WO2024144084A1 - High-dose dutasteride pharmaceutical composition in tablet form for once-weekly administration and preparation method therefor - Google Patents

Abstract

Disclosed in the present invention are: a pharmaceutical composition of dutasteride, being capable of being administered orally once a week, and increasing the convenience of administration by reducing the number of administrations; and a preparation method for the pharmaceutical composition.

Description

High-dose dutasteride pharmaceutical composition in tablet form for once-weekly administration and method for manufacturing the same

The present invention relates to a pharmaceutical composition of high-dose dutasteride for administration once a week (QW) and a method for preparing the same. Specifically, the present invention relates to a pharmaceutical composition of dutasteride for hair loss treatment by reducing the frequency of administration to once a week. It is a pharmaceutical composition of high content dutasteride that increases the convenience of administration, and relates to dutasteride solubilized in a self-emulsifying composition, a pharmaceutical composition containing the same, and a method for manufacturing the same.

Dutasteride is a compound disclosed in U.S. Patent Publication No. 5,565,467 (17β-N-[2,5-bis(trifluoromethyl)]phenylcarbamoyl-4-aza-5α-androst-1-en-3 -on), which has a mechanism to inhibit both 5-alpha reductase Type-I and Type-II, which convert the male hormone testosterone into dihydrotestosterone, and is used to treat benign prostatic hyperplasia, prostate cancer, and androgentetic alopecia. ) is used in the treatment of.

Looking at the pharmacokinetic/pharmacological properties of dutasteride, when administered orally at a dose of 0.5 mg, it reduces dihydrotestosterone by about 80% after 7 days and shows maximum effect within 1-2 weeks. And the terminal half-life of dutasteride is about 5 weeks, so when administered orally repeatedly, the drug accumulates in the body and can lead to a continuous decrease in dihydrotestosterone. The current dosage of dutasteride for indications is 0.5 mg once a day, but no research has been conducted on high-dose preparations with reduced administration frequency considering the pharmacokinetic/pharmacological characteristics of dutasteride.

Currently, Avodart ⁽ Glaxosmithkline) is the original product of dutasteride, and contains 0.5 mg of dutasteride as the active ingredient, and contains 349.5 mg of caprylic/capric acid monomer to solubilize dutasteride, which has poorly soluble properties. - And it is commercially available by dissolving it in di-glyceride oil and 0.035 mg butylated hydroxytoluene and filling it in a soft capsule made of gelatin (Avodart ^® , FDA drug approval package).

However, soft capsules have problems such as adsorption and infiltration of the drug into the gelatin film, discoloration, hardening, dissolution or softening of the gelatin film during manufacturing, and the drug may deteriorate at high temperatures or be easily affected by humidity. have Because separate manufacturing equipment is required, facility investment must be made, and soft capsules may be damaged during manufacturing, storage, and movement. In addition, in order to solubilize a high dose of a poorly soluble drug, the amount of solubilizing agent is increased and the dosage form becomes very large, which has the disadvantage of reducing the patient's convenience in taking it. Therefore, there is a need for research and development on formulations, especially tablets, that can overcome the shortcomings of Avodart, a soft capsule formulation.

[Prior art literature]

[Patent Document]

(Patent Document 1) U.S. Patent No. 5,565,467

(Patent Document 2) U.S. Patent Publication No. 2009/0069364

(Patent Document 3) Korean Patent No. 10-0962447

(Patent Document 4) Korean Patent No. 10-1055412

The purpose of the present invention is to provide a pharmaceutical composition of high-dose dutasteride that reduces the number of administrations of dutasteride medicine, which is administered once a day, to once a week, and a method for manufacturing the same.

Specifically, the present invention is a high-dose Dutasteride drug that can solubilize high-dose dutasteride, a poorly soluble drug, through self-emulsifying emulsion technology and formulate it in a tablet form that can overcome the disadvantages of the soft capsule formulation. The object is to provide a pharmaceutical composition of lead and a method for producing the same.

In order to solve the above problems, the present invention discloses the following means.

In one aspect, the present invention provides a pharmaceutical composition in the form of a tablet containing dutasteride as an active ingredient, for oral administration once a week.

