KR101590072B1 - Composition for self-emulsifying drug delivery system comprising dutasteride - Google Patents

Abstract

The present invention relates to a composition for a self-emulsifying drug delivery system comprising dutasteride, oil, and PEG-40 hydrogenated castor oil as a surfactant. The composition for a self-emulsifying drug delivery system comprising dutasteride is capable of enhancing the convenience of administration by reducing the size of a medicine by reducing the amount of a diluting agent used in making of dutasteride, and shows excellent bioavailability by being emulsified into a stable emulsion in an aqueous solution and dissolution stability of the drug when stored for a long period of time under particular conditions, thereby being useful for preventing or treating benign prostatic hyperplasia, prostatic cancer, or alopecia.

Description

Technical Field [0001] The present invention relates to a composition for self-emulsifying drug delivery system comprising dutasteride,

(PEG-40 Hydrogenated castor oil) as a dutasteride, an oil, and a surfactant. The present invention relates to a composition for a self-emulsifying drug delivery system comprising dutasteride, To a composition for a self emulsifying drug delivery system.

An azaseroid-based compound is one of the most important pharmaceutically active compounds, among which the 5-alpha reductase inhibitor ditasteride (chemical name: 17? -N- (2,5-bis (trifluoromethyl) Phenylcarbamoyl-4-aza-5? -Androst-1-en-3-one) is known to be useful in the treatment of benign prostatic hyperplasia, prostate cancer and male alopecia (see US Pat. No. 5,565,467).

U.S. Patent Application Publication No. 2009/0069364 discloses that 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 the capsule MCM NF (Capmul MCM NF), 1.34 g / 100 g.

Doota Ste fluoride is present trade name ahbodateu (AVODART ^®) are commercially available as, ahbodateu is 349.5mg of the Doota Ste fluoride of 0.5mg caprylic / capric acid in the car mono- and di-glyceride oils and butylated hydroxytoluene (BHT) and filled in soft capsules. It is used as a treatment for benign prostatic hyperplasia, prostate cancer or alopecia of male. However, since the amount of the excipient that constitutes the product is relatively larger than that of the active ingredient, the volume of the soft capsule is large, which is disadvantageous for taking.

In order to solve this problem, the present inventors have developed a self emulsifying drug delivery system which is smaller in volume than avodart and exhibits excellent bioavailability (Korean Patent Application Laid-Open Publication No. 2013-0086551), but also a hydrogentate castor oil HCO-50 (PEG-50 Hydrogenated castor oil) causes the retardation of the disintegration of the dutasteride when stored for a long period under certain conditions, resulting in a deterioration of the dissolution stability of the dutasteride.

Therefore, the present inventors have tried to improve the dissolution stability of dutasteride, and by using hydrogencontaster oil having appropriate degree of substitution, it is possible to maintain the dissolution rate of the drug at the initial stage even under long-term storage under certain conditions The present invention has been completed.

U.S. Patent No. 5565467 U.S. Published Application 2009/0069364 Korean Patent Application Publication No. 2013-0086551

It is therefore an object of the present invention to provide a composition for a self emulsifying drug delivery system comprising dutasteride which exhibits excellent bioavailability even with the use of a smaller amount of excipient and which is excellent in dissolution stability even under long term storage under certain conditions .

In order to achieve the above object, the present invention provides a composition comprising (a) 0.1 to 1% by weight of dutasteride; (b) 50 to 95% by weight of an oil; And (c) 4 to 40% by weight of PEG-40 Hydrogenated castor oil as a surfactant.

The composition for a self-emulsifying drug delivery system comprising the dutasteride according to the present invention can reduce the size of the formulation by reducing the amount of the excipient used in the dutasteride formulation, And exhibits excellent drug elution stability even under long-term storage under certain conditions, and thus can be effectively used for the prophylaxis or treatment of benign prostatic hyperplasia, prostate cancer or alopecia areata.

1 shows the results of measuring the dissolution rate (at the time of 45 minutes) after storage for 3 months and 6 months under the conditions of initial 40 ° C. and 75% RH for the compositions of Examples 1 to 4 and Comparative Examples 1 and 2 will be.
Fig. 2 shows the results of comparing the dissolution rates (at the time of 45 minutes) after storing the compositions of Example 1 and Comparative Examples 1 and 2 under the conditions of 40 占 폚 and 75% RH for 6 months.
FIG. 3 shows the results of comparing the elution deviations (%) for each time after storing the compositions of Example 1 and Comparative Example 1 under the conditions of 40 ° C. and 75% RH for 6 months.

