WO2017160106A2 - Dutasteride- and tamsulosin-containing hard capsule complex and preparation method therefor - Google Patents

Abstract

An aspect of the present invention provides a hard capsule complex and a preparation method therefor, the hard capsule complex comprising, in a separate state: a dutasteride independent part comprising a dutasteride or a pharmaceutically acceptable salt thereof; and a tamsulosin independent part comprising a tamsulosin or a pharmaceutically acceptable salt thereof, wherein the dutasteride independent part is a preparation containing a self-emulsifying emulsion consisting of a dutasteride, an oil and a surfactant; the tamsulosin independent part is a solid preparation containing a sustained-release agent; the dutasteride independent part and the tamsulosin independent part are included in a separate state and can be filled into capsules 0 to 3.

Description

Dutasteride and tamsulosin-containing hard capsule complex and preparation method thereof

The present invention relates to a hard capsule complex containing dutasteride and tamsulosin as active ingredients. More specifically, the size of the hard capsule complex is reduced to improve drug compliance and show fast drug efficacy of dutasteride. It relates to a hard capsule complex containing a ride and tamsulosin and a method for producing the same.

Benign prostatic hyperplasia is a common disease in men over 50 years of age. It is a disease that causes urination disorder due to an increase in the size of the prostate gland. Benign prostatic hyperplasia can lead to complications such as urinary tract infection, urolithiasis, hematuria, and renal failure.

Dutasteride, a 5-alpha reductase inhibitor (chemical name: 17β-N- (2,5-bis (trifluoromethyl)) phenylcarbamoyl-4-a-5-5-androst-1-ene-3-) On) is known to be useful for treating benign prostatic hyperplasia, prostate cancer and androgenetic alopecia (Patent Document 1). Dutasteride is currently marketed under the trade name AVODART, which comprises 0.5 mg of dutasteride and 349.5 mg of capryl / capric acid mono- and di-glyceride oils and butylated hydroxytoluene ( A soft capsule, dissolved in a mixture of BHT) and filled into a soft capsule, is used for treating benign prostatic hyperplasia, prostate cancer and androgenetic alopecia.

Tamsulosin is α _1a As a blocker, it is effective not only for treating benign prostatic hyperplasia but also for treating chronic prostatitis and chronic abdominal pain syndrome. It is also effective in treating urolithiasis through muscle relaxation mechanism through α _1a blockade. Tamsulosin was developed by Yamanouchi pharmaceuticals in 1996, and various products containing tamsulosin hydrochloride are now known (Patent Document 2).

As described above, dutasteride and tamsulosin, which are treatments for benign prostatic hypertrophy, having different mechanisms of action, are known to have an advantage in that a better therapeutic effect and side effects are reduced when they are used concurrently or at intervals of time. Therefore, a hard capsule complex containing a separate form of dutasteride and tamsulosin in a hard capsule is developed and marketed in the United States under the trade name Jalyn (GlaxoSmithKline). Jalyn is an immediate release soft capsule in a HPMC hard capsule filled with dutasteride in a mixture of mono- and di-glyceride oils of capryl / capric acid and butylated hydroxytoluene (BHT) in a soft capsule. Is a form containing tamsulosin sustained-release granules (see https://www.gsksource.com/pharma/content/gsk/source/us/en/brands/jalyn.html , see section 11.description). . The Jalyn is known to be effective in the treatment of prostate hyperplasia and the like due to the independent action of each component, including immediate release dutasteride and sustained-release tamsulosin existing in one complex formulation. However, since Jalyn has a hard capsule size of 00, the compliance rate of patients is poor when the elderly patient layer is considered, and the initial dissolution rate of dutasteride is lower than that of dutasteride monolithic agent, so that the efficacy of dutasteride is inferior. There is a tendency.

[Preceding technical literature]

[Patent Documents]

Patent Document 1: US Patent Registration 5,565,467

Patent Document 2: US Patent Publication 2004-0058896

An object of the present invention is to reduce the size of the dutasteride and tamsulosin-containing hard capsules to significantly improve the patient's medication compliance and to increase the initial dissolution rate of dutasteride and dutasteride and tamsulosin It is to provide a composite hard capsule containing.

Another object of the present invention is to provide a method for preparing the dutasteride and tamsulosin-containing complex hard capsule.

One aspect of the invention

A hard capsule complex comprising a dutasteride independent portion comprising dutasteride or a pharmaceutically acceptable salt thereof and a tamsulosin independent portion comprising tamsulosin or a pharmaceutically acceptable salt thereof,

The dutasteride independent portion is a formulation containing a self-emulsifying emulsion comprising dutasteride, an oil and a surfactant;

The tamsulosin independent part is a solid preparation containing a sustained release base;

The dutasteride independent part and the tamsulosin independent part are included in a state separated from each other, and provides a hard capsule composite agent 0 to 3 capsules can be filled.

