KR102382963B1 - Dutasteride composition in tablet form with improved stability - Google Patents

Abstract

The present invention relates to a dutasteride composition in tablet form with improved stability. In more detail, the dutasteride composition in tablet form according to the present invention includes light anhydrous silicic acid as a stabilizer, and it relates to a dutasteride tablet showing excellent stability by preventing the generation of related substances during the dutasteride formulation manufacturing process. .

Description

Dutasteride composition in tablet form with improved stability

The present invention relates to a tablet-form composition containing dutasteride.

Dutasteride is a compound represented by the following formula (I), and according to the nomenclature, 17β-N-[2,5-bis(trifluoromethyl)]phenylcarbamoyl-4-aza-5α-androst-1- They are called en-3-one compounds.

<Formula I>

Dutasteride inhibits the action of 5-alpha reductase, which converts testosterone, a male hormone, into dihydrotestosterone, the causative agent of androgenetic alopecia and benign prostatic hyperplasia (benign prostatic hyperplasia) and androgenetic alopecia used in the treatment of

In general, dutasteride is in the form of a white powder having a melting point of 242 to 250°C (WO 06/099121), 44 mg/mL in ethanol, 64 mg/mL in methanol, 3 mg/mL in polyethylene glycol 400 , It is a poorly soluble drug with a solubility of 0.038 ng/mL in water (AVODART ^® , FDA clinical pharmacology biopharmaceutics review). It is also known that dutasteride is mainly degraded by oxidation and hydrolysis. [Subba Rao & Radhakrishnanand, Chromatopia 67, 841-845 (2008)]

Dutasteride with these properties is marketed under the trade name of Avodart (AVODART ^® , Glaxosmithkline). Avodart is a drug that is solubilized so that it can be absorbed in the gastrointestinal tract during oral administration at the same time as dutasteride is stabilized. As a stabilizer for anti-inflammatory drugs), 0.035 mg is dissolved in 349.5 mg of mono-diglyceride of capric acid/caprylic acid, which is an oil phase, and then filled in a soft gelatin capsule made of gelatin and sold [AVODART ^® , FDA chemistry review].

However, due to the sensitivity of gelatin, the main component of soft capsules, to heat and moisture during storage, Avodart 1) changes in properties due to softening and hardening of the capsule shell, 2) adhesion between capsules due to increased adhesion of the capsule shell, 3) capsule shell There is a very high risk of deterioration of stability during storage, which is essential as a pharmaceutical, because there are phenomena such as leakage of the internal solution due to rupture and 4) delayed disintegration due to gelatin crosslinking due to the reaction between the internal solution and the film.

In addition, butylated hydroxyl toluene, which is added to Avodart as a stabilizer to prevent the decomposition of dutasteride due to oxidation, is a kind of phenol derivative that can cause carcinogenicity, asthma, and behavioral disorders in infants and children. Controversy continues over its feasibility [Butylated hydroxytoluene (BHT), IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 1986;40:161-206], and its use is limited in pharmaceuticals.

In order to overcome the shortcomings of the soft capsule formulation, AVODART ^® , research on changing the formulation to a solid formulation containing dutasteride has been actively conducted.

Korean Patent Publication No. 10-1055412 discloses dutasteride, an adsorbent, an excipient, a primary coating solution containing a mixture of a water-soluble polymer and a water-insoluble polymer, and a secondary coating solution containing a water-insoluble polymer. Solidification of dutasteride formulations are disclosed. The technology is characterized in that the tablet is prepared by dissolving dutasteride, a surfactant, poloxamer, and an oil-based solubilizer, propylene glycol monocaprylate, in ethanol, and then adsorbing it to an adsorbent composed of silicified microcrystalline cellulose and silicon dioxide. . However, the use of such ethanol has the potential to change the crystallinity of dutasteride during the manufacturing process, and as a result, the generation of dutasteride related substances is accelerated during the manufacturing process and storage, and there is a risk of poor stability. There is a disadvantage that a stabilizer such as hydroxytoluene must be used together.

Korean Patent Publication No. 10-0962447 discloses a self-emulsifying composition for solubilization of dutasteride and a tablet prepared therefrom. In the above patent, a self-emulsifying emulsion composition is prepared by dissolving dutasteride in a large amount of surfactant and an oily solubilizer, and the mixed solution obtained by mixing it with ethanol is added to an adsorbent such as a diluent and disintegrant to solidify dutasteride. as its manufacturing method. The self-emulsifying emulsion composition contains surfactants such as poloxamer and sucrose ester to form an emulsion in which the oily solubilizer containing dutasteride is spontaneously dispersed into small oil droplets of 1000 nm or less upon contact with water. It has the disadvantage that it must contain a large amount. However, since surfactants are irritating to the mucous membrane and may cause gastrointestinal disorders when taken in the human body, it is inappropriate to formulate drugs such as dutasteride, which must be taken daily, into a self-emulsifying emulsion composition containing a large amount of surfactant. .