The present invention provides a composition for a self-emulsifying drug delivery system comprising dutasteride, oil and a surfactant. The composition for a self-emulsifying drug delivery system of the present invention is characterized in that an emulsion is formed by self-emulsification when mixed with water.

According to one embodiment of the present invention, the composition of the present invention comprises (a) 0.1 to 1% by weight of dutasteride; (b) 50 to 95% by weight of an oil; And (c) 4 to 40% by weight of a PEG-40 hydrogencarbonate oil as a surfactant.

According to another embodiment of the present invention, the composition of the present invention comprises (a) 0.1 to 1% by weight of dutasteride; (b) 59 to 95% by weight of an oil; And (c) 4 to 40% by weight of a PEG-40 hydrogencarbonate oil as a surfactant.

Preferably, the composition of the present invention comprises 0.3 to 0.6% by weight of dutasteride, 70 to 85% by weight of oil and 4 to 40% by weight of PEG-40 hydrogencarbonate oil as a surfactant, .

Preferably, the composition of the present invention comprises 0.3 to 0.6% by weight of dutasteride, 70 to 85% by weight of oil and 14 to 28% by weight of PEG-40 hydrogencarbonate oil as a surfactant, .

(a) Dutasteride

The dutasteride used as the active ingredient in the composition for self-emulsifying drug delivery system of the present invention may be contained in an amount of 0.1 to 1% by weight, preferably 0.3 to 0.6% by weight, based on the total weight of the composition. When the content of the dutasteride is 0.1% by weight or more, the amount of the excipient and the mass of the capsule can be reduced, and convenience of taking can be achieved. When the content of the dutasteride is less than 1% It is easy to dissolve the components and is easy to be made into soft capsules. In addition, the dose of ditrastaride is fixed at 0.5 mg.

(b) oil

The oil used in the composition for the self-emulsifying drug delivery system of the present invention is well mixed with a surfactant, emulsified in water to form a stable emulsion, and has sufficient solubility to the active ingredient, dutasteride. Can be used. Examples of oils usable in the present invention include the following.

1) Mono-, di- or mono / di-glycerides of fatty acids, preferably mono- or di-glycerides of caprylic / capric acid (trade name: Capmul MCM)

(2) Fatty acid triglycerides, preferably intermediate fatty triglycerides, can be used. For example, fractionated coconut oil (trade name: Capriol)

(3) an ester compound of a fatty acid and a monohydric alkanol, preferably an ester compound of a fatty acid having 8 to 20 carbon atoms and a monohydric alkanol having 2 to 3 carbon atoms, such as isopropyl myristate, isopropyl palmitate, Eate or ethyl oleate; And

④ Free fatty acids, preferably liquid oleic acid or linoleic acid.

In the composition for the self-emulsifying drug delivery system of the present invention, the oil may be contained in an amount of 50 to 95% by weight, preferably 70 to 85% by weight, based on the total weight of the composition. If the oil content is more than 50% by weight, it is possible to sufficiently dissolve the main components to prevent precipitation, and the oil content should be 95% by weight or less so that the emulsifying ability of the preparation can be maintained by maintaining the used amount of the surfactant.

(c) Surfactant: PEG-40 Hydrogenated castor oil

The surfactant used in the composition for a self-emulsifying drug delivery system of the present invention functions to stably emulsify an oil component in water to form an emulsion. Hydrogenated castor oil (HCO) used in the composition of the present invention is a nonionic surfactant having extremely high stability and is known to have little irritation or hemolysis. The hydrogenated castor oil is characterized by having a significantly higher molecular weight than other ethylene oxide addition type nonionic surfactants, and is excellent as a solubilizing agent for dissolving a lipophilic substance in water.

The hydrogeneized castor oil may be divided into several classes according to the degree of ethoxylation substituted per PEG unit as shown in Table 1 below.

