KR102199667B1 - Pharmaceutical composition comprising dutasteride - Google Patents

Abstract

The present invention relates to: a pharmaceutical composition including dutasteride. Particularly, the present invention relates to a pharmaceutical composition including dutasteride, glycerol monocaprylocaprate and propylene glycol monocaprylate, wherein a weight ratio of glycerol monocaprylocaprate to propylene glycol monocaprylate is 9 : 1 to 6 : 4; to a capsule formulation including the composition; and to a formulation method of the composition into the capsule formulation. The pharmaceutical composition can stably include dutasteride at a high concentration without using a separate surfactant, and can be produced with ease at low costs. The formulation including the pharmaceutical composition can be formed to have a small size while containing a high concentration of dutasteride, or can be formed to include a large amount of dutasteride in one formulation, and thus can provide improved administration compliance. In addition, such an excellent dutasteride formulation can be obtained through a simple process by the formulation method according to the present invention.

Description

Pharmaceutical composition comprising dutasteride {Pharmaceutical composition comprising dutasteride}

The present invention relates to a pharmaceutical composition comprising dutasteride, specifically comprising dutasteride, glycerol monocaprylocaprate and propylene glycol monocaprylate, glycerol monocaprylocaprate and propylene glycol monocar It relates to a pharmaceutical composition having a weight ratio of prylate of 9:1 to 6:4, a capsule formulation comprising the composition, and a method of formulating the capsule formulation.

Dutasteride is a drug that suppresses androgens, a male hormone, and is used to treat benign prostatic hyperplasia and android type alopecia. It is widely used on the market under the brand name AVODART. This is a 9 oblong soft capsule formulation with a long axis of about 19.1 mm, a short axis of about 6.7 mm, and a weight of about 380 mg. Since Dutasteride is poorly soluble, a large amount of oil is used to dissolve it, so the size of the formulation is large, and accordingly, there is a problem that the medication compliance is low.

In this regard, Korean Patent No. 10-1679380 discloses that the capsule contents contain 84.0% by weight or more of propylene glycol monolaurate and a surfactant having an HLB value of 10 or more to increase the solubility of Dootasteride. It proposes a method to improve medication compliance by reducing the size. However, when using a surfactant having a high HLB value, there is a possibility that over time, disintegration delay due to crosslinking and a decrease in dissolution rate may occur due to reaction with gelatin, which is a capsule base. In addition, the propylene glycol monolaurate contained in 84.0% by weight or more in the above method is a relatively expensive oil, so there is a problem that the unit cost of the product is increased.

In addition, Korean Patent Registration No. 10-1833280 contains a surfactant in the contents to solubilize dutasteride, and a method of improving stability by using Succinylated Gelatin and crosslinking inhibitors (glycine and citric acid) as a capsule film. Are presented. However, there is an inconvenience in the process of including various surfactants and water to solubilize dutasteride and adding a crosslinking inhibitor to the capsule film.

Therefore, in order to overcome the problems of the prior art as described above, the present inventors can improve the solubility of dutasteride without including a surfactant, particularly a surfactant having a high HLB value, and use a material with a relatively low unit cost. We tried to develop a technology that can lower the unit price of the product and increase the ease of the process.

Korean Patent Registration No. 10-1679380 Korean Patent Registration No. 10-1833280

Therefore, the main object of the present invention is to provide a pharmaceutical composition that does not contain a surfactant, particularly a surfactant having a high HLB value, but can stably contain dutasteride at a high concentration and can be easily prepared at a low cost. have.

Another object of the present invention is to provide a capsule formulation capable of improving medication compliance using the composition.

Another object of the present invention is to provide a formulation method that can be easily carried out through a simple process as a method capable of preparing the capsule formulation as described above.

According to one aspect of the present invention, the present invention comprises dutasteride, glycerol monocaprylocaprate and propylene glycol monocaprylate, wherein the weight ratio of glycerol monocaprylocaprate and propylene glycol monocaprylate is 9: It provides a pharmaceutical composition of 1 to 6: 4.

In the composition of the present invention, it is preferable to contain 0.1 to 1% by weight of dutasteride.

