COMPOSITION COMPRISING DUTASTERIDE

Abstract

A composition of the present invention relates to a composition comprising dutasteride, wherein said composition may maintain a constant concentration of dutasteride in blood and continuously release a drug thereof for a long period of time while not precipitating dutasteride in a solid form when being administered into the human body, and also has an excellent safety without causing local irritations in an administration site.

Claims

1. A composition comprising dutasteride, optical isomers thereof or pharmaceutically acceptable salts thereof, lipid and an organic solvent.

2. The composition according to claim 1, wherein lipid is selected from the group consisting of tocopherol, tocopherol acetate, castor oil, safflower oil, sesame oil, olive oil, almond oil, camellia oil, corn oil, cottonseed oil, soybean oil, medium chain triglyceride (MCT), pharmaceutically acceptable salts thereof and mixtures thereof.

3. The composition according to claim 1, wherein lipid is selected from the group consisting of tocopherol, tocopherol acetate, pharmaceutically acceptable salts thereof and mixtures thereof.

4. The composition according to claim 1, wherein the organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl benzoate, benzyl alcohol, dimethylacetamide, ethanol and mixtures thereof.

5. The composition according to claim 1, wherein the organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl benzoate and mixtures thereof.

6. The composition according to claim 1, wherein said composition is for treating benign prostatic hyperplasia or androgenetic alopecia.

7. The composition according to claim 1, wherein said composition is administered through an injection.

8. The composition according to claim 1, wherein a route of said composition administration is a subcutaneous injection, an intradermal injection or an intramuscular injection.

9. A method for preventing or treating benign prostatic hyperplasia or androgenetic alopecia by administering a therapeutically effective dose of a composition containing dutasteride, optical isomers thereof or pharmaceutically acceptable salts thereof, lipid and an organic solvent into subjects in need of treatment.

10. A use of a composition comprising dutasteride, optical isomers thereof or pharmaceutically acceptable salts thereof, lipid and an organic solvent in preparation of a medicament for preventing or treating benign prostatic hyperplasia or androgenetic alopecia.

11. A use of a composition comprising dutasteride, optical isomers thereof or pharmaceutically acceptable salts thereof, lipid and an organic solvent for preventing or treating benign prostatic hyperplasia or androgenetic alopecia.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0047] FIG. 1 is a graph of showing a viscosity of Comparative Example 3 and Example 21.

[0048] FIG. 2 is a graph of showing an in vitro drug release behavior of Comparative Example 1 and Example 32.

[0049] FIG. 3 is a graph of showing an in vivo drug release behavior of Comparative Example 2 and Example 32.

[0050] FIG. 4 is a graph of showing an in vivo drug residual amount in an administration site of Comparative Example 2 and Example 32.

[0051] FIG. 5 is an image of identifying an in vivo safety of a composition of Example 21.

MODE FOR THE INVENTION

[0052] Hereinafter, the present invention will be described in more detail through the following examples and experimental examples. However, the following examples and experimental examples are provided only for the purpose of illustrating the present invention, and thus the scope of the present invention is not limited thereto.

[0053] The additives used in the present invention were the excipients according to the standards of the pharmacopoeia and a reagent purchased from Aldrich, Croda.

[Examples 1 to 38] Preparation of the Inventive Pharmaceutical Composition

Examples 1 to 38

[0054] A preparation of the present invention was produced by using the ingredients and contents as shown in the following tables 1 to 3.

[0055] Particularly, an active ingredient, i.e., dutasteride was mixed with an organic solvent, and then dissolved at room temperature (25° C.) with a stirrer under the condition of 1,000-3,000 rpm for 0.5-1 hour, after which the presented lipid was added into the resulting solution. After that, the resulting mixture was dissolved in the stirrer under the condition of about 1,000-3,000 rpm for about 5-30 minutes to prepare a pharmaceutical composition in a liquid phase.

TABLE-US-00001 TABLE 1 Examples (Unit: mg) 1 2 3 4 5 6 7 8 9 10 11 Dutasterid 9 9 9 9 9 9 9 9 27 27 27 Tocopherol 150 300 150 Tocopherol acetate 15 Castor oil Safflower oil 136 Sesame oil 136 Olive oil 136 Almond oil 136 Camellia oil Corn oil 136 Cottonseed oil 136 Soybean oil 136 Medium-chain triglyceride(MCT) N-methylpyrrolidone 45 45 45 45 45 45 45 45 101 101 101 Dimethyl sulfoxide 29 29 29 29 29 29 29 29 Benzyl benzoate Benzyl alcohol 101 Dimethyl acetamide Ethanol

TABLE-US-00002 TABLE 2 Examples (Unit: mg) 12 13 14 15 16 17 18 19 20 21 22 23 24 Dutasterid 27 27 27 27 27 27 27 27 27 56 27 27 27 Tocopherol 150 300 300 229 152 150 300 100 100 312 Tocopherol acetate Castor oil 68 33 126 128 133 78 Safflower oil Sesame oil Olive oil Almond oil Camellia oil Corn oil Cottonseed oil Soybean oil Medium-chain triglyceride(MCT) N-methylpyrrolidone 101 101 101 101 210 101 Dimethyl sulfoxide 87 33 33 33 68 Benzyl benzoate 300 450 100 50 100 Benzyl alcohol 229 305 200 Dimethyl acetamide 136 Ethanol

