KR100314992B1 - Soft capsules containing antifungal agents such as itraconazole - Google Patents

Abstract

The present invention relates to a soft capsule containing itraconazole, a therapeutic agent for dermatitis, and a method for preparing the same. More specifically, the present invention relates to at least one antifungal agent selected from itraconazole, glyceroflavin, ketoconazole, terbininapine, naphthypine, etc. 10 to 50% by weight, 0.1 to 10% by weight of polyethylene glycol as a hydrophilic base, 30 to 60% by weight of at least one selected from labrasol and cremophor RH40 (cured castor oil polyoxyl 40) as a surfactant, and cosurfactant The present invention relates to a soft capsule containing an antifungal agent prepared by preparing a contents solution consisting of 3 to 20% by weight of low-prolol olle WL 1173 and 0.1 to 1% by weight of polyvinylpyrrolidone.

Description

Soft capsule containing antifungal agents such as itraconazole

The present invention relates to a soft capsule containing itraconazole, which is a skin fungal treatment agent, and a method for manufacturing the same. A soft capsule containing an itraconazole emulsion, which is emulsified by mixing an antifungal agent, itraconazole, a hydrophilic base, a surfactant, a cosurfactant, and a dispersant as a main component. More specifically, gelatin is used to emulsify the antifungal agent obtained by mixing a hydrophilic base, a surfactant, a cosurfactant, and a dispersant as an excipient base when at least one antifungal component is used as a soft capsule. The present invention relates to a soft capsule produced by molding to a film and a method for producing the same.

As the formulation containing the antifungal component used in the present invention, hard capsules and tablets are commercially available. Such formulations have a problem of slow absorption in the body and lower bioavailability when taken compared to soft capsules. Also taking is inconvenient.

However, in the case of soft capsules, it is effective to enhance the absorption of the antifungal agent in the body, thereby improving the bioavailability of the drug.

In the present invention, a soft capsule comprising a triazole derivative, which is poorly soluble in water as an active ingredient, itraconazole as an active ingredient, and a method for preparing the same, are used to maximize the advantages of the soft capsule. The excipient base is polyethylene glycol 400, 600, 1500, 4000 as hydrophilic base, labrasol as surfactant, RH40 (cured castor oil polyoxyl 40) as surfactant, prurol oleic WL 1173 as cosurfactant, polyvinyl as dispersant The drug was solubilized using a mixture of pyrrolidone, and soft capsules were prepared after film formation.

In addition, as an antifungal agent, in addition to itraconazole as an antifungal agent, glycoflavin, ketoconazole, terbininapine, naphthypine components, and the like are included as soft capsules, and as a hydrophilic base, polyethylene glycol 400, 600, 1500, 4000, and surfactants. The drug was emulsified by mixing Brasol, Cremopher RH40 (cured castor oil polyoxyl 40), prurol oleic WL 1173 as a cosurfactant, and polyvinylpyrrolidone as a dispersant, and a soft capsule was prepared after film formation. . On the other hand, even if the water instability occurs during the preservation distribution, the absorption rate of the drug effect does not decrease, maintaining the uniformity of the content, and has been developed a formulation that can prevent the degradation of the content during the long term storage period.

Therefore, the present invention is 10 to 50% by weight based on the total weight of the contents of at least one antifungal agent selected from itraconazole, glyceroflavin, ketoconazole, teribinapine, naphthypine, 0.1 to 10% by weight of polyethylene glycol as a hydrophilic base, surfactant 30 to 60% by weight of at least one selected from Labrasol and Cremofur RH40 (cured castor oil polyoxyl 40), 3 to 20% by weight of prurol oleic WL 1173 as cosurfactant, and 0.1 to polyvinylpyrrolidone It is to provide a soft capsule containing an antifungal agent prepared by preparing a contents solution consisting of 1% by weight and then peeling off the coating.

In addition, the antifungal agent used itraconazole, polyethylene glycol 400, 600, 1500, 4000, etc. as a hydrophilic base material, and LaBollasol and cremoper RH40 (cured castor oil polyoxyl 40 having an HLB value of 13 to 15 as a surfactant). At least one selected from), characterized in that the use of a co-surfactant is mixed with a polyvinylpyrrolidone as a dissolving agent, Prurol Olake WL 1173 having a HLB value of 9-11, polyethylene glycol 400 10-30 weight %, Polyethylene glycol 600 0 to 10% by weight, polyethylene glycol 1500 0 to 10% by weight, polyethylene glycol 4000 0 to 5% by weight are used in a suitable ratio.

