be carefully considered.

The second method is to solubilize or suspend the active ingredient drug in an aqueous base such as polyethylene glycol and propylene glycol. However, in the present invention, when aceclofenac is used as a soft capsule formulation to improve the dissolution rate, it is difficult to expect the dissolution rate as a method of suspending it in a base having an oily property, which is the first method. In addition, the method of suspending aceclofenac in a mixture of components having a susceptibility such as a base such as polyethylene glycol 400 among the method using a water-based base, which is a second method, will improve the dissolution rate than the suspension method of the oil-based base, but this is also expected greatly It's hard to do.

Aceclofenac is currently marketed as soft capsule formulations solubilized with water soluble solubilizers to rapidly express drug expression. However, due to the properties of aceclofenac, which is susceptible to hydrolysis, stability problems are emerging during long-term storage.

Therefore, as a result of studying various compositions that can increase the dissolution characteristics and stability for aceclofenac, the dissolution rate of aceclofenac and the stability of the product are excellent by using a novel soft capsule containing aceclofenac, an oil-soluble mixture and a suspending agent. The present invention was completed.

The present invention solves the stability problems occurring during long-term storage with the properties of aceclofenac that is susceptible to hydrolysis, and provides a soft capsule of aceclofenac excellent in dissolution rate and stability.

According to a preferred embodiment of the present invention, the soft capsule containing aceclofenac contains an aceclofenac liquid composition prepared by mixing and solubilizing aceclofenac, oils and suspending agents.

According to another embodiment of the present invention, the oils are macadamia oil, hydrogenated high-eruc acid rapeseed oil, olive oil, jojoba oil, mixed sunflower oil, ninse oil, wild rose oil, peanut oil, corn oil, sesame oil, rapeseed oil, cottonseed oil. And at least one mixture selected from the group consisting of palm oil, soybean oil, coconut oil, castor oil, polyoxylhydrogenated castor oil, mineral oil, ceresin and ozokerit.

According to another embodiment of the present invention, the oils may be a mixture of palm oil and one oil selected from the group consisting of sunflower oil, corn oil, cottonseed oil, polyoxyl hydrogenated castor oil, sesame oil and mineral oil.

According to another embodiment of the present invention, the mass ratio of the oil and palm oil selected from the group consisting of sunflower oil, corn oil, cottonseed oil, polyoxyl hydrogenated castor oil, sesame oil and mineral oil is 3: 1 to 7: 1. .

 According to yet another embodiment of the present invention, the suspending agent may be at least one mixture selected from the group consisting of lead, beeswax and beeswax.

The soft capsule of aceclofenac according to the present invention is excellent in its dissolution and content stability, and thus hardly changes in content, dissolution, and properties under accelerated conditions and room temperature conditions, and shows superior stability and dissolution rate compared to conventional commercial aceclofenac soft capsules. .

The soft capsule according to the present invention is prepared by dissolving or suspending aceclofenac, a pharmacologically active ingredient, in oils and mixed phases to fill the gelatinous coating composition with liquid or paste filling contents.

As a soft capsule formulation, the general prescription and preparation of the internal drug is a method of solubilizing or suspending the main ingredient drug in an aqueous base such as polyethylene glycol and propylene glycol. However, because of the characteristics of aceclofenac, which is susceptible to hydrolysis, there is a stability problem in long-term preservation like conventional products. This is because the water-soluble solubilizer contains a small amount of water.

In order to solve this problem, the present invention simply suspends aceclofenac in oils instead of a solubilizing agent containing water, and has a constant particle size through a general micronization process, thereby maintaining a constant dissolution rate while remaining in the oil phase. Aceclofenac, a soluble activator, is characterized by blocking the contact with water in the gelatinous coating to inhibit the hydrolysis of aceclofenac.

In a general micronization process, for example, a process of micronizing suspended aceclofenac by grinding the oil phase itself using a mixed oil phase as a colloid mill may be used.