In another aspect, the present invention includes the steps of (S1) preparing a self-emulsifying composition by mixing dutasteride, oil, surfactant and co-surfactant; (S2) dissolving the self-emulsifying composition in an organic solvent; (S3) mixing a solution in which the self-emulsifying composition is dissolved in an organic solvent with an adsorbent to prepare an adsorbent to which the self-emulsifying composition is adsorbed; and (S4) mixing one or more pharmaceutical additives selected from the group consisting of an adsorbent to which the self-emulsifying composition is adsorbed, an excipient, a disintegrant, and a lubricant, and then compressing the tablet. .

The present invention has the advantage of increasing the convenience of taking medication by reducing the number of doses of dutasteride medicine that must be administered every day.

Specifically, the present invention can solubilize a high dose of dutasteride, a poorly soluble drug, through self-emulsifying emulsion technology and provide it in tablet form.

The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within the scope apparent to those skilled in the art from the contents described below.

Figure 1 shows 0.5 mg of Avodart ^® , an existing commercially available preparation, using 900 mL of 0.1 N HCl eluate containing 2.0% sodium dodecyl sulfate (SLS) as an eluent according to the FDA dissolution methods database. (1 capsule), Avodart ^® 1.5 mg (3 capsules), and the tablet of Example 14 were incubated at a rotation speed of 50 rpm for 60 minutes ( The results of comparative dissolution experiments (5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes) are shown.

Figure 2 shows the existing commercially available preparations, Avodart soft capsule (Avodart ^® ) 0.5 mg (1 capsule) and Avodart soft capsule (Avodart ^® ) 3.0 mg (6), to compare the pharmacodynamic dynamics and predict the effect on the expression of drug effects in the human body. capsule), and 1.5 mg (2 tablets) of the tablets of Example 14, showing the results of confirming the pharmacokinetic properties for up to 168 hours after single administration in beagle dogs.

Figure 3 shows the existing commercially available preparations, Avodart soft capsule (Avodart ^® ) 0.5 mg (1 capsule) administered once a day, and Avodart soft capsule (Avodart ^® ) 3.0 mg (6 capsules) based on the results of single-dose beagle pharmacokinetics. This shows the results of a repeated administration simulation for 672 hours (4 weeks) of administration once a week and administration of the 1.5 mg tablet (2 tablets) of Example 14 once a week.

Hereinafter, this specification will be described in more detail.

This is explained in detail as follows. The terms used in this specification are general terms that are currently widely used as much as possible while considering the function in the present invention, but this may vary depending on the intention or precedent of a person working in the art, the emergence of new technology, etc. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, rather than simply the name of the term.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the technical field to which the present invention pertains.

Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless clearly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.

The numerical range includes the values defined in the range above. Every maximum numerical limit given throughout this specification includes all lower numerical limits as if the lower numerical limit were explicitly written out. Every minimum numerical limit given throughout this specification includes every higher numerical limit as if such higher numerical limit was clearly written. All numerical limits given throughout this specification will include all better numerical ranges within the broader numerical range, as if the narrower numerical limits were clearly written.

Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered limited by the specific description set forth below.

Expressions such as “comprising” used in this specification should be understood as open-ended terms that imply the possibility of including other embodiments.

The inventors of the present invention identified the problem that Avodart ^® , an existing hair loss treatment agent, must be prescribed at 0.5 mg/day (QD) for more than 3 months, and must be administered continuously every day thereafter. Accordingly, while conducting research and development to develop a high-dose Dutasteride drug that could reduce the number of doses of Dutasteride administered once a day to once a week, Dutasteride, a poorly soluble drug, was found to be poorly soluble. It was recognized that it would be difficult to develop a soft capsule because the amount of solubilizing agent would increase and the dosage form would become very large. Accordingly, during research and development for the development of other dosage forms, dutasteride, a poorly soluble drug, was developed through self-emulsifying emulsion technology. When a high dose of dutasteride is solubilized and formulated into a tablet form that can overcome the shortcomings of the soft capsule form, it is improved over Avodart soft capsule (Avodart ^® ) even if administered once a day to once a week. The present invention was completed by confirming that the dissolution rate was high, that there was no significant difference in pharmacokinetic evaluation, and that the blood concentration of Avodart ^® was similar to that of Avodart soft capsules during repeated administration simulations.