INCI name PEG-10 Hydrogenated Castor Oil PEG-20 Hydrogenated Castor Oil PEG-30 Hydrogenated Castor Oil PEG-40 Hydrogenated Castor Oil PEG-50 Hydrogenated Castor Oil PEG-60 Hydrogenated Castor Oil

According to the experimental results of the present invention, PEG-40 hydrogenated castor oil (for example, NIKKOL ^® HCO-40 Or Cremophor ^® RH40) soft capsule formulations containing the PEG-60 dihydro originating suited castor oil (for example, NIKKOL ^® HCO-60) or PEG-50 dihydro originating suited castor oil (for example, NIKKOL ^® HCO-50 ) Than that of the soft capsule formulation. Also, PEG-40 dihydro originating suited soft capsule formulations containing castor oil is PEG-30 dihydro originating suited castor oil (for example, NIKKOL ^® HCO-30) or PEG-20 dihydro originating suited castor oil (e.g., NIKKOL ( ^R ) HCO-20) is superior in emulsion forming ability.

The HCO-40 used as a surfactant in the composition for the self-emulsifying drug delivery system of the present invention is contained in an amount of 4 to 40% by weight, preferably 17 to 33% by weight or 14 to 28% by weight, based on the total weight of the composition . The amount of the surfactant should be 4 wt% or more to achieve the desired emulsion formation. If the content of the surfactant is less than 40 wt%, excellent emulsion formation relative to the addition amount can be achieved.

In the composition for a self-emulsifying drug delivery system of the present invention, the ratio of the components is 1: 100-500: 1-100, 1: 100-400: 1-90, 1: 100-350: 1-85, 1: 100-300: 1-80 or 1: 100-200: 1-70, preferably 1: 160: 60.

The composition for a self-emulsifiable delivery system of the present invention may further comprise an additional stabilizer selected from the group consisting of water, ethanol, glycine, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, dimethylisosorbide, cetyl alcohol and mixtures thereof , Which may preferably be water, ethanol or glycine. In addition, the composition for a self-emulsifiable delivery system of the present invention may further include other pharmaceutically acceptable additives.

The composition for the self-emulsifiable delivery system of the present invention is divided into one to several doses so that a daily dose generally known to the dutasteride (in the case of an adult, 0.5 mg once a day is usually administered once a day) Can be administered appropriately.

The composition for a self emulsified delivery system of the present invention is useful as a pharmaceutical composition for preventing or treating benign prostatic hyperplasia, prostate cancer or alopecia of the male.

The present invention also provides a capsule formulation comprising the composition for the self-emulsifying drug delivery system described above. The capsule formulation may be prepared by filling a composition for a self-emulsifying drug delivery system of the present invention with a capsule, preferably a soft capsule, according to a conventional pharmaceutical manufacturing process.

The capsule dosage form according to the present invention may have a total amount of the filled contents of 90 mg to 150 mg, preferably 100 mg to 120 mg. (Oval # 2) or 3 oval (oval # 3), 3 oblong (oblong # 3), or the like, since the weight of the filling content of the capsule preparation according to the present invention is smaller than that of the existing commercial product avodate ) And the like. The volume according to the oval number and the oblong number is well known in the prior art. For example, 2 oval corresponds to 0.092 to 0.142 ml, 3 oval corresponds to 0.148 to 0.185 ml, 3 oblong corresponds to 0.142 to 0.185 ml . The capsule formulation according to the present invention has a smaller volume (weight) of the soft capsule as compared with a conventional formulation, which is superior in ease of taking.

The composition for dutasteride self-emulsifying drug delivery system of the present invention is a composition for the self-emulsifying drug delivery system of the present invention having a large volume prepared by dissolving 0.5 mg of dutasteride in 349.5 mg of mono- and di-glyceride oil of caprylic / capric acid Compared with conventional Avodat, even when prepared by dissolving 0.5 mg of dutasteride in a mixture of 110 mg of oil and a surfactant, a stable emulsion is formed in an aqueous solution to exhibit an equivalent in-vivo absorption rate. In addition, PEG-40 hydrogel as a surfactant When used with castrated castor oil, it exhibits excellent drug dissolution stability.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  1 to 4: as a surfactant PEG -40 Hydrogenated  Preparation of Soft Capsule Formulations Containing Castor Oil

Ditasteride was dissolved in Capmul MCM oil as described in Table 2 below, and then Cremophor RH40 (BASF) or HCO-40 (NIKKOL), a PEG-40 hydrogencinating castor oil, was added as a surfactant to prepare a self emulsion emulsion preparation To obtain a concentrate (self-emulsifying emulsion).