Oils include macadamia ternifolia nut oil, hydrogenated hi-erucic acid rape seed oil, olive oil, jojoba oil, and hybrid sunflower oil. (helian thus annuus) oil), neen (mdlia azadirachta) seed oil, dog rose (rosa canina) lips oil, peanut oil, corn oil, sesame oil oil, canbra oil, cottonseed oil, palm oil, soybean oil, coconut oil, castor oil and castor hydrogenated castor oilated Hydrogenated vegetable oils such as polyoxyl) may be used, and mineral oils such as mineral oil, ceresin, and ozokerite may be used.

The oils may be one kind or a mixture of two or more kinds, preferably a mixture of two or more kinds of oils. Two or more mixtures can enhance the stability and maintain dissolution rate of aceclofenac without special stabilizers, solubilizers.

The oils include macadamia oil, hydrogenated high-eruc acid rapeseed oil, olive oil, jojoba oil, mixed sunflower oil, ninseed oil, wild rose oil, peanut oil, corn oil, sesame oil, rapeseed oil, cottonseed oil, soybean oil, coconut oil, castor oil, It may be a mixture of palm oil and one oil selected from the group consisting of polyoxyl hydrogenated castor oil, mineral oil, ceresin and ozokerite.

According to an embodiment of the present invention, the stability of the soft capsule is different depending on the mixing ratio of oils, which are mixtures, preferably when the mass ratio of the mixture of oils other than palm oil and palm oil is 3: 1 to 7: 1. Good stability.

Suspending agents include white wax, paraffin wax, bees wax, animal stearates, wax mixtures, aluminum monosterate, etocel, ethylcellulose), polyethylene glycol 4000 and 6000 (polyethylene glycol), lecithin and acetylated monoglycerides, and the like may be used. Preferably, wax, beeswax, beeswax may be used.

 The soft capsule prepared by the present invention was excellent in its dissolution and content stability, and as a result of measuring the change with time under accelerated conditions and room temperature conditions, there was almost no change in content, dissolution and properties over time, which was superior to conventional commercial aceclofenac soft capsules. Stability and dissolution rate were shown. Therefore, the effect of the present invention is to invent a formulation having superior stability and dissolution rate compared to the conventional formulation.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples. However, these examples do not limit the scope of the present invention.

<Example 1>

Prescription 1 is a soft capsule containing aceclofenac liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 176 mg of soybean oil and 50 mg of palm oil, 3 mg of lead wax, a suspending agent, 30 mg of lecithin, and 1 mg of antioxidant BHT (Butylated Hydroxy Toluene). In the present invention, the soft capsule coating is prepared by a conventional preparation method by soft gel formulation of gelatin and plasticizer which are generally used. In addition, the soft capsule that improves the stability of the aceclofenac of the present invention is manufactured by a conventional charging method using a rotary automatic charger which is currently a general method, followed by drying and sorting.

Formula 2 is the same as Formula 1 except that 30 mg of dimethylisosorbide is used as a solvent, 30 mg of palm oil and 20 mg of lecithin.

Formula 3 is the same as Formula 1 except that 30 mg of carbitol is used instead of dimethylisosorbide.

Table 1 is a table showing the content and ratio of the components of the formulations 1 to 3, Table 2 is a table showing the stability test results of the formulations 1 to 3.

<Stability Experiment>

Stability test was conducted at room temperature and 40 ° C 75% (humidity) constant temperature and humidity chamber, taking about 20 capsules or more, weighing the contents and mixing well, and accurately taking 10 mg equivalent as aceclofenac, dissolving in methanol Prepare the solution to make 100ml as the sample solution. Separately, take 10 mg of aceclofenac standard precisely, dissolve in methanol to make 100 ml, and use the standard solution as the standard solution. Test the liquid chromatograph method under the following general test methods and obtain the peak areas At and As of the sample solution and aceclofenac. .

Instrument condition: Ultraviolet absorbance photometer (277nm)

Column: C18 ODS

Column temperature: 40 ℃

Mobile phase: Acetonitrile: Buffer (68: 32)

Flow rate: 1.0ml / min

buffer: Adjust pH to 7.4 with 5mM phosphate buffer, and filter by 0.45um membrane filter.

