AU2017233134A1 - Dutasteride- and tamsulosin-containing hard capsule complex and preparation method therefor - Google Patents

Dutasteride- and tamsulosin-containing hard capsule complex and preparation method therefor Download PDF

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AU2017233134A1
AU2017233134A1 AU2017233134A AU2017233134A AU2017233134A1 AU 2017233134 A1 AU2017233134 A1 AU 2017233134A1 AU 2017233134 A AU2017233134 A AU 2017233134A AU 2017233134 A AU2017233134 A AU 2017233134A AU 2017233134 A1 AU2017233134 A1 AU 2017233134A1
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Prior art keywords
dutasteride
tamsulosin
weight
independent
hard capsule
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AU2017233134A
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Jae Ho Kim
Jin Cheul Kim
Yong Il Kim
Benjamin Joon LEE
Jae Hyun Park
Jong Soo Woo
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Hanmi Pharmaceutical Co Ltd
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Publication of AU2017233134A1 publication Critical patent/AU2017233134A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A61K9/5057—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

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  • Chemical & Material Sciences (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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

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.
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DUTASTERIDE- AND TAMSULOSIN-CONTAINING HARD CAPSULE COMPLEX
AND PREPARATION METHOD THEREFOR
TECHNICAL FIELD [0001] The present disclosure relates to a hard capsule composite formulation including dutasteride and tamsulosin as active ingredients, and more particularly, to a hard capsule composite formulation including dutasteride and tamsulosin, in which the hard capsule composite formulation has improved drug compliance and exhibits fast acting efficacy of dutasteride by having a reduced size, and a method of preparing the hard capsule composite formulation.
BACKGROUND ART [0002] Benign prostatic hyperplasia, which is one of the typical diseases that frequently occur in men aged 50 years or older, causes dysuria due to enlargement of the prostate. Benign prostatic hyperplasia also causes complications such as urinary tract infections, urolithiasis, hematuria, renal failure, etc.
[0003] Dutasteride, which is a 5-alpha reductase inhibitor (chemical name:
17p-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-4-aza-5a-androst-1 -en-3-one), is known to be useful in the treatment of benign prostatic hyperplasia, prostate cancer, and male pattern alopecia (Patent Document 1). Dutasteride is currently offered on the market under the trade name of AVODART. AVODART is a soft capsule formulation prepared by dissolving 0.5 mg of dutasteride in 349.5 mg of a mixture of mono- and di-glyceride oil of caprylic/capric acid and butylated hydroxytoluene (BHT), and then filling the resultant into a soft capsule, and AVODART is used as a therapeutic agent for benign prostatic hyperplasia, prostate cancer, and male pattern alopecia.
[0004] Tamsulosin is an aia blocker that is effective in the treatment of symptoms of benign prostatic hyperplasia, chronic prostatitis, and chronic abdominal pain. In addition, by blocking aia, tamsulosin is also effective in the treatment of urolithiasis via a skeletal muscle relaxation mechanism. Tamsulosin was developed by 1
Yamanouchi Phannaceutical Co., Ltd. in 1996, and various products containing tamsulosin hydrochloride are known (Patent Document 2).
[0005] When dutasteride and tamsulosin, which are therapeutic agents for benign prostatic hyperplasia that have mechanisms of action different from each other, are administered simultaneously or at intervals as a combined therapy, there are advantages in terms of better therapeutic effects and fewer side-effects. Therefore, a hard capsule composite formulation was developed in which dutasteride and tamsulosin are contained in a completely separated state in a hard capsule, and is currently offered on the market under the trade name of Jalyn (GlaxoSmithKline) in the US. Jalyn includes, in an HPMC hard capsule, sustained-release tamsulosin granules together with an immediate-release soft capsule formulation which is prepared by dissolving dutasteride in a mixture of mono- and di-glyceride oils of caprylic/capric acid and butyl hydroxyl toluene (BHT), and then filling the resultant into a soft capsule (see https://www.gsksource.com/pharma/content/gsk/source/us/en/brands/jalyn.html, .description). It is known that since Jalyn includes immediate-release dutasteride and sustained-release tamsulosin which each exist independently in one composite formulation, it may be effectively used in the treatment of benign prostatic hyperplasia due to independent actions of the ingredients. However, the hard capsule of Jalyn has a very large size of No. 00, and thus drug compliance is poor among elderly patients, and its initial dissolution rate of the dutasteride is lower than that of a single dutasteride formulation, which tends to decrease the rapid action of dutasteride.
[0006] [Prior Art Documents] [0007] [Patent Documents] [0008] Patent Document 1: US Patent No. 5,565,467 [0009] Patent Document 2: US Patent Publication No. 2004-0058896
DESCRIPTION OF EMBODIMENTS
TECHNICAL PROBLEM [0010] An object of the present disclosure is to provide a hard capsule composite formulation including dutasteride and tamsulosin, in which drug compliance of a patient may be remarkably improved and an initial dissolution rate of dutasteride may be increased by reducing a size of the hard capsule composite formulation including dutasteride and tamsulosin.
[0011] Another object of the present disclosure is to provide a method of preparing the hard capsule composite formulation including dutasteride and tamsulosin.
SOLUTION TO PROBLEM [0012] An aspect of the present disclosure provides a hard capsule composite formulation including an independent dutasteride part including dutasteride or a pharmaceutically acceptable salt thereof; and an independent tamsulosin part including tamsulosin or a pharmaceutically acceptable salt thereof, wherein the independent dutasteride part is a formulation including a self-emulsifying emulsion including dutasteride, an oil, and a surfactant, the independent tamsulosin part is a solid formulation including a sustained-release agent, and the independent dutasteride part and the independent tamsulosin part may be included in a separated state and filled into a capsule of size Nos. 0 to 3.
