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WO2016114521A1 - Composition de dutastéride sous forme de comprimé présentant une stabilité améliorée - Google Patents

Composition de dutastéride sous forme de comprimé présentant une stabilité améliorée Download PDF

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Publication number
WO2016114521A1
WO2016114521A1 PCT/KR2016/000069 KR2016000069W WO2016114521A1 WO 2016114521 A1 WO2016114521 A1 WO 2016114521A1 KR 2016000069 W KR2016000069 W KR 2016000069W WO 2016114521 A1 WO2016114521 A1 WO 2016114521A1
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WIPO (PCT)
Prior art keywords
dutasteride
preparing
prepared
solubilizer
propylene glycol
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PCT/KR2016/000069
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English (en)
Korean (ko)
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김병문
손미원
장선우
이상진
김정수
민동훈
김용민
원동한
김종오
조혁준
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동아에스티 주식회사
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Priority to JP2017537224A priority Critical patent/JP6426293B2/ja
Publication of WO2016114521A1 publication Critical patent/WO2016114521A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia

Definitions

  • the present invention relates to a composition in the form of a tablet containing dutasteride.
  • Dutasteride is a compound represented by the following formula (I) and, according to the nomenclature, 17 ⁇ -N- [2,5-bis (trifluoromethyl)] phenylcarbamoyl-4-aza-5 ⁇ -androst-1- It is called an en-3-one compound.
  • Dutasteride inhibits the action of 5-alpha reductase, which converts testosterone, a male hormone, to dihydrotestosterone, the causative agent of alopecia and benign prostatic hyperplasia, by inhibiting benign prostatic hyperplasia and androgenetic alopecia.
  • dutasteride is in the form of a white powder having a melting point of 242 ⁇ 250 °C (WO 06/099121), 44 mg / mL in ethanol, 64 mg / mL in methanol, 3 mg / mL in polyethylene glycol 400 , I represents the solubility in water of 0.038ng / mL is soluble drug (AVODART ®, FDA clinical pharmacology biopharmaceutics review).
  • Dutasteride is also known to degrade mainly by oxidation and hydrolysis. [Subba Rao & Radhakrishnanand, Chromatopia 67, 841-845 (2008)]
  • Dutasteride with this property is marketed under the trade name AVODART ® , Glaxosmithkline.
  • Avorot is a drug that is solubilized so that it can be absorbed in the gastrointestinal tract upon stabilization of dutasteride and oral administration.
  • 0.5 mg of dutasteride and butylated hydroxytoluene (oxidation and hydrolysis 0.035 mg is dissolved in 349.5 mg of mono-diglyceride of capric acid / caprylic acid, which is an oil phase, and then filled into a soft gelatin capsule composed of gelatin [AVODART ® , FDA chemistry review].
  • avocados are characterized by the sensitivity of heat and water to gelatin, which is the main ingredient of soft capsules, during storage. 1) Deformation due to softening and curing of capsule capsules, 2) Intercapsular adhesion due to increased adhesion of capsule capsules, and 3) Capsule coatings. 4) There is a high risk of deterioration of stability during storage as a medicament leaks due to rupture and 4) delayed disintegration due to gelatin crosslinking due to reaction between the solution and the coating.
  • butylated hydroxyl toluene which is added to arborite as a stabilizer to prevent the degradation of dutasteride, is a phenol derivative and can cause behavioral disorders in carcinogenicity, asthma and infants.
  • BHT Butylated hydroxytoluene
  • Korean Patent Publication No. 10-1055412 discloses solidification of dutasteride including a primary coating solution containing a mixture of dutasteride, an adsorbent, an excipient, a water-soluble polymer and a water-insoluble polymer, and a second coating solution containing a water-insoluble polymer.
  • Formulations are disclosed. The above technique is characterized in that tablets are prepared by dissolving both dutasteride and poloxamer, a surfactant, and propylene glycol monocaprylate, an oil-soluble solubilizer, in ethanol and then adsorbing it to an adsorbent composed of microcrystalline cellulose and silicon dioxide. .
  • ethanol may change the crystallinity of dutasteride during the manufacturing process, thereby accelerating the generation of dutasteride flexible material during the manufacturing process and storage, which may lead to poor stability.
  • a stabilizer such as hydroxytoluene must be used together.
  • Korean Patent Publication No. 10-0962447 discloses a self-emulsifying composition for solubilizing dutasteride and tablets prepared therefrom.
