WO2005032516A1

WO2005032516A1 - Formulation and manufacturing process of self-microemulsified aceclofenac soft capsules

Info

Publication number: WO2005032516A1
Application number: PCT/KR2004/001791
Authority: WO
Inventors: Young-Sig Gil; Chang-Hun Yu; Ki-Hoon Choung; Geon-Seok Ahn; Seok-Cheon Hong; Ki-Young Ahn; Geun-Woo Yang
Original assignee: Korea United Pharm, Inc
Priority date: 2003-10-09
Filing date: 2004-07-19
Publication date: 2005-04-14
Also published as: KR20050034299A

Abstract

The present invention relates to a method for preparing a self-microemulsifying composition by dissolving water-poorly soluble aceclofenac in a mixed solvent of polyethylene glycol, a polyoxyethylene castor oil derivative (trade name: Cremophor, HCO), isosorbide dimethylether, middle chain fatty acid, butylated hydroxyanisole, butylated hydroxytoluene and tocopherol, and the like, as well as a method for preparing an aceclofenac-containing formulation having increased stability and improved drug solubility, by filling the composition into a soft capsule. The present invention allows the preparation of a solubilized aceclofenac-containing composition having a characteristic and advantage in that it has high in vivo drug absorption rate and thus shows a more rapid therapeutic effect than that of the prior art formulation, as well as the preparation of a soft capsule formulation containing this composition.

Description

FORMULATION AND MANUFACTURING PROCESS OF SELF- MICROEMULSIFIED ACECLOFENAC SOFT CAPSULES

Technical Field

Aceclofenac (2- [(2, 6- dichlorophenyl) amino] phenylacetoxyacetic acid), which is a known compound represented by the following formula, is a phenylacetic acid-based anti-inflammatory analgesic drug showing an excellent efficacy against chronic joint diseases, including rheumatoid arthritis, osteoarthrosis and ankylosing spendylitis, as well as detnalgia, post- operation pain or post-delivery pain. This drug shows an excellent therapeutic effect in that it is easily penetrated into inflammatory tissues occurring in a joint and the like and thus exhibits the excellent action of inhibiting prostaglandin production, as compared to other anti-inflammatory analgesic drugs, including naproxen and dichlorofenac On the other hand, this drug shows weak inhibition of normal prostaglandin production in gastric mucosa and thus has a reduced effect on gastrointestinal troubles, so that it is suitable for long-term application. Particularly, this drug is characteristic in that it inhibits the production of interleukin-1 causing the destruction of joint cartilage and promotes the production of glycosaminoglycan found in joint cartilage, thus preventing rheumatoid arthritis, osteoarthrosis and the like from being worse.

Background Art

Aceclofenac (2-[(2,6- dichlorophenyl) amino] phenylacetoxyacetic acid) has characteristics in that it is readily soluble in an organic solvent and relatively poorly soluble in water. Acelofenac is absorbed rapidly in the gastrointestinal tract upon oral administration, and distributed in kidneys, vesica, liver, thyroid gland and the like at high concentration but distributed in eye, brain, and fat tissues and the like at low concentration. Upon oral administration, aceclofenac shows an onset time shorter than 30 minutes, a time to maximum blood concentration (T_max) of about 1.5-2.5 hours, and a duration time of about 12 hours. Upon oral administration, 46-75% of the administered drug is present as aceclofenac at the time to maximum blood concentration (Tmax) and widely metabolized after T_max. In this case, a main metabolite is 4-hydroxyaceclofenac, which also shows activity, and it is known that 4-hydroxydichlorofenac and indole derivatives are also observed as other metabolites. It is known that, upon oral administration, about 66.8% of the administered aceclofenac is eliminated in urine and about 18% is eliminated in feces, and aceclofenac has an elimination half-life of about 4 hours. Aceclofenac showed acute toxicity in a dose-dependent manner. This acute toxicity was more sensitive in females than males, and showed gastrointestinal diseases. The LD₅₀ of aceclofenac was 146.2 mg/kg in females and 199.5 mg/kg in males. With respect to subacute toxicity, when administered to rats at a dose of 3 mg/kg/day, aceclofenac showed safety, and at a dose of 6 mg/kg/day, it showed a slight increase in spleen weight and a change in serum for only females and thus is believed to have drug-fastness .