[0013] Another aspect of the present disclosure provides a method of preparing the hard capsule composite formulation according to an aspect of the present disclosure, the method including:
[0014] preparing a self-emulsifying emulsion of dutasteride by mixing dutasteride or a pharmaceutically acceptable salt thereof, an oil, and a surfactant;
[0015] preparing a soft capsule of dutasteride including the self-emulsifying emulsion of dutasteride;
[0016] granulating tamsulosin or a pharmaceutically acceptable salt thereof along with a pharmaceutically acceptable additive to produce granules of tamsulosin, or tableting the granules into a tablet of tamsulosin; and [0017] filling en empty capsule with the soft capsule of dutasteride and the granules or the tablet of tamsulosin to obtain one hard capsule including the soft capsule of dutasteride and the granules or the tablet of tamsulosin.
ADVANTAGEOUS EFFECTS OF DISCLOSURE [0018] A hard capsule composite formulation including dutasteride and tamsulosin, according to an aspect of the present disclosure, may have a smaller hard capsule size than that of known commercially available formulations, thereby remarkably improving drug compliance of patients. In addition, the hard capsule composite formulation including dutasteride and tamsulosin according to an aspect of the present disclosure may have a remarkably high initial dissolution rate of the dutasteride, as compared with known commercially available formulations, and thus faster drug efficacy may be expected.
BRIEF DESCRIPTION OF DRAWINGS [0019] FIG. 1 illustrates a hard capsule composite formulation according to a specific embodiment of the present disclosure;
[0020] FIG. 2 is a photograph of a soft capsule (bottom) including a dutasteride-containing self-emulsifying emulsion, according to an embodiment of the present disclosure, and a soft capsule (top) according to Comparative Example 1; [0021] FIG. 3 is a photograph of a hard capsule composite formulation (bottom) according to an embodiment of the present disclosure and a hard capsule composite formulation (top) according to Comparative Example 1;
[0022] FIG. 4 is a graph showing results of testing dissolution rates of dutasteride in hard capsule composite formulations of Examples 1 to 4 and Comparative Example 1; and [0023] FIG. 5 is a graph showing results of testing dissolution rates of tamsulosin in hard capsule composite formulations of Examples 1 to 4 and Comparative Example 1.
BEST MODE [0024] Unless defined otherwise, all technical terms used herein have the same meanings as those generally understood by one of ordinary skill in the art to which the present disclosure belongs. Further, although methods or samples are described herein, those similar or equivalent thereto are also incorporated in the scope of the present disclosure. The numerical values described herein are considered to include the meaning of “about”, unless otherwise specified. The contents of all the publications disclosed as references herein are incorporated in the present disclosure.
[0025] An aspect of the present disclosure provides a hard capsule composite formulation including an independent dutasteride part including dutasteride or a pharmaceutically acceptable salt thereof; and an independent tamsulosin part including tamsulosin or a pharmaceutically acceptable salt thereof, wherein the independent dutasteride part is a formulation including a self-emulsifying emulsion including dutasteride, an oil and a surfactant, the independent tamsulosin part is a solid formulation including a sustained-release agent, and the independent dutasteride part and the independent tamsulosin part may be included in a separated state and filled into a capsule of size Nos. 0 to 3.
[0026] The “including, in a separated state, the independent dutasteride part and the independent tamsulosin part” means that the respective active ingredients are filled, as separate formulations, into a hard capsule to prevent physical mixing thereof. [0027] In the hard capsule composite formulation, the independent dutasteride part may be prepared as a soft capsule formulation including a self-emulsifying emulsion, which allows the poorly soluble pharmacological active ingredient to be filled into a small size of soft capsule. Therefore, it is expected that the size of the final hard capsule may be reduced to increase drug compliance of patients.
[0028] The self-emulsifying emulsion refers to a composition which may forms an emulsion by self-emulsification when being mixed with water. The self-emulsifying emulsion may include more specifically dutasteride of 0.1% by weight to 1% by weight, the oil of 50 to 98% by weight, and the surfactant of 1% by weight to 40% by weight, based on a total weight of the self-emulsifying emulsion.
[0029] The self-emulsifying emulsion may include dutasteride of 0.1% by weight to 1% by weight, more specifically 0.3% by weight to 0.7% by weight, and much more specifically 0.4% by weight to 0.6% by weight, the oil of 50% by weight to 98% by weight, more specifically 60% by weight to 96% by weight, and much more specifically 65% by weight to 95% by weight, and the surfactant of 1% by weight to 40% by weight, more specifically 3% by weight to 40% by weight, and much more specifically 4% by weight to 35% by weight, based on a total weight of the self-emulsifying emulsion.
[0030] When the content of dutasteride which is the active ingredient of the self-emulsifying emulsion is less than 0.1% by weight, based on a total weight of the self-emulsifying emulsion, a relative amount of an excipient is increased to increase a volume of the capsule, which makes it inconvenient to swallow. When the content is more than 0.1% by weight, there is a difficulty in the preparation of the soft capsule, because it is difficult to dissolve the active ingredient.
[0031] The oil is well miscible with the surfactant, and emulsified in water to form a stable emulsion, and has sufficient solubility for dutasteride which is the active ingredient. A pharmaceutically acceptable oil may be used. In a specific embodiment, the oil may be an oil selected from φ fatty acid mono-, di-, or mono/di-glycerides, for example, mono- or di-glycerides of caprylic/capric acid (trade name: Capmul MCM), φ fatty acid triglycerides, more specifically, medium-chain fatty acid triglycerides, for example, fractionated coconut oil (trade name: Capryol), φ esters of fatty acids and monovalent to trivalent alkanols, more specifically, esters 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 φ free fatty acids, for example, liquid oleic acid or linoleic acid.
[0032] A content of the oil may be 50% by weight to 98% by weight, based on a total weight of the self-emulsifying emulsion. When the content of the oil is less than 50% by weight, the oil may not sufficiently dissolve the active ingredient to generate precipitates. When the content of the oil is more than 98% by weight, use of the surfactant may be decreased to deteriorate emulsifying ability of the formulation.
[0033] As experimental results of examining solubility of dutasteride using Capmul
MCM oil, a minimum amount of the oil needed to dissolve 0.5 mg of dutasteride is 32 mg, which indicates that an entire amount of oil to be used exceeds 50 mg. However, 6 considering miniaturization of the soft capsule, the amount of the oil may not exceed
200 mg. Thus, when the self-emulsifying emulsion includes 0.5 mg of dutasteride, the oil may be used in an amount of about 50 mg to about 200 mg.
