KR102352888B1 - Oral pharmaceutical composition comprising dutasteride - Google Patents

Abstract

The present invention relates to an oral pharmaceutical composition comprising dutasteride, and more particularly, to a self-microemulsifying pharmaceutical composition comprising dutasteride and an emulsifier, wherein the emulsifier has an HLB value within the range of 1 to 6 It consists of a phosphorus first emulsifier, a second emulsifier having an HLB value within a range of 12 to 20, and a third emulsifier having an HLB value within a range of 3 to 10, and the total average HLB value of the emulsifiers is within the range of 4.5 to 7.5 It is a self-microemulsifying pharmaceutical composition comprising dutasteride, characterized in that The pharmaceutical composition containing dutasteride according to the present invention has excellent stability, and can exhibit the same absorption rate and pharmacokinetics as the reference drug even when a smaller amount of the emulsifier is used. Accordingly, it is possible to significantly reduce the dosage size to improve the convenience of taking, and also, it is possible to manufacture it with a low cost and a simple process in the manufacturing method, as well as various types of formulations of soft capsules and tablets.

Description

Oral pharmaceutical composition comprising dutasteride {ORAL PHARMACEUTICAL COMPOSITION COMPRISING DUTASTERIDE}

The present invention relates to an oral pharmaceutical composition comprising dutasteride.

Dutasteride is currently marketed under the trade name AVODART®, which contains 0.5 mg dutasteride butylated with 349.5 mg caprylic/capric acid mono- and di-glyceride oils. It is a product that is dissolved in a mixture of hydroxytoluene (BHT) and filled in a soft capsule. It is used as a treatment for benign prostatic hyperplasia, prostate cancer and androgenetic alopecia.

However, as can be seen from the examples of commercially available Avodart, Dutasteride, the main component, is a poorly soluble drug (US Patent Application Publication No. 2009/0069364 (Patent Document 1)) Disclosed, where the solubility of dutasteride is 4.4 g / 100 g in ethanol, 3.06 g / 100 g in isopropanol, 2.75 g / 100 g in Capmul MCM NF (Capmul MCM NF), and 1.34 g / 100 g in propylene glycol. ), it requires a fairly large amount of emulsifiers, surfactants and other excipients to dissolve it and increase bioavailability.

That is, the reference drug [AVODATRT] Soft capsule] is dissolved in the emulsifier 'diglyceryl caprylate/caprate (product name: CAPMUL MCM NF)' to form a soft capsule. In order to improve the absorption rate of dutasteride, various emulsifiers are used to form soft capsules.

Accordingly, it is inevitable that the amount of the emulsifier and the like is relatively large compared to the amount of the main component, and the size of the soft capsule or tablet is subsequently increased, thereby hindering the convenience of taking.

Although, the method of using the self-microemulsifying drug delivery (SMEDDS) technology to increase the bioavailability of dutasteride, a poorly soluble drug, is well known in the prior art, because it still uses a large amount of emulsifier, There is still a lot of room for improvement in terms of feel and absorption.

Accordingly, the present inventors made research efforts to develop a self-emulsifying drug delivery system that exhibits excellent bioavailability while having a smaller volume than Avodart in which the drug is simply dissolved in oil. The present invention was completed by confirming that the active ingredient is emulsified in an aqueous solution to exist in a stable emulsion state, and the solubilization is greatly improved so that even with a small amount of excipients it exhibits superior bioavailability than the existing Avodart. .

US 2009/0069364 A1 (2009. 03. 12.)

It is an object of the present invention to construct a self-emulsifying solution drug delivery system (SESDDS) composition that can exhibit the same absorption rate even with a small amount of emulsifier by improving stability while using SMEDDS (self-microemulsifying drug delivery system) technology and An object of the present invention is to provide a composition that can be used not only as a soft capsule formulation, but also as a tablet formulation that can overcome the limitations of commonly known soft capsule formulations.

The present invention has been devised to solve the problems of the prior art described above,

As a self-microemulsifying pharmaceutical composition comprising dutasteride and an emulsifier,

The emulsifier is a first emulsifier having an HLB value within the range of 1 to 6,

A second emulsifier having an HLB value within the range of 12 to 20, and

It consists of a third emulsifier with an HLB value within the range of 3 to 10,

It provides a self-microemulsifying pharmaceutical composition comprising dutasteride, characterized in that the total average HLB value of the emulsifiers is within the range of 4.5 to 7.5.

In addition, in the present invention, the first emulsifier provides a pharmaceutical composition comprising dutasteride, characterized in that 50 to 85% by weight, based on the total weight of the composition.