European Patent Publication No. 2468262 proposes a method for preparing a solid adsorbate prepared by dissolving dutasteride in an oil-type solubilizer and then adsorbing it to the adsorbent. After mixing the adsorbate thus obtained with a mixture of excipients, a tablet is prepared by a wet granulation method using a binder solution prepared using water or an organic solvent. The fact that this manufacturing method is divided into a step of adsorbing dutasteride dissolved in a solubilizer and a step of preparing wet granules using a binding solution is suggested in Korean Patent Publication Nos. 10-1055412 and 10-0962447 There is a difference with one method. However, in general, since the solubilizer of dutasteride is an oily liquid, its amount should be minimized as much as possible for the manufacture of a solid preparation. Therefore, when a small amount of the solubilizer in which dutasteride is dissolved is directly adsorbed to the adsorbent and solidified, it is difficult to evenly distribute the content of dutasteride in the adsorbent. Accordingly, in Korean Patent Publication Nos. 10-1055412 and 10-0962447, in order to prepare a solid adsorbate containing dutasteride homogeneously, ethanol in an amount of 5 times or more is diluted compared to propylene glycol monocaprylate, an oil-based solubilizer. It is used as a solvent to homogeneously adsorb dutasteride to the adsorbent. However, since it is difficult to homogeneously adsorb dutasteride only with a solution in which dutasteride is dissolved in an oily solubilizer as in European Patent Application Laid-Open No. 2468262, it is difficult to secure the content uniformity of the commercially available Avodart ^® level.

In another attempt to compensate for the shortcomings of the soft capsule formulation, European Patent Application Laid-Open No. 2050436, different from the techniques introduced above, excludes the use of an oil-phase solubilizer and applies dry granulation or wet granulation to prepare a tablet. is described as By not using an oily solubilizer, the granular composition provided in the present invention contains dutasteride in powder form, and the composition provided in this way is difficult to obtain sufficient bioavailability of dutasteride, a poorly soluble drug. There are disadvantages. In addition, in fact, no bioavailability evaluation results were presented in European Patent Application Laid-Open No. 2050436.

Accordingly, the present inventors have established a method for manufacturing dutasteride-containing solid preparations that do not use stabilizers harmful to the human body, such as organic solvents ethanol and butylated hydroxytoluene, and have better storage stability than soft capsules. In the present invention, an emulsion obtained by suspending light anhydrous silicic acid in an oil phase and/or a separate aqueous solution containing dutasteride and homogeneously emulsifying these solutions is added to a solid excipient such as a disintegrant, a diluent, etc. to wet granulation The present invention was completed by confirming that the tablet form manufactured by compression molding after manufacturing granules by this method exhibits superior storage stability than the commercially available Avodart ^® soft capsule, minimizes the generation of related substances, and confirms that the content uniformity is excellent.

The present invention shows excellent storage stability by minimizing the generation of related substances even if butylated hydroxytoluene, which is known to be harmful to the human body, is not used as a stabilizer in a solid preparation containing dutasteride, a poorly soluble drug, An object of the present invention is to provide a uniformly contained solid preparation and a method for preparing the same.

In order to achieve the above object, the present invention provides a method for preparing a solid preparation in the form of a solid preparation, particularly a tablet, using a solid pharmaceutical composition containing dutasteride, light anhydrous silicic acid as a solubilizer and a stabilizer.

In addition, the present invention provides a solid preparation comprising dutasteride using the pharmaceutical composition prepared by the above preparation method.

The manufacturing method of dutasteride-containing solid preparation provided by the present invention,

i) preparing a solution in which 1 part by weight of dutasteride is dissolved in 20 to 60 parts by weight of a solubilizer;

ii) preparing a solution in which 0.3 to 1 parts by weight of light anhydrous silicic acid is stirred and suspended in the solution prepared in step i);

iii) preparing a solution in which 5-30 parts by weight of light anhydrous silicic acid is stirred and suspended in 100-1000 parts by weight of separate purified water;

iv) preparing an emulsion emulsified by mixing the solution prepared in ii) and the solution prepared in iii);

ⅴ) preparing granules in which the emulsion prepared in iv) is mixed and dried by adding a binding solution to the mixed powder of solid excipients such as a disintegrant, adsorbent, and diluent; and

ⅵ) A method of manufacturing a dutasteride-containing solid preparation comprising the step of preparing a solid preparation from the granules prepared in v) in a conventional manufacturing method.

is characterized by

In the manufacturing method of the present invention, light anhydrous silicic acid is suspended in only one of steps ii) or iii) in the manufacturing method of the present invention and then emulsified in step iv) is also included in the present invention.