Hereinafter, the present invention will be described in detail.

Pharmaceutical composition in tablet form

In one aspect, the present invention discloses a pharmaceutical composition in tablet form containing dutasteride as an active ingredient, which is for oral administration once a week.

In the present invention, the term active ingredient refers to dutasteride, which has the effect of improving, preventing, or treating benign prostatic hyperplasia or androgenetic alopecia.

In the present invention, the pharmaceutical composition in the form of a tablet is characterized in that it is for oral administration once a week. In the case of Avodart ^® , an existing hair loss treatment agent, the dosage is 0.5 mg/day (QD). There is a problem in that it must be prescribed for more than 3 months and then administered continuously every day, but the technical significance of the present invention is that it increases the convenience of administration by reducing the number of administrations to once a week by implementing it for oral administration once a week. It will be said that there is.

In the present invention, the pharmaceutical composition may be administered orally with dutasteride as an active ingredient in an amount of 3.0 mg or more once a week, specifically, 3.0 mg or more and 4.0 mg or less or 3.5 mg or less of dutasteride. Can be administered orally once a week, and more specifically, the pharmaceutical composition may be administered orally with 3.0 to 3.5 mg of dutasteride as an active ingredient, but is not limited thereto.

Specifically, the present invention exhibits improved dissolution rate and pharmacokinetics compared to the existing commercially available Avodart soft capsule (Avodart ^® ) administered once a day through administration of a high dose of 3.0 mg or more of dutasteride once a week. There was no significant difference in the evaluation, and during the repeated administration simulation, the Avodart soft capsule (Avodart ^® ) blood concentration was 1.5 mg or more, specifically 1.5 mg or more, but 2.0 mg or less, or 1.75 mg or less so that the blood concentration could be expressed similarly. There is an advantage in that taking two tablets containing dutasteride reduces the number of administrations and increases the convenience of taking.

In the present invention, the pharmaceutical composition may include dutasteride solubilized in a self-emulsifying composition, but is not limited thereto.

In the present invention, the self-emulsifying composition may include dutasteride, oil, surfactant, and co-surfactant, but is not limited thereto.

In the present invention, the oil is for solubilizing dutasteride, a poorly soluble drug, and specifically, propylene glycol monocaprylate, propylene glycol caprylate/caprate, propylene glycol monolaurate, and glyceryl monocarboxylate. It may be one or more of prilate or glyceryl monocaprate, but is not limited thereto.

In the present invention, the surfactant is used to stably disperse dutasteride when forming a self-emulsifying emulsion, and specifically, polyoxyl castor oil (e.g. polyoxyl 35 hydrogenated castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 50 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl hydrogenated castor oil), polyoxyl stearic acid, polyoxyl sorbitan fatty acid ester, polyoxyl glyceride, tocopherol polyethylene glycol succinate or polyoxy It may be one or more of ethylene-polyoxypropylene copolymers, but is not limited thereto.

In the present invention, the co-surfactant acts with other surfactants when forming a self-emulsifying emulsion to further reduce the surface tension of the liquid to stably disperse dutasteride. Diethylene glycol monoethyl ether, polyethylene glycol 200 , polyethylene glycol 300, or polyethylene glycol 400, but is not limited thereto.

In the present invention, the organic solvent may be anhydrous ethanol, but is not limited thereto.

Specifically, the present invention must contain a high dose of dutasteride for administration once a week. Dutasteride, known as a poorly soluble drug, is administered once a week by solubilizing a high dose of the drug through self-emulsifying emulsion technology. It can contain a high content of dutasteride for.