[0034] The surfactant serves to form a stable emulsion by stably emulsifying the oil component in water. As the surfactant, a non-ionic surfactant may be used. The non-ionic surfactant may include Tweens, Spans, Labrasols, Brij, Myrj, castor oils such as polyoxyl castor oil, substituted castor oils such as Cremophor or hydrogenated Cremophor, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene-polyoxypropylene copolymers (trade name: Pluronics), mono- or di-glycerides of caprylic/capric acid (trade name: Imwitors), etc. 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 copolymer may include Poloxamer 407, Poloxamer 188, or Poloxamer 124. The substituted castor oils may include a hydrogenated castor oil such as HCO-50 (PEG50 Hydrogenated castor oil) or HCO-40 (PEG40 Hydrogenated castor oil), or a polyoxyethylated castor oil such as Cremophor® EL or Cremophor RH40 etc.
[0035] The surfactant may be included in an amount of 1% by weight to 40% by weight, based on a total weight of the self-emulsifying emulsion. When the amount of the surfactant is less than 1% by weight, emulsion-forming ability may be decreased, and when the amount of the surfactant is more than 40% by weight, it is difficult to obtain a desired effect, as compared with the addition amount.
[0036] In a specific embodiment, the self-emulsifying emulsion may include dutasteride of 0.3% by weight to 0.7% by weight, the oil of 60% by weight to 96% by weight, and the surfactant of 3% by weight to 40% by weight, based on a total weight of the self-emulsifying emulsion.
[0037] In a specific embodiment, the self-emulsifying emulsion may include dutasteride of 0.4% by weight to 0.6% by weight, the oil of 65% by weight to 95% by weight, and the surfactant of 4% by weight to 35% by weight, based on a total weight of the self-emulsifying emulsion.
[0038] Considering a minimum amount of the oil needed to dissolve an effective amount of dutasteride and miniaturization of the soft capsule, the self-emulsifying emulsion may be included in an amount of 70 mg to 200 mg in the independent dutasteride part. In a specific embodiment, the independent dutasteride part may be a soft capsule including about 70 mg to about 200 mg of the self-emulsifying emulsion.
[0039] In a specific embodiment, the independent dutasteride part may be a soft capsule including 70 mg to 200 mg of the self-emulsifying emulsion including dutasteride of 0.1% by weight to 1% by weight, the oil of 50% by weight to 98% by weight, and the surfactant of 1% by weight to 40% by weight, based on a total weight of the self-emulsifying emulsion.
[0040] In a specific embodiment, the independent dutasteride part may be a soft capsule including 70 mg to 200 mg of the self-emulsifying emulsion including dutasteride of 0.3% by weight to 0.7% by weight, the oil of 60% by weight to 96% by weight, and the surfactant of 3% by weight to 40% by weight, based on a total weight of the self-emulsifying emulsion.
[0041] In a specific embodiment, the self-emulsifying emulsion of dutasteride may include dutasteride: oil: surfactant at a weight ratio of about 1: 100 - 500: 1 - 100, specifically about 1: 150 - 250: 5 - 80, more specifically about 1: 150 - 200: 40 - 80. [0042] The self-emulsifying emulsion of dutasteride may further include a property stabilizer. The property stabilizer may provide the active ingredient with appropriate solubility suitable for preparation, and also helps to stabilize properties of the active ingredient, thereby preventing phase separation and precipitation even during preservation of the formulation and ensuring uniformity of the composition.
[0043] The property stabilizer may be selected from the group consisting of water, ethanol, glycerin, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether (trade name: transcutols), dimethyl isosorbide (trade name: Arlasolve), cetyl alcohol, and any combination thereof, and for example, water, ethanol, or glycerin. [0044] The property stabilizer may be included in an amount of 0.5% by weight to 3% by weight, or 1% by weight to 3% by weight, based on a total weight of the self-emulsifying emulsion.
[0045] The self-emulsifying emulsion of dutasteride may further include a pharmaceutically acceptable additive for oral administration, for example, an antioxidant. The antioxidant may be selected from lipophilic tocopherol, dibutylhydroxy toluene, hydrophilic ascorbic acid, sodium sulfite, sodium pyrosulfite, and any combination thereof.
[0046] In a specific embodiment, the independent dutasteride part may be a soft capsule including the self-emulsifying emulsion, and the soft capsule may be prepared using a soft capsule of size Nos. 2 to 4 having a volume of 0.07 cc to 0.30 cc. Further, the soft capsule may be prepared using a round, oblong, or oval soft capsule. In a specific embodiment, the soft capsule may be prepared using a round soft capsule of size Nos. 2 to 4 (0.07 cc to 0.25 cc), an oval soft capsule of size Nos. 2 to 4 (0.09 cc to 0.25 cc), or an oblong soft capsule of size Nos. 2 to 4 (0.08 cc to 0.30 cc), more specifically, a round soft capsule of size Nos. 2 to 3 (0.07 cc to 0.19 cc) or an oval soft capsule of size Nos. 2 to 3 (0.09 cc to 0.19 cc), and much more specifically, a round or oval soft capsule of size No. 2 (see Catalent, Inc., https://www.catalent.com/index.php/content/download/1230/14867/file/Catalent_Sha pes_Sizes_lnfo.pdf., and EP 2 575 788 A1).
[0047] The soft capsule may be a soft capsule which is made of a material commonly used in the pharmaceutical field.
[0048] The independent tamsulosin part may be in a form of a tablet, capsule, or granule.
[0049] To be prepared as the above formulation, the independent tamsulosin part may further include a pharmaceutically acceptable additive. The additive may include a diluent, a disintegrant, a binder, a stabilizer, a lubricant, a coloring agent, and any combination thereof.
[0050] The diluent may be selected from the group consisting of microcrystalline cellulose, lactose, Ludipress, mannitol, calcium dihydrogen phosphate, starch, low-substituted hydroxypropyl cellulose, and any combination thereof. The diluent may be used in an amount of about 1% by weight to about 95% by weight, specifically, about 5% by weight to about 95% by weight, based on a total weight of the granules, tablet, or capsule.