At a dose of 12 mg/kg/day, aceclofenac showed only general toxic symptoms, which are well known in a nonsteroidal inflammatory drug. Thus, aceclofenac is believed to be relatively safe. With respect to chronic toxicity, when administered to rats at a dose of 1.5 mg/kg/day, aceclofenac showed only a slight body weight reduction and change in [Ca⁺⁺] and inorganic salts in blood during 2 months of the last stage of an experiment, and at a dose of

3.6 mg/kg/day, it showed a change in body weight and blood chemical components from 2 months after administration, and caused ulcer formation and bleeding in jejunum and caecum.

With respect to teratogenic toxicity, when administered to females at 2.5, 5.0 and 10.0 mg/kg/day, aceclofenac had no effect on clinical symptoms, the viability of corpus luteum, and the ratio between implanted females and males of died or survived embryos. In the case of survived embryos, aceclofenac did not cause a significant change in injury of external appearance, teratogenicity, and organs. Thus, aceclofenac does not show teratogeniity in rats under the above conditions. Aceclofenac has the following clinical characteristics.

It inhibits the production of interleukin-1 causing the destruction of joint cartilage and promotes the production of glycosaminoglycan found in joint cartilage, so that it is suitable for the prevention of rheumatoid arthritis and osteoarthrosis. Aceclofenac has a reduced effect on normal prostaglandin production in a gastric mucosa such that gastrointestinal trouble is minimized. Aceclofenac is penetrated into an inflammatory site, such as a joint, at high concentration, so that it has the powerful effect of inhibiting prostaglandin production in foci. Aceclofenac showing this powerful effect of alleviating pain is currently developed and marketed in a tablet form. However, a tablet among pharmaceutical formulations requires several processes in which the tablet must be first disintegrated upon oral administration, and a drug mixed with excipients is absorbed only after it was dissolved in digestive fluid or body fluid. Furthermore, if a drug is a substance poorly soluble in water, such as aceclofenac, the tablet generally has slow drug dissolution rate leading to low in vivo absorption rate and low bioavailability. For this reason, the onset time of the tablet will be necessarily delayed as compared to the case where pre-dissolved drugs, such as liquid formulations or soft capsules, are administered. Accordingly, the present inventors have conducted a study to develop a formulation, which can overcome shortcomings with the prior tablet and eliminate rejection against drugs. As a result of this study, the present inventors have succeeded in developing a soft capsule formulation capable of further maximizing the therapeutic effect of the drug as in the present invention. Methods for formulating an internal use drug into a soft capsule are broadly divided into three categories as follows. First, there is a generally known method wherein an active component drug is suspended in an oily base, such as vegetable oil (e.g., soybean oil, coconut oil, sunflower seed oil, sesame oil, perilla oil or olive oil), or middle chain fatty acid triglyceride, using a suspending agent such as bees-wax. This method may also cause a delay in the dissolution of the drug and thus its use must be carefully considered. Second, there are methods wherein an active component drug is solubilized or suspended in a water-soluble base, such as polyethylene glycol or propylene glycol. Third, there are methods for preparing a nano-emulsion concentrate using the concept of a self-microemulsifying drug delivery system, wherein a drug is dissolved by the addition of the water-soluble base, a dissolution aid, oils and a stabilizer. However, when aceclofenac is formulated into a soft capsule formulation in order to increase the dissolution rate thereof, the first method in which aceclofenac is suspended in the oily base is difficult to achieve the desired dissolution rate. Of the second methods using the aqueous soluble base, a method of suspending aceclofenac in a base such as polyethylene glycol 400 provides an improvement in drug dissolution rate as compared to the method of suspending aceclofenac in the oily base, but is also difficult to achieve a significant increase in dissolution rate. Korean Patent Application No. 10-1999- 0027950 discloses a method of using polyethylene glycol, glycerin, and purified water to solubilize nitrendipine . However, this method is not regarded as a recommendable method since a soft capsule formulation can be softened or degraded by purified water. Moreover, US Patent No. 5,141,961 discloses an ethanol-containing liquid pharmaceutical composition obtained by solubilizing ibuprofen using ethanol, polyethylene glycol and polyvinyl pyrrolidone. US Patent No. 5,071,643 discloses a method of solubilizing ibuprofen using an ionizable solvent system comprising glycerin, polyethylene glycol, polyvinyl pyrrolidone and water, but is not a recommendable method since it can affect the softening and hardening of a soft capsule formulation. The composition disclosed in US Patent 5,141,961 is an ethanol-containing liquid pharmaceutical composition and thus is pointed as a problem in that its safety is reduced upon long-term storage (i.e., its contents are precipitated due to a change in ethanol content) , resulting in a reduction in its bioavailability. Thus, a method of solubilizing a drug with the minimum possible use of purified water or ethanol will allow the more effective preparation of a soft capsule formulation. Accordingly, the present inventors have conducted studies to develop a formulation which has a higher drug dissolution rate and in vivo drug absorption rate than those of the existing formulations, thus showing the most rapid expression of a drug in patients. As a result, the present inventors have developed a soft capsule formulation having high in vivo drug absorption rate. However, even in the case of the soft capsule formulation, the generally known formulation method of suspending an active component drug in an oily base, such as vegetable oil (e.g., soybean oil, coconut oil and wheat germ oil) , mineral oil or middle chain triglyceride (MCT) , using a suspending agent such as bees-wax, has a shortcoming in that it is difficult to greatly increase the dissolution rate of a moderately poorly soluble drug, such as aceclofenac. Furthermore, even in a more advanced method in which an active ingredient drug is suspended in a mixture of a hydrophilic liquid base (e.g., polyethylene glycols 300- 600) known to be widely used in the preparation of a transparent soft capsule with a hydrophilic semi-solid or solid substance (e.g., polyethylene glycols 1500-20000), the dissolution rate of the drug can be increased as compared to the general formulation method but an increase in the effect and stability of the drug cannot be expected. Disclosure of Invention