TABLE 1

Classification ingredient Prescription 1 Prescription 2 Prescription 3 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Aceclofenac 100 27.8 100 27.8 100 27.8 solvent Carbitol - - - - 30 8.3 solvent Dimethyl isosorbide - - 30 8.3 - - Oils Soybean oil 176 48.9 176 48.9 176 48.9 Oils palm oil 50 13.9 30  8.3 30 8.3 Suspending agent White lead 3 0.8 3 0.8 3 0.8 Suspending agent lecithin 30 8 20 5.6 20 5.6 Antioxidant BHT One 0.3 One 0.3 One 0.3 Date of Manufacture 06.08.18 06.08.18 06.08.18

TABLE 2

Exam date stability(%) Prescription 1 Prescription 2 Prescription 3 06.08.25 97.6 105.6 105.8 06.09.22 96.8 101.3 102.4 06.10.25 93.5 99.2 98.1 06.12.16 92.3 98.7 97.2

<Example 2>

Formula 4 is a soft capsule containing aceclofenac liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 205 mg of soybean oil and 50 mg of palm oil, 10 mg of lead wax as a suspending agent, and 1 mg of antioxidant BHT (Butylated Hydroxy Toluene). The manufacturing process of the soft capsule agent is the same as that of Example 1.

Prescription 5 is the same as Prescription 4, except that 3mg of Paik is used and no antioxidant BHT is used.

Formula 6 is the same as Formula 5 except that 207 mg of soybean oil is used.

Formula 7 is the same as Formula 5, except that 210 mg of soybean oil is used.

Formula 8 is the same as Formula 5 except that 207 mg of soybean oil and 20 mg of SiO ₂ , a suspending agent, are used.

Table 3 is a table showing the component content and the content ratio of the formulations 4 to 8, Table 4 is a table showing the stability test results of the formulations 4 to 8.

TABLE 3

Classification ingredient Prescription 4 Prescription 5 Prescription 6 Prescription 7 Prescription 8 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Aceclofenac 100 27.3 100 27.9 100 27.8 100 27.5 100 26.3 Oils Soybean oil 205 56.0 205 57.3 207 57.5 210 57.9 207 54.5 Oils palm oil 50 1,7 50 14 50 13.9 50 13.8 50 13.2 Suspending agent White lead 10 2.7 3 0.8 3 0.8 3 0.8 3 0.8 Suspending agent SiO ₂ - - - - - - - - 20 5.3 Antioxidant BHT One 0.3 - - - - - - - Date of Manufacture 06.10.15 06.10.15 06.10.15 06.10.15 06.10.15 Soybean oil: the ratio of palm oil 4.10: 1 4.10: 1 4.14: 1 4.20: 1 4.14: 1

TABLE 4

Exam date stability(%) Prescription 4 Prescription 5 Prescription 6 Prescription 7 Prescription 8 06.10.20 99.87 103.2 101.0 102.3 102.5 06.12.21 99.5 102.9 101.8 102.1 102.1 07.03.25 99.8 102.1 101.2 102.5 102.3 07.06.16 98.6 101.9 101.5 102.3 101.8 07.09.12 98.2 101.5 101.4 102.2 100.9 07.12.09 98.1 101.9 100.9 102.2 101.2 08.03.12 97.9 101.2 100.8 102.1 100.8

<Example 3>

Formula 9 is a soft capsule containing aceclofenac liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, a mixture of 207 mg of sunflower oil and 50 mg of palm oil, and 3 mg of lead wax, which is a suspending agent. Same as 1.

Formula 10 is the same as Formula 9 except that 207 mg of corn oil is used instead of sunflower oil.

Formula 11 is the same as Formula 9 except that 207 mg of cottonseed oil is used instead of sunflower oil.

Formula 12 is the same as Formula 9 except that 207 mg of polyoxyl hydrogenated castor oil is used instead of sunflower oil.

Formula 13 is the same as Formula 9 except that 207 mg of sesame oil is used instead of sunflower oil.

Formula 14 is the same as Formula 9 except that 207 mg of mineral oil is used instead of sunflower oil.