[0051] The disintegrant may be selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or sodium salts thereof, and any combination thereof.
The disintegrant may be used in an amount of about 0.1% by weight to about 30% by 9 weight, specifically about 2% by weight to about 15% by weight, based on a total weight of the granules, tablet, or capsule.
[0052] The binder may be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate, polyvinyl pyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light anhydrous silicic acid, silicate derivatives such as synthetic aluminum silicate, calcium silicate, or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and any combination thereof. The binder may be used in an amount of about 0.1% by weight to about 30% by weight, specifically about 2% by weight to about 20% by weight, based on a total weight of the granules, tablet, or capsule.
[0053] The lubricant may be selected from the group consisting of stearic acid, metal salts thereof such as calcium stearate or magnesium stearate, talc, colloid silica, sucrose fatty acid ester, hydrogenated vegetable oil, high-melting point wax, glyceryl fatty acid esters, glycerol dibehenate, and any combination thereof. The lubricant may be used in an amount of about 0.3% by weight to about 5% by weight, specifically about 0.5% by weight to about 3% by weight, based on a total weight of the granules, tablet, or capsule.
[0054] The independent tamsulosin part, in particular, the tamsulosin granules or the tablet may be coated with a pharmaceutically acceptable coating agent. The coating agent may be a coating agent commonly used in the art.
[0055] In a specific embodiment, the independent tamsulosin part may be a sustained-release or enteric granules or tablet obtained by coating the tamsulosin granules or tablet with a sustained-release coating agent or an enteric coating agent. The sustained-release coating agent may be selected from povidone, methyl cellulose, ethyl cellulose, triethyl citrate, hypromellose, cellulose acetate, polyvinyl acetate, propylene glycol, talc, and any combination thereof, and the enteric coating agent may be selected from a methacrylic acid-ethyl acrylate copolymer, triacetin, cellulose acetate succinate, hypromellose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, sodium alginate, and any combination thereof. The coating agents may be used alone or in any combination thereof to coat the tamsulosin granules or tablet. By introduction of the coating agent, the independent 10 tamsulosin part may exhibit sustained-release or enteric property, and thus it may be effectively used, along with immediate-release dutasteride, in the treatment of prostatic hyperplasia.
[0056] In a specific embodiment, the coating agent may be selected from the group consisting of povidone, propylene glycol, polyvinyl acetate, methacrylic acid-ethyl acrylate copolymers, talc, and any combination thereof, but is not limited thereto. [0057] When the enteric coating agent is used as the coating agent, a plasticizer may be further added in order to prevent an enteric coating film from breaking even when stored for a long period of time. The plasticizer may be acetylated monoglyceride, triacetin, a mixture thereof, etc.
[0058] Use of the coating agent may be maintained in a minimal amount for an optimal formulation size and effective preparation. For example, the coating agent may be used in an amount of 0.1% by weight to 20 % by weight, specifically 2% by weight to 10 % by weight, based on a total weight of the independent tamsulosin part. [0059] In a specific embodiment, the hard capsule composite formulation according to the present disclosure may be, as shown in the illustration of FIG. 1, in a form including both the dutasteride soft capsule and the tamsulosin granules in the hard capsule.
[0060] In the hard capsule composite formulation, the hard capsule (i.e., hard capsule empty capsule) including the independent dutasteride part and the independent tamsulosin part may be any vacant capsule known in the art.
[0061] In a specific embodiment, the hard capsule including the independent dutasteride part and the independent tamsulosin part may be selected from a gelatin hard gelatin hard capsule and an HPMC hard capsule.
[0062] In a specific embodiment, the hard capsule may be a gelatin hard capsule. [0063] When the gelatin hard capsule is used, an initial dissolution rate of the dutasteride may be remarkably improved, as compared with use of the HPMC hard capsule, and as a result, there is an advantage that fast-acting property of dutasteride may be obtained. Accordingly, intended immediate-release property of the immediate-release independent dutasteride part may be further increased, thereby obtaining enhanced fast-acting property of dutasteride without influencing the sustained-release independent tamsulosin part. Thus, there is an advantage that the 11 fast-acting property of dutasteride may be selectively increased without influencing the sustained-release property of tamsulosin (see Experimental Example 1).
[0064] In a specific embodiment, the hard capsule may be the HPMC hard capsule. [0065] The HPMC hard capsule may be advantageous in terms of storage stability and dissolution rate of the active ingredient under high-temperature, humid storage conditions, as compared with the gelatin hard capsule, because the gelatin capsule may stick to the internal dutasteride soft capsule to age under high-temperature, humid conditions, and thus there is a risk that the dissolution rate of the dutasteride may be lowered.
[0066] In the present disclosure, the “HPMC hard capsule” refers to a hard capsule prepared by using hydroxypropyl methylcellulose as a main base material.
[0067] In the present disclosure, the “gelatin hard capsule” refers to a hard capsule prepared by using gelatin as a main base material.
[0068] In a specific embodiment, the hard capsule composite formulation of the present disclosure may be a hard capsule composite formulation having more than about 85%, and more specifically more than about 90%, of a dissolution rate of the dutasteride in 15 minutes, according to a dissolution test conducted according to the paddle method of the dissolution test of the United States Pharmacopoeia (USP). [0069] In a specific embodiment, the hard capsule composite formulation of the present disclosure may be a hard capsule composite formulation having about 80% or more of a dissolution rate of the dutasteride in 30 minutes, according to a dissolution test conducted according to the paddle method of the dissolution test of the USP.
[0070] In a specific embodiment, the hard capsule composite formulation may be orally administered.
[0071] The vacant capsule which is packed with the independent dutasteride part and the independent tamsulosin part in order to prepare the hard capsule composite formulation has any size without limitation, as long as the size is a general capsule size used in medicinal products.