In the present invention, light silicic anhydride is added to obtain a stabilizing effect by suppressing the generation of related substances of dutasteride during the manufacturing process, and the process of suspending light silicic anhydride is soluble in step ii) and/or iii). A stabilizing effect appears by suppressing the generation of related substances of dutasteride by the manufacturing method of suspending light anhydrous silicic acid in a topical mixed solution and/or purified water.

However, if light silicic anhydride as a stabilizer is not included in both steps ii) and iii) or if light silicic anhydride is added in step v) in powder form, related substances of dutasteride are generated during the manufacturing process, resulting in sufficient stabilization effect does not indicate

Step i) of the present invention is to prepare an oily solution by dissolving dutasteride in a solubilizing agent. Considering the solubility of the solubilizer for dissolving dutasteride, it is preferable to dissolve 1 part by weight of dutasteride in 20 to 60 parts by weight of the solubilizer.

In the present invention, in step ii) and/or iii), that is, when light anhydrous silicic acid is suspended in a solubilizing agent mixed solution and/or purified water, in step ii), 0.3 to 1 weight of light anhydrous silicic acid per 1 part by weight of dutasteride In step iii), it is preferable to suspend 5 to 30 parts by weight of light anhydrous silicic acid in 100 to 1000 parts by weight of purified water. When suspending in an amount greater than 1 part by weight of light anhydrous silicic acid in a solubilizing agent solution containing 1 part by weight of dutasteride in step ii) or suspending in an amount greater than 30 parts by weight of light anhydrous silicic acid in purified water in step iii), after In the emulsification stage, the viscosity of the emulsion becomes too strong, so it may be difficult to prepare granules by the wet granulation method.

In addition, without the emulsification process using the aqueous phase of step iii), the oil phase in which dutasteride is dissolved in step ii) is directly added to a solid excipient such as a disintegrant or diluent in step v) to prepare granules, adsorption of dutasteride This does not happen evenly, so there is a possibility that granules with non-uniform content may be produced.

In the present invention, the "solubilizer" is an organic solvent, and it is preferable that the solubility in dutasteride at room temperature is 10 mg/g or more. When a solubilizing agent with low solubility for dutasteride is used, the amount of the solubilizer used to exhibit a sufficient solubilizing effect is increased, and this is not preferable because the size of the tablet increases. Examples of the solubilizer having a solubility of 10 mg/g or more for dutasteride include propylene glycol monocaprylate, propylene glycol monolaurate, diethylene glycol monoethyl ether, glyceryl monocaprylate, glyceryl monocaprate And it may be selected from the group consisting of mixtures thereof, but is not limited thereto.

In general, since the solubilizing agent is an oily liquid, a solubilizing agent with low solubility for dutasteride should be used in a relatively large amount to achieve sufficient solubilizing effect of dutasteride. However, as the amount of the liquid solubilizing agent added increases, the amount of the adsorbent required for solidification increases, and even after solidification, the solubilizer may be separated from the adsorbent. Therefore, it is important to select a solubilizer with excellent solubility for dutasteride.

The solid pharmaceutical composition provided by the present invention may include a diluent, a binder, a lubricant or a coating base in addition to a pharmaceutically acceptable excipient, for example, a disintegrant.

The disintegrant that can be used in the present invention is crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, etc. In general, solid preparations such as tablets and hard capsules are rapidly in contact with water. It may be selected from the group consisting of substances used for the purpose of causing disintegration and mixtures thereof, but is not limited thereto.

The diluent that can be used in the present invention is microcrystalline cellulose, powdered cellulose, pregelatinized starch, lactose hydrate, mannitol, sorbitol, formalin-casein, low-substituted hydroxypropyl cellulose (L-HPC), chitin, chitosan, polymerized agar acrylamide , xylan, smecta, key-jo-clay, cross-linked carboxymethyl guar and modified tapioca starch, alginic acid or alginates, hydroxypropyl cellulose and other cellulose derivatives, polacryl Lean potassium, croscarmellose sodium (Ac-Di-Sol, CLD-2), starch, carboxymethyl starch, gellan gum, and the like.

In the present invention, adsorbents that can be used to more easily solidify the emulsion include calcium silicate, magnesium metasilicate aluminate, and the like.

The binder that can be used in the present invention is polyvinylpyrrolidone (povidone), a copolymer of vinylpyrrolidone and other vinyl derivatives (copovidone), microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose etc.