On the other hand, in the preparation of the soft capsule of the present invention, polyethylene glycol 1500, 4000 as a hydrophilic base in the preparation container, labrasol as a surfactant, Labrasol having an HLB value of 13 to 15, cremophor RH40 (cured castor oil polyoxyl 40) After the addition of Prurol Olake WL 1173 having a HLB value of 9-11 as a cosurfactant, the temperature of the vessel was warmed to about 60 ° C. to dissolve and homogenize the components, and then the temperature of the mixed solution was 40-50. It is characterized by cooling to about ℃ to disperse the antifungal agent such as itraconazole as an antifungal agent and to disperse by mixing and dispersing the polyvinylpyrrolidone as a dispersant.

Hereinafter will be described in more detail of the present invention.

Looking at the components of the present invention, as an antifungal agent, itraconazole, glyceroflavin, ketoconazole, teribinapine, naphtipine components are all applicable, but in the present invention, one of the selected itraconazole was prescribed by soft capsule.

As the base material of drug substance, Labrasol (chemical name: PEG-8 glyceryl caprylate / caprate HLB 14) with polyethylene glycol 400, 600, 1500, 4000 as a hydrophilic base material and HLB value 13-15 as a surfactant, cremopher RH40 (curing Castor oil polyoxyl 40, Chemical name: PEG-40 Hydrogenated castor oil), Prurol oleic WL 1173 (chemical name: polyglyceryl-6 dioleate) with HLB value of 9-11 as cosurfactant, Polyvinylpyrrolidone as dispersant Used.

As an antifungal agent, it is characterized by using components such as itraconazole, glyceroflavin, ketoconazole, terbininapine, and naphtipin as antifungal agents.

In the composition ratio of the present invention, at least one antifungal component is used, and the component ratio is preferably 10 to 50% by weight based on the total weight of the internal drug. If the above components are less than 10% of the weight of the contents, the size of the capsule may become large, there may be a discomfort in taking the drug, and the value of the product may be reduced, and if it is more than 50% by weight, the antifungal component of itraconazole as an excipient Not only is it difficult to emulsify, but there is a problem in that the emulsified state is dispersed.

Characteristic of the present invention is a hydrophilic substrate, polyethylene glycol 400, 600, 1500, 4000, HLB value 13-15 as a surfactant, Labrasol, Cremoper RH40 (cured castor oil polyoxyl 40), HLB as a co-surfactant When using Pyrrole Olake WL 1173 having a value of 9 to 11, the component ratio is preferably 30 to 50% by weight relative to the content weight. If the hydrophilic base used is polyethylene glycol, surfactant Labrasol, Cremoper RH40, or co-surfactant, Pyrrole Olake WL 1173 is less than 30% by weight based on the weight of the contents, there is no effect on drug release. When the content is 50 wt% or more, it is difficult to secure the content homogeneity of the drug substance, and there is a problem in that the leakage, film hardening, and deposition occur when the soft capsule is manufactured.

In the case of using the above components in the present invention, the method of preparing the drug substance using the above-mentioned components is a polyethylene glycol 400, 600, 1500, 4000 as a hydrophilic base in the preparation container, the HLB value is 13-15 Labursol, Cremopher RH40 (cured castor oil polyoxyl 40), and 30 to 50% by weight of the content of Prurol Oleic WL 1173 with an HLB value of 9 to 11 based on the weight of the container Warm to about 50 ~ 60 ℃ to dissolve and homogenize the added ingredients. Next, the temperature of the homogenized mixture is cooled to about 25 to 30 ° C., then it is dissolved and emulsified with itraconazole with an antifungal component having a content of 30 to 60 wt% based on the weight of the contents, and then the temperature of the contents is lowered to room temperature to obtain the contents.

In the present invention, the coating composition of the soft capsule is a gelatine for soft capsule and a gelatin coating solution by a known production method using a concentrated glycerin, dissorbitol solution, purified water as a plasticizer. At this time, the composition ratio of the gelatinous coating is a suitable amount of a colorant and a light-shielding agent as 40 to 60% by weight of gelatin per soft capsule, 20 to 40% by weight of concentrated glycerin, and 5 to 20% by weight of dissorbitol solution.