The present invention has been made to solve the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a method for solubilizing aceclofenac using a self-microemulsifying drug delivery system, the method comprising dissolving 1-35 parts by weight, based on the total weight of contents, of aceclofenac, in a mixture in 10-90 parts by weight of polyethylene glycol, 1-50 parts by weight of polyoxyethylene hydrogenated castor oil (trade name: Cremophor, Nikkol HCO) or dimethyl isosorbide, 0.1-10 parts by weight of oil, 1-40 parts by weight of polysorbate (trade name: Tween) , 0.0001-0.5 parts by weight of butylated hydroxyanisole or butylated hydroxytoluene, and 0.001-5 parts by weight of tocopherol . Another object of the present invention is provide a solubilized aceclofenac-containing liquid composition using a self-microemulsifying drug delivery system, the composition being prepared by dissolving 1-35 parts by weight, based on the total weight of contents, of aceclofenac, in a mixture of 10-90 parts by weight of polyethylene glycol, 1-50 parts by weight of polyoxyethylene hydrogenated castor oil or dimethyl isosorbide, 0.1-10 parts by weight of oils, 1-40 parts by weight of polysorbate, 0.0001-0.5 parts by weight of butylated hydroxyanisole or butylated hydroxytoluene, and 0.001-5 parts by weight of tocopherol. Still another object of the present invention is to provide a soft capsule formulation including a solubilized aceclofenac-containing composition using a self- microemulsifying drug delivery system, the composition being prepared by dissolving 1-35 parts by weight, based on the total weight of contents, of aceclofenac, in a mixture of 10-90 parts by weight of polyethylene glycol, 1-50 parts by weight of polyoxyethylene hydrogenated castor oil or dimethyl isosorbide, 0.1-10 parts by weight of oils, 1-40 parts by weight of polysorbate, 0.0001-0.5 parts by weight of butylated hydroxyanisole or butylated hydroxytoluene, and 0.001-5 parts by weight of tocopherol. The present invention relates to a method for preparing a solubilized aceclofenac-containing composition, the method comprising dissolving aceclofenac in a mixed solvent system of a dissolution agent, a dissolution aid, oil and a stabilizer, such that the composition is self- microemulsified by body fluid upon oral administration into the human body, as well as a soft capsule formulation containing the composition. More particularly, the present invention relates to a method for preparing a self- microemulsifying composition having greatly increased dissolution rate, by completely dissolving aceclofenac with heating in a mixture of polyethylene glycol, dimethyl isosorbide or polyoxyethylene 40 hydrogenated castor oil (trade name: Cremophor RH40 or HCO40) or polyoxyethylene 60 hydrogenated castor oil (trade name: Cremophor RH60 or HCO60) , middle chain fatty acid or mono- or di-glycerides, and tocopherol, as well as a soft capsule formulation containing the composition.