Lubricants that can be used in the present invention include calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodite, kaolin, petrolatum, sodium stearate, cacao fat, sodium salicylate, magnesium salicylate, polyethylene glycol 4000, polyethylene glycol 6000, liquid paraffin , Hydrogenated soybean oil, aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acid, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, acetic acid sodium, sodium oleate, and the like.

The manufacturing method of the present invention does not contain phenolic antioxidants such as butylated hydroxytoluene, which are known to be harmful to the human body in the conventionally disclosed dutasteride-containing formulations, including the commercially available product Avodart ^® , so that the dutasteride-containing solid formulation has excellent safety. In addition to being able to manufacture the product, it has the advantage of excellent storage stability because the amount of related substances is less than that of Avodart ^® , which is a commercial product, and there is no risk of change in properties during storage.

In addition, the dutasteride-containing solid preparation prepared by the present invention can improve the content uniformity, it is possible to minimize the content deviation of the preparation.

1 is a result of evaluating the dutasteride related substances of Examples 1, 2, 3, 4, 5, 7, 10, 11 and Comparative Examples 1, 2, 3 formulations.
2 is a result of evaluating the accelerated 4 months related substances of Example 6.
3 is a result of evaluating the accelerated 4-month related substances of Comparative Example 4.
4 is a photograph showing the properties of Example 6 and Comparative Example 4 after accelerated storage for 4 months.

Hereinafter, the present invention will be described in more detail through examples. These Examples are for describing the present invention in detail, and the scope of the present invention is not limited by these Examples.

< Example 1 to 5> According to the present invention in which an emulsion is used as a binder without a binder Dutasteride manufacture of tablets

The following examples are intended to show that the method for preparing a solid formulation of the present invention is feasible without the use of a binder, and only an emulsion was prepared as a binder without a separate binder when manufacturing granules.

Using propylene glycol monocaprylate and diethylene glycol monoethyl ether as solubilizers, dutasteride tablets were prepared with the composition shown in Table 1 below in the following manner, respectively, as Examples 1 to 5. Table 1 below shows the content per tablet.

1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and was dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer (Korea Science HT-120DX).

2) Light anhydrous silicic acid was added to the solution of 1) and homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.

3) Light anhydrous silicic acid was added to separate purified water and homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.

4) The suspension of 3) was stirred at 800-1000 rpm, and the suspension of 2) was added and emulsified to prepare a homogeneous emulsion.

5) Add the emulsion of 4) as a binder to a powder mixture of microcrystalline cellulose and mannitol as a diluent and low-substituted hydroxypropyl cellulose as a disintegrant, and knead using a High Shear Mixer (Diosna), followed by a top-type dryer Granules were prepared by drying at 60°C for 12 hours using

6) The granules of 5) were sized by passing through a No. 18 sieve, and magnesium stearate was added to lubricate the granules.

7) The final mixture of 6) was compression molded to prepare tablets.

8) The tablets of 7) were coated with Opadry Yellow (03B620017) to prepare film-coated tablets.

< Example 6 to 7> as a binder in powder form hydroxypropyl cellulose according to the invention used Dutasteride manufacture of tablets

Propylene glycol monocaprylate and diethylene glycol monoethyl ether were used as solubilizers and hydroxypropyl cellulose was used together as binders to prepare dutasteride tablets with the composition shown in Table 2 below. Table 2 below shows the content per tablet.

1) An emulsion was prepared in the same manner as in 1) to 4) of Example 1.

2) The emulsion prepared above was added to a mixture of mannitol as a diluent, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose as a disintegrant and hydroxypropyl cellulose as a binder, and kneaded using a kneading machine, and then 60 The granules were prepared by wet granulation method by drying at ℃ for 12 hours.

3) Hereinafter, Examples 6 and 7 were prepared in the same manner as 6) to 8) of Example 1, respectively.

<Example 8> Preparation of dutasteride tablet according to the present invention used by dissolving hydroxypropyl cellulose in the aqueous phase of the emulsion as a binder

Using propylene glycol monocaprylate as a solubilizing agent and adding hydroxypropyl cellulose as a binder by dissolving it in an aqueous phase, the composition of Table 3 below was used to prepare dutasteride tablets by the following method. Table 3 below shows the content per tablet.

1) Dutasteride was added to propylene glycol monocaprylate, a solubilizing agent, and dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer.

2) Light anhydrous silicic acid was added to the solution of 1) and homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.

3) After dissolving hydroxypropyl cellulose as a binder in separate purified water, light anhydrous silicic acid as a stabilizer was added and stirred at 800 to 1000 rpm using a mechanical stirrer to homogeneously suspend.

4) The suspension of 3) was stirred at 800-1000 rpm, and the suspension of 2) was added and emulsified to prepare a homogeneous emulsion.