In the present invention, the preparation of the soft capsule is a 250 ~ 500mg of the drug in the mold of OVAL 6 TYPE in a rotary die soft capsule automatic charger with the drug and gelatin coating solution prepared by the above manufacturing method and the tray 5-7 days Drying (tray) to prepare a soft capsule.

The present invention will be described in more detail with reference to the following examples. However, these examples do not limit the scope of the present invention.

(Comparative Example 1)

1 capsule content in 300 mg weight

Itraconazole 100 mg

Fractionated palm oil (MCT) 200 mg

10 mg of lead

With the drug substance prepared as described above and the gelatine coating solution prepared according to the above-mentioned general manufacturing method, 300 mg of the drug substance was filled with OVAL 6 TYPE MOLD in a rotary die soft capsule automatic charger and dried in a tray for 5 to 7 days. Produces soft capsule products.

(Example 1)

Itraconazole 100.0 mg

Polyethylene glycol 1500 10.0 mg

Polyethylene glycol 4000 5.0 mg

Labrasol 142.5 mg

Cremopher RH40 20.5 mg

Prurol Olake WL 1173 20.5 mg

1.5 mg polyvinylpyrrolidone

Preparation of the soft capsule of Example 1 is carried out in the same manner as in Comparative Example 1 to a soft capsule.

Example 2

Itraconazole 100.0 mg

Polyethylene glycol 400 58.5 mg

Polyethylene glycol 600 10.0 mg

Polyethylene glycol 4000 10.0 mg

Labrasol 80.0 mg

Cremopher RH40 20.0 mg

Prurol Olake WL 1173 20.0 mg

1.5 mg polyvinylpyrrolidone

Preparation of the soft capsule of Example 2 is carried out in the same manner as in Comparative Example 1 to soften the capsule.

Example 3 Dissolution Comparison Test

The dissolution test was carried out in accordance with the 11th Amendment General Test Method 46 and 2 of the Pharmacopoeia, and the rotational speed was 100 rpm, the eluent was 37 ℃, 900ml, pH 1.2, 4.0, 6.5. In the first method, pH 4.0 was tested with 0.1 M acetic acid buffer and pH 6.5 was 0.05 M phosphate buffer. The dissolution test of the antifungal component was carried out at 75% acceleration condition and the results are shown in Table 1.

From the experimental results, the dispersibility of Comparative Example 1 and Example 1 at room temperature and 40 ° C RH 75% acceleration condition showed the same dispersibility as the initial stage.

Results of Dissolution Comparison Test of Antifungal Agents (pH 1.2) Commercial tablets Comparative Example 1 Example 1 Room temperature Room temperature 40 ℃ RH75% Room temperature 40 ℃ RH75% Date of Manufacture Early 10 days 30 days 60 days Early 30 days 10 days 30 days 60 days 5 minutes 80% 50% 50% 51% 48% 65% 63% 60% 62% 60% 10 minutes 85% 90% 89% 88% 85% 92% 93% 90% 90% 90% 15 minutes 85% 85% 82% 83% 80% 98% 98% 96% 95% 95% 20 minutes 92% 95% 96% 95% 92% 101% 100% 101% 98% 98%

Results of Dissolution Comparison Test of Antifungal Agents (pH 4.0) Commercial tablets Comparative Example 1 Example 1 Room temperature Room temperature 40 ℃ RH75% Room temperature 40 ℃ RH75% Date of Manufacture Early 10 days 30 days 60 days Early 30 days 10 days 30 days 60 days 5 minutes 80% 45% 42% 45% 40% 55% 55% 53% 52% 55% 10 minutes 85% 85% 87% 85% 84% 90% 91% 90% 89% 90% 15 minutes 88% 90% 92% 89% 88% 100% 100% 100% 99% 100% 20 minutes 100% 98% 98% 95% 95% 101% 100% 101% 100% 100%

Results of Dissolution Comparison Test of Antifungal Agents (pH 6.8) Commercial tablets Comparative Example 1 Example 1 Room temperature Room temperature 40 ℃ RH75% Room temperature 40 ℃ RH75% Date of Manufacture Early 10 days 30 days 60 days Early 30 days 10 days 30 days 60 days 5 minutes 80% 85% 83% 85% 84% 85% 83% 80% 82% 85% 10 minutes 85% 90% 92% 90% 89% 95% 94% 95% 96% 95% 15 minutes 85% 92% 93% 90% 91% 98% 98% 96% 95% 95% 20 minutes 92% 92% 95% 92% 95% 101% 100% 101% 99% 98%

As described above, the soft capsules prepared by Examples 1 and 2 of the present invention did not change over time in room temperature and accelerated conditions at 40 ° C. RH 75% to maintain stability of the drug substance, thus completing the present invention.

