WO2010008135A1

WO2010008135A1 - Oral soft capsule of aceclofenac having improved stability

Info

Publication number: WO2010008135A1
Application number: PCT/KR2009/002249
Authority: WO
Inventors: Youn-Woong Choi; Sang-Min Cho; Dae-Chul Ha; Seung-Ho An
Original assignee: Korea United Pharm Inc
Current assignee: Korea United Pharm Inc
Priority date: 2008-07-18
Filing date: 2009-04-29
Publication date: 2010-01-21
Anticipated expiration: 2011-01-18
Also published as: KR20100009175A; KR101096429B1

Abstract

The present invention relates to an aceclofenac-containing soft capsule formulation having improved stability and the preparation thereof, and more particularly to a method of preparing a soft capsule by dissolving or dispersing aceclofenac, which is unstable in an aqueous solution, in oil or a mixture of oils. The aceclofenac-containing soft capsule contains an aceclofenac-containing liquid composition prepared by mixing and solubilizing aceclofenac, oil and a suspending agent. The soft capsule can maintain stability for 3 years or more and has improved active ingredient dissolution compared to existing soft capsules, thus increasing the bioavailability of the active ingredient.

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. More particularly, the present invention relates to a method of improving the dissolution rate and bioavailability of aceclofenac easy to hydrolyze by suspending aceclofenac in an oily base using a suspending agent so as to reduce the contact of aceclofenac with water.

Aceclofenac (2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid), which is a known compound represented by the following structural formula, is a phenylacetic acid-based anti-inflammatory analgesic drug showing an excellent efficacy against chronic joint diseases, including rheumatoid arthritis, osteoarthrosis and ankylosing spondylitis, as well as dentalgia, post-operation pain or post-delivery pain. This drug shows an excellent therapeutic effect in that it easily penetrates into inflammatory tissues occurring in a joint and the like, and thus exhibits an 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 gastroenteric 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.

Aceclofenac (2-[(2,6-dichlorphenyl)amino]-phenylacetoxyacetic acid) is characteristic in that it is easily soluble in an organic solvent and relatively poorly soluble in water. Aceclofenac, when administered orally, is absorbed rapidly in the gastrointestinal tract and distributed in kidneys, bladder, liver, thyroid gland and the like at high concentrations but distributed in eye, brain, fat tissue and the like at low concentrations. 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 (T_max) 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 has the following clinical characteristics. (1) Aceclofenac 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. (2) Aceclofenac has a reduced effect on normal prostaglandin production in a gastric mucosa such that gastroenteric trouble is minimized. (3) Aceclofenac penetrates into an inflammatory site, such as a joint, at high concentration, so that it has a powerful effect of inhibiting prostaglandin production in foci.

In order to improve the dissolution and bioavailability of poorly soluble drugs, various formulation means for improving the solubilization or dissolution rate of poorly soluble drugs have been developed. For example, various means, including a micronization method, a micelle method, a solid dispersion method, a spray drying method, an inclusion complex method, and a solubilization method employing water-soluble polymers or surfactants, are used, but the increase in solubility of drugs is not constant depending on the method used, and the commercial use of such means is greatly limited in terms of preparation method, commercial viability and efficiency.

Also, when a poorly soluble drug is formulated into a tablet which is a pharmaceutical formulation, the tablet 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 such as aceclofenac, which is poorly soluble in water, is formulated into a tablet, 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.

General soft gelatin capsules are composed of a capsule content (fill) and an outer shell (gelatin). The capsule content consists of at least one active ingredient and bases (excipients), and the shell consists of gelatin and given amounts of a plasticizer and water. The bases which are used in the capsule content include oils, water-soluble polymer bases, fatty acids, surfactants, etc. In order to improve the dissolution rate of poorly soluble aceclofenac, prior formulations have been used in the form of an emulsion or microemulsion which contains oils, fatty acids, or mixtures thereof. However, aceclofenac easy to hydrolyze is hydrolyzed not only in the case of using a water-soluble base, but also even by a small amount of water present in the gelatin shell, so that it is converted into diclofenac.

Methods for formulating an internal use drug into a soft capsule are broadly divided into two categories as follows. First, there is a generally known method wherein an active ingredient 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 ingredient drug is solubilized or suspended in a water-soluble base, such as polyethylene glycol or propylene glycol. However, when aceclofenac is formulated into a soft capsule in order to increase the dissolution rate thereof, it is difficult for the first method of suspending aceclofenac in the oily base to achieve the desired dissolution rate. Of the second methods using the water-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 it is also difficult for this method to achieve a significant increase in dissolution rate.

Currently, aceclofenac is being marketed as soft capsule formulations solubilized with water-soluble solubilizers in order to show rapid onset of action. However, the soft capsule formulations have a stability problem upon long-term storage due to the property of aceclofenac easy to hydrolyze.