5) Add the emulsion of 4) as a binder to a powder mixture of microcrystalline cellulose and mannitol as a diluent and low-substituted hydroxypropyl cellulose as a disintegrant, and knead using a High Shear Mixer (Diosna), followed by a top-type dryer Granules were prepared by drying at 60°C for 12 hours using

6) Hereinafter, Example 8 was prepared in the same manner as 6) to 8) of Example 1.

<Example 9> Preparation of dutasteride tablet according to the present invention by adding calcium silicate as an adsorbent

Using propylene glycol monocaprylate and diethylene glycol monoethyl ether as solubilizers, and adding calcium silicate as adsorbents, dutasteride tablets were prepared according to the composition of Table 4 below. Table 4 below shows the content per tablet.

1) An emulsion was prepared in the same manner as in the steps 1) to 4) of Example 1.

2) The prepared emulsion is added to a mixture of calcium silicate as an adsorbent, mannitol as a diluent, microcrystalline cellulose, low-substituted hydroxypropyl cellulose as a disintegrant, and hydroxypropyl cellulose as a binder, and then kneaded using a kneading machine, followed by upper mold Granules were prepared using a wet granulation method by drying at 60° C. for 12 hours using a dryer.

3) Hereinafter, Example 9 was prepared in the same manner as 6) to 8) of Example 1.

< Example 10> only for a fee Light anhydrous silicic acid include According to the invention prepared Dutasteride manufacture of tablets

In order to compare and evaluate the stabilizing effect according to the addition method of light anhydrous silicic acid, dutasteride tablets were prepared with the composition of Table 5 below, including light silicic anhydride only in the oil phase, and no light silicic anhydride in the aqueous phase.

1) In the same manner as in 1) and 2) of Example 1, an oily solution in which dutasteride was suspended was prepared.

2) The prepared suspension was added to purified water and emulsified to prepare a homogeneous emulsion.

3) The emulsion prepared above was added to a mixture of mannitol as a diluent, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose as a disintegrant, and hydroxypropyl cellulose as a binder, and kneaded using a kneading machine, and then 60 The granules were prepared by wet granulation method by drying at ℃ for 12 hours.

4) Hereinafter, Example 10 was prepared in the same manner as 6) to 8) of Example 1, respectively.

<Example 11> Preparation of dutasteride tablet according to the present invention prepared by including light anhydrous silicic acid only in the aqueous phase

In order to compare and evaluate the stabilizing effect according to the addition method of light anhydrous silicic acid, light anhydrous silicic acid was included only in the aqueous phase, and light anhydrous silicic acid was not added to the oil phase. Dutasteride tablets were prepared with the composition shown in Table 6 below.

1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and was dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer.

2) Light anhydrous silicic acid was added to separate purified water, and the mixture was homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.

3) The suspension of 2) was stirred at 800-1000 rpm, and the solution of 2) was added and emulsified to prepare a homogeneous emulsion.

4) The emulsion prepared above was added to a mixture of mannitol, a diluent, microcrystalline cellulose, and a disintegrant, such as low-substituted hydroxypropyl cellulose and a binder, hydroxypropyl cellulose, and kneaded using a kneading machine, followed by 60 using an upper type dryer. The granules were prepared by wet granulation method by drying at ℃ for 12 hours.

5) Hereinafter, Example 11 was prepared in the same manner as 6) to 8) of Example 1 above.

<Examples 12 and 13> Preparation of other solid preparations using the present invention

Hard capsules and granules containing dutasteride were prepared with the composition shown in Table 7 below.

1) Dutasteride was added to propylene glycol monocaprylate and diethylene glycol monoethyl ether as solubilizers, and stirred at 300 to 500 rpm for 30 minutes using a mechanical stirrer to dissolve.

2) Light anhydrous silicic acid was added to the solution of 1) and homogeneously suspended by stirring at 800-1000 rpm using a mechanical stirrer.

3) Light anhydrous silicic acid was added to separate purified water, and the mixture was homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.

4) The suspension of 3) was stirred at 800-1000 rpm, and the suspension of 2) was added and emulsified to prepare a homogeneous emulsion.

5) The emulsion prepared in 4) was added to the powder mixture prepared with the diluent mannitol, microcrystalline cellulose, the disintegrant low-substituted hydroxypropyl cellulose, and the binder hydroxypropyl cellulose as a binder, and kneaded. and dried at 60° C. for 12 hours.

6) Granules of 5) were passed through a No. 18 sieve to prepare granules, which was referred to as Example 12.

7) Magnesium stearate was added to the sized granules of 6), lubricated, and filled into No. 3 hard gelatin capsules to prepare hard capsules, which was referred to as Example 13.