Another aspect of the invention

Preparing a self-emulsifying emulsion of dutasteride comprising admixing dutasteride or a pharmaceutically acceptable salt, oil and surfactant thereof;

Preparing a dutasteride soft capsule comprising a self-emulsifying emulsion of dutasteride;

Granulating tamsulosin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive or tableting the granules to tablet; And

Filling the dutasteride soft capsule, and the tamsulosin granules or tablets inside the empty capsule to be included in one hard capsule,

It provides a method for producing a hard capsule composite according to an aspect of the present invention.

Dutasteride and tamsulosin-containing hard capsule complexes according to one aspect of the present invention can reduce the size of the hard capsules compared to conventional commercial complexes, thereby significantly improving patient compliance. In addition, the dutasteride and tamsulosin-containing hard capsule complexes according to one aspect of the present invention can be expected to be faster than the conventional dissolution of the initial dissolution rate of dutasteride significantly increased.

1 is a schematic diagram of a hard capsule composite according to an embodiment of the present invention.

FIG. 2 is a photograph of a soft capsule (bottom) including a dutasteride-containing self-emulsifying emulsion according to an embodiment of the present invention and a soft capsule (top) according to Comparative Example 1. FIG.

Figure 3 is a photograph of the hard capsule composite (lower) and the hard capsule composite (top) according to Comparative Example 1 according to an embodiment of the present invention.

Figure 4 is a graph showing the dissolution rate test results of dutasteride of the hard capsule composite of Examples 1 to 4 and Comparative Example 1.

Figure 5 is a graph showing the dissolution rate test results of tamsulosin of the hard capsule composite of Examples 1 to 4 and Comparative Example 1.

All technical terms used in the present invention, unless defined otherwise, are used in the meaning as commonly understood by those skilled in the art in the related field of the present invention. In addition, although a preferred method or sample is described herein, similar or equivalent things are included in the scope of the present invention. In addition, numerical values described in this specification are considered to include the meaning of "about", even if not specified. The contents of all publications that are incorporated herein by reference are incorporated by reference in their entirety.

One aspect of the invention

A hard capsule complex comprising a dutasteride independent portion comprising dutasteride or a pharmaceutically acceptable salt thereof and a tamsulosin independent portion comprising tamsulosin or a pharmaceutically acceptable salt thereof,

The dutasteride independent portion is a formulation containing a self-emulsifying emulsion comprising dutasteride, an oil and a surfactant;

The tamsulosin independent part is a solid preparation containing a sustained release base;

The dutasteride independent part and the tamsulosin independent part are included in a state separated from each other, and provides a hard capsule composite agent 0 to 3 capsules can be filled.

"Including the dutasteride independent portion and tamsulosin independent portion" means that the hard capsules are filled in separate, separate formulations so that no physical mixing of the respective active ingredients takes place.

The hard capsule complex may prepare the dutasteride independent portion into a soft capsule containing a self-emulsifying emulsion so that the poorly soluble pharmacologically active ingredient may be filled into a small size soft capsule, thereby reducing the size of the final hard capsule. It is expected that this will increase patient compliance with the medication.

The self-emulsifying emulsion refers to a composition capable of forming an emulsion by self-emulsification when mixed with water. More specifically, the self-emulsifying emulsion may include 0.1 to 1% by weight of dutasteride, 50 to 98% by weight of oil and 1 to 40% by weight of surfactant based on the total weight of the self-emulsifying emulsion.

The self-emulsifying emulsion comprises 0.1 to 1% by weight of dutasteride, more specifically 0.3 to 0.7% by weight, even more specifically 0.4 to 0.6% by weight based on the total weight of the self-emulsifying emulsion, 50 to oil 98 wt%, more specifically 60-96 wt%, even more specifically 65-95 wt%, 1-40 wt% surfactant, more specifically 3-40 wt%, even more specific It may include 4 to 35% by weight.

Dootasteride, the active ingredient of the self-emulsifying emulsion, has a disadvantage in that it is inconvenient to take the capsule when the content of the self-emulsifying emulsion is less than 0.1% by weight based on the total weight of the self-emulsifying emulsion, due to the increase in the amount of excipients. If it is more than%, it is difficult to prepare a soft capsule because the active ingredient is difficult to dissolve.

The oil is well mixed with the surfactant, emulsified in water to form a stable emulsion, and has sufficient solubility in the active ingredient dutasteride, and a pharmaceutically acceptable oil can be used. In one embodiment, the oil is ① fatty acid mono-, di- or mono / di-glycerides, for example mono- or di-glycerides of capryl / capric acid (trade name: Capmul MCM), ② Fatty acid triglycerides, more specifically intermediate fatty acid triglycerides can be used, for example fractionated coconut oil (trade name: capriol), ③ ester compounds of fatty acids and monovalent to trivalent alkanols, more specifically Ester compounds of fatty acids having 8 to 20 carbon atoms and monovalent to trivalent alkanols having 2 to 3 carbon atoms, for example isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate or propylene glycol monolaurate ; And ④ free fatty acids, for example an oil selected from liquid oleic acid or linoleic acid.