Accordingly, the present inventors have conducted studies on various compositions capable of increasing the dissolution properties and stability of aceclofenac and, as a result, have found that, when a novel soft capsule containing poorly soluble aceclofenac, a mixture of oils, and a suspending agent, shows high drug dissolution rate and excellent product stability, thereby completing the present invention.

Therefore, the present invention provides an aceclofenac-containing soft capsule which solves a stability problem occurring upon long-term storage due to the property of aceclofenac easy to hydrolyze and has excellent dissolution rate and stability.

According to a suitable embodiment of the present invention, a soft capsule containing aceclofenac contains an aceclofenac-containing liquid composition prepared by mixing and solubilizing aceclofenac, oil and a suspending agent.

According to another embodiment of the present invention, the oil may be one or a mixture of two or more selected from the group consisting of macadamia ternifolia nut oil, hydrogenated hi-erucic acid rape seed oil, olive oil, jojoba oil, hybrid sunflower (Helian thus annuus) oil, neem (Melia azadirachta) seed oil, dog rose (Rosa canina) lips oil, peanut oil, corn oil, sesame oil, canbra oil, cottonseed oil, palm oil, soybean oil, coconut oil, castor oil, polyoxyl hydrogenated castor oil, mineral oil, ceresin and ozokerite.

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

According to still aspect embodiment of the present invention, the mass ratio of palm oil and at least one selected from sunflower oil, corn oil, polyoxyl hydrogenated castor oil, sesame oil and mineral oil is 1:3 to 1:7.

According to still another embodiment of the present invention, the suspending agent may be one or a mixture of two or more selected from the group consisting of white wax, paraffin wax and bees wax.

A soft capsule according to the present invention has excellent dissolution rate and stability. Thus, it has little or no change in the content, dissolution and property thereof with the passage of time at accelerated and room temperature conditions and shows excellent stability and dissolution rate as compared to existing commercial soft capsules containing aceclofenac.

FIG. 1 shows dissolution test results for soft capsule formulations containing given amounts of aceclofenac, prepared in Formulation 6 of Example 2 and Formulations 9 to 14 of Example 3 of the present invention.

A soft capsule according to the present invention is prepared by dissolving or suspending the pharmacologically active ingredient aceclofenac in oil or a mixture of oils and filling the resulting liquid or paste content into a gelatin shell composition.

A general method for formulating an internal use drug into a soft capsule is a method of solubilizing or suspending the active ingredient drug in a water-soluble base such as polyethylene glycol or propylene glycol. However, the soft capsule has a stability problem upon long-term storage due to the property of aceclofenac easy to hydrolyze, in the same manner as existing products. This is because water is contained in the water-soluble solubilizer, even though the amount thereof is small.

In order to solve such a problem, the present invention is characterized in that aceclofenac is simply suspended in oil in place of a solubilizer containing water, and then subjected to a conventional micronization process so as to have a given particle size, such that the poorly soluble active ingredient aceclofenac suspended in the oil phase maintains a constant dissolution rate while reducing contact with water in the gelatin shell, thus inhibiting the hydrolysis of aceclofenac.

As the micronization process, a process of grinding the mixed oil phase itself with a colloidal mill to micronize the suspended aceclofenac may be used.

As the oils, hydrogenated vegetable oils, including macadamia ternifolia nut oil, hydrogenated hi-erucic acid rape seed oil, olive oil, jojoba oil, hybrid sunflower (Helian thus annuus) oil, neem (Melia azadirachta) seed oil, dog rose (Rosa canina) lips oil, peanut oil, corn oil, sesame oil, canbra oil, cottonseed oil, palm oil, soybean oil, coconut oil, castor oil or polyoxyl hydrogenated castor oil, may be used. In addition, minerals, including mineral oil, ceresin and ozokerite, may also be used.

The oil may be one or a mixture of two or more oils, but is preferably a mixture of two or more oils. A mixture of two or more oils can increase the stability of aceclofenac and maintain the dissolution rate of aceclofenac without using a special stabilizer and solubilizer.

The oil may be a mixture of palm oil and at least one selected from the group consisting of macadamia ternifolia nut oil, hydrogenated hi-erucic acid rape seed oil, olive oil, jojoba oil, hybrid sunflower (Helian thus annuus) oil, neem (Melia azadirachta) seed oil, dog rose (Rosa canina) lips oil, peanut oil, corn oil, sesame oil, canbra oil, cottonseed oil, soybean oil, coconut oil, castor oil and polyoxyl hydrogenated castor oil, mineral oil, ceresin and ozokerite.

According to Examples of the present invention, the stability of the soft capsule changes depending on the mixing ratio of the oils. Preferably, the soft capsule shows a better stability when the mass ratio of palm oil and oils other than palm oils is 1:3 to 1:7.