Table 5 is a table showing the component content and the content ratio of the formulations 9 to 14, Table 6 is a table showing the results of the stability experiment of the formulations 9 to 14.

TABLE 5

Classification ingredient Prescription 9 Prescription 10 Prescription 11 Prescription 12 Prescription 13 Prescription 14 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Aceclo penac 100 27.8 100 27.8 100 27.8 100 27.8 100 27.8 100 27.8 Oils Sunflower oil 207 57.5 - - - - - - - - - - Oils Corn oil - - 207 57.5 - - - - - - - - Oils Cottonseed oil - - - 207 57.5 - - - - - - Oils Polyoxyl hydrogenated horse oil - - - - - - 207 57.5 - - - - Oils Sesame oil - - - - - - - - 207 57.5 - - Oils Mineral oil - - - - - - - - - - 207 57.5 Oils palm oil 50 13.9 50 13.9 50 13.9 50 13.9 50 13.9 50 13.9 Suspending agent White lead 3 0.8 3 0.8 3 0.8 3 0.8 3 0.8 3 0.8 Date of Manufacture 06.10.25 06.10.25 06.10.25 06.10.25 06.10.25 06.10.25

TABLE 6

Exam date stability(%) Prescription 9 Prescription 10 Prescription 11 Prescription 12 Prescription 13 Prescription 14 06.10.26 100.8 101.2 100.3 101.2 101.3 100.5 06.12.28 100.2 101.3 100.3 101.1 101.3 100.3 07.03.28 100.3 101.0 100.4 100.98 100.9 100.2 07.06.26 100.4 100.9 100.1 101.1 101.2 100.6 07.09.23 100.1 101.1 99.89 100.89 100.9 100.3 07.12.18 100.2 101.2 100.0 100.9 101.3 100.5 08.03.20 100.1 100.9 100.1 100.9 101.2 100.5

Dissolution Rate Experiment

A certain amount of aceclofenac-containing soft capsules prepared in Formulation 6 and Formulations 9 to 14 of Example 2 was tested for dissolution by the Pharmacopeia No. 7 revised dissolution test method. PH 7.8 phosphate buffer was used as the eluent. The elution was performed using the paddle method, the eluent was 900ml, the stirring speed was 100rpm, and the elution temperature was 37 ± 0.5 ℃. 5 ml of the sample was taken at 0, 5, 10, 15, 30, 45, and 60 minutes, and the same amount of eluent was added. Assay conditions, the solution obtained in the above dissolution test was filtered with a 0.45㎛ membrane filter to quantify aceclofenac using HPLC. Analytical wavelength was 277nm, mobile phase was acetonitrile: pH 7.4 phosphate buffer = 68:32 solution, flow rate was 1.0ml / min, column was C18 ODS.

The results are shown in FIG.

Comparative Example 1

Prescription 15 is aceclofenac prepared by mixed solubilization using 100 mg of aceclofenac, 200 mg of PEG 400 (polyethylene glycol 400) as a solvent, 50 mg of dimethylisosorbide, 2.13 mg of tocopherol acetate as an antioxidant and 2.5 mg of ascorbic acid. It is a soft capsule agent containing a liquid composition, and the manufacturing process of a soft capsule film and a soft capsule agent is the same as that of Example 1.

Formula 16 is a soft capsule containing aceclofenac liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac and 218 mg of PEG 400 (polyethylene glycol 400) as a solvent, and the manufacturing process of the soft capsule film and the soft capsule agent is Same as 1.

Formula 17 is the same as Formula 16 except that 0.25 mg of butylated hydroxy toluene (BHT) is used as an antioxidant.

Formula 18 is the same as Formula 17 except that 1.25 mg of sodium lauryl sulfate (SLS) is used as a solubilizer.

Formula 19 is the same as Formula 16 except that 4 mg of PVP K-30 (poly vinyl pyrrolidone K-30) and 0.13 mg of butylated hydroxy toluene (BHT) as antioxidants are used.

Table 7 is a table showing the component content and the content ratio of the formulations 15 to 19, Table 8 is a table showing the stability test results of the formulations 15 to 19.