The oil may be 50 to 98% by weight based on the total weight of the self-emulsifying emulsion, when the content of the oil is less than 50% by weight, the active ingredient may not be sufficiently dissolved and precipitation may occur, exceeding 98% by weight. In this case, the amount of surfactant is reduced, which may lower the emulsifying ability of the preparation.

As a result of the test, the solubility of dutasteride was investigated using Capmul MCM oil, and it was found that the minimum amount of oil required to dissolve 0.5 mg of dutasteride is 32 mg and the total amount of oil used must exceed 50 mg. there was. However, in consideration of miniaturization of the soft capsule, it is preferable that the amount of oil does not exceed 200 mg. When the self-emulsifying emulsion contains 0.5 mg of dutasteride, the content of oil may be used as about 50 mg to 200 mg.

The surfactant serves to stably emulsify the oil component in water to form a stable emulsion. As the surfactant, a nonionic surfactant may be used, and the nonionic surfactant may be casters such as tweens, spans, labrasol, brij, myrj, and polyoxyl caster oil. Oils, substituted castor oils such as Cremophor or hydrogenated Cremophor, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene-polyoxypropylene copolymers (trade name: Pluronic) ), Capryl / capric acid mono- or di-glycerides (trade name: Imwitor) and the like can be used. More specifically, the surfactant may be selected from the group consisting of substituted castor oils, polyoxyethylene-polyoxypropylene block copolymers, and any combination thereof. The polyoxyethylene-polyoxypropylene block copolymers include poloxamer 407, poloxamer 188 or poloxamer 124. The substituted castor oils are Cremophor ^® EL which is hydrogen substituted caster oil, HG-50 (PEG50 Hydrogenated castor oil), HCO-40 (PEG40 Hydrogenated castor oil) or Polyoxyethylated castor oil. (Cremophor ^® EL), Cremophor RH40 and the like.

The surfactant may be 1 to 40% by weight based on the total weight of the self-emulsifying emulsion, when the surfactant is less than 1% by weight, the emulsion forming ability is lowered, and when the amount exceeds 40% by weight, a desired effect is obtained compared to the amount added. It is difficult.

In one embodiment, the self-emulsifying emulsion may include 0.3 to 0.7% by weight dutasteride, 60 to 96% by weight oil and 3 to 40% by weight surfactant based on the total weight of the self-emulsifying emulsion.

In one embodiment, the self-emulsifying emulsion may include 0.4 to 0.6% by weight of dutasteride, 65 to 95% by weight of oil and 4 to 35% by weight of surfactant based on the total weight of the self-emulsifying emulsion.

The self-emulsifying emulsion may be contained 70 to 200 mg in the dutasteride independent portion, considering the minimum amount of oil required to dissolve an effective amount of dutasteride and miniaturization of the soft capsule. In one embodiment the dutasteride independent portion is a soft capsule containing about 70-200 mg of the self-emulsifying emulsion.

In one embodiment, the dutasteride independent portion, 70 to self-emulsifying emulsion comprising 0.1 to 1% by weight of dutasteride, 50 to 98% by weight oil and 1 to 40% by weight surfactant based on the total weight of the self-emulsifying emulsion It is a soft capsule containing 200 mg.

In one embodiment, the dutasteride independent portion 70 to self-emulsifying emulsion comprising 0.3 to 0.7% by weight, 60 to 96% by weight of oil and 3 to 40% by weight of surfactant based on the total weight of the self-emulsifying emulsion It is a soft capsule containing 200 mg.

In one embodiment, the dutasteride self-emulsifying emulsion comprises about 1: 100 to 500: 1 to 100, specifically 1: 150 to 250: 5 to 80, more specifically About 1: 150-200: 40-80.

The self-emulsifying emulsion of dutasteride may further comprise a phase stabilizer. The phase stabilizer not only provides the solubility suitable for formulation to the active ingredient, but also helps to stabilize the phase, thereby preventing the occurrence of layer separation and precipitation and securing the uniformity of the composition even during the preservation of the formulation. .

The property stabilizer is water, ethanol, glycerin, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether (trade name: transcutol), dimethyl isosorbide (trade name: Arlasolve), cetyl alcohol ( cetyl alcohol) and any combination thereof, and may be, for example, water, ethanol or glycerin.

The property stabilizer may be included in 0.5 to 3% by weight, preferably 1 to 3% by weight based on the total weight of the self-emulsifying emulsion.

The self-emulsifying emulsion of dutasteride may further comprise a pharmaceutically acceptable additive, such as an antioxidant, for oral administration. The antioxidant may be selected from lipophilic tocopherols, dibutylhydroxytoluene, hydrophilic ascorbic acid, sodium sulfite, sodium pyrosulfite, and any combination thereof.