In the composition of the present invention, it is preferable not to contain a surfactant having an HLB value of 6 or more.

In the composition of the present invention, it is preferable to further include an antioxidant.

According to another aspect of the present invention, the present invention provides a capsule formulation comprising the pharmaceutical composition.

In the formulation of the present invention, it is preferable that the coating is made of a coating containing gelatin succinate.

According to another aspect of the present invention, the present invention includes dutasteride, glycerol monocaprylocaprate, and propylene glycol monocaprylate, but the weight ratio of glycerol monocaprylocaprate and propylene glycol monocaprylate is 9 : 1 to 6: 4 to prepare the capsule contents; And encapsulating the capsule contents with a succinic acid gelatin-containing film.

In the method of the present invention, it is preferable to prepare the capsule contents by including 0.1 to 1% by weight of dutasteride.

In the method of the present invention, it is preferable to prepare the capsule contents without including a surfactant having an HLB value of 6 or more.

In the method of the present invention, it is preferable to further include an antioxidant to prepare the capsule contents.

The pharmaceutical composition of the present invention can stably contain dutasteride at a high concentration without containing a separate surfactant, and can be easily prepared at a low cost. The formulation of the present invention contains such a pharmaceutical composition and contains dutasteride at a high concentration, but can be made in a small size, or can be made to contain a large amount of dutasteride in one formulation, thereby improving medication compliance. . In addition, if the formulation method of the present invention is used, it is possible to prepare an excellent dutasteride formulation as described above through a simple process.

1 is a chemical structure of dutasteride.
Figure 2 shows the solubility of dutasteride according to the composition ratio of glycerol monocaprylocaprate (Capmul MCM) and propylene glycol monocaprylate (Capryol 90).
Figure 3 shows a comparison of the dissolution patterns of the capsule and the Avodart capsule according to an embodiment of the present invention.

The composition of the present invention includes dutasteride, glycerol monocaprylocaprate and propylene glycol monocaprylate, and the weight ratio of glycerol monocaprylocaprate and propylene glycol monocaprylate is 9: 1 to 6: 4 It features.

In the present invention, dutasteride is a compound having the chemical structure of FIG. 1.

In the present invention, glycerol monocaprylocaprate is preferably glycerol monocaprylocaprate of type 1 according to the European Pharmacopeia (EP) standard, and more preferably Capmul MCM (Capmul MCM).

In the present invention, propylene glycol monocaprylate is preferably type 2 propylene glycol monocaprylate according to the United States Pharmacopeia (USP) standard, and more preferably Capryol 90 to be.

The composition of the present invention preferably contains 0.1 to 1% by weight of dutasteride.

The composition of the present invention preferably comprises 50 to 99.9% by weight of glycerol monocaprylocaprate and propylene glycol monocaprylate in total, more preferably 60 to 99.9%, more preferably 70 to 99.9%, More preferably, it is included in 80 to 99.9%.

In the composition of the present invention, the weight ratio of glycerol monocaprylocaprate and propylene glycol monocaprylate is preferably 8:2 to 7:3.

The composition of the present invention may consist of only the above ingredients, that is, dutasteride, glycerol monocaprylocaprate, and propylene glycol monocaprylate, and may further include other ingredients in addition to these ingredients. These additional ingredients may include drugs other than dutasteride, auxiliary ingredients for stabilization or delivery of drugs, and other pharmaceutically acceptable additives. Preferably, it further contains an antioxidant. At this time, as an antioxidant, for example, butylhydroxytoluene may be used.

The composition of the present invention may further contain additional oils or surfactants in addition to the glycerol monocaprylocaprate and propylene glycol monocaprylate. However, preferably, a surfactant having an HLB value of 6 or higher is not included, and preferably, propylene glycol monolaurate is not included. More preferably, it does not contain additional oils or surfactants other than the glycerol monocaprylocaprate and propylene glycol monocaprylate.

The composition of the present invention may be a composition for various uses requiring the medicinal effect of dutasteride. Dutasteride can inhibit androgens, a male hormone, and thus can be used for the prevention, treatment or improvement of android type alopecia or benign prostatic hyperplasia. Accordingly, the composition of the present invention may be a composition for use as described above, that is, for the prevention, treatment or improvement of android type alopecia or benign prostatic hyperplasia. In addition, it may be a composition for other uses in which the drug effect of dutasteride is required.