<Comparative Example 1> Preparation of dutasteride tablets without light anhydrous silicic acid as a stabilizer

In order to compare and evaluate the stabilizing effect according to the addition method of light anhydrous silicic acid, dutasteride tablets were prepared with the composition of Table 8 below without light anhydrous silicic acid.

1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and was dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer.

2) The solution was stirred at 800-1000 rpm and emulsified by adding to purified water to prepare a homogeneous emulsion.

3) After adding mannitol as a diluent, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose as a disintegrant and hydroxypropyl cellulose as a binder to the prepared emulsion, knead the mixture, and then dry it at 60° C. Granules were prepared by a granulation method.

4) Hereinafter, Comparative Example 1 was prepared in the same manner as 6) to 8) of Example 1.

< comparative example 2> Prepared by diluting the solubilizer solution in ethanol Dutasteride manufacture of tablets

After dissolving dutasteride using propylene glycol monocaprylate as a solubilizer, it was added to a solid excipient such as a disintegrant and a diluent using a suspension diluted with an organic solvent without emulsifying it in an aqueous phase, Comparative Example 2 of tablets were prepared. The composition of Comparative Example 2 is shown in Table 9 below.

1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and was dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer.

2) The solution of 1) was stirred at 800-1000 rpm, and light anhydrous silicic acid was added and suspended.

3) Separately, a mixed solution of purified water and ethanol was stirred at 800-1000 rpm to suspend light silicic anhydride.

4) 2) and 3) were mixed to prepare a mixed solution in which light anhydrous silicic acid was suspended.

5) Using the suspension prepared in step 4) as a binding solution, it was added to a powder mixture of mannitol as a diluent, microcrystalline cellulose, low-substituted hydroxypropyl cellulose as a disintegrant, and hydroxypropyl cellulose as a binder, and kneaded with a top-type dryer. and dried at 60° C. for 12 hours using a wet granulation method to prepare granules.

6) Hereinafter, Comparative Example 2 was prepared in the same manner as in Examples 6) to 8) of Example 1.

<Comparative Example 3> Preparation of tablets in which the solubilizer is directly adsorbed onto the solid excipient

After dissolving dutasteride using propylene glycol monocaprylate as a solubilizer with poor miscibility with water, it is added directly to a solid excipient such as a disintegrant or a diluent without emulsifying it in an aqueous phase or diluting it in an organic solvent. Tablets of Comparative Example 3 were prepared. The composition of Comparative Example 3 is shown in Table 10 below.

1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and was dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer.

2) Using the solution of 1) as a binder, it was added to a powder mixture of mannitol as a diluent, microcrystalline cellulose, calcium silicate as an adsorbent, light anhydrous silicic acid as a stabilizer, low-substituted hydroxypropyl cellulose as a disintegrant, and hydroxypropyl cellulose as a binder. was added and mixed.

3) Separately, purified water was added to the mixture of 2), kneaded, and dried at 60° C. for 12 hours using a vertical dryer to prepare granules by a wet granulation method.

4) Hereinafter, Comparative Example 3 was prepared in the same manner as 6) to 8) of Example 1.

< comparative example 4> a commercial product Abbott ^®

For comparative evaluation of accelerated stability with the dutasteride composition in tablet form provided by the present invention, a commercially available product Avodart (AVODART ^® , GlaxoSmithKline, Lot No. 064481A) was used as Comparative Example 4.

< Experimental example 1> of dutasteride related substances evaluation

In order to examine the stabilizing effect of light anhydrous silicic acid, the content of related substances of dutasteride was evaluated using Examples 1 to 5, Examples 7, 10, 11 and Comparative Examples 1 to 3. The content of total related substances was evaluated as a percentage (%) occupied by the sum of the peak areas of dutasteride related substances among the sum of all peak areas. At this time, peaks derived from excipients other than dutasteride were excluded. The results of HPLC analysis are shown in FIG. 1 . The following HPLC conditions were used for the test method for the evaluation of related substances of dutasteride.

- HPLC analysis conditions -

Column: Zorbax SB C18 (250 X 4.6 mm, 5 μm)

Detector: UV absorbance spectrometer (measurement wavelength 210 nm)

Flow rate: 1.0 mL/min

Column temperature: 30℃

Injection volume: 10 μL

Analysis time: 60 minutes

Mobile phase A: Dissolve 1.3609 g of potassium dihydrogen phosphate in 1,000 mL of ultrapure water, adjust the pH to 3.0 using 10% phosphoric acid solution, and degas before use.