In one embodiment, the dutasteride independent portion may be a soft capsule containing a self-emulsifying emulsion, and the soft capsule may be prepared as Nos. 2 to 4 soft capsules having a volume of 0.07 cc to 0.30 cc. The soft capsule may also be made of a soft capsule in the form of round, oblong, or oval. In one embodiment, the soft capsule is a soft capsule in the form of 2 to 4 rounds (0.07 to 0.25 cc), 2 to 4 ovals (0.09 to 0.25 cc), or 2 to 4 O'Brien (0.08 to 0.30 cc) It may be prepared as, more specifically, 2 to 3 round (0.07 ~ 0.19 cc) or oval (0.09 ~ 0.19 cc) soft capsules, more specifically No. 2 round or 2 oval soft capsules Can be. (See Catallent, Inc., https://www.catalent.com/index.php/content/download/1230/14867/file/Catalent_Shapes_Sizes_Info.pdf ., And EP 2 575 788 A1)

The soft capsule may be a soft capsule of a material commonly used in the pharmaceutical field.

The tamsulosin standalone can be in the form of tablets, capsules, or granules.

The tamsulosin independent part may further comprise a pharmaceutically acceptable additive for formulation into the formulation. The additives may include diluents, disintegrants, binders, stabilizers, lubricants, colorants, or any combination thereof.

The diluent may be selected from microcrystalline cellulose, lactose, rudipress, mannitol, calcium dihydrogen dioxide, starch, low-substituted hydroxypropyl cellulose, and any combination thereof. The diluent may be used in an amount ranging from about 1 to 95 weight percent, specifically about 5 to 95 weight percent, based on the total weight of the granules, tablets, or capsules.

The disintegrant may be selected from crospovidone, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid or its sodium salt, and any combination thereof. The disintegrant may be used in an amount ranging from about 0.1 to 30% by weight, specifically about 2 to 15% by weight, based on the total weight of the granules, tablets, or capsules.

The binder is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetic acid, polyvinylpyrrolidone, copovidone, macrogol, sodium lauryl sulfate, hard anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate Silicate derivatives such as, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and any combination thereof. The binder may be used in an amount ranging from about 0.1 to 30% by weight, specifically from 2 to 20% by weight, based on the total weight of the granules, tablets, or capsules.

The glidants include stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glyceryl fatty acid esters, glycerol dibehe Nate, and any combination thereof. The glidants may be used in amounts ranging from 0.3 to 5% by weight, specifically from 0.5 to 3% by weight, based on the total weight of the granules, tablets, or capsules.

The tamsulosin independent part, in particular the tamsulosin granules or tablets may be coated with a pharmaceutically acceptable coating. The coating agent may be a coating agent commonly used in the art.

In one embodiment, the tamsulosin independent portion may be a sustained-release or enteric granule or tablet coated with a sustained-release coating or enteric coating on the tamsulosin granules or tablets. The sustained release coating agent may be selected from povidone, methyl cellulose, ethyl cellulose, triethyl citrate, hypromellose, cellulose acetate, polyvinylacetate, propylene glycol, talc, and any combination thereof, and the enteric composition. The coating agent may be selected from methacrylic acid-ethyl acrylate copolymer, triacetin, cellulose acetate succinate, hypromellose phthalate, hypromellose acetate succinate, polyvinylacetate phthalate, sodium alginate, and any combination thereof. have. A coating agent, each or optionally combined with the coating agent, may be coated on the tamsulosin granules or tablets. With the introduction of the coating, the tamsulosin independence shows sustained or enteric release, and can be effectively used for the treatment of enlarged prostate with rapid release dutasteride.

In one embodiment, the coating agent may be selected from the group consisting of povidone, propylene glycol, polyvinylacetate, ethyl methacrylate-ethyl acrylate copolymer, talc, and any combination thereof, but is not limited thereto.

When the enteric coating agent is used as the coating agent, a plasticizer may be additionally used to prevent the enteric coating layer from breaking even when stored for a long time. The plasticizers include acetylated monoglycerides, triacetin, or mixtures thereof.

The amount of coating used is preferably kept to a minimum for providing optimal formulation size and for efficient production. For example, the coating agent may be used in an amount in the range of 0.1 to 20% by weight, specifically 2 to 10% by weight, based on the total weight of tamsulosin independent portion.

In one embodiment, the hard capsule complex according to the present invention is a form including both dutasteride soft capsule and tamsulosin granules in the hard capsule, as shown in the schematic diagram of FIG.

The hard capsule (ie, hard capsule cocapsule) including the dutasteride independent portion and the tamsulosin independent portion in the hard capsule combination may be any cocapsule known in the art.

In one embodiment, the hard capsule comprising the dutasteride independent portion and the tamsulosin independent portion may be selected from gelatin hard capsules and HPMC hard capsules.

In one embodiment, the hard capsule is a gelatin hard capsule.

When using the gelatin hard capsules, the initial dissolution rate of dutasteride can be significantly improved compared to the HPMC hard capsules, and thus there is an advantage that can be obtained fast-acting of dutasteride. Thus, the immediate release of dutasteride independence further increases the intended rapid release and thus obtains the improved fastness of dutasteride, but does not affect the sustained release of tamsulosin independence, thus affecting the sustained release of tamsulosin. There is an advantage that it selectively increases only the fastness of dutasteride (see Test Example 1).

In one embodiment, the hard capsule is an HPMC hard capsule.