TABLE 7

Classification ingredient Prescription 15 Prescription 16 Prescription 17 Prescription 18 Prescription 19 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Aceclofenac 100 28.2 100 31.4 100 31.4 100 31.3 100 28.24 solvent PEG 400 200 56.4 218 68.6 218 68.5 218 68.2 250 70.60 solvent Dimethyl isosorbide 50 14.1 - - - - - - - - Solubilizer PVP K-30 - - - - - - - - 4 1.13 Solubilization SLS - - - - - - 1.25 0.4 - - Antioxidant Tocopherol acetate 2.13 0.6 - - - - - - - - Antioxidant BHT - - - - 0.25 0.1 0.25 0.1 0.13 0.03 Antioxidant Ascorbic acid 2.5 0.7 - - - - - - - - Date of Manufacture 05.05.13 05.10.02 05.10.07 05.10.08 05.10.22

TABLE 8

Exam date stability(%) Prescription 15 Prescription 16 Prescription 17 Prescription 18 Prescription 19 05.05.16 99.6% - - - - 05.07.11 96.4% - - - - 05.09.19 79.7% - - - - 05.10.02 - 100.6% - - - 05.10.13 - - 100.1% - - 05.10.16 - - - 99.9% - 05.10.20 - 97.3% 97.4% - - 05.11.04 - - - - 102.2% 05.12.12 - 90.0% 88.4% 90.66% 91.19% 06.08.12 - 62.6% 63.4% 64.46% 68.08%

Comparative Example 2

Prescription 20 is 100 mg of aceclofenac, 250 mg of PEG 400 (polyethylene glycol 400) as a solvent, 4 mg of PVP K-30 (poly vinyl pyrrolidone K-30) as a solubilizer, 1.25 mg of sodium lauryl sulfate (SLS), BHT as an antioxidant (Butylated Hydroxy Toluene) A soft capsule containing aceclofenac liquid composition prepared by mixed solubilization using 0.25 mg and 2 mg of ascorbic acid, and the manufacturing process of the soft capsule film and the soft capsule agent is the same as in Example 1.

Formula 21 is the same as Formula 20 except that SLS, a solubilizer, is not used, and 0.5 mg of BHT (bytylated hydroxy toluene) is used.

Formula 22 is the same as Formula 21, except that 4 mg of PVP K-12 is used instead of PVP K-30 as a solubilizer and 0.25 mg of Butylated Hydroxy Toluene (BHT) as an antioxidant.

Formula 23 is aceclofenac liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 200 mg of PEG 400 (polyethylene glycol 400), 20 mg of triacetin and 40 mg of dimethylisosorbide, and 0.36 mg of vitamin E as an antioxidant. It is a soft capsule agent to contain, and the manufacturing process of a soft capsule film and a soft capsule agent is the same as that of Example 1.

Prescription 24 is 100 mg of aceclofenac, 255 mg of PEG 400 as a solvent, 3.75 mg of PVP K-30 (polyvinyl pyrrolidone K-30) as a solubilizer, 1.25 mg of sodium lauryl sulfate (SLS), and butylated hydroxyanisole as an antioxidant ) Is a soft capsule containing aceclofenac liquid composition prepared by mixing solubilization using 0.25 mg, the manufacturing process of the soft capsule film and the soft capsule agent is the same as in Example 1.

Prescription 25 is a soft capsule containing aceclofenac liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 125 mg of oleic acid as a solvent, 125 mg of tween 80 as a surfactant, and 1.875 mg of butylated hydroxyanisole (BHT) as an antioxidant. The manufacturing process of a soft capsule film and a soft capsule agent is the same as that of Example 1.

Table 9 is a table showing the component content and the content ratio of the formulation 20 to 25, Table 10 is a table showing the results of the stability experiment of the formulation 20 to 25.