[0072] The hard capsule composite formulation may be introduced with the soft capsule including the self-emulsifying emulsion, thereby decreasing a volume of the independent dutasteride part, and as a result, all of the independent dutasteride part and the independent tamsulosin part may be filled in pharmaceutically effective amounts into a hard capsule (the hard capsule having an internal capacity of about 0.27 cc to 0.68 cc) of size Nos. 0 to 3. The capsule may have a variety of internal capacity depending on the size number of the capsule. For example, a capsule of size No. 00 has an internal capacity of about 0.95 cc, a capsule of size No. 0 about 0.68 cc, a capsule of size No. 1 about 0.47 cc, a capsule of size No. 2 about 0.37 cc, a capsule of size No. 3 about 0.27 cc, and a capsule of size No. 4 about 0.20 cc (SUHEUNG Co., Ltd., see http://www.suheung.com/korea/embocaps31.html).
[0073] Therefore, in a specific embodiment, the size of the hard capsule composite formulation may be remarkably reduced, as compared with known commercially available formulations (see Examples 1 and 2), thereby significantly increasing convenience of patients upon oral administration. In a specific embodiment, the vacant capsule of the hard capsule composite formulation may be a hard capsule of size No. 0, 1, 2, or 3.
[0074] The hard capsule composite formulation may include dutasteride, which is a 5-alpha reductase inhibitor, as a first active ingredient, thereby showing a rapid effect in the treatment of benign prostatic hyperplasia, prostate cancer, and male pattern alopecia, and may include tamsulosin, which is an aia blocker, as a second active ingredient, thereby showing a sustained effect in the treatment of benign prostatic hyperplasia, chronic prostatitis, chronic abdominal pain, urinary disorder such as urolithiasis, etc. In a specific embodiment, the hard capsule composite formulation may be used in the treatment of benign prostatic hyperplasia.
[0075] The hard capsule composite formulation may include dutasteride and tamsulosin in a unit formulation during preparation as the composite formulation, and may include any known contents thereof. For example, the hard capsule composite formulation may include about 0.2 mg to about 1 mg of the dutasteride as a free base and about 0.1 mg to about 0.8 mg of the tamsulosin as a free base in a unit formulation. In a specific embodiment, the hard capsule composite formulation may include about 0.5 mg of a free base of the dutasteride as the active ingredient of the independent dutasteride part and about 0.4 mg of tamsulosin hydrochloride as the active ingredient of the independent tamsulosin part.
[0076] Another aspect of the present disclosure provides a fixed-dose composite formulation which is a unit dosage formulation including an independent dutasteride part including dutasteride or a pharmaceutically acceptable salt thereof and an independent tamsulosin part including tamsulosin or a pharmaceutically acceptable salt thereof, wherein the independent dutasteride part includes the dutasteride or the pharmaceutically acceptable salt thereof in an amount of about 0.5 mg, calculated as a free base of the dutasteride, per unit dosage, and a dissolution rate of the dutasteride is about 80% by weight or more in 30 minutes, and more specifically, a dissolution rate of the dutasteride is more than about 85 % by weight in 15 minutes according to a dissolution test conducted according to the paddle method of the dissolution test of the USP, and the independent tamsulosin part includes tamsulosin or the pharmaceutically acceptable salt thereof in an amount of 0.2 mg or 0.4 mg, calculated as a free base of the tamsulosin, per unit dosage, and a dissolution rate of the tamsulosin is 34% by weight or less in two hours, a dissolution rate of the tamsulosin is about 47% by weight to 68 % by weight in three hours, and a dissolution rate of the tamsulosin is about 80% by weight or more in eight hours according to a dissolution test conducted according to the paddle method of the dissolution test of the USP.
[0077] Further, the fixed-dose composite formulation is a capsule composite formulation including, in a separated state, the independent dutasteride part and the independent tamsulosin part, which may be filled into a capsule of size Nos. 0 to 3. [0078] Further, the fixed-dose composite formulation is a formulation including the independent dutasteride part including a self-emulsifying emulsion including dutasteride, an oil and a surfactant; and the independent tamsulosin part including a solid formulation including a sustained-release agent.
[0079] Still another aspect of the present disclosure provides a method of preparing the hard capsule composite formulation according to an aspect of the present disclosure, the method including:
[0080] preparing a self-emulsifying emulsion of dutasteride by mixing dutasteride or a pharmaceutically acceptable salt thereof, an oil, and a surfactant;
[0081] preparing a soft capsule of dutasteride including the self-emulsifying emulsion of dutasteride;
[0082] preparing tamsulosin granules by granulating tamsulosin or a pharmaceutically acceptable salt thereof along with a pharmaceutically acceptable additive to produce granules of tamsulosin, or tableting the granules into a tablet of tamsulosin; and [0083] filling an empty capsule with the soft capsule of dutasteride and the granules or the tablet of tamsulosin to obtain one hard capsule including the soft capsule of dutasteride and the granules or the tablet of tamsulosin.
[0084] Provided is a method of preparing the hard capsule composite formulation according to an aspect of the present disclosure.
[0085] The description of the hard capsule composite formulation according to one aspect of the present disclosure may be also applied to a detailed description of the method of preparing the hard capsule composite formulation.
[0086] The self-emulsifying emulsion of dutasteride may be prepared in a form of a liquid by mixing and stirring dutasteride, the oil, and the surfactant to homogeneously dissolve the mixture, and as needed, a property stabilizer and/or an antioxidant may be further added thereto, followed by mixing and stirring.
[0087] The dutasteride soft capsule including the self-emulsifying emulsion of dutasteride may be prepared by filling a soft capsule with the self-emulsifying emulsion of dutasteride according to a common pharmaceutical preparation process. [0088] Preparation of the tamsulosin granules or tablet may be performed according to a common method of preparing granules or a tablet. For the preparation of the granules or tablet, the method may further include a process of coating the granules or tablet with a coating agent, for example, a sustained-release coating agent or an enteric coating agent according to a common coating method, as needed.
MODE OF DISCLOSURE [0089] [Example] [0090] Hereinafter, the present disclosure will be described in detail with reference to the following Examples. However, these Examples are for illustrative purposes only, and the scope of the present disclosure is not intended to be limited thereby.