The HPMC hard capsules may be advantageous in terms of storage stability and dissolution rate of the active ingredient compared to gelatin hard capsules in a high temperature and high humidity storage environment. This is because gelatin capsules are aging due to entanglement with internal soft dutasteride capsules under high temperature and high humidity conditions, thereby reducing the dissolution rate of dutasteride.

As used herein, the term “HPMC hard capsule” refers to a hard capsule manufactured using hydroxypropyl methylcellulose as a periodic agent.

As used herein, the term “gelatin hard capsule” refers to a hard capsule prepared using gelatin as a periodic agent.

In one embodiment, the hard capsule complex of the present invention more specifically, the dissolution rate of the dutasteride in the dissolution test according to the paddle method of the USP dissolution test item is more than about 85% in 15 minutes, more specifically Is more than about 90% hard capsule combination.

In one embodiment, the hard capsule complex of the present invention is a hard capsule complex having a dissolution rate of dutasteride of about 80% or more in 30 minutes in the dissolution test according to the paddle method of the USP dissolution test item.

In one embodiment, the hard capsule combination may be administered orally.

The empty capsule for filling the dutasteride independent portion and tamsulosin independent portion for the preparation of the hard capsule complex is possible without limitation as long as the general capsule size used in medicine.

The hard capsule complex may reduce the volume of the dutasteride independent portion by introducing a soft capsule containing the self-emulsifying emulsion, so that the hard capsules of 0 to 3 hard capsules (hard capsules having an internal filling amount of about 0.27 cc to 0.68 cc) ) Can be filled with both pharmaceutically effective amounts of dutasteride independent and tamsulosin independent. The capsules have various internal capacities depending on the number of capsules.The number 00 capsule is about 0.95 cc, the number 0 capsule is about 0.68 cc, the number 1 capsule is about 0.47 cc, the number 2 capsule is about 0.37 cc, the number 3 capsule is About 0.27 cc, 4 capsules have an internal dose of about 0.20 cc. (See Seoheung, http://www.suheung.com/korea/embocaps31.html )

Thus, in one embodiment, the hard capsule combination can be significantly reduced in size compared to conventional commercial formulations (see Examples 1 and 2), which can significantly increase the ease of taking the patient during oral administration. In one embodiment, the blank capsule of the hard capsule combination may be 0, 1, 2, or 3 hard capsules.

The hard capsule complex has a rapid effect on the treatment of benign prostatic hyperplasia, prostate cancer and androgenetic alopecia by containing dutasteride, a 5-alpha reductase inhibitor, as the first active ingredient, α _1a By containing tamsulosin, a blocking agent, as a second active ingredient, it can have a continuous effect on the treatment of urination disorders such as benign prostatic hyperplasia, chronic prostatitis, chronic abdominal pain syndrome symptoms, urolithiasis, and the like. In one embodiment, the hard capsule combination may be used for the treatment of benign prostatic hyperplasia.

The hard capsule complex may include any amount known to be contained in the preparation of dutasteride and tamsulosin per unit dosage form, for example, about 0.2 of dutasteride per unit dosage form as free base. ~ 1 mg, may comprise about 0.1 to 0.8 mg of tamsulosin as free base. In one embodiment, the hard capsule complex contains about 0.5 mg of dutasteride free base as an active ingredient of the dutasteride independent portion, and about 0.4 mg of tamsulosin hydrochloride as the active ingredient of the tamsulosin independent portion.

Another aspect of the invention

In a unit dosage form comprising dutasteride independent portion comprising dutasteride or a pharmaceutically acceptable salt thereof and tamsulosin independent portion comprising tamsulosin or a pharmaceutically acceptable salt thereof,

The dutasteride independent portion contains dutasteride or a pharmaceutically acceptable salt thereof in an amount of about 0.5 mg in terms of dutasteride free base, and is eluted according to the paddle method of the USP dissolution test item. In the test, the dissolution rate of dutasteride is about 80% by weight or more in 30 minutes, more specifically, the dissolution rate of dutasteride exceeds about 85% by weight in 15 minutes,

The tamsulosin independent part contains 0.2 mg or 0.4 mg of tamsulosin or a pharmaceutically acceptable salt thereof per unit dosage in terms of tamsulosin free base, and according to the paddle method of the USP dissolution test item. Thus, in the dissolution test, the dissolution rate of the tamsulosin is about 34 wt% or less in 2 hours, about 47 to 68 wt% in 3 hours, and about 80 wt% or more in 8 hours.

In addition, the fixed-dose complexing agent includes the dutasteride independent portion and the tamsulosin independent portion separated from each other, and provides capsule composites filled with 0 to 3 capsules.

In addition, the fixed dose combination agent is a formulation containing a self-emulsifying emulsion comprising dutasteride, an oil and a surfactant; The tamsulosin independent part may include a solid preparation containing a sustained release base.