TABLE-US-00003 TABLE 3 Examples (Unit: mg) 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Dutasterid 27 27 27 56 56 9 6 27 27 27 27 56 9 9 Tocopherol 300 312 312 300 300 300 150 156 Tocopherol acetate 50 5 Castor oil 275 700 Safflower oil 263 Sesame oil 263 Olive oil Almond oil Camellia oil 136 Corn oil Cottonseed oil Soybean oil Medium-chain 50 triglyceride(MCT) N-methylpyrrolidone 101 210 210 33 30 101 120 120 101 210 45 34 Dimethyl sulfoxide 408 408 68 68 20 33 68 29 29 Benzyl benzoate 100 100 100 200 Benzyl alcohol Dimethyl acetamide Ethanol 3

Comparative Examples 1 to 31

Comparative Examples 1 to 3

[0056] The active ingredient, i.e., a raw substance of dutasteride was used in Comparative Example 1.

[0057] In Comparative Examples 2 to 3 of the following table 4, the active ingredient, i.e., dutasteride was mixed with an organic solvent or lipid, and then dissolved at room temperature (25° C.) with the stirrer under the condition of 1,000-3,000 rpm for 0.5-12 hours to prepare a pharmaceutical composition in a liquid phase.

TABLE-US-00004 TABLE 4 Comparative Examples (Unit: mg) 1 2 3 Dutasterid 56 97 56 Tocopherol 312 Tocopherol acetate Castor oil Safflower oil Sesame oil Olive oil Almond oil Camellia oil Corn oil Cottonseed oil Soybean oil Medium-chain triglyceride(MCT) N-methylpyrrolidone 101 Dimethyl sulfoxide 33 Benzyl benzoate Benzyl alcohol Dimethyl acetamide Ethanol

[Experimental Example 1] Identification of Content of Pharmacological Active Ingredients in Composition

[0058] To identify a content of a pharmacologically active substance in the pharmaceutical composition prepared through Examples of the present invention, the content of dutasteride, used as the pharmacologically active substance, was identified and the results thereof were shown in the following table 5. The content of dutasteride was quantified with HPLC and analysis conditions were as follows.

[0059] <HPLC Analysis Conditions for Dutasteride> [0060] Column: 4.6 mm×250 mm, 5 μm [0061] Column temperature: 35° C. [0062] Detector: Ultraviolet absorption spectrophotometer (wavelength: 220 nm) [0063] Flow rate: 1.0 mL/min. [0064] Injection volume: 10 μl [0065] Mobile phase: Water, acetonitrile and trifluoroacetic acid (48:52:0.025)

TABLE-US-00005 TABLE 5 Comparative Examples Examples (Unit: %) 2 3 9 19 21 33 Content 103.1 100.7 102.0 101.9 100.5 98.5

[0066] As shown in the table 5, the pharmaceutical compositions of Comparative Example 2, Comparative Example 3, Example 9, Example 19, Example 21 and Example 33 showed a very ideal measured value within ±3% compared to a reference content (100%) of dutasteride.

[Experimental Example 2] Identification of Viscosity of Pharmaceutical Composition In Vitro

[0067] A viscosity of the inventive compositions in vitro was identified through the following experiment. The viscosity of Example 21 containing dutasteride, lipid and an organic solvent, and the viscosity of Comparative Example 3 excluding the organic solvent were compared with each other with a viscosity measuring apparatus. Conditions for viscosity measurement are as follows.

[0068] <Conditions for Measuring Viscosity of Pharmaceutical Composition> [0069] Viscometer: Rheometer (RHEOSENSE Inc.) [0070] Analysis temperature: 25±0.5° C.

[0071] Viscosity was measured and analyzed with the rheometer in which a thermostat is installed, and the results thereof were shown in FIG. 1. The results of FIG. 1 show an average of viscosity values measured five times.

[0072] In case of Comparative Example 3 excluding the organic solvent from Example 21, the results of measuring the viscosity five times were 2,553, 2,565, 2,557, 2,547 and 2,543 mPa respectively, thus showing that an average viscosity is 2,553 mPa. On the other hand, in case of Example 21 containing dutasteride, lipid and the organic solvent, the results of measuring the viscosity five times were 40.5, 40.4, 40.4, 40.9 and 40.8 mPa respectively, thus showing that an average viscosity is 40.6 mPa. From the results, it was identified that the composition of the present invention contains the organic solvent to reduce the viscosity of the composition and thus may be easily administered into the human body.