In addition, in the present invention, the second emulsifier provides a pharmaceutical composition comprising dutasteride, characterized in that it is included in 10 to 40% by weight, based on the total weight of the composition.

In addition, in the present invention, the third emulsifier provides a pharmaceutical composition comprising dutasteride, characterized in that it is contained in an amount of 2 to 8% by weight, based on the total weight of the composition.

In addition, in the present invention, the first emulsifier provides a pharmaceutical composition comprising dutasteride, characterized in that propylene glycol monolaurate.

In addition, in the present invention, the second emulsifier provides a pharmaceutical composition comprising dutasteride, characterized in that polyoxyl 40 hydrogenated castor oil.

In addition, in the present invention, the third emulsifier provides a pharmaceutical composition comprising dutasteride, characterized in that the sucrose fatty acid ester.

In addition, in the present invention, the dutasteride, based on the total weight of the composition, provides a pharmaceutical composition comprising dutasteride, characterized in that contained in 0.5 to 4% by weight.

In addition, there is provided a solid preparation comprising dutasteride solidified by further including the composition of the present invention, an adsorbent, or an adsorbent and a pharmaceutically acceptable excipient.

In addition, in the solid formulation of the present invention, the adsorbent provides a solid formulation comprising dutasteride, characterized in that magnesium metasilicate aluminate.

In addition, in the solid formulation of the present invention, the adsorbent provides a solid formulation comprising dutasteride, characterized in that it is included in a weight ratio of 0.5 to 1.5 compared to the composition.

In addition, there is provided a soft capsule formulation for oral use carrying the pharmaceutical composition of the present invention.

Also provided is a tablet comprising the solid preparation of the present invention.

The pharmaceutical composition containing dutasteride according to the present invention has excellent stability, and can exhibit the same absorption rate and pharmacokinetics as the reference drug even when a smaller amount of the emulsifier is used. Accordingly, it is possible to significantly reduce the dosage size to improve the convenience of taking, and also, it is possible to manufacture it with a low cost and a simple process in the manufacturing method, as well as various types of formulations of soft capsules and tablets.

1 shows the results of a comparative dissolution experiment according to the adsorbent.
Figure 2 shows the comparative dissolution results of the composition of the present invention and the control drug.
3 shows the bioequivalence test results of the composition of the present invention and the reference drug.
Figure 4 shows the evaluation results of the properties for the self-emulsifying emulsion formation of the composition of the present invention.
5 shows the freeze-thaw stability test results for the composition of the present invention.
Figure 6 shows the results of the centrifugation stability test for the composition of the present invention.
7 shows the long-term storage stability test results for the composition of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention is

As a self-microemulsifying pharmaceutical composition comprising dutasteride and an emulsifier,

The emulsifier is a first emulsifier having an HLB value within the range of 1 to 6,

A second emulsifier having an HLB value within the range of 12 to 20, and

It consists of a third emulsifier with an HLB value within the range of 3 to 10,

It is characterized in that the total average HLB value of the emulsifiers is within the range of 4.5 to 7.5.

HLB (Hydrophile-Lipophile Balance) value is an index indicating the balance between hydrophilicity and lipophilicity (hydrophobicity) of an emulsifier, and when HLB is large, the ratio of hydrophilicity is large, and when it is small, it means that the ratio of hydrophilicity is small. Each emulsifier has its own HLB value, and the more hydrophilic the material, the larger the HLB value. For example, in the case of surfactant, depending on the HLB value, in the case of 1.5 to 3, an antifoaming agent, 4 to 6 is a W/O emulsifier, 7 to 9 is a dispersing agent, 8 to 18 is an O/W emulsifier, 13 to 15 is a detergent, 15-18 can be used as a solubilizer. Since the HLB value is a concept widely used in the art, the definition in the art will be followed, and a more detailed description will be omitted.

In general, only one emulsifier is used, but in the present invention, three or more emulsifiers with different HLB values are mixed and used to improve stability. It can achieve the effect of greatly improving, and also greatly reducing the volume of the formulation.

The first emulsifier, as a substance having an HLB value within the range of 1 to 6, serves as a solubilizer or a main emulsifier for dissolving dutasteride, a poorly soluble active ingredient, based on the total weight of the composition, 50 to 85% by weight may be included. . A preferred example for this is propylene glycol monolaurate. As shown in Table 1 below, propylene glycol-mono-laurate (product name: Lauroglycol90), which shows high solubility in propylene glycol-mono-caprylate and propylene glycol-mono-laurate, and has relatively high solubility, is used. Therefore, it can be emulsified in a smaller amount than glycerol-tri-caprylate/caprate (product name: Capmul MCM) used in the reference drug.