The present invention relates to a pharmaceutical composition in the form of a tablet, which can overcome the disadvantages of the soft capsule formulation. Specifically, soft capsules have problems during manufacturing such as adsorption and infiltration of the drug into the gelatin film, discoloration, hardening, dissolution or softening of the gelatin film, the drug deteriorates at high temperatures, and is susceptible to humidity. In order to solubilize a high dose of a poorly soluble drug, the amount of solubilizing agent is increased and the dosage form becomes very large, so the aim is to provide a pharmaceutical composition in the form of a tablet to solve the problem of poor patient convenience in taking it.

In the present invention, the pharmaceutical composition may include a self-emulsifying composition and one or more pharmaceutical additives selected from the group consisting of an adsorbent to which the self-emulsifying composition is adsorbed, an excipient, a disintegrant, and a lubricant, but is not limited thereto.

In the present invention, the adsorbent to which the self-emulsifying composition is adsorbed is an adsorbent carrier for preparing the liquid self-emulsifying composition in the form of powder-type granules, and includes magnesium aluminosilicate, magnesium aluminometasilicate, and low-substituted hydroxypropyl. It may be one or more selected from the group consisting of cellulose, silicon dioxide, colloidal silicon dioxide, calcium silicate, bentonite, and kaolin, but is not limited thereto.

In the present invention, the excipient is a substance intended to increase productivity and stability and increase the volume or quantity of tablets, and may be any one or more of lactose, D-mannitol, or silicate microcrystalline cellulose, but is not limited thereto.

In the present invention, the disintegrant is used to promote disintegration of the formulation to improve dissolution of the drug, and may specifically be any one or more of crospovidone, croscarmellose sodium, or low-substituted hydroxypropyl cellulose. It is not limited.

In the present invention, the lubricant may be magnesium stearate, but is not limited thereto.

In the present invention, the pharmaceutical composition contains 0.1 to 0.6 parts by weight of dutasteride, based on 100 parts by weight of the pharmaceutical composition; 2.5 parts by weight to 9.5 parts by weight of oil; 10.0 parts by weight to 30.0 parts by weight of surfactant; and a self-emulsifying composition containing 4.0 to 20.0 parts by weight of a co-surfactant and 15.0 to 70.0 parts by weight of an adsorbent to which the self-emulsifying composition is adsorbed; 10.0 parts by weight to 40.0 parts by weight of excipient; 1.0 parts by weight to 10.0 parts by weight of disintegrant; and 0.25 parts by weight to 5.0 parts by weight of a lubricant. Specifically, the pharmaceutical composition may include 0.1 parts by weight to 0.6 parts by weight of dutasteride, based on 100 parts by weight of the pharmaceutical composition. 3.5 parts by weight to 7.5 parts by weight of oil; 12.0 parts by weight to 20.0 parts by weight of surfactant; and a self-emulsifying composition containing 6.0 to 13.0 parts by weight of a co-surfactant, and 20.0 to 55.0 parts by weight of an adsorbent to which the self-emulsifying composition is adsorbed; 15.0 parts by weight to 35.0 parts by weight of excipient; 2.5 parts by weight to 6.0 parts by weight of disintegrant; and 0.5 to 1.5 parts by weight of a lubricant, but is not limited thereto.

Here, the term parts by weight refers to the weight ratio between each component, and is specifically interpreted to mean the relative weight ratio of other components mixed when assuming that the standard component is 100 parts by weight. Therefore, the parts by weight in the above can be viewed as indicating the relative ratio of each ingredient included in the pharmaceutical composition, assuming that the entire pharmaceutical composition as a standard is 100 parts by weight.

In the present invention, when the pharmaceutical composition in the form of a tablet is eluted in 0.1N HCl containing 2.0% SLS (sodium lauryl sulfate), more than 85% of dutasteride may be of an immediate-release type that is eluted within 15 minutes. and is not limited to this.

In the present invention, the pharmaceutical composition in the form of a tablet may be a preparation for the treatment of benign prostatic hyperplasia or androgenetic alopecia, but is not limited thereto.