[0091] Example 1: Preparation of Hard Capsule Composite Formulation (1) [0092] An independent dutasteride part and an independent tamsulosin part were prepared according to the following prescriptions:
[0093] - Independent dutasteride part -
[0094] Dutasteride 0.50 mg
[0095] Mono- and diglyceride 90.00 mg
[0096] Hydrogenated castor oil 20.00 mg
[0097] Butyl hydroxy toluene 0.01 mg
[0098] - Independent tamsulosin part -
[0099] Tamsulosin hydrochloride 0.4 mg
[00100] Polyvinyl acetate dispersion 20.0 mg
[00101] Microcrystalline cellulose 150.0 mg
[00102] Hypromellose 5.0 mg
[00103] Povidone 0.2 mg
[00104] Propylene glycol 0.3 mg
[00105] methacrylic acid-ethyl acrylate copolymer 5.0 mg
[00106] Triacetin 0.2 mg
[00107] Sucrose stearate 0.1 mg
[00108] Purified water (100.0 mg)
[00109] The independent dutasteride part was prepared by dissolving dutasteride in mono- and diglyceride oil, adding all the remaining components thereto, and dissolving the mixture to prepare a self-emulsifying emulsion. The prepared self-emulsifying emulsion was filled into a soft capsule to prepare a dutasteride soft capsule. In detail, a capsule base material having gelatin:glycerin:glycine at a weight ratio of 81:46:1 was used to prepare a coating composition according to a common method of preparing a coating. Next, a rotary-type automatic filling machine was used to fill the prepared self-emulsifying emulsion into a shape of 2 round and a ribbon thickness of 0.65 mm, or a shape of 2 oval and a ribbon thickness of 0.75 mm according to a common filling method, and then trimmed and dried to prepare a dutasteride soft capsule formulation. A photograph ofthe prepared capsule is shown in FIG. 2 (bottom).
[00110] The independent tamsulosin part was prepared by mixing all of the listed tamsulosin hydrochloride, microcrystalline cellulose, and hypromellose in a 16 powder form, and using a binder solution which was prepared by dissolving 18 mg of polyvinyl acetate per capsule in water to prepare granules. Next, an inner coating solution prepared by dissolving povidone and propylene glycol, and 2 mg of polyvinyl acetate per capsule in water was used to coat the prepared tamsulosin granules, and then further coated with an external coating solution which was prepared by dissolving a methacrylic acid-ethyl acrylate copolymer and triacetin in water, thereby preparing tamsulosin hydrochloride granules, to which sucrose stearate was added and mixed.
[00111] The prepared dutasteride soft capsule and tamsulosin granules were filled into a gelatin hard capsule of size No. 1 (SUHEUNG Co., Ltd.), thereby preparing a gelatin hard capsule composite formulation including 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride. A photograph of the prepared capsule is shown in FIG. 3 (bottom).
[00112] Example 2: Preparation of Hard Capsule Composite Formulation {21 [00113] Tamsulosin granules were prepared in the same manner as in Example 1, and then further mixed with 9 mg (5%) of crospovidone as a disintegrant, and then tableted by a circular punch having a diameter of 6.5 mm. The resulting tamsulosin tablet and the dutasteride soft capsule were filled into a gelatin hard capsule of size No. 0 (SUHEUNG Co., Ltd.), thereby preparing a capsule composite formulation. [00114] Example 3: Preparation of Hard Capsule Composite Formulation {31 [00115] An independent dutasteride part was prepared in the same manner as in Example 1, and an independent tamsulosin part was prepared by the following prescription:
[00116] - Independent tamsulosin part -
[00117] Tamsulosin hydrochloride 0.4 mg
[00118] Microcrystalline cellulose 107.6 mg
[00119] Hypromellose 4.0 mg
[00120] Talc 9.0 mg
[00121] methacrylic acid-ethyl acrylate copolymer 19.0 mg
[00122] Triacetin 1.9 mg
[00123] [00124]
Sucrose stearate
Purified water
0.1 mg (110.0 mg) [00125] The independent tamsulosin part was prepared by mixing all of the listed tamsulosin hydrochloride, microcrystalline cellulose, hypromellose, and 6.0 mg of talc in a powder form, and using a binder solution which was prepared by dissolving 12.0 mg of methacrylic acid-ethyl acrylate copolymer in water to prepare granules. Next, an enteric coating solution prepared by dissolving 7.0 mg of the methacrylic acid-ethyl acrylate copolymer, triacetin, and 3.0 mg of talc in water was used to coat the prepared tamsulosin granules, thereby preparing tamsulosin hydrochloride granules. Sucrose stearate was added thereto and mixed therewith to prepare tamsulosin granules.
[00126] The resulting tamsulosin granules and the dutasteride soft capsule prepared in Example 1 were filled into a gelatin hard capsule of size No.
1(SUHEUNG Co., Ltd.), thereby preparing a gelatin hard capsule composite formulation including 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride.
[00127] Example 4: Preparation of Hard Capsule Composite Formulation 141 [00128] An HPMC hard capsule composite formulation including 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride was prepared in the same manner as in Example 1, except that an HPMC hard capsule of size No. 1 (Qualicap®) was used instead of the gelatin hard capsule of size No. 1 in Example 1.
[00129] Comparative Example 1: Preparation of Hard Capsule Composite Formulation (5) [00130] Jalyn capsule formulation commercially available from GlaxoSmithKline in US was used as Comparative Example 1. The hard capsule of the Jalyn capsule formulation was found to have size No. 00. A photograph of the hard capsule is shown in FIG. 3 (top), and a dutasteride soft capsule formulation existing inside the hard capsule is shown in FIG. 2 (top).
[00131] Experimental Example 1: Dissolution Test [00132] The hard capsule composite formulations including dutasteride and tamsulosin of Examples 1 to 4 and Comparative Example 1 were subjected to a dissolution test according to the following conditions.
[00133] <Dutasteride dissolution conditions>
[00134] A dissolution test was conducted using 900 mL of a 0.1 N hydrochloric acid solution containing 1%(w/v) cetyl trimethylammonium bromide(CTAB) according to the paddle method of the dissolution test of the United States Pharmacopoeia (USP). Dissolution test samples were collected at an initial point, and at 5 minutes, minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after start of the test, and subjected to liquid chromatography under the following conditions to calculate dissolution rates of the dutasteride.