The composition of the present invention may be a composition for dutasteride capsule formulation. It is preferably a composition for soft capsule formulation.

The capsule formulation of the present invention is characterized in that it comprises the composition.

The capsule formulation of the present invention is preferably a soft capsule formulation, more preferably a soft capsule formulation comprising a film containing succinate gelatin.

The capsule formulation of the present invention can be used for various purposes requiring the medicinal effect of dutasteride. For example, it can be used for the above-mentioned uses, that is, for the prevention, treatment or amelioration of androgenetic alopecia or benign prostatic hyperplasia, or for other uses in which the efficacy of dutasteride is required.

The amount of the composition contained in the capsule formulation of the present invention is not particularly limited, and may be appropriately set according to the use of the capsule formulation. For example, the capsule formulation of the present invention may contain 50 to 200 mg of the composition of the present invention per capsule, but is not limited thereto.

The composition and capsule formulation of the present invention may be administered to a subject in an appropriate amount according to each use as described above based on the content of dutasteride contained. The dosage of dutasteride related to this is well known in this field, and will be administered to a subject in a wide range depending on the subject's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease. I will be able to.

The formulation method of the present invention is a method that can be formulated into a capsule formulation as described above, and includes dutasteride, glycerol monocaprylocaprate and propylene glycol monocaprylate, but glycerol monocaprylocaprate and propylene glycol Preparing capsule contents by setting the weight ratio of monocaprylate to 9: 1 to 6: 4; And encapsulating the capsule contents with a succinate gelatin-containing film.

In the formulation method of the present invention, preferably, the capsule contents are prepared by including 0.1 to 1% by weight of dutasteride.

In the formulation method of the present invention, preferably, glycerol monocaprylocaprate and propylene glycol monocaprylate are added in an amount of 50 to 99.9% by weight to prepare the capsule contents, more preferably 60 to 99.9%, more Preferably 70 to 99.9%, more preferably 80 to 99.9% to prepare the capsule contents.

In the formulation method of the present invention, preferably, the weight ratio of glycerol monocaprylocaprate and propylene glycol monocaprylate is 8:2 to 7:3.

In the formulation method of the present invention, the capsule contents may be prepared by including only dutasteride, glycerol monocaprylocaprate, and propylene glycol monocaprylate, and other ingredients in addition to these ingredients may be further included to prepare the capsule contents. May be. These additional ingredients may include drugs other than dutasteride, auxiliary ingredients for stabilization or delivery of drugs, and other pharmaceutically acceptable additives. Preferably, an antioxidant is further included. At this time, as an antioxidant, for example, butylhydroxytoluene may be used.

In addition, in the formulation method of the present invention, in addition to the glycerol monocaprylocaprate and propylene glycol monocaprylate, additional oils or surfactants may be further included to prepare the capsule contents. However, preferably, a surfactant having an HLB value of 6 or more is not included in the capsule contents, and preferably propylene glycol monolaurate is not included. More preferably, the capsule contents do not contain additional oils or surfactants other than the glycerol monocaprylocaprate and propylene glycol monocaprylate.

The technology of Korean Patent No. 10-1679380, developed to improve the dosage compliance of Dootasteride, that is, Avodart, contains more than 84% by weight of propylene glycol monolaurate in the composition (capsule contents), and the unit cost of this oil Since it is about twice as high as glycerol monocaprylocaprate used in Avodart, there is a problem that the unit price of the formulation is increased. Capmul MCM, glycerol monocaprylocaprate, is traded at about 52,000 won per kg, while Lauroglycol FCC, a type 1 propylene glycol monolaurate, is about 124,000 won per kg and the second Type propylene glycol monolaurate, Lauroglycol 90, is traded for about 115,000 won per kg. The unit cost of the propylene glycol monocaprylate used in the present invention is also similar to the propylene glycol monolaurate. Type 1 propylene glycol monocaprylate, Capryol PGMC, is traded at about 120,000 won per kg, and Type 2 propylene glycol monocaprylate, Capryol 90, is traded at about 147,000 won per kg. However, in the present invention, since this oil is used less and glycerol monocaprylocaprate, which has a low unit price, is used, there is an advantage that the unit price can be lowered while improving medication compliance.