Method for preparing pharmaceutical compositions in tablet form

In another aspect, the present invention includes the steps of (S1) preparing a self-emulsifying composition by mixing dutasteride, oil, surfactant and co-surfactant; (S2) dissolving the self-emulsifying composition in an organic solvent; (S3) mixing a solution in which the self-emulsifying composition is dissolved in an organic solvent with an adsorbent to prepare an adsorbent to which the self-emulsifying composition is adsorbed; and (S4) mixing one or more pharmaceutical additives selected from the group consisting of adsorbents to which the self-emulsifying composition is adsorbed, excipients, disintegrants, and lubricants, and then compressing into tablets. .

In the present invention, the step (S2) is mixing 1,500 to 2,500 parts by weight of oil, 4,000 to 6,000 parts by weight of surfactant, and 2,000 to 4,000 parts by weight of cosurfactant with respect to 100 parts by weight of dutasteride. It may be a step, and specifically, it is a step of mixing 1600 to 1800 parts by weight of oil, 4500 to 5500 parts by weight of surfactant, and 2500 to 3000 parts by weight of cosurfactant with respect to 100 parts by weight of dutasteride. It can be done and is not limited to this.

In the present invention, the step (S3) may be a step of preparing an adsorbent to which the self-emulsifying composition is adsorbed by mixing 50.0 to 250.0 parts by weight of an adsorbent with respect to 100 parts by weight of the self-emulsifying composition. Specifically, the self-emulsifying composition 100 parts by weight. This may be a step of preparing an adsorbent to which the self-emulsifying composition is adsorbed by mixing 66.0 to 198.0 parts by weight of the adsorbent, but is not limited to this.

In the present invention, the step (S4) includes 10.0 parts by weight to 70.0 parts by weight of an excipient, 1.0 parts by weight to 15.0 parts by weight of a disintegrant, and 0.1 parts by weight of a lubricant based on 100 parts by weight of the adsorbent to which the self-emulsifying composition is adsorbed. This may be a step of mixing 2.5 parts by weight and tableting, and specifically, 20.0 parts by weight to 60.0 parts by weight of excipient, 5.0 parts by weight to 10.0 parts by weight of disintegrant, and lubricant for 100 parts by weight of adsorbent to which the self-emulsifying composition is adsorbed. This may be a step of mixing 1.0 to 2.0 parts by weight and tableting, but is not limited to this.

The information regarding the pharmaceutical composition in the form of a tablet described above can be applied to all methods for producing the pharmaceutical composition in the form of a tablet, as long as there is no conflict with each other.

Hereinafter, the present invention will be described in detail based on examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example

Example 1. Preparation of dutasteride-containing adsorbent

In a 200 mL beaker, add 0.15 g of dutasteride, 2.1 g of propylene glycol monocaprylate, 0.525 g of propylene glycol monolaurate, 7.9875 g of polyoxyl 40 hydrogenated castor oil, 4.3875 g of diethylene glycol monoethyl ether, and 15 g of absolute ethanol. It was added and stirred to obtain a dutasteride-containing solution. 30 g of magnesium aluminometasilicate was added to a 250 mL beaker, the dutasteride-containing solution was added, and the mixture was stirred with a mechanical stirrer at a speed of 800 rpm to obtain a mixture. The obtained mixture was dried in a hot air dryer to prepare a dutasteride-containing adsorbent in which the self-emulsifying composition was adsorbed on an adsorbent.

Example 2. Preparation of dutasteride-containing adsorbent

In a 200 mL beaker, add 0.15 g of dutasteride, 2.1 g of propylene glycol monocaprylate, 0.525 g of propylene glycol monolaurate, 7.9875 g of polyoxyl 40 hydrogenated castor oil, 4.3875 g of diethylene glycol monoethyl ether, and 15 g of absolute ethanol. It was added and stirred to obtain a dutasteride-containing solution. 10 g of magnesium aluminometasilicate was added to a 250 mL beaker, the dutasteride-containing solution was added, and the mixture was stirred with a mechanical stirrer at a speed of 800 rpm to obtain a mixture. The obtained mixture was dried in a hot air dryer to prepare a dutasteride-containing adsorbent in which the self-emulsifying composition was adsorbed on an adsorbent.