Best Mode for Carrying Out the Invention

In the present invention, aceclofenac can be dissolved at the amount of 1-40 parts by weight, and in view of the expression of a drug effect, aceclofenac can be solubilized at the amount of 1-30 parts by weight such that its dissolution and content stabilities can be ensured. Agents for solubilizing aceclofenac include polyethylene glycol and polysorbate. Particularly, polyethylene glycol 400 is used as a main base. Polyethylene glycol 400 is preferably used at the amount of 10-90 parts by weight, and more preferably 30-60 parts by weight. Furthermore, a polyoxyethylene hydrogenated castor oil derivative (trade name: Cremophor, HCO) is preferably used at the amount of 1-50 parts by weight and more preferably 1-30 parts by weight. Oils such as middle chain fatty acid are preferably used at the amount of 0.1-10 parts by weight and more preferably 0.1-5 parts by weight. Polysorbate is preferably used at the amount of 1-40 parts by weight and more preferably 5-8 parts by weight. Butylated hydroxyanisole or butylated hydroxytoluene as a stabilizer is preferably used at the amount of 0.0001-0.5 parts by weight and more preferably 0.001-0.4 parts by weight. Tocopherol as another stabilizer is preferably used at the amount of 0.001-5 parts by weight and more preferably 0.2-2 parts by weight. The above components are mixed to prepare a solvent system as a self- microemulsifying drug delivery system. At less than the lower limit of each of the use amount ranges, it will impossible to solubilize the drug, and at more than the upper limit, the size of a formulation will be increased, resulting in reduction of marketability. In a method for preparing an internal use drug using the above components, polyethylene glycol 400 and polysorbate are blended, warmed and mixed at a temperature of about 50-80 °C. To the mixture, polyoxyethylene hydrogenated castor oil, oils, butylated hydroxyanisole or butylated hydroxytoluene, and tocopherol, are added and completely dissolved. As the solvent system is completely dissolved to obtain transparent liquid, a purified aceclofenac raw material is added slowly to the solvent system at a temperature of about 50 °C, and the transparent drug which had been completely dissolved is cooled to room temperature with slow stirring. Then, bubbles are removed using a vacuum pump, thus obtaining a solubilized composition. In the present invention, a soft capsule coating film is prepared by a conventional method using a generally used soft-gel formulation containing gelatin and plasticizers . Also, the inventive soft capsule containing solubilized aceclofenac is formed using an automatic rotary filling machine according to a conventional filling method, and then subjected to drying and sorting processes, thus obtaining a test product. Furthermore, the soft capsule formulation prepared according to the present invention has excellent drug dissolution rate and content stability. When this soft capsule formulation was measured for a change with time for six months under accelerated conditions and room temperature conditions, it showed little or no change in content and property with time and outstandingly excellent dissolution rate compared to the existing commercial aceclofenac tablet. Accordingly, the present invention provides a formulation having excellent aceclofenac dissolution rate and high stability, as compared to the existing commercial formulation. The present invention will hereinafter be described in further detail by examples and comparative examples. It is to be understood that the scope of the present invention is not limited to or by the examples. Example 1 200 g of polyethylene glycol-400, 50 g of polyoxyethylene hydrogenated castor oil, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 362 g of a solubilized aceclofenac- containing composition. Example 2 200 g of polyethylene glycol-400, 50 g of dimethyl isosorbide, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 362 g of a solubilized aceclofenac-containing composition. Example 3 200 g of polyethylene glycol-400, 25 g of polyoxyethylene hydrogenated castor oil, 25 g of dimethyl isosorbide, 0.25 g of butylated hydroxytoluene, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 362 g of a solubilized aceclofenac-containing composition. Example 4 125 g of polyethylene glycol-400, 125 g of polyoxyethylene hydrogenated castor oil, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 362 g of a solubilized aceclofenac- containing composition. Example 5 125 g of polyethylene glycol-400, 100 g of polyoxyethylene hydrogenated castor oil, 7 g of polysorbate-20, 7 g of polysorbate-80, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 351 g of a solubilized