However, since propylene glycol-mono-laurate is more preferably selected, since it is longer than propylene glycol-mono-caprylate in the carbon chain, it is possible to broaden the selection of the second and third emulsifiers to be described later. , because it can contribute to the miscibility with them and the formation of a stable emulsion.

The second emulsifier is a material having an HLB value within the range of 12 to 20, and serves as an auxiliary emulsifier, and may be included in an amount of 10 to 40% by weight, based on the total weight of the composition. A preferred example of this is polyoxyl 40 hydrogenated castor oil. When propylene glycol-mono-laurate, the main emulsifier, forms an emulsion, it can relieve stress between carbon chains and maintain a stable emulsion. have. In particular, polyoxyl castor oil has different physical properties at room temperature depending on the chain length. Polyoxyl 40 hydrogenated castor oil is a wax form at room temperature, but dissolves well with propylene glycol-mono-laurate to form a stable emulsifier.

The third emulsifier is a substance having an HLB value within the range of 3 to 10, and serves as another emulsifying aid, and may be included in an amount of 2 to 8% by weight, based on the total weight of the composition. A preferred example of this is sucrose fatty acid ester. Sucrose fatty acid ester (L-1695) is a lauryl fatty acid and has the same chain length as Lauroglycol90, an emulsifier. It can play a role in helping you build.

As such, the emulsifier in which the first emulsifier, which is the main emulsifier, and the second and third emulsifiers, which are two auxiliary emulsifiers, are combined quickly forms an emulsion in the aqueous phase and is very stable. Furthermore, due to a specific combination of auxiliary emulsifiers such as the second emulsifier and the third emulsifier, the content of the first emulsifier, which is the main emulsifier, can be significantly lowered compared to the conventional one, which is directly related to the reduction in the size of dosage forms such as tablets or capsules. A more detailed understanding of this may be made through Examples and Experimental Examples to be described later.

It is preferable that the total average HLB value of the emulsifiers including the first emulsifier, the second emulsifier, and the third emulsifier is within the range of 4.5 to 7.5.

In the present invention, since the emulsifier is a case of combining three types, it should be determined by calculating the average HLB value of the combined emulsifier.

According to the study of the present inventor, when the total HLB value of the emulsifier in which dutasteride is solubilized is adjusted to between 4.5 and 7.5 and an O/W (Oil-in-Water) emulsion is used, excellent absorption rate and pharmacokinetics are obtained in-vivo. It can show PK results equivalent to that of the reference drug. In the dissolution test, which is an in-vitro experiment to determine this, an approximate trend can be grasped at pH 5.5 and pH 6.8, which are the absorption pH points in the body. will be able

The total average HLB value may be calculated as the sum of the average HLB values calculated as in Equation 1 below.

The dutasteride, as an active ingredient of the composition of the present invention, is preferably contained in an amount of 0.5 to 4% by weight, based on the total weight of the composition. Below this range, the total amount of the emulsifier becomes unnecessarily higher, which is not preferable in terms of tablet size reduction, and dissolution equivalence with the reference drug cannot be guaranteed. There may be a problem in the stability of , or the formation itself may not be smooth.

The self-microemulsifying pharmaceutical composition of the present invention may be prepared in the form of a pharmaceutical by putting it in a supported formulation such as a soft capsule.

In addition, the self-microemulsifying pharmaceutical composition of the present invention may be prepared as a solidified formulation further comprising an adsorbent or an adsorbent and a pharmaceutically acceptable excipient.

As the adsorbent, a well-known adsorbent in the art may be used, but magnesium metasilicate is preferable in terms of dissolution characteristics or process. That is, magnesium metasilicate aluminate exhibits easier dissolution properties compared to other adsorbents, and it is advantageous in terms of the process because it does not blow fine powder. A more detailed understanding of this may be made through Examples and Experimental Examples to be described later.

In addition, the adsorbent is preferably included in a weight ratio of 0.5 to 1.5 with respect to the self-microemulsifying pharmaceutical composition. Below the above range, although oil phase adsorption is possible, a problem in which granules are formed may occur and flowability may also be poor. In addition, if it exceeds the above range, the size of the tablet is unnecessarily increased by including too many adsorbents, which may impair the purpose of the present invention, and may also adversely affect dissolution.

The solidified formulation may be manufactured in the form of a tablet through a process such as tableting/coating, or may be prepared in the form of a capsule by putting it in a supported formulation such as a soft capsule.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, it is clear that the following examples and experimental examples are only for detailed description, and are not intended to limit the scope of rights thereby.