Example 4 Content Analysis Result Test

The soft capsule and the prototype of the present invention were tested as follows, and the test results are shown in Table 4.

(Preparation of Inspection)

Take 20 capsules of Aliquot and accurately weigh the contents. Take 50mg of itraconazole and place it in a 100ml volumetric flask.

Approx. 50 ml of chloroform: methanol (1: 1) mixture is added, warmed for about 5 minutes in a water bath, cooled, and charged to the same volume with the same solvent. When filtering, first 10 ml of the filtrate is taken, then 1 ml of the filtrate is placed in a 50 ml volumetric flask and filled up to the volume with methanol.

(Standard solution)

Accurately weigh about 50 mg of itraconazole standard solution into a 100 ml volumetric flask, dissolve in a mixture of chloroform and methanol (1: 1) and fill up to the volume.

Take 1 ml of this solution into a 50 ml volumetric flask and fill it with methanol.

(manual)

Measure the absorbance AT and AS at 262 nm for the sample and standard solutions.

For the control solution, a mixture of 1 ml of chloroform: methanol (1: 1) mixture and 49 ml of methanol is used.

AT 230 WS

Itraconazole Content (%) = --- × ---- × ---- × 100

AS WT 50

AT: absorbance of standard solution, AS: absorbance of sample solution,

WT: Sample collection amount (mg), WS: Standard sample collection (mg)

Ingredients and Results Content analysis result Comparative Example 1 Example 1 Example 2 Itraconazole 90.6% 99.8% 99.4%

As shown in Table 4 above, the content of the present invention is a reference value.

It can be seen that it is suitable for 95.0 to 105.0%.

The effect of the present invention is a soft capsule containing an antifungal component, tablets containing itraconazole and hard capsules are commercially available, and a pharmacological synergistic effect can be expected compared to such formulations. It is to provide a soft capsule formulation that can have excellent stability at room temperature.

Claims (3)

Itraconazole is 10 to 50% by weight based on the total weight of the contents, 0.1 to 10% by weight of polyethylene glycol as a hydrophilic base, caprylocaproyl macrogel-8 glyceride (labrasol) as a surfactant, hardened castor oil polyoxyl 40 ( 30 to 60% by weight of one or more surfactants selected from Cremofur RH 40), 3 to 20% by weight of polyglyceryl-6 dioleate (Prurol oleic WL 1173) as cosurfactant, and 0.1% of polyvinylpyrrolidone Soft capsule containing itraconazole prepared by preparing a solution consisting of ˜1% by weight and then coating a gelatin coating A caprylocaproyl macrogel-8 glyceride (labrasol) having a HLB value of 13 to 15 as a surfactant is used as a hydrophilic base material, and a cured castor according to claim 1 At least one selected from free polyoxyl 40 (Cremopher RH 40), polyglyceryl-6 dioleate (prurol oleic WL 1173) having a HLB value of 9-11 as cosurfactant, polyvinylpyrrolidone as a dispersant Soft capsules, characterized by mixing Polyethylene glycol as a hydrophilic base material as an excipient base in the preparation container, caprylocaproyl macrogel-8 glyceride (Labrasol) as a surfactant, polyglycerol oil polyoxyl 40 (Cremopher RH 40) as a surfactant, polyglyceride as a cosurfactant After the polyvinylpyrrolidone was mixed with the reel-6 dioleate (Prurol oleic WL 1173) and a dispersant, the temperature of the input container was heated to about 60 ° C. to dissolve and homogenize the input component, and then the temperature was decreased. Method of producing a soft capsule, characterized in that after cooling to about 30 ~ 40 ℃ to emulsify gelatin coating by adding emulsified 30 ~ 50% by weight of itraconazole to the total weight of the contents