Example 3. Preparation of dutasteride-containing adsorbent

In a 200 mL beaker, add 0.15 g of dutasteride, 2.1 g of propylene glycol monocaprylate, 0.525 g of propylene glycol monolaurate, 7.9875 g of polyoxyl 40 hydrogenated castor oil, 4.3875 g of diethylene glycol monoethyl ether, and 15 g of absolute ethanol. It was added and stirred to obtain a dutasteride-containing solution. 15 g of magnesium aluminometasilicate was added to a 250 mL beaker, the dutasteride-containing solution was added, and the mixture was stirred using a mechanical stirrer at a speed of 800 rpm to obtain a mixture. The obtained mixture was dried in a hot air dryer to prepare a dutasteride-containing adsorbent in which the self-emulsifying composition was adsorbed on an adsorbent.

[Table 1]

(The raw drug quantity in Table 1 refers to the content of the dutasteride-containing adsorbent for manufacturing 100 tablets containing dutasteride.)

Examples 4 and 5. Preparation of tablets containing dutasteride

According to the composition in Table 2 below, 45.15 g of the dutasteride-containing adsorbent onto which the self-emulsifying composition prepared in Example 1 was adsorbed was sieved through a 35 mesh and placed in a polyethylene bag, and crospovidone sieved through a 35 mesh was added thereto. Alternatively, 3.0 g of croscarmellose sodium and 11.25 g of silicate microcrystalline cellulose were added and mixed 100 times. Here, 0.6 g of magnesium stearate sieved through a 35 mesh was added and mixed 50 times. The mixture was compressed into tablets with a total weight of 600 mg per tablet and a hardness of approximately 8 to 12 kp to prepare tablets containing dutasteride.

[Table 2]

Examples 6 to 8. Preparation of tablets containing dutasteride

According to the composition in Table 3 below, 25.15 g of the dutasteride-containing adsorbent onto which the self-emulsifying composition prepared in Example 2 was adsorbed was sieved through a 35 mesh and placed in a polyethylene bag, and crospovidone sieved through a 35 mesh was added thereto. , 2.0 g of croscarmellose sodium or low-substituted hydroxypropyl cellulose, and 12.45 g of silicate microcrystalline cellulose were added and mixed 100 times. Here, 0.4 g of magnesium stearate sieved through a 35 mesh was added and mixed 50 times. The mixture was compressed into tablets with a total weight of 400 mg per tablet and a hardness of approximately 6 to 10 kp to prepare tablets containing dutasteride.

[Table 3]

Examples 9 to 13. Preparation of tablets containing dutasteride

According to the composition in Table 4 below, 30.15 g of the dutasteride-containing adsorbent onto which the self-emulsifying composition prepared according to Example 3 was adsorbed was sieved through a 35 mesh and placed in a polyethylene bag, and Croscarmel was sieved through a 35 mesh. 2.0 g of lost sodium, silicate microcrystalline cellulose, lactose (anhydrous lactose and lactose hydrate), D-mannitol, or 12.4 g of a mixture of the above excipients were added and mixed 100 times. Here, 0.45 g of magnesium stearate sieved through a 35 mesh was added and mixed 50 times. The mixture was compressed into tablets with a total weight of 450 mg per tablet and a hardness of approximately 6 to 10 kp to prepare tablets containing dutasteride.

[Table 4]

Example 14. Preparation of tablets containing dutasteride

According to the composition in Table 5 below, 30.15 g of the dutasteride-containing adsorbent onto which the self-emulsifying composition prepared in Example 3 was adsorbed was sieved through a 35 mesh and placed in a polyethylene bag, and Croscarmel sieved through a 35 mesh was added. 2.5 g of lost sodium, 12.4 g of silicate microcrystalline cellulose, and 4.45 g of lactose hydrate were added and mixed 100 times. Here, 0.5 g of magnesium stearate sieved through a 35 mesh was added and mixed 50 times. The mixture was compressed into tablets with a total weight of 500 mg per tablet and a hardness of approximately 6 to 10 kp to prepare tablets containing dutasteride.

[Table 5]

(The raw drug amount of each ingredient in Tables 2 to 5 above represents the content of each ingredient for manufacturing 100 tablets containing Dutasteride. Dutasteride contained in one tablet manufactured according to Examples 4 to 14 The steride content is 1.5 mg.)