Example

Example One

Dutasteride, propylene glycol monolaurate, polyoxyl 40 hydrogenated castor oil, and sucrose fatty acid ester were put in a SUS container and dissolved using a homomixer to prepare a self-emulsifying emulsion solution (total average HLB value was 5.6).

Example 2

A self-emulsifying emulsion solution was prepared in the same manner as in Example 1.

Thereafter, the self-emulsifying emulsion solution was adsorbed to magnesium metasilicate aluminate, mixed, tableted, and coated to prepare tablets.

Example 3

Tablets were prepared in the same manner as in Example 2, except that the self-emulsifying emulsion solution was adsorbed to silicon dioxide (Syloid FP244).

Example 4

Tablets were prepared in the same manner as in Example 2, except that the self-emulsifying emulsion solution was adsorbed to calcium silicate (Florite R).

Example 5

A self-emulsifying emulsion solution was prepared in the same manner as in Example 1.

Then, the self-emulsifying emulsion solution was adsorbed to magnesium aluminate metasilicate, and the necessary excipients and lubricants were mixed, compressed, and coated to prepare tablets.

The final prescription was shown in Table 2 below.

comparative example (contrast treaty)

Avordart™ 0.5mg commercially available

Experimental example

- Comparative dissolution test for each adsorbent

Comparative dissolution test was performed at pH 5.5 for Examples 2 to 4. Overall, magnesium metasilicate aluminate and calcium silicate showed favorable properties for dissolution. However, calcium silicate was unfavorable to management in the manufacturing process because a lot of powder was blown. The results were the same as in FIG. 1 .

- Comparative dissolution test with reference drug

A comparative dissolution test was performed comparing the tablet prepared with the final prescription of Example 5 to the commercially available control drug (Comparative Example).

The results were as shown in FIG. 2 .

- Bioequivalence test

The tablet prepared by the final prescription of Example 5 was subjected to a bioequivalence test with a commercially available control drug (comparative example). The results were shown in Table 3 and FIG. 3 .

- self-emulsifying emulsion Evaluation of properties and stability

In order to evaluate the properties and stability of the self-emulsifying emulsion, the self-emulsifying emulsion composition of Example 1 was subjected to a test as shown in Table 4 below.

SMEDDS Evaluation Method A evaluation result was as shown in FIG. 4 . An emulsion was rapidly formed immediately upon addition, and it became slightly opaque, and there was no change after 1 hour had elapsed.

Stability Test Method I evaluation results were as shown in FIG. 5 . The transparent properties were maintained at 50°C, and although it was in an opaque shape at -4°C, it was cooled to uniform properties without phase separation.

Stability Test Method II evaluation results were as shown in FIG. 6 . Phase separation did not occur even after centrifugation at 3500 rpm and the same properties as the first were maintained.

The evaluation result of Stability Test Method Ⅲ was shown in FIG. 7 . Uniform properties were maintained without phase separation for 3 months of long-term storage.

Claims (13)

As a self-microemulsifying pharmaceutical composition comprising dutasteride, and an emulsifier,
The emulsifier is a first emulsifier having an HLB value within the range of 1 to 6,
A second emulsifier having an HLB value within the range of 12 to 20, and
It consists of a third emulsifier with an HLB value within the range of 3 to 10,
The first emulsifier is propylene glycol monolaurate,
The second emulsifier is polyoxyl 40 hydrogenated castor oil,
The third emulsifier is sucrose lauryl acid ester,
Self-microemulsifying pharmaceutical composition comprising dutasteride, characterized in that the total average HLB value of the emulsifiers is within the range of 4.5 to 7.5. The pharmaceutical composition according to claim 1, wherein the first emulsifier is comprised of 50 to 85% by weight based on the total weight of the composition. The pharmaceutical composition according to claim 1, wherein the second emulsifier is comprised of 10 to 40% by weight, based on the total weight of the composition. The pharmaceutical composition according to claim 1, wherein the third emulsifier is comprised of 2 to 8% by weight based on the total weight of the composition. delete delete delete The pharmaceutical composition according to claim 1, wherein the dutasteride is, based on the total weight of the composition, 0.5 to 4% by weight. A solid formulation comprising the composition of any one of claims 1 to 4, and 8, and dutasteride solidified by further comprising an adsorbent, or an adsorbent and a pharmaceutically acceptable excipient. The solid formulation of claim 9, wherein the adsorbent is magnesium aluminate metasilicate. The solid formulation of claim 9, wherein the adsorbent is included in an amount of 0.5 to 1.5 by weight compared to the composition. An oral soft capsule formulation carrying the pharmaceutical composition of any one of claims 1 to 4 and 8. A tablet comprising the solid formulation of claim 9 .

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