As the suspending agent, white wax, paraffin wax, bees wax, animal stearate, a wax mixture, aluminum monosterate, Ethocel (ethylcellulose), polyethylene glycol 4000 or 6000, lecithin acetylated monoglyceride may be used. Preferably, white wax, paraffin wax or bees wax may be used.

The soft capsule prepared according to the present invention had excellent dissolution rate and content stability and showed little or no change in the content, dissolution and property thereof with the passage of time at accelerated and room temperature conditions. Also, the soft capsule showed excellent stability and dissolution rate compared to those of existing commercial soft capsules containing aceclofenac. Accordingly, the present invention provides a formulation having excellent stability and high drug dissolution rate compared to those of the prior formulations.

Hereinafter, the present invention will be described in further detail with reference to examples and comparative examples. It is to be understood, however, that the scope of the present invention is not limited to these examples.

Example 1

Formulation 1 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, a mixed oil of 176 mg of soybean oil and 50 mg of palm oil, 3 mg of white wax and 30 mg of lecithin as suspending agents, and 1 mg of antioxidant BHT (butylated hydroxy toluene), and the soft capsule shell in the present invention is prepared by a conventional method using a generally used soft gel formulation containing gelatin and plasticizers. Also, the inventive soft capsule having improved aceclofenac stability is formed using an automatic rotary filling machine according to a conventional filling method, and then subjected to drying and sorting processes.

Formulation 2 is the same as Formulation 1, except that 30 mg of dimethyl isosorbide is used as a solvent and that 30 mg of palm oil and 20 mg of lecithin are used.

Formulation 3 is the same as Formulation 1, except that 30 mg of carbitol is used instead of dimethyl isosorbide as a solvent.

Table 1 below shows the components, contents and content ratios of Formulations 1 to 3, and Table 2 below shows stability test results for Formulations 1 to 3.

Stability test

A stability test was carried out in a constant temperature and humidity chamber at room temperature and 40 at a humidity of 75%. More than 20 capsules were taken, and the contents thereof were weighed and sufficiently mixed, and then 10 mg of the mixture as aceclofenac was precisely weighed and dissolved in methanol to reach a marked line of 100 ml, thus obtaining a test solution. Meanwhile, for use as a standard solution, 10 mg of an aceclofenac was precisely weighed and dissolved in methanol to obtain 100 ml of a solution. The peak area values of aceclofenac in the test solution and the standard solution (At and As) were calculated by performing a test according to a liquid chromatography method among general test methods described in Korea Pharmacopeia under the following instrumental conditions.

Instrumental condition: UV absorption spectrophotometer (277 nm)

Column: C18 ODS

Column temperature: 40 ℃

Mobile phase: acetonitrile: buffer (68 : 32)

Flow rate: 1.0 ml/min

Buffer: 5 mM phosphate buffer, which has been adjusted to a pH of 7.4, and then filtered through a 0.45 um membrane filter.

Stability (%) = At/As x 100

Table 1

Table 2

Example 2

Formulation 4 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, a mixed oil of 205 mg of soybean oil and 50 mg of palm oil, 10 mg of white wax as a suspending agent, and 1 mg of antioxidant BHT (butylated hydroxy toluene), and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Formulation 5 is the same as Formulation 4, except that 3 mg of white wax is used and the antioxidant BHT is not used.

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

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

Formulation 8 is the same as Formulation 5, except that 207 mg of soybean oil and 20 mg of suspending agent SiO₂are used.

Table 3 below shows the components, contents and content ratios of Formulations 4 to 8, and Table 4 below shows stability test results for Formulations 4 to 8.

Table 3

Table 4

Example 3

Formulation 9 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, a mixed oil of 207 mg of sunflower oil and 50 mg of palm oil, and 3 mg of white wax as a suspending agent, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

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

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

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

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

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

Table 5 below shows the components, contents and content ratios of Formulations 9 to 14, and Table 6 below shows stability test results for Formulations 9 to 14.

Table 5

Table 6

Dissolution test

The soft capsules containing given amounts of aceclofenac, prepared in Formulation 6 of Example 2 and Formulations 9 to 14 of Example 3, were subjected to a dissolution test according to the dissolution test method described in Korea Pharmacopeia, 7^th revised edition. As a dissolution medium, phosphate buffer (pH 7.8) was used, and the dissolution test was carried out using a paddle method in 900 ml of the dissolution medium at a paddle rotating speed of 100 ppm at a temperature of 37 0.5 ℃. At 0, 5, 10, 15, 30, 45 and 60 min, 5 ml of the sample was collected and the same amount of the dissolution medium was added. In analysis, the sample obtained in the dissolution test was filtered through a 0.45 membrane filter and quantified for aceclofenac using HPLC. The analysis of the sample was carried out in the following conditions. Wavelength: 277 nm, mobile phase: acetonitrile: phosphate buffer (pH 7.4) = 68:32; flow rate: 1.0ml/min; and column: C18 ODS. The analysis results are shown in FIG. 1.