TABLE 9

TABLE 10

Exam date stability(%) Prescription 20 Prescription 21 Prescription 22 Prescription 23 Prescription 24 Prescription 25 05.11.10 101.8% 101.9% 101.5% - - - 05.11.15 - - - 100.2% 96.9%  Crystal formation 05.11.27 101.4% 101.8% 101.0% - - - 05.01.02 93.6% 93.61% 92.15% 96.94% 94.3% - 06.08.12 70.68% 71.29% 70.12% 69.21% 70.14% -

Comparative Example 3

Formula 26 is aceclofenac liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 147 mg of PEG 400 (polyethylene glycol 400) and 156 mg of carbitol, and 1 mg of butylated hydroxy toluene (BHT) as an antioxidant. It is a soft capsule agent to contain, and the manufacturing process of a soft capsule film and a soft capsule agent is the same as that of Example 1.

Formula 27 is the same as Formula 26 except that PEG 400 is used as a solvent and 256 mg of carbitol and 142 mg of triacetin are used.

Formula 28 is a soft capsule containing aceclofenac liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 150 mg of carbitol, 110 mg of oleic acid, and 64 mg of Labrafill M1944CS as a surfactant. The manufacturing process of a soft capsule film and a soft capsule agent is the same as that of Example 1.

Prescription 29 contains aceclofenac liquid composition prepared by mixed solubilization using 100 mg of aceclofenac, 220 mg of carbitol as solvent, 50 mg of dimethylisosorbide, and 150 mg of medium chain triglyceride (MCT). It is a soft capsule agent, and the manufacturing process of a soft capsule film and a soft capsule agent is the same as that of Example 1.

Table 11 is a table showing the component content and the content ratio of the prescription 26 to 29, Table 12 is a table showing the results of the stability experiment of the prescription 26 to 29.

TABLE 11

Classification ingredient Prescription 26 Prescription 27 Prescription 28 Prescription 29 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Aceclofenac 100 24.75 100 20.04 100 23.58 100 19.23 solvent PEG 400 147 36.69 - - - - - - solvent Carbitol 156 38.61 256 51.30 150 35.38 220 42.31 solvent Triacetin - - 142 28.46 - - - - solvent Dimethyl isosorbide - - - - - - 50 9.62 solvent Oleic acid - - - - 110 25.94 - - solvent MCT - - - - - - 150 28.85 Surfactants Labrador M1944CS - - - - 64 15.09 - - Antioxidant BHT One 0.25 One 0.20 - - - - Date of Manufacture 06.03.11 06.03.11 06.03.17 06.03.17

TABLE 12

Exam date stability(%) Prescription 26 Prescription 27 Prescription 28 Prescription 29 06.03.22 103.5% 105.2% 102.1% 100.9% 06.05.24 101.1% 102.2% 99.89% 95.9% 06.07.19 98.73% 99.29% 95.24% 92.1% 06.08.17 88.24% 90.24% 89.15% 83.93%

1 is a dissolution rate test results of a certain amount of aceclofenac-containing soft capsules prepared in Formulations 6 and 3 of Examples 2 to 9 of the present invention.

Claims (5)

A soft capsule containing aceclofenac liquid composition prepared by mixing and solubilizing aceclofenac, oils and suspending agents. The oil of claim 1, wherein the oils are macadamia oil, hydrogenated high-eruc acid rapeseed oil, olive oil, jojoba oil, hybrid sunflower oil, ninse oil, wild rose oil, peanut oil, corn oil, sesame oil, rapeseed oil, cottonseed oil, palm oil, A soft capsule, characterized in that at least one mixture selected from the group consisting of soybean oil, coconut oil, castor oil, polyoxyl hydrogenated castor oil, mineral oil, ceresin and ozokerite. The soft capsule of claim 2, wherein the oil is a mixture of one oil selected from the group consisting of sunflower oil, corn oil, cottonseed oil, polyoxyl hydrogenated castor oil, sesame oil, and mineral oil and palm oil. The mass ratio of one oil selected from the group consisting of sunflower oil, corn oil, cottonseed oil, polyoxyl hydrogenated castor oil, sesame oil and mineral oil and palm oil is 3: 1 to 7: 1. Soft capsules. The soft capsule of claim 1, wherein the suspending agent is at least one mixture selected from the group consisting of beeswax, lead and beeswax.

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