Hereinafter, the present invention will be described in detail based on experimental examples. However, the following experimental examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Experimental Example 1: Dissolution test

Test Methods

A comparative dissolution test was conducted on the high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention and the commercially available Avodart soft capsule (Avodart ^® ).

According to the FDA dissolution methods database, a dissolution test was performed under the conditions of 900 mL of 0.1 N HCl eluate containing 2.0% SLS (sodium lauryl sulfate), paddle speed of 50 rpm, and temperature of 37.0 ± 0.5°C.

1 high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention, 1 Avodart ^® capsule, and 3 Avodart ^® capsules were each added to the eluate, 5, 5 mL of samples were collected at 10, 15, 30, 45, and 60 minutes, and the amount of dutasteride dissolved in the eluate was quantitatively analyzed using High Performance Liquid Chromatography (HPLC). The results of the comparative dissolution test are shown in Figure 1.

HPLC analysis conditions are as follows.

<HPLC analysis conditions>

Eluent: 0.1N HCl (900mL) containing 2.0% SLS (sodium lauryl sulfate)

Dissolution device: Paddle

Rotation speed: 50rpm

Temperature: 37.0±0.5℃

Preparation of test solution: 1 high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention, 1 Avodart ^® capsule, and 3 Avodart ^® capsules were added to the eluate. , 5 mL of the sample solution was taken at 5, 10, 15, 30, 45, and 60 minutes, filtered through a 0.45 μm PVDF syringe filter, and used as the sample solution for the dissolution test.

Preparation of standard solution: Place approximately 15 mg of dutasteride standard in a 50 mL volumetric flask, add diluent to completely dissolve, and then adjust to the marking line. Take 5 mL of this solution, place it in a 50 mL volumetric flask, adjust the mark with the diluent, and then filter the solution through a 0.45 μm PVDF syringe filter and use it as the standard solution.

Detector: Ultraviolet absorption spectrophotometer (measurement wavelength 240 nm)

Column: C18 (4.6 mm × 150 mm, 5 μm particle size)

Column temperature: about 30℃

Flow rate: 2.0 mL/min

Mobile phase: pH3.0 phosphate buffer:acetonitrile = 35:65

* pH 3.0 phosphate buffer solution: Dissolve 1.37 g of potassium dihydrogen phosphate in 1 L of purified water and adjust it to pH 3.0 with phosphoric acid.

Diluent: Eluate

Test result

As can be seen in Figure 1, the high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention exhibits an improved dissolution rate compared to the control group, Avodart soft capsule (Avodart ^® ), and is effective for 15 minutes in the specified dissolution test solution. It was confirmed that more than 85% of the drug was eluted. Through this, it was confirmed that the high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention was of immediate release type.

Experimental Example 2. Pharmacokinetic evaluation

Test Methods

Pharmacokinetic evaluation of high-dose dutasteride prepared according to the present invention was performed and compared with the pharmacokinetics of Avodart soft capsules (Avodart ^® ). Specifically, high-dose dutasteride-containing tablets prepared according to Example 14 of the present invention were used as a test group, and commercially available Avodart soft capsules (Avodart ^® ) were used as a control group.

In the pharmacokinetic test, 9 healthy male beagle dogs (9-10 months old) were divided into 3 groups of 3 each. Group 1 was administered Avodart soft capsules (Avodart ^® ) 0.5 mg orally as a single dose, 1 capsule at a time, and Group 2 was administered 0.5 mg of Avodart ® soft capsules. The group was administered a single oral dose of 0.5 mg of Avordart soft capsules (Avordart ^® ), 6 capsules (total 3.0 mg) once, and the third group was administered a high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention once. Two tablets (total 3.0 mg) were administered orally as a single dose.

Blood was collected through the jugular vein, before administration of the test substance (0 hours) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 72, 120, and 168 hours after oral administration (15 points in total) ) Blood was collected at the time point, and the concentration of dutasteride in the blood was quantitatively analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). The pharmacokinetic test results are shown in Figure 2 and Table 6.