Another aspect of the invention

Preparing a self-emulsifying emulsion of dutasteride comprising admixing dutasteride or a pharmaceutically acceptable salt, oil and surfactant thereof;

Preparing a dutasteride soft capsule comprising a self-emulsifying emulsion of dutasteride;

Preparing tamsulosin granules or tablets which granulate tamsulosin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive, or tableting and granulating the granules; And

Filling the dutasteride soft capsule, and the tamsulosin granules or tablets inside the empty capsule to be included in one hard capsule,

It provides a method for producing a hard capsule composite according to an aspect of the present invention.

Details of the method for producing a hard capsule composite may be applied to the description of the hard capsule composite according to an aspect of the present invention.

The self-emulsifying emulsion of dutasteride may be prepared in the form of a liquid by homogeneously dissolving dutasteride, oil and surfactant by mixing and stirring, and if necessary, add a phase stabilizer and / or an antioxidant to It may further comprise adding and mixing and stirring.

Dutasteride soft capsules comprising the self-emulsifying emulsion of dutasteride may be prepared by filling the soft capsule with the self-emulsifying emulsion of dutasteride according to a conventional pharmaceutical preparation process.

The step of preparing tamsulosin granules or tablets may be prepared according to a conventional method for producing granules or tablets. If necessary for the manufacture of the granules or tablets, the granules or tablets may further comprise the step of coating according to a conventional coating method using the coating, for example, a sustained release coating or enteric coating.

EXAMPLE

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

Example  1: Preparation of Hard Capsule Composite (1)

Dutasteride independent portion and tamsulosin independent portion were prepared according to the following prescription.

-Dutasteride Independent Department-

Dutasteride 0.50 mg

Mono and diglycerides 90.00 mg

Cured Castor Oil 20.00 mg

Butylhydroxytoluene 0.01 mg

-Tamsulosin Independence Department-

Tamsulosin hydrochloride 0.4 mg

20.0 mg of polyvinyl acetate dispersion

Microcrystalline Cellulose 150.0 mg

Hypromellose 5.0 mg

Povidone 0.2 mg

Propylene glycol 0.3 mg

5.0 mg of methacrylic acid-ethyl acrylate copolymer

Triacetin 0.2 mg

Sucrose stearate 0.1 mg

Purified water (100.0 mg)

The dutasteride independent part dissolved the dutasteride in mono and diglyceride oil, and then added and dissolved all the remaining components to prepare a self-emulsifying emulsion. The self-emulsifying emulsion was prepared in a soft capsule to prepare a dutasteride soft capsule. Specifically, gelatin: glycerin: glycine using a capsule base of 81: 46: 1 weight ratio to prepare a coating composition according to the conventional coating method. Then, the prepared self-emulsifying emulsion was filled with a ribbon thickness of 0.65 mm in two rounds or a ribbon thickness of 0.75 mm in two ovals using a rotary automatic charger. Then, it was molded and dried to prepare a dutasteride soft capsule. A photograph of the prepared capsule is shown in FIG. 2 (bottom).

The tamsulosin independent unit mixed all of the above-mentioned tamsulosin hydrochloride, microcrystalline cellulose, and hypromellose in powder form, and then granulated the solution by dissolving 18 mg of polyvinyl acetic acid in one capsule as a binding solution. Was prepared. Then, the tamsulosin granules prepared above were coated with a solution of povidone, propylene glycol, and 2 mg of polyvinyl acetic acid in one capsule in water as an endothelial coating solution, and then the methacrylic acid-ethyl acrylate copolymer and tria The coat was further coated with a coating solution dissolved in cetine to prepare tamsulosin hydrochloride granules, and then sucrose stearate was added and mixed.

The prepared dutasteride soft capsule and tamsulosin granules were filled in gelatin hard capsule No. 1 (Seoheung Co., Ltd.) to prepare a gelatine hard capsule complex containing 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride. A photograph of the prepared capsule is shown in FIG. 3 (bottom).

Example  2: Preparation of Hard Capsule Composite (2)

After preparing tamsulosin granules as in Example 1, 9 mg (5%) of crospovidone was added as a disintegrating agent, mixed, tableted using a circular punch having a diameter of 6.5 mm, and combined with dutasteride soft capsule. It was filled into gelatin hard capsule No. 0 (Seoheung Co., Ltd.) to prepare a capsule composite.

Example  3: Preparation of Hard Capsule Composite (3)

The dutasteride independent part was prepared in the same manner as in Example 1, and the tamsulosin independent part was prepared as in the following prescription.

-Tamsulosin Independence Department-

Tamsulosin hydrochloride 0.4 mg

107.6 mg of microcrystalline cellulose

Hypromellose 4.0 mg

Talc 9.0 mg

Methacrylic acid-ethyl acrylate copolymer 19.0 mg

Triacetin 1.9 mg

Sucrose stearate 0.1 mg

Purified water (110.0 mg)

The tamsulosin independent unit mixed all of the above-mentioned tamsulosin hydrochloride, microcrystalline cellulose, hypromellose, and talc 6.0 mg in powder form, and then combined the solution of 12.0 mg of methacrylic acid-acrylic acid copolymer in water. Granules were prepared. Then, the tamsulosin hydrochloride granules were prepared by coating the tamsulosin hydrochloride granules using 7.0 mg of methacrylic acid-acrylic acid copolymer, triacetin, and 3.0 mg of talc in water as an enteric coating solution. Stearate was added and mixed to prepare tamsulosin granules.