aceclofenac-containing composition. Example 6 100 g of polyethylene glycol-400 and 100 g of triacetin are mixed and solubilized. To the mixture, 50 g of polyoxyethylene hydrogenated castor oil, 8 g of polysorbate-20, 0.25 g of butylated hydroxytoluene, 2 g of tocopherol, and 10 g of middle chain fatty acid are added, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 370 g of ~a solubilized aceclofenac- containing composition. Example 7 100 g of polyethylene glycol-400 and 100 g of diethyleneglycol monoethylether are mixed and solubilized. To the mixture, 50 g of polyoxyethylene hydrogenated castor oil, 8 g of polysorbate-20, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are added, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 370 g of a solubilized aceclofenac-containing composition. Example 8 100 g of polyethylene glycol-400, 50 g of triacetin, 50 g of propylene glycol are mixed and solubilized. To the mixture, 50 g of polyoxyethylene hydrogenated castor oil, 8 g of polysorbate-20, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are added, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 370 g of a solubilized aceclofenac- containing composition. Preparation of coating film A soft ' capsule coating film used in the present invention is prepared by a conventional method using a generally known soft gel formulation which contains 324 mg gelatin, 145 mg glycerin, 30 mg polyethylene glycol-400, 1.0 mg methyl paraoxybenzoate, 1.0 mg propyl paraoxybenzoate per capsule. A soft capsule formulation including the inventive composition containing solubilized aceclofenac is prepared by forming the composition into an Oval 6 type by a conventional filling method using a general automatic rotary filling machine, and then drying and sorting the resulting capsule. The obtained soft capsule is used as a test product . Comparative Example 1 100 g of aceclofenac is mixed with 250 g of middle chain fatty acid, and the mixture is sufficiently crushed using a colloid mill, to which 10 g of Span-80 is then added and mixed well. This gives 360 g of an aceclofenac- containing composition. This composition is used as a comparative soft capsule composition. Then, the formulation of a gelatin coating film and the preparation of a soft capsule containing the composition are carried out in the same manner as described above . Test Example 1 : Dissolution rate test and comparative evaluation The comparative evaluation of dissolution rates was carried out with the inventive soft capsule formulations (Examples 1-8) each including the self-microemulsifying composition containing the solubilized aceclofenac drug, the comparative soft capsule formulation (Comparative Example 1) having the aceclofenac suspended in the oil- soluble base, and a commercial tablet (trade name: Airtal) . The results are given in Table 1 below. A dissolution test for aceclofenac was carried out according to a dissolution test method for Clanza tablet, an aceclofenac-containing tablet marketed in the name of this applicant. The dissolution test was carried out at a paddle rotating speed of 100 rpm in 900 mL of phosphate buffer (pH 7.8) according to a dissolution test method of this applicant, and it was carried out according to the second dissolution method of general test methods described in Korea Pharmacopeia. As a sample solution, a solution, which had been filtered through a 0.45 μm membrane filter, was used. Meanwhile, for use as a standard solution, lOOmg of an aceclofenac standard was precisely weighed and dissolved in 900ml of the dissolution solution. The contents of aceclofenac in these solutions were analyzed by liquid chromatography.

Amount of dissolved aceclofenac in sample solution (mg)= amount of aceclofenac standard taken (mg) X peak area of sample solution/peak area of standard solution Table 1: Results of dissolution rate test of self- microemulsifying aceclofenac formulation

As evident from Table 1, the solubilized aceclofenac formulation using a micro-emulsifying system as in the present invention is a soft capsule formulation having a higher dissolution rate than that of the prior formulation. Thus, the inventive soft capsule formulation -. has a characteristic in that it shows increased aceclofenac dissolution rate leading to a great increase in the in vivo absorption rate of aceclofenac, thus greatly increasing the pharmacological effect of aceclofenac. Test Example 2: Test for stability with time For the comparative evaluation of stabilities, the soft capsule formulations according to Examples 1-5 and Comparative Example 1 were tested for a change with time under a room temperature condition and an accelerated condition of 40 °C for six months. The results are given in Table 2.