The self-emulsifying emulsion pre-concentrate prepared above was filled in a soft capsule to prepare a capsule formulation. Specifically, a coating composition was prepared according to a conventional coating method using a manufacturing component (43 mg of small gelatin per 1 capsule (65 mg), 19 mg of glycerin and 0.5 mg of glycine) containing commonly known gelatin, plasticizer and the like Respectively. Next, using a conventional soft capsule filling machine (Bochang Machinery, Korea), the ribbon was formed into a round shape with a ribbon thickness of 0.65 mm by a normal filling method, and the self emulsified emulsion concentrate prepared above was charged Which was molded and dried to prepare a soft capsule formulation.

mg / unit Example 1 Example 2 Example 3 Example 4 Filling
contents Dutta Stride 0.5 0.5 0.5 0.5 Capmul MCM NF 80 90 80 90 Cremophor RH40 (BASF) 30 20 - - HCO-40 (NIKKOL) - - 30 20 Soft capsule shell Bovine gelatin 43 43 43 43 glycerin 19 19 19 19 Glycine 0.5 0.5 0.5 0.5 Purified water Suitable amount Suitable amount Suitable amount Suitable amount

Comparative Example  1 to 4: as a surfactant PEG -60, PEG -50, PEG -30 or PEG -20 Hydrogenated  Preparation of Soft Capsule Formulations Containing Castor Oil

Except that HCO-60 (NIKKOL), HCO-50 (NIKKOL), HCO-30 (NIKKOL) or HCO-20 (NIKKOL) were used in place of Cremophor RH40 , And the process of Example 1 was repeated to produce soft capsule formulations of Comparative Examples 1 to 4.

mg / unit Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Filling
contents Dutta Stride 0.5 0.5 0.5 0.5 Capmul MCM NF 80 80 80 80 HCO-60 (NIKKOL) 30 - - - HCO-50 (NIKKOL) - 30 - - HCO-30 (NIKKOL) - - 30 - HCO-20 (NIKKOL) - - - 30 Soft capsule shell Bovine gelatin 43 43 43 43 glycerin 19 19 19 19 Glycine 0.5 0.5 0.5 0.5 Purified water Suitable amount Suitable amount Suitable amount Suitable amount

Test Example  One: Self-emulsification  Particle Size Comparison of Compositions for Drug Delivery Systems

The self-emulsifying emulsion pre-concentrate prepared in Examples 1 to 4 and Comparative Examples 1 to 4 was diluted 100 times with distilled water, and then the particle flow in the fluid was measured using Nanophox (Sympatec, Germany) The particle size was measured by a photon cross correlation spectroscopy (PCCS) principle which was observed by an optical method. The results of each period are shown in Table 4 below.

Particle Size (nm) Example 1 18.2 ± 1.5 Example 2 22.5 ± 2.3 Example 3 16.3 ± 2.2 Example 4 24.9 ± 1.1 Comparative Example 1 20.1 + 1.7 Comparative Example 2 25.8 ± 2.9 Comparative Example 3 171.7 ± 21.3 Comparative Example 4 248.8 ± 30.4

As shown in Table 4, the compositions of Examples 1 to 4 and Comparative Examples 1 and 2 formed emulsions having small particles of 100 nm or less, whereas the compositions of Comparative Examples 3 and 4 formed large particles It can be expected that absorption in the body is not easy. The results show that hydrogendic castor oil of the PEG-30 grade or lower has a low HLB value, which is easy to dissolve the main component, but does not form small emulsion of the particles, and therefore is not suitable for the present formulation.

Test Example  2: Evaluation of dissolution stability

In order to examine the dissolution stability of the soft capsules prepared in the present invention, the soft capsules prepared in Examples 1 to 4 and Comparative Examples 1 and 2 were packed in an HDPE bottle containing 1 g of silica gel and dried under conditions of 40 DEG C and 75% RH After storage, the dissolution test was carried out at the initial, 3-month and 6-month time points. The dissolution test was performed according to the following conditions and analyzed using HPLC (HITACHI, Model 2000, JAPAN).