The tamstatosin granules and the dutasteride soft capsules prepared in Example 1 were filled in gelatin hard capsule No. 1 (Seohheung), and a gelatin hard capsule complex comprising 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride Was prepared.

Example  4: Preparation of Hard Capsule Composite (4)

Except for using the HPMC hard capsule No. 1 (Qualicap®) instead of gelatin hard capsule No. 1 in Example 1, in the same manner as in Example 1, 0.5 mg of dutasteride and 0.4 of tamsulosin hydrochloride 0.4 HPMC hard capsule complex containing mg was prepared.

Comparative example  1: Preparation of Hard Capsule Composite (5)

A Jalyn capsule of GlaxoSmithKline, currently commercially available in the United States, was used as Comparative Example 1. It was confirmed that the size of the hard capsule of the Jalyn capsule was 00. A photo of the hard capsule is shown in FIG. 3 (top), and the dutasteride soft capsule present therein is shown in FIG. 2 (top).

Test Example  1: elution evaluation

Elution evaluation was performed for the dutasteride and tamsulosin-containing hard capsule complexes of Examples 1 to 4 and Comparative Example 1 according to the following conditions.

Dutasteride elution conditions

The dissolution test was performed using 900 mL of 0.1 N hydrochloric acid solution containing 1% (w / v) cetyltrimethylammonium bromide (CTAB) according to the Paddle method in the USP dissolution test section. Elution test solution samples were taken at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after the initial stage and the start of the test, and liquid chromatography was performed under the following conditions to calculate dutasteride dissolution rate.

Column: A column packed with a phenyl silica gel for liquid chromatograph with a particle diameter of 3.5 μm in a stainless tube having an internal diameter of about 4.6 mm and a length of 15 cm (Zorbax SB-Phenyl, Agilent Zorbax)

-Detector: ultraviolet absorbance photometer (wavelength 210nm)

Flow rate: 1.0 mL / min

Injection volume: 100 μl

Column temperature: 40 ° C

Mobile phase: acetonitrile: mixed solution of purified water (60:40, v / v)

Dissolution medium: 0.1N hydrochloric acid solution containing 1% (w / v) cetyltrimethylammonium bromide (CTAB)

<Explosion path dissolution condition>

Following the paddle method of the USP dissolution test, the solution was placed in a sinker and eluted for 120 minutes using 750 mL of acidic solution at 50 rpm, followed by 250 mL of buffer test solution. . Samples were taken with 10 mL of the dissolution test solution at 120 minutes, 180 minutes, 240 minutes, 360 minutes and 480 minutes after the initial and test start. The collected sample was subjected to liquid chromatography under the following conditions and the tamsulosin dissolution rate was calculated.

Column: A column filled with octadecylsilylated silica gel for liquid chromatograph with a particle diameter of 5 μm in a stainless tube having an internal diameter of about 4.6 mm and a length of 5 cm (Kromasil Eternity-5-C18, AkzoNobel)

Detector: ultraviolet absorption photometer (wavelength 225 nm)

Flow rate: 1.3 mL / min

Injection volume: 100 μl

-Column temperature: 30 ℃

Mobile phase: 8.7 mL of perchloric acid and 3.0 g of sodium hydroxide were dissolved in 1900 mL of water, adjusted to pH 2.0 with sodium hydroxide, and added to water to 2000 mL. 480 mL of acetonitrile was added to 1520 mL of this solution to obtain a mobile phase.

-Eluent: acid solution-0.1N hydrochloric acid solution

Buffer Test Solution-0.2M Trisodium Phosphate (12-hydrate), pH6.8

Dutasteride elution results are shown in Table 1 and Figure 4, the tamsulosin elution results are shown in Table 2 and Figure 5 below.

As shown in Table 1 and Figure 4, the gelatin capsule complexes according to Examples 1, 2, 3, the initial dissolution rate of dutasteride 30 minutes before the HPMC capsule complexes according to Comparative Examples 1 and 4 markedly It was found that the difference between the tamsulosin formulations of Examples 1, 2, and 3 did not significantly affect the dissolution of dutasteride. Therefore, the gelatin hard capsule complex according to one embodiment of the present invention is expected to be fast-acting dutasteride.

According to the results of Table 2 and FIG. 5, in the case of Example 3 and Comparative Example 1, since the prescription is different, the acid resistance is strong, but the gelatin capsule composite according to Examples 1 and 2, and the HPMC capsule composite according to Example 4 The dissolution results were all similar. Therefore, it was confirmed that changing the cocapsule of the hard capsule did not affect the sustained release form of the independent tamsulosin.

According to the above results, the gelatin capsule complex according to an embodiment of the present invention, the immediate release of the dutasteride independent portion is improved in the intended immediate release, while the fast release of the dutaslide, while in the sustained-release tamsulosin independent portion As it did not affect the effect of tamsulosin was confirmed.