Hereinafter, the present invention will be described in more detail through examples. Since these examples are for illustrative purposes only, the scope of the present invention is not to be construed as being limited by these examples.

[Example]

1. Investigation of the solubility of dutasteride according to the oil composition ratio

'Capmul MCM' was used as glycerol monocaprylocaprate, and'Capryol 90' was used as propylene glycol monocaprylate.

The raw materials in the amount specified in Table 1 below were put in a 50 ml beaker and stirred for about 1 hour at room temperature (about 25° C.) using a magnetic bar. After allowing to stand at room temperature for 24 hours, about 1 ml was taken and centrifuged at about 11,000 rpm, the supernatant was taken, filtered, and then dutasteride was quantified using liquid chromatography.

Dootasteride Capmul MCM Capryol 90 Experimental group 1 0.3 20 0 Experimental group 2 0.3 18 2 Experiment group 3 0.3 16 4 Experiment group 4 0.3 14 6 Experimental group 5 0.3 12 8 Experimental group 6 0.3 10 10 Experimental group 7 0.3 8 12 Experimental group 8 0.3 6 14 Experimental group 9 0.3 4 16 Experimental group 10 0.3 2 18 Experimental group 11 0.3 0 20

* Unit: g

As a result, as shown in Table 2 and FIG. 2, the solubility of propylene glycol monocaprylate was found to be about 5 times higher than that of glycerol monocaprylocaprate. In addition, when the weight ratio of glycerol monocaprylocaprate and propylene glycol monocaprylate in the experimental group in which the two oils were mixed was 9: 1 to 6: 4, dutasteride solubility was remarkably excellent, and the weight ratio was 7 : It was found to be the most excellent in case of 3.

Oil composition ratio (%) Solubility (mg/g) Capmul MCM Capryol 90 Experimental group 1 100 0 2.13 Experimental group 2 90 10 9.40 Experiment group 3 80 20 10.37 Experiment group 4 70 30 10.59 Experimental group 5 60 40 9.27 Experimental group 6 50 50 2.79 Experimental group 7 40 60 2.06 Experimental group 8 30 70 1.83 Experimental group 9 20 80 2.23 Experimental group 10 10 90 3.72 Experimental group 11 0 100 9.88

2. Capsule formulation manufacturing

In a 500 ml beaker, the amount of raw materials specified in Table 3 was added, and dutasteride was completely dissolved while stirring using a mechanical stirrer.

Ingredient name Composition 1 Composition 2 Composition 3 Dootasteride 0.5 0.5 0.5 Glycerol monocaprylocaprate 71.465 83.465 95.465 Propylene glycol monocaprylate 48 36 24 Butylhydroxytoluene 0.035 0.035 0.035

* Unit: g

Separately, to prepare a soft capsule film, a film was prepared using gelatin succinate and a plasticizer in the composition shown in Table 4 below, and then a soft capsule was manufactured using a rotary automatic filling molding machine.

Ingredient name Weight(g) Succinate Gelatin 469 glycerin 216 Purified water 315 system 1000

The weight and size of the finally produced soft capsule are shown in Table 5.

Content (mg/capsule) Composition 1 Composition 2 Composition 3 Dootasteride 0.5 mg 0.5 mg 0.5 mg Glycerol monocaprylocaprate 71.465 mg 83.465 mg 95.465 mg Propylene glycol monocaprylate 48 mg 36 mg 24 mg Butylhydroxytoluene 0.035 mg 0.035 mg 0.035 mg Content weight 120 mg 1 capsule total weight 230 mg Capsule size 2 Oval Long axis (mm) 10.1 mm Short axis(mm) 6.1 mm

3. Stability test

The composition shown in Table 6 was used to evaluate the stability of Dootathreid according to the composition.