Mobile phase B: After mixing acetonitrile and water in a ratio of 9:1, use degassing

Gradient elution conditions:

As a result, as shown in Figure 1, including the step of forming an emulsion by mixing an oil phase and an aqueous phase, Examples 1 to according to the present invention comprising light anhydrous silicic acid as a stabilizer on any one of the emulsions In the case of 5, Example 7, Example 10 and Example 11, the amount of dutasteride related substances generated during the manufacturing process was low as 0.31 to 0.44%, but Comparative Example 1 (including light anhydrous silicic acid as a stabilizer) 0.89%, 0.72%, and 0.97 in the case of tablets not used), Comparative Example 2 (tablets prepared by diluting a solubilizer with ethanol) and Comparative Example 3 (tablets prepared using light anhydrous silicic acid as a stabilizer in powder form) %, indicating a high content of related substances.

Therefore, it can be seen that the present invention can suppress the generation of related substances of dutasteride by using light anhydrous silicic acid as a stabilizer during the manufacturing process. In other words, referring to that the related substances standards of the commercially available product, Avodart ^® , are managed at 0.5% or less of the total related substances, the result shown in FIG. 1 shows a very good effect. In addition, manufacturing wet granules with a binding solution prepared by suspending light anhydrous silicic acid, which is a stabilizer, in an emulsion by emulsifying a solubilizer solution in which dutasteride is dissolved in an aqueous phase, prevents the occurrence of related substances of dutasteride during the manufacturing process. It can be seen that it exhibits an excellent effect in suppression.

<Experimental Example 2> Formulation Uniformity Assessment

Avodart ^® , a commercially available product, is a soft capsule containing dutasteride, which is dissolved in dutasteride and butylated hydroxytoluene, a stabilizer, in mono-diglyceride of capric/caprylic acid and then filled into a soft capsule. In the case of products provided by this manufacturing method, the probability of occurrence of non-uniformity in the content of individual capsules is very low.

However, in order to manufacture a tablet containing dutasteride, a process step for dissolving dutasteride in a small amount of solubilizer (oil phase) and homogeneously adsorbing it to a large amount of powdered excipient or adsorbent is absolutely necessary.

Accordingly, the degree of content uniformity of the dutasteride tablet prepared in the present invention was evaluated using the HPLC analysis conditions of Experimental Example 1. The results of evaluating the content uniformity of Examples 1 to 7 and Comparative Examples 1 to 3 of the present invention are shown in Table 11 below. The unit is in %.

Examples 1 to 7 and Comparative Example 1 are tablets prepared by adding an emulsion obtained by evenly dispersing an oil phase obtained by dissolving dutasteride in a solubilizer in an aqueous phase to a solid excipient, Comparative Example 2 is an emulsion It is a tablet prepared by diluting the oil phase in which dutasteride is dissolved with about 5 to 10 times 50% ethanol without forming , and adding it to a solid excipient.

As shown in Table 11, in Examples 1 to 7, Comparative Examples 1 and 2, it can be seen that very uniform tablets were prepared with content uniformity determination values within 5, but dutasteride was added to the solubilizing agent as in Comparative Example 3 In the case of tablets manufactured by directly adsorbing the dissolved oil phase to a solid excipient, the content uniformity determination value is 15 or more because the oil phase containing dutasteride is not evenly dispersed in the solid excipient. was found to be severe.

<Experimental Example 3> Accelerated Stability Assessment

Example 6 prepared by the present invention and Comparative Example 4 The stability of the commercial product Avodart ^® was comparatively evaluated. In Example 6, silica gel, which is a moisture absorbent, was put in an HDPE bottle for general pharmaceutical packaging, and Avodart ^® is a commercially available product packaged in PVC-aluminum foil PTP as it is stored under accelerated conditions (40℃ 75%RH) for 4 months, and the flexibility of dutasteride It is shown in FIGS. 2 to 4 by evaluating whether the material has changed .

Commercial product Avodart ^® contains 0.035 mg of butylated hydroxytoluene per capsule as a stabilizer, whereas Example 6 provided by the present invention does not contain any antioxidants, although the commercial product of Comparative Example 4 It showed the stability of related substances equivalent to phosphorus Avodart ^® .

In addition, as shown in FIG. 4, Comparative Example 4 was a soft capsule, and softening and denaturation of the soft film occurred under accelerated stability evaluation conditions, so that the capsules adhered to each other or the capsules were attached to the packaging material. On the other hand, in the case of Example 6 according to the present invention, it can be seen that since no change in properties was observed, excellent stability was exhibited.

Claims (18)

i) preparing a solution in which 1 part by weight of dutasteride is dissolved in 20 to 60 parts by weight of a solubilizer;
ii) preparing a solution in which 0.3 to 1 parts by weight of light anhydrous silicic acid is stirred and suspended in the solution prepared in step i);
iii) preparing a solution in which 5-30 parts by weight of light anhydrous silicic acid is stirred and suspended in 100-1000 parts by weight of separate purified water;
iv) preparing an emulsion emulsified by mixing the solution prepared in ii) and the solution prepared in iii); and
ⅴ) Preparation of granules in which the emulsion prepared in iv) is mixed and dried by adding a binder solution to the mixed powder of a disintegrant and a diluent
A method for producing a dutasteride-containing solid pharmaceutical composition comprising a.