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (18)

As a hard capsule combination comprising a dutasteride independent portion comprising dutasteride or a pharmaceutically acceptable salt thereof and a tamsulosin independent portion comprising tamsulosin or a pharmaceutically acceptable salt thereof; The dutasteride independent portion is a formulation containing a self-emulsifying emulsion comprising dutasteride, an oil and a surfactant; The tamsulosin independent part is a solid preparation containing a sustained release base; The dutasteride independent part and the tamsulosin independent part is contained in a state separated from each other, hard capsule complex formulations 0 to 3 hard capsules can be filled. The hard capsule composite according to claim 1, wherein the dutasteride independent portion contains 70-200 mg of an autoemulsifying emulsion. The self-emulsifying emulsion according to claim 1 or 2, wherein the dutasteride independent part comprises 0.1 to 1% by weight of dutasteride, 50 to 98% by weight of oil and 1 to 40% by weight of surfactant based on the total weight of the self-emulsifying emulsion. Hard capsule composite that is a soft capsule containing. The self-emulsifying emulsion according to claim 1 or 2, wherein the dutasteride independent part comprises 0.3 to 0.7 wt% of dutasteride, 60 to 96 wt% of oil, and 3 to 40 wt% of surfactant based on the total weight of the self-emulsifying emulsion. Hard capsule composite that is a soft capsule containing. The self-emulsifying emulsion according to claim 1 or 2, wherein the dutasteride independent portion comprises 0.4 to 0.6% by weight of dutasteride, 65 to 95% by weight of oil and 4 to 35% by weight of surfactant based on the total weight of the self-emulsifying emulsion. Hard capsule composite that is a soft capsule containing. The hard oil according to claim 1, 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 monovalent to trivalent alkanols, and free fatty acids. Capsule Complex. The hard capsule composite according to claim 1, wherein the surfactant is selected from the group consisting of substituted castor oils, polyoxyethylene-polyoxypropylene block copolymers, and any combination thereof. The hard capsule complex of claim 1, wherein the self-emulsifying emulsion further comprises an antioxidant. The hard capsule composite according to claim 1, wherein the dissolution rate of dutasteride exceeds 85% in 15 minutes in the dissolution test according to the paddle method of the USP dissolution test item. The hard capsule composite according to claim 1, wherein the tamsulosin independent part is a solid preparation selected from the group consisting of tablets, capsules, and granules. The granule or tablet according to claim 10, wherein the tamsulosin independent part is a granule or tablet coated with a coating selected from the group consisting of povidone, propylene glycol, polyvinylacetate, methacrylic acid-ethyl acrylate copolymer, talc, and any combination thereof. Hard capsule complex. The hard capsule combination according to claim 1, wherein the pharmaceutically acceptable salt of tamsulosin is tamsulosin hydrochloride. The hard capsule complex according to claim 1, wherein the hard capsule complex contains 0.2 to 1 mg of dutasteride as a free base and 0.1 to 0.8 mg of tamsulosin as a free base. The hard capsule combination according to claim 1, which is for treating benign prostatic hyperplasia. In a unit dosage form comprising dutasteride independent portion comprising dutasteride or a pharmaceutically acceptable salt thereof and tamsulosin independent portion comprising tamsulosin or a pharmaceutically acceptable salt thereof, The dutasteride independent unit contains dutasteride or a pharmaceutically acceptable salt thereof in an amount of 0.5 mg in terms of dutasteride free base, and the dissolution test according to the paddle method of the USP dissolution test item. The dissolution rate of the dutasteride is more than 80% by weight in 30 minutes, The tamsulosin independent part contains 0.2 mg or 0.4 mg of tamsulosin or a pharmaceutically acceptable salt thereof per unit dosage in terms of tamsulosin free base, and according to the paddle method of the USP dissolution test item. According to the dissolution test, the dissolution rate of the tamsulosin is 34% by weight or less in 2 hours, 47 to 68% by weight in 3 hours, 80% by weight or more in 8 hours. The fixed dose composite of claim 15, wherein the dutasteride independent portion and the tamsulosin independent portion are separated from each other, and are filled in Nos. 0 to 3 capsules. The method according to claim 15, wherein the dutasteride independent portion is a formulation containing a self-emulsifying emulsion comprising dutasteride, oil and a surfactant; The tamsulosin independent portion is a fixed dose combination comprising a solid preparation containing a sustained release base. Preparing a self-emulsifying emulsion of dutasteride comprising admixing dutasteride or a pharmaceutically acceptable salt, oil and surfactant thereof; Preparing a dutasteride soft capsule comprising a self-emulsifying emulsion of dutasteride; Granulating tamsulosin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive or tableting the granules to tablet; And Filling the dutasteride soft capsule, and the tamsulosin granules or tablets inside the empty capsule to be included in one hard capsule, The method for producing a hard capsule composite according to any one of claims 1, 2, and 6 to 14.

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