[Experimental Example 3] Identification of Dissolution Rate of Pharmaceutical Composition In Vitro

[0073] A dissolution rate of the inventive compositions in vitro was identified through the following experiment. Example 32 was filled into a disposable syringe in such an amount that corresponds to 56 mg of dutasteride and then injected into a dissolution medium, and Comparative Example 1 was directly put into a rotating basket in such an amount that corresponds to 56 mg of dutasteride. This experiment was performed according to the dissolution test method I in the 10th revision of the Korean Pharmacopoeia and the conditions for dissolution are as follows.

[0074] <Conditions for Dissolution of Pharmaceutical Composition> [0075] Dissolution method: Method I of the Korean Pharmacopoeia (Apparatus I—Basket) [0076] Dissolution medium: 900 mL of solution containing 1% w/v sodium dodecyl sulfate [0077] Dissolution temperature: 37±0.5° C. [0078] Rotation speed: 100 rpm [0079] Test hour: 1, 3, 6, 12 and 24 hours

[0080] With regard to a concentration of dutasteride in a dissolution sample, a dissolution rate for 24 hours was analyzed with HPLC under the condition of Experimental Example 1 and the results thereof were shown in FIG. 2.

[0081] In case of directly administering Comparative Example 1 into the dissolution medium containing surfactants, a part of the drug only was dissolved into the dissolution medium and a dissolution rate was hardly increased with an elapse of time from one hour after. However, in case of administering Example 32 containing lipid, it was identified that dutasteride is not precipitated in a form of solid powder in the dissolution medium and a dissolution rate is slowly increased with an elapse of time.

[Experimental Example 4] Identification of PK of Pharmaceutical Composition In Vivo

[0082] A drug release behavior of the inventive compositions in vivo was identified through the following experiment. Each of the compositions of Comparative Example 2 and Example 32 was filled into a disposable syringe, and then intramuscularly injected into the thigh of six SD rats (male) respectively, which were nine weeks old and weighed 300 g on average, in such an amount that corresponds to 27 mg of dutasteride.

[0083] The concentration of dutasteride in a plasma sample of SD rats was analyzed with regard to a PK (pharmacokinetic) profile by using the LC-MS/MS (liquid chromatography/mass spectrometer), and the results thereof were shown in FIG. 3.

[0084] In case of Example 32, i.e., a lipid composition containing dutasteride, it was identified that a constant blood concentration thereof is maintained for more than one month when being administered in vivo. On the other hand, in case of Comparative Example 2, i.e., a composition not containing lipid, the concentration of dutasteride in blood is very low compared to Example 32. It was identified through the following Experimental Example 5 that the cause is due to the precipitation of dutasteride in powder form at the administration site.

[0085] From the results, it was identified that the composition of the present invention maintains a constant blood concentration for more than one month and thus shows an excellent sustained release, while not precipitating dutasteride in a form of powder at the administration site.

[Experimental Example 5] Identification of Drug Residual Amount in Administration Site In Vivo

[0086] Through the following experiment, the composition was administered in vivo to identify a residual amount of the drug in an administration site with an elapse of certain time. Each of the compositions of Comparative Example 2 and Example 32 was filled into a disposable syringe, and then intramuscularly injected into the thigh of six SD rats (male) respectively, which were nine weeks old and weighed 300 g on average, in such an amount that corresponds to 27 mg of dutasteride.

[0087] In 30 days later, the rats were subjected to autopsy to collect muscle tissues from an area into which the composition was administered. 20 mL of ethanol was added to the collected muscle tissues, and then crushed with a homogenizer for about 30 minutes. After that, the crushed tissues were centrifuged at 3,000 rpm for 20 minutes by using a centrifugal separator, after which supernatant thereof was collected therefrom and quantified under the analysis conditions for dutasteride in Experimental Example 1, and the results thereof were shown in FIG. 4.

[0088] It was identified for Example 32 that a residual amount of dutasteride is about 28% in an administration site in one month after administration and thus 72% of the drug administered is absorbed in vivo. On the other hand, it was identified for Comparative Example 2 that about 96% of dutasteride remains in the administration site even with an elapse of one month after administration.

[0089] From the results, it was identified that the inventive composition containing lipid is continuously absorbed in the administration site when being administered in vivo and thus may maintain a constant concentration of the drug in blood for a long period of time, but it was also identified for Comparative Example 2, i.e., the composition not containing lipid that most of the drug is not absorbed at all while staying in the administration site when being administered in vivo. This may be explained as a cause of the in vivo PK test results in Experimental Example 3.

[Experimental Example 6] Identification of Local Tolerance of Pharmaceutical Composition In Vivo

[0090] The safety of the inventive composition in vivo was identified through the following experiment. The composition of Example 21 was filled into a disposable syringe, and then intramuscularly injected into the thigh of six SD rats (male), which were nine weeks old and weighed 300 g on average, in such an amount that corresponds to 27 mg of dutasteride. After administration into the SD rats, the presence of edema, redness, hardening, necrosis and exudate was identified with the naked eye from the administration site through autopsy in 7, 14, 30 and 60 days later, and the results thereof were shown in FIG. 5.

[0091] As shown in FIG. 5, it was identified that the composition of the present invention is a safe composition without irritations such as edema, redness, hardening, etc. observed from the administration site in all points of autopsy time.