Table 2 : Results of stability test on aceclofenac formulations

As evident from Table 2 , the soft capsule formulations prepared according to the present invention did not show browning, layer separation or precipitation, which occurred in the formulation of Comparative Example 1.

Industrial Applicability

As described above, the present invention provides the solubilized aceclofenac-containing composition which has high in vivo drug absorption rate and thus shows a more rapid therapeutic effect than that of the existing formulation, as well as the soft capsule containing the composition. In other words, the addition of aceclofenac to a mixture solution of a hydrophilic solubilizing base (e.g., polyethylene glycol 400) , a surfactant, oil and a stabilizer, results in a significant increase in the solubility of aceclofenac, thus greatly increasing the bioavailability of aceclofenac. By filling this composition into a soft capsule by a conventional method, a soft capsule formulation which shows a great increase in the dissolution rate of aceclofenac can be provided. Thus, the present invention allows the development of new formulation products which show an increase in the dissolution of poorly soluble drugs and an improvement in the in vivo absorption rate of the drugs, which were not achieved by the existing similar formulations.

Claims

What Is Claimed Is:

1. A self-microemulsifying composition containing solubilized aceclofenac, the composition being prepared by dissolving aceclofenac in a mixed solvent of a hydrophilic solubilizing agent, a surfactant, a stabilizer and oil.

2. The composition of Claim 1, wherein the hydrophilic solubilizing agent is one or a mixture of two or more selected from the group consisting of polyethylene glycol, propylene glycol, triacetin, diethyleneglycol monoethylether, glycerin, and sorbitol .

3. The composition of Claim 1, wherein the surfactant is one or a mixture of two or more selected from the group consisting of polyoxyethylene hydrogenated castor oil and derivatives thereof, Tween and dimethyl isosorbide.

4. The composition of Claim 1, wherein the stabilizer is one or a mixture of two or more selected from the group consisting of tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, and ascorbyl palmitate.

5. The composition of Claim 1, wherein the oil is one or a mixture of two or more selected from the group consisting of soybean oil, corn oil, safflower oil, sunflower seed oil, caprylic/capric triglyceride, isopropyl palmiritate, isopropyl palmitate, and tocopherol.

6. A soft capsule formulation containing the self- microemulsifying composition as set forth in any one of Claims 1 to 5 .

7. A self-mocroemulsifying composition containing solubilized aceclofenac, the composition being prepared by mixing 1-35 parts by weight of aceclofenac, 10-90 parts by weight of polyethylene glycol, 1-40 parts by weight of polysorbate, 1-50 parts by weight of polyoxyethylene hydrogenated castor oil or dimethyl isosorbide, 0.0001-0.5 parts by weight of butylated hydroxyanisole, 0.001-5 parts by weight of tocopherol and 0.1-10 parts by weight of oils with heating, so as to solubilize the aceclofenac.

8. A soft capsule formulation which is prepared by the steps of: mixing 1-35 parts by weight, based on the total weight of the core of the soft capsule formulation, of aceclofenac, 10-90 parts by weight of polyethylene glycol, 1-40 parts by weight of polysorbate, 1-50 parts by weight of polyoxyethylene hydrogenated castor oil or dimethyl isosorbide, 0.0001-0.5 parts by weight of butylated hydroxyanisole, 0.001-5 parts by weight of tocopherol and 0.1-10 parts by weight of oils with heating, to prepare a solubilized aceclofenac-containing self-microemulsifying composition; and filling the prepared composition into a soft gelatin capsule.

9. The composition of Claim 7 or the soft capsule formulation of Claim 8, wherein the polyethylene glycol is polyethylene glycol 300 or polyethylene glycol 400.

10. The soft capsule formulation of Claim 8, which is transparent .