Test result

As can be seen in Figure 2 and Table 6, the blood concentration time of 3.0 mg of 2 high-dose dutasteride-containing tablets prepared according to Example 14 of the present invention and 3.0 mg of 6 Avodart ^® soft capsules It was confirmed that there was no significant difference in the area under the curve (AUC _0-168 ). In addition, it was confirmed that the C _max and T _max of 3.0 mg, 2 high-dose dutasteride-containing tablets prepared according to Example 14 of the present invention, were similar to 3.0 mg of 6 capsules of Avodart ^® , the control group. .

[Table 6]

Experimental Example 3. Repeated administration simulation

Test Methods

To predict the pharmacokinetics of the once-weekly repeated administration of the high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention, a simulation program (Pharsight's Phoenix WinNonlin) was used using the parameters obtained above for 4 weeks. Pharmacokinetics during repeated administration were predicted.

Specifically, 3.0 mg of 2 high-dose dutasteride-containing tablets prepared according to Example 14 obtained according to the present invention and 3.0 mg of 6 Avodart ^® soft capsules were used in a simulation program once a week for 4 weeks. A repeated administration simulation was conducted through a repeated administration simulation using Avodart soft capsule (Avodart ^® ) 0.5 mg once a day for 4 weeks. The pharmacokinetic parameters resulting from the repeated administration simulation obtained by performing a repeated administration simulation are shown in Figure 3.

Test result

As can be seen from the results of Figure 3, the blood concentration of Avodart soft capsule (Avodart ^® ) 0.5 mg administered repeatedly for 4 weeks once a day and the high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention It was confirmed that the blood concentration of Avodart soft capsule (Avodart ^® ) 3.0 mg administered repeatedly once a week for 4 weeks was similar.

Through the above repeated administration simulation, the frequency of administration of the once-daily dutasteride drug can be reduced to once a week by using the high-dose dutasteride-containing tablet prepared according to Example 14 of the present invention. was confirmed.

As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (7)

A pharmaceutical composition in tablet form containing dutasteride as an active ingredient, for oral administration once a week. The pharmaceutical composition according to claim 1, wherein dutasteride as an active ingredient is orally administered in an amount of 3.0 mg or more once a week. The pharmaceutical composition in the form of a tablet according to claim 1, wherein the pharmaceutical composition contains dutasteride solubilized with a self-emulsifying composition. The pharmaceutical composition in the form of a tablet according to claim 3, wherein the pharmaceutical composition includes a self-emulsifying composition and one or more pharmaceutical additives selected from the group consisting of an adsorbent to which the self-emulsifying composition is adsorbed, an excipient, a disintegrant, and a lubricant. The method of claim 4, wherein the pharmaceutical composition contains 0.1 to 0.6 parts by weight of dutasteride, based on 100 parts by weight of the pharmaceutical composition; 3.5 parts by weight to 7.5 parts by weight of oil; 12.0 parts by weight to 20.0 parts by weight of surfactant; and a self-emulsifying composition containing 6.0 to 13.0 parts by weight of a co-surfactant, and 20.0 to 55.0 parts by weight of an adsorbent to which the self-emulsifying composition is adsorbed; 15.0 parts by weight to 35.0 parts by weight of excipient; 2.5 parts by weight to 6.0 parts by weight of disintegrant; and 0.5 to 1.5 parts by weight of a lubricant. The pharmaceutical composition in the form of a tablet according to claim 1, wherein the pharmaceutical composition contains 1.5 mg or more of dutasteride as an active ingredient. (S1) preparing a self-emulsifying composition by mixing dutasteride, oil, surfactant, and co-surfactant; (S2) dissolving the self-emulsifying composition in an organic solvent; (S3) mixing a solution in which the self-emulsifying composition is dissolved in an organic solvent with an adsorbent to prepare an adsorbent to which the self-emulsifying composition is adsorbed; and (S4) mixing one or more pharmaceutical additives selected from the group consisting of adsorbents to which the self-emulsifying composition is adsorbed, excipients, disintegrants, and lubricants, and then compressing them into tablets. A method for producing a pharmaceutical composition in tablet form comprising a.

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