The method according to claim 1, wherein the solubilizing agent is selected from the group consisting of propylene glycol monocaprylate, propylene glycol monolaurate, diethylene glycol monoethyl ether, glyceryl monocaprylate, glyceryl monocaprate, and mixtures thereof. Method for producing a dutasteride-containing solid pharmaceutical composition, characterized in that.

The method of claim 2, wherein the solubilizing agent is propylene glycol monocaprylate or a mixture of propylene glycol monocaprylate and diethylene glycol monoethyl ether.

The method of claim 1, wherein in step iii) or step v), further adding a binder selected from hydroxypropyl cellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, povidone, and copovidone Method for producing a dutasteride-containing solid pharmaceutical composition, characterized in that.

The method of claim 1, wherein in step v), an adsorbent of calcium silicate or magnesium aluminate metasilicate is additionally added to the dutasteride-containing solid pharmaceutical composition.

In the preparation for treatment of benign prostatic hyperplasia or androgenetic alopecia,
A solid preparation comprising a solid pharmaceutical composition prepared by any one of the manufacturing methods according to any one of claims 1 to 5.

i) preparing a solution in which 1 part by weight of dutasteride is dissolved in 20 to 60 parts by weight of a solubilizer;
ii) preparing a solution in which 0.3 to 1 parts by weight of light anhydrous silicic acid is stirred and suspended in the solution prepared in step i);
iii) preparing an emulsion emulsified by mixing the solution prepared in ii) and purified water; and
iv) Preparation of granules in which the emulsion prepared in iii) is mixed and dried by adding a binding solution to the mixed powder of a disintegrant and a diluent
A method for producing a dutasteride-containing solid pharmaceutical composition comprising a.

The method of claim 7, wherein the solubilizing agent is selected from the group consisting of propylene glycol monocaprylate, propylene glycol monolaurate, diethylene glycol monoethyl ether, glyceryl monocaprylate, glyceryl monocaprate, and mixtures thereof. Method for producing a dutasteride-containing solid pharmaceutical composition, characterized in that.

The method of claim 8, wherein the solubilizing agent is propylene glycol monocaprylate or a mixture of propylene glycol monocaprylate and diethylene glycol monoethyl ether.

The doota according to claim 7, wherein a binder selected from hydroxypropyl cellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, povidone, and copovidone is further added in step iv). A method for preparing a solid pharmaceutical composition containing steroids.

The method of claim 7, wherein in step iv), an adsorbent of calcium silicate or magnesium aluminate metasilicate is additionally added to the dutasteride-containing solid pharmaceutical composition.

In the preparation for treatment of benign prostatic hyperplasia or androgenetic alopecia,
12. A solid preparation comprising a solid pharmaceutical composition prepared by any one of the manufacturing methods according to claim 7 to 11.

i) preparing a solution in which 1 part by weight of dutasteride is dissolved in 20 to 60 parts by weight of a solubilizer;
ii) preparing a solution in which 5-30 parts by weight of light anhydrous silicic acid is stirred and suspended in 100-1000 parts by weight of separate purified water;
iii) preparing an emulsion emulsified by mixing the solution prepared in i) and the solution prepared in ii); and
iv) Preparation of granules in which the emulsion prepared in iii) is mixed and dried by adding a binding solution to the mixed powder of a disintegrant and a diluent
A method for producing a dutasteride-containing solid pharmaceutical composition comprising a.

14. The method of claim 13, wherein the solubilizing agent is selected from the group consisting of propylene glycol monocaprylate, propylene glycol monolaurate, diethylene glycol monoethyl ether, glyceryl monocaprylate, glyceryl monocaprate, and mixtures thereof. Method for producing a dutasteride-containing solid pharmaceutical composition, characterized in that.

15. The method of claim 14, wherein the solubilizing agent is propylene glycol monocaprylate or a mixture of propylene glycol monocaprylate and diethylene glycol monoethyl ether.

According to claim 13, Doota characterized in that in step iv), a binder selected from hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, povidone, and copovidone is further added. A method for preparing a solid pharmaceutical composition containing steroids.

[Claim 14] The method of claim 13, wherein an adsorbent of calcium silicate or magnesium aluminate metasilicate is further added in step iv).

In the preparation for treatment of benign prostatic hyperplasia or androgenetic alopecia,
A solid preparation comprising a solid pharmaceutical composition prepared by any one of the manufacturing methods according to any one of claims 13 to 17.

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