<HPLC Conditions>

Column: Zorbax SB-phenyl (4.6 mm X 15 mm, 3.5 um)

Flow rate: 1.0 ml / min

Column temperature: 40 ° C

Mobile phase: acetonitrile: purified water = 6: 4 (v / v)

Injection amount: 100 uL

Analysis wavelength: 210 nm

&Lt; Dissolution test conditions >

Test method: Dissolution test method 2 of the Korean Pharmacopoeia 8

Test Solution: Purified water

Test liquid temperature: 37.5 ° C

Stirring speed: 50 rpm

The above results are shown in Tables 5 and 6 and Figs. Table 5 shows the results of elution after 45 minutes in the initial stage and 3 months and 6 months after storage. Table 6 shows the elution results after 6 months in storage. Fig. 1 is a graph of the results of Table 5, 2 shows the elution result after 6 months of storage (at 45 minutes), and FIG. 3 shows the elution deviation at each time after 6 months of storage.

The leaching outcome (45 minutes) Early 3 months 6 months Example 1 99.1 98.4 99.6 Example 2 97.9 96.3 95.8 Example 3 98.7 97.8 96.3 Example 4 95.2 94.8 97.7 Comparative Example 1 97.3 77.5 58.4 Comparative Example 2 96.1 87.1 67.3

After 6 months, Example 1 Comparative Example 1 Comparative Example 2 5 minutes 8.4 0.0 0.0 15 minutes 85.6 33.4 38.5 30 minutes 90.2 42.9 55.2 45 minutes 99.6 58.4 67.3 60 minutes 98.3 68.2 73.2

As shown in Tables 5 and 6 and FIGS. 1 and 2, when PEG-60 hydrogencontaster oil or PEG-50 hydrogencarbonate oil was used as a surfactant, the release of soft capsules Was delayed due to the fact that the PEG-60 or PEG-50 hydrogencontaster oil promotes crosslinking of the gelatin due to the difference in ethoxylation degree of substitution resulting in a delayed disintegration of the soft capsules. On the other hand, the formulation of the present invention using PEG-40 hydrogencontaster oil showed no early crosslinking with gelatin, indicating that the early release was remarkably fast.

The above results show that by using PEG-40 hydrogencontaster oil, the elution stability can be secured during long-term storage, and thus the drug efficacy can be constantly expressed.

Further, the formulations of Example 1 and Comparative Example 1 were stored for 6 months under the conditions of 40 ° C. and 75% RH, and the dissolution rates were measured at 15 minutes, 30 minutes, 45 minutes, and 60 minutes, %). As a result, it was found that the formulation of the present invention using PEG-40 hydrogencontaster oil had a relatively smaller dissipation deviation than the formulation containing PEG-60 hydrogencontaster oil (see FIG. 3).

The results show that using the PEG-40 hydrogencarbonate oil as a surfactant as in the present invention can reduce the difference between the samples and achieve equivalent effects.

Claims (9)

(a) 0.1 to 1% by weight of dutasteride;
(b) 50 to 95% by weight of an oil; And
(c) 4 to 40% by weight of PEG-40 Hydrogenated castor oil as a surfactant,
Wherein the oil is selected from the group consisting of fatty acid mono-, di- or mono / di-glycerides, fatty acid triglycerides, ester compounds of fatty acids and monohydric alkanols and free fatty acids.
The method according to claim 1,
(a) 0.3 to 0.6% by weight of dutasteride;
(b) 70 to 85% by weight of an oil; And
(c) 14 to 28% by weight of PEG-40 hydrogencarbonate oil as surfactant
&Lt; / RTI &gt;
delete The composition of claim 1, wherein said composition is used for the prophylaxis or treatment of benign prostatic hyperplasia, prostate cancer or alopecia areata.
11. An oral capsule dosage form comprising a composition according to any one of claims 1, 2 and 4.
The oral capsule formulation of claim 5, wherein the capsule is a soft capsule.
[Claim 7] The oral capsule preparation of claim 5, wherein the total amount of the contents of the capsule is 90 mg to 150 mg.
The oral capsule formulation of claim 6, wherein the soft capsule is in the form and size of 2 oval to 3 oval.
The oral capsule formulation according to claim 6, characterized in that the soft capsule is in the form and size of 3 oblong.

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