[00135] - Column: a column in which a stainless steel tube having an inner diameter of about 4.6 mm and a length of about 15 cm was packed with phenyl silica gel for liquid chromatography having a particle size of about 3.5 pm (Zorbax SB-Phenyl, Agilent Zorbax) [00136] - Detector: UV spectrophotometer (measurement wavelength: 210 nm) [00137] - Flow rate: 1.0 ml/min [00138] - Input volume: 100 pi [00139] - Column temperature: 40°C [00140] - Mobile phase: a mixed solution of acetonitrile and purified water (60:40, v/v) [00141] - Dissolution medium: 0.1 N hydrochloric acid solution containing
1%(w/v) cetyl trimethylammonium bromide (CTAB) [00142] <Tamsulosin dissolution conditions>
[00143] According to the paddle method of the dissolution test of the USP, a dissolution test was performed using a sinker and 750 mL of an acidic solution at 50 rpm for initial 120 minutes, and then the dissolution test was further performed by adding 250 mL of a buffer test solution thereto until 480 minutes after the start of the test. As samples, 10 mL of the dissolution test solution was collected at an initial point and at 120 min, 180 min, 240 min, 360 min, and 480 min after the start of the test. The collected samples were subjected to liquid chromatography under the following conditions to calculate dissolution rates of the tamsulosin.
[00144] - Column: a column in which a stainless steel tube having an inner diameter of about 4.6 mm and a length of about 5 cm was packed with octadecylsilyl silica gel for liquid chromatography having a particle size of about 5 pm (Kromasil
Eternity-5-C18, AkzoNobel) [00145] - Detector: UV spectrophotometer (measurement wavelength: 225 nm) [00146] - Flow rate: 1.3 ml/min [00147] - Input volume: 100 pi [00148] - Column temperature: 30°C [00149] - Mobile phase: 8.7 mL of perchloric acid and 3.0 g of sodium hydroxide were dissolved in 1900 mL of water, a pH of the solution was adjusted to pH 2.0 with sodium hydroxide, and then water was added up to 2000 mL. 480mL of acetonitrile was added to 1520 mL of this solution, which was used as a mobile phase.
[00150] - Dissolution medium: acidic solution-0.1 N hydrochloric acid solution [00151] Buffer test solution -0.2 M trisodium phosphate (12 hydrate), pH 6.8 [00152] Dutasteride dissolution results are shown in the following Table 1 and
FIG. 4, and tamsulosin dissolution results are shown in the following Table 2 and FIG. 5.
[00153] [Table 1]
Section Dutasteride dissolution rate
0 min 5 min 10 min 15 min 30 min 45 min 60 min
Example 1 0.0% 0.0% 50.3% 97.4% 99.5% 100.2% 100.1%
Example 2 0.0% 0.0% 47.8% 95.3% 98.9% 99.3% 100.2%
Example 3 0.0% 0.0% 49.8% 97.7% 99.3% 100.1% 99.9%
Example 4 0.0% 0.0% 14.2% 42.6% 99.7% 101.0% 99.7%
Comparative Example 1 0.0% 0.0% 20.7% 68.3% 98.8% 99.8% 101.2%
[00154] According to Table 1 and FIG. 4, the gelatin capsule composite formulations of Examples 1, 2, and 3 showed remarkably high initial dissolution rates of the dutasteride before 30 minutes, as compared with the HPMC capsule composite formulations of Comparative Example 1 and Example 4, and difference between the tamsulosin formulations of Examples 1, 2, and 3 did not greatly influence dissolution of dutasteride. Accordingly, the gelatin hard capsule composite formulations according to a specific embodiment of the present disclosure are expected to have fast-acting property of dutasteride.
[00155] [Table 2]
Section Tamsulosin dissolution rate
0 hr 2 hr 3 hr 4 hr 6 hr 8 hr
Example 1 0.0% 28.4% 55.7% 64.8% 77.0% 86.0%
Example 2 0.0% 23.2% 51.5% 62.4% 73.1% 82.8%
Example 3 0.0% 0.0% 59.1% 70.2% 79.8% 88.2%
Example 4 0.0% 27.2% 53.0% 65.3% 75.2% 84.3%
Comparative Example 1 0.0% 8.2% 50.1% 65.4% 74.5% 84.7%
[00156] According to Table 2 and FIG. 5, the formulations of Examples 3 and Comparative Example 1 showed high acid resistance due to the different prescriptions, whereas the gelatin capsule composite formulations of Examples 1 and 2 and the HPMC capsule composite formulation of Example 4 showed similar dissolution results. Accordingly, it was confirmed that change of the vacant capsule of the hard capsule formulation does not influence sustained-release dissolution patterns of the independent tamsulosin part.
[00157] The above results taken together showed that the gelatin capsule composite formulation according to a specific embodiment of the present disclosure may acquire a fast-acting property of dutasteride due to improvement in the intended immediate-release property of the immediate-release independent dutasteride part while not influencing efficacy of tamsulosin due to no influence on the sustained-release independent tamsulosin part.
[00158] The present disclosure has been described with reference to preferred embodiments thereof. It will be understood by those skilled in the art to which the present disclosure pertains that the present disclosure may be implemented in a different specific form without changing the essential characteristics thereof.
Therefore, it should be understood that the above embodiments are is not limitative, but illustrative in all aspects. The scope of the present disclosure is defined by the appended claims rather than by the foregoing description, and all differences within 21 the scope of equivalents thereof should be construed as being included in the present disclosure.

Claims (18)

1. A hard capsule composite formulation comprising:
an independent dutasteride part comprising dutasteride or a pharmaceutically acceptable salt thereof; and an independent tamsulosin part comprising tamsulosin or a pharmaceutically acceptable salt thereof, wherein the independent dutasteride part is a formulation comprising a self-emulsifying emulsion comprising dutasteride, an oil, and a surfactant, the independent tamsulosin part is a solid formulation comprising a sustained-release agent, and the independent dutasteride part and the independent tamsulosin part are comprised in a separated state and filled into a hard capsule of size Nos. 0 to 3.
2. The hard capsule composite formulation of claim 1, wherein the independent dutasteride part comprises 70 mg to 200 mg of the self-emulsifying emulsion.