Comparative Example 1

Formulation 15 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 200 mg of polyethylene glycol (PEG) 400 and 50 mg of dimethyl isosorbide as solvents, 2.13 mg of tocopherol acetate as an antioxidant and 2.5 mg of ascorbic acid, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Formulation 16 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac and 218 mg of polyethylene glycol (PEG) 400 as a solvent, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

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

Formulation 18 is the same as Formulation 16, except that 1.25 mg of SLS (sodium lauryl sulfate) is used as a solubilizing agent.

Formulation 19 is the same as Formulation 16, except that 4 mg of PVP K-30 (poly vinyl pyrrolidone K-30) as a solubilizing agent and 0.13 mg of BHT (butylated hydroxy toluene) as an antioxidant are used.

Table 7 below shows the components, contents and content ratios of Formulations 15 to 19, and Table 8 below shows stability test results for Formulations 15 to 19.

Table 7

Table 8

Comparative Example 2

Formulation 20 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 250 mg of polyethylene glycol (PEG) 400 as a solvent, 4 mg of PVP K-30 (poly vinyl pyrrolidone K-30) and 1.25 mg of SLS (sodium Lauryl sulfate) as solubilizing agents, and 0.25 mg of BHT (Butylated Hydroxy Toluene) and 2 mg of ascorbic acid as antioxidants, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Formulation 21 is the same as Formulation 20, except that the solubilizing agent SLS is not used and 0.5 mg of the antioxidant BHT (bytylated hydroxy toluene) is used.

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

Formulation 23 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 200 mg of polyethylene glycol (PEG) 400), 20 mg of triacetin and 40 mg of dimethyl isosorbide as solvents, and 0.36 mg of vitamin E as an antioxidant, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Formulation 24 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 255 mg of polyethylene glycol (PEG) 400, 3.75 mg of PVP K-30 (poly vinyl pyrrolidone K-30) and 1.25 mg of SLS (sodium Lauryl sulfate) as solubilizing agents and 0.25 mg of BHA (butylated hydroxyanisole) as an antioxidant, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Formulation 25 is a soft capsule containing an aceclofenac-containing 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 BHT (butylated hydroxyanisole) as an antioxidant, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Table 9 and 10 below shows the components, contents and content ratios of Formulations 20 to 25, and Table 11 below shows stability test results for Formulations 20 to 25.

Table 9

Table 10

Table 11

Comparative Example 3

Formulation 26 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 147 mg of polyethylene glycol (PEG) 400 and 156 mg of carbitol as solvents, and 1 mg of BHT (Butylated Hydroxy Toluene) as an antioxidant, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Formulation 27 is the same as Formulation 26, except that the solvent PEG 400 is not used and 256 mg of carbitol and 142 mg of triacetin are used.

Formulation 28 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, 150 mg of carbitol and 110 mg of oleic acid as solvents, and 64 mg of Labrafil M1944CS as a surfactant, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Formulation 29 is a soft capsule containing an aceclofenac-containing liquid composition prepared by mixing and solubilizing 100 mg of aceclofenac, and 220 mg of carbitol, 50 mg of dimethyl isosorbide and 150 mg of medium-chain triglyceride (MCT) as solvents, and the soft capsule shell and the process for preparing the soft capsule are the same as described in Example 1.

Table 12 below shows the components, contents and content ratios of Formulations 26 to 29, and Table 13 below shows stability test results for Formulations 26 to 29.

Table 12

Table 13

Claims

A soft capsule containing an aceclofenic-containing liquid composition prepared by mixing and solubilizing aceclofenac, oil and a suspending agent.
The soft capsule of Claim 1, wherein the oil is one or a mixture of two or more selected from the group consisting of macadamia ternifolia nut oil, hydrogenated hi-erucic acid rape seed oil, olive oil, jojoba oil, hybrid sunflower (Helian thus annuus) oil, neem (Melia azadirachta) seed oil, dog rose (Rosa canina) lips oil, peanut oil, corn oil, sesame oil, canbra oil, cottonseed oil, palm oil, 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 palm oil and one selected from the group consisting of sunflower oil, corn oil, cottonseed oil, polyoxyl hydrogenated castor oil, sesame oil and mineral oil.
The soft capsule of Claim 3, wherein the mass ratio of palm oil and one selected from the group consisting of sunflower oil, corn oil, cottonseed oil, polyoxyl hydrogenated castor oil, sesame oil and mineral oil is 1:3 to 1:7.
The soft capsule of Claim 1, wherein the suspending agent is one or a mixture of two or more selected from the group consisting of white wax, paraffin wax and bees wax.