Ingredient name Experimental group 12 Experimental group 13 Experimental group 14 Dootasteride 0.5 g 0.5 g 0.5 g Glycerol monocaprylocaprate 111.5 g 75.5 g - Propylene glycol monocaprylate - 36 g 111.5 g 30% hydrogen peroxide (H ₂ O ₂ ) 8 g 8 g 8 g

In order to confirm the stability of dutasteride in the mixture of glycerol monocaprylocaprate, the oil used in Avodart products, and propylene glycol monocaprylate, the oil used in the present invention, severe conditions (60℃, 2% H) ₂ O ₂ containing) stability was compared.

5 ml of each of the experimental group solutions in Table 6 were put in a 10 ml transparent vial, sealed, and stored in a 60°C chamber, and the amount of related substances was investigated using liquid chromatography. The amount of related substances compared to dutasteride was calculated as a percentage and shown in Table 7 below.

As shown in Table 7, compared to the case where glycerol monocaprylocaprate, an oil used in Avodart products, was used alone (Experimental Group 12), when propylene glycol monocaprylate was used alone (Experimental group 14) and when used in combination ( Experimental group 13) showed relatively excellent stability of dutasteride under severe conditions.

Ingredient name Experimental group 12 Experimental group 13 Experimental group 14 Early none none none 3 days 0.13% none none 1 week 0.26% none none 2 weeks 1.34% 0.58% 0.19%

4. Dissolution experiment

A comparative dissolution test was conducted on the soft capsule formulation prepared with Composition 2 in Example 2 and the commercially available AVODART 0.5 mg soft capsule (containing Dutasteride 0.5 mg per capsule) under the following test conditions (n = 6) did it.

<Dissolution test conditions>

Test method: Korean Pharmacopoeia dissolution test method 2 (paddle method)

Test solution: 900 ml of 0.1N hydrochloric acid solution containing 2% sodium lauryl sulfate

Rotation speed: 50rpm

As a result, as shown in Tables 8 and 9 and FIG. 3 below, the capsule formulation of the present invention exhibited a dissolution pattern similar to that of the existing Avodart capsules.

Dissolution test result of Avodart capsule 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Test 1 2.1 32.5 70.9 97.2 97.4 Test 2 25.4 48.3 73.3 79.8 101.8 Test 3 2.1 34.2 50.3 90.4 92.6 Test 4 2.1 44.5 87.5 88.2 92.4 Test 5 2.1 47.6 83.4 94.3 95.2 Test 6 2.4 45.3 79.0 95.4 96.3 Average 6.0 42.1 74.1 90.9 96.0 Standard Deviation 9.5 6.9 13.2 6.4 3.5

* unit: %

Dissolution test result of the capsule of the present invention 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Test 1 0.5 38.4 78.4 93.8 94.9 Test 2 1.2 25.3 74.3 95.4 95.9 Test 3 1.1 31.2 77.0 91.8 94.3 Test 4 0.8 26.6 78.2 92.9 96.3 Test 5 1.3 34.2 87.7 93.6 93.9 Test 6 0.4 36.8 68.1 93.4 94.7 Average 0.9 32.1 77.3 93.5 95.0 Standard Deviation 0.4 5.4 6.4 1.2 0.9

* unit: %

Claims (10)

A pharmaceutical composition comprising dutasteride, glycerol monocaprylocaprate and propylene glycol monocaprylate, wherein the weight ratio of glycerol monocaprylocaprate and propylene glycol monocaprylate is 9: 1 to 6: 4. The method of claim 1,
A composition comprising 0.1 to 1% by weight of dutasteride. delete The method of claim 1,
The composition further comprising an antioxidant. A capsule formulation comprising the composition of any one of claims 1, 2 and 4. The method of claim 5,
A formulation in which the coating is made of a coating containing succinate gelatin. Dootasteride, glycerol monocaprylocaprate and propylene glycol monocaprylate are included, but the weight ratio of glycerol monocaprylocaprate and propylene glycol monocaprylate is 9: 1 to 6: 4 to prepare a capsule contents The step of doing; And
Encapsulating the capsule contents with a succinic acid gelatin-containing film. The method of claim 7,
A method for preparing the capsule contents by including 0.1 to 1% by weight of dutasteride. delete The method of claim 7,
A method for preparing the capsule contents by further including an antioxidant.

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