3. The hard capsule composite formulation of claim 1 or 2, wherein the independent dutasteride part is a soft capsule comprising the self-emulsifying emulsion comprising dutasteride of 0.1% by weight to 1% by weight, the oil of 50% by weight to 98% by weight, and the surfactant of 1% by weight to 40% by weight, based on a total weight of the self-emulsifying emulsion.
4. The hard capsule composite formulation of claim 1 or 2, wherein the independent dutasteride part is a soft capsule comprising the self-emulsifying emulsion comprising dutasteride of 0.3% by weight to 0.7% by weight, the oil of 60% by weight to 96% by weight, and the surfactant of 3% by weight to 40% by weight, based on a total weight of the self-emulsifying emulsion.
5. The hard capsule composite formulation of claim 1 or 2, wherein the independent dutasteride part is a soft capsule comprising the self-emulsifying emulsion comprising dutasteride of 0.4% by weight to 0.6% by weight, the oil of 65% 23 by weight to 95% by weight, and the surfactant of 4% by weight to 35% by weight, based on a total weight of the self-emulsifying emulsion.
6. The hard capsule composite formulation of claim 1, wherein the oil is selected from the group consisting of fatty acid mono-, di-, or mono/di-glycerides; fatty acid triglycerides; esters of fatty acids and monovalent to trivalent alkanols; and free fatty acids.
7. The hard capsule composite formulation of claim 1, wherein the surfactant is selected from the group consisting of substituted castor oils, polyoxyethylene-polyoxypropylene block copolymers, and any combination thereof.
8. The hard capsule composite formulation of claim 1, wherein the self-emulsifying emulsion further comprises an antioxidant.
9. The hard capsule composite formulation of claim 1, wherein a dissolution rate of the dutasteride is more than 85% in 15 minutes according to a dissolution test conducted according to the paddle method of the dissolution test of the United States Pharmacopoeia (USP).
10. The hard capsule composite formulation of claim 1, wherein the independent tamsulosin part is a solid formulation selected from the group consisting of a tablet, a capsule, and granules.
11. The hard capsule composite formulation of claim 10, wherein the independent tamsulosin part is granules or a tablet, wherein the granules or the tablet are coated with a coating agent selected from the group consisting of povidone, propylene glycol, polyvinyl acetate, a methacrylic acid-ethyl acrylate copolymer, talc, and any combination thereof.
12. The hard capsule composite formulation of claim 1, wherein the pharmaceutically acceptable salt of tamsulosin is tamsulosin hydrochloride.
13. The hard capsule composite formulation of claim 1, wherein the hard capsule composite formulation comprises, per unit dosage, 0.2 mg to 1 mg of a free base of the dutasteride and 0.1 mg to 0.8 mg of a free base of the tamsulosin.
14. The hard capsule composite formulation of claim 1, wherein the hard capsule composite formulation is for the treatment of benign prostatic hyperplasia.
15. A fixed-dose composite formulation which is a unit dosage formulation comprising an independent dutasteride part comprising dutasteride or a pharmaceutically acceptable salt thereof and an independent tamsulosin part comprising tamsulosin or a pharmaceutically acceptable salt thereof, wherein the independent dutasteride part comprises the dutasteride or a pharmaceutically acceptable salt thereof in an amount of about 0.5 mg, calculated as a free base of the dutasteride, per unit dosage, and a dissolution rate of the dutasteride is about 80% by weight or more in 30 minutes according to a dissolution test conducted according to the paddle method of the dissolution test of the United States Pharmacopoeia (USP), and the independent tamsulosin part comprises the tamsulosin or a pharmaceutically acceptable salt thereof in an amount of 0.2 mg or 0.4 mg, calculated as a free base of the tamsulosin, per unit dosage, and a dissolution rate of the tamsulosin is 34% by weight or less in two hours, a dissolution rate of the tamsulosin is about 47% by weight to 68 % by weight in three hours, and a dissolution rate of the tamsulosin is about 80% by weight or more in eight hours according to a dissolution test conducted according to the paddle method of the dissolution test of the USP.
16. The fixed-dose composite formulation of claim 15, wherein the independent dutasteride part and the independent tamsulosin part are comprised in a separated state and filled into a capsule of size Nos. 0 to 3.
17. The fixed-dose composite formulation of claim 15, wherein the independent dutasteride part is a formulation comprising a self-emulsifying emulsion 25 comprising dutasteride, an oil, and a surfactant; and the independent tamsulosin part is a solid formulation comprising a sustained-release agent.
18. A method of preparing the hard capsule composite formulation of any one of claims 1, 2, and 6 to 14, the method comprising:
preparing a self-emulsifying emulsion of dutasteride by mixing dutasteride or a pharmaceutically acceptable salt thereof, an oil, and a surfactant;
preparing a soft capsule of dutasteride comprising the self-emulsifying emulsion of dutasteride;
granulating tamsulosin or a pharmaceutically acceptable salt thereof along with a pharmaceutically acceptable additive to produce granules of tamsulosin, or tableting the granules into a tablet of tamsulosin; and filling an empty capsule with the soft capsule of dutasteride and the granules or the tablet of tamsulosin to obtain one hard capsule comprising the soft capsule of dutasteride and the granules or the tablet of tamsulosin.
1/3
DRAWINGS [FIG. 1]
2/3 [FIG. 3]
DISSOLUTION RATE (%) [FIG. 4]
DUTASTERIDE DISSOLUTION
3/3
DISSOLUTION RATE (%) [FIG. 5]
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EP2949319A1 (en) * 2014-05-26 2015-12-02 Galenicum Health S.L. Pharmaceutical compositions comprising an active agent
KR101590072B1 (en) * 2014-12-23 2016-01-29 한미약품 주식회사 Composition for self-emulsifying drug delivery system comprising dutasteride

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PH12018501985A1 (en) 2019-07-08
KR101968754B1 (en) 2019-04-12
BR112018068686A2 (en) 2019-01-15
WO2017160106A2 (en) 2017-09-21
KR20170107933A (en) 2017-09-26
EA201891843A1 (en) 2019-04-30

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