  • dootasteride is dissolved in a large amount of a surfactant and an oil-soluble solubilizer to prepare a self-emulsifying emulsion composition, and the mixed solution obtained by mixing it with ethanol is added to an adsorbent such as a diluent and a disintegrant to solidify the dutasteride.
  • an adsorbent such as a diluent and a disintegrant to solidify the dutasteride.
  • the self-emulsifying emulsion composition comprises a surfactant such as poloxamer, sucrose, etc.
  • dutasteride spontaneously dispersed into small oil droplets of 1000 nm or less upon contact with water.
  • the disadvantage is that it must be contained in large amounts.
  • surfactants are irritating to the mucous membranes, gastrointestinal disorders may occur when taken in the human body, it is inappropriate to formulate drugs such as dutasteride, which should be taken daily, into a self-emulsifying emulsion composition containing a large amount of surfactant. .
  • European Patent Publication No. 2468262 proposes a method for preparing a solid adsorbate prepared by dissolving dutasteride in an oil type solubilizer and then adsorbing the adsorbent.
  • the adsorbate thus obtained is blended into a mixture of excipients and then tablets are prepared by wet granulation using a binder prepared using water or an organic solvent.
  • Such a manufacturing method is presented in the Republic of Korea Patent Publication Nos. 10-1055412 and 10-0962447 that the step of adsorbing the dutasteride dissolved in the solubilizing agent and the step of producing the wet granules using a binder solution. There is a difference from one method.
  • European Patent Publication No. 2050436 another attempt to remedy the drawbacks of soft capsule formulations, differs from the techniques introduced above in detailing a method for preparing tablets by applying dry granules or wet granules, excluding the use of solubilizing agents in oil. It is described.
  • the granule composition provided in the present invention contains dutasteride in powder form, and the composition provided by this method is difficult to obtain sufficient bioavailability of dutasteride, a poorly soluble drug. There are disadvantages.
  • European Patent Publication No. 2050436 no bioavailability evaluation results are presented.
  • the present inventors have established a method for preparing a dutasteride-containing solid formulation, which does not use a stabilizer harmful to the human body, such as ethanol and butylated hydroxytoluene, which are organic solvents, and has better storage stability than soft capsules.
  • a stabilizer harmful to the human body such as ethanol and butylated hydroxytoluene, which are organic solvents
  • the emulsion obtained by suspending light silicic anhydride in an oil phase and / or a separate aqueous solution containing dutasteride and homogeneously emulsifying these solutions is added to a solid granule such as a disintegrant, diluent, etc.
  • the present invention in the solid preparations containing dutasteride, a poorly water-soluble drug, exhibits excellent storage stability by minimizing the generation of flexible substances even when butylated hydroxytoluene, which is known to be harmful to the human body, is not used as a stabilizer. It is an object to provide a solid preparation that is uniformly contained and a method for producing the same.
  • the present invention provides a method for producing a solid formulation, in particular in the form of a solid formulation using a solid pharmaceutical composition comprising hard silicic acid as a dutasteride, a solubilizer and a stabilizer.
  • the present invention provides a solid preparation comprising dutasteride using the pharmaceutical composition prepared by the above method.
  • step 2 a step of preparing a solution suspended by stirring 0.3 ⁇ 1 parts by weight of hard silicic anhydride in the solution prepared in step 1;
  • a method for producing a dutasteride-containing solid preparation comprising the step of preparing a solid preparation in the usual manufacturing method granules in 5.
  • step 4 the method of emulsifying in step 4 after suspending light anhydrous silicic acid in only one step of step 2 or step 3 is also included in the present invention.
  • the hard silicic anhydride is added to obtain a stabilizing effect by suppressing the generation of a flexible material of dutasteride during the manufacturing process, the process of suspending the hard anhydrous silicic acid in step 2 and / or 3, that is, solubilizer mixed
  • the stabilizing effect is obtained by suppressing the generation of the soft substance of dutasteride by the manufacturing method of suspending light silicic anhydride in solution and / or purified water.
  • Step 1 of the present invention is to dissolve dutasteride in a solubilizer to prepare an oily solution.
  • a solubilizer for dissolving dutasteride, it is preferable to dissolve 1 part by weight of dutasteride in 20 to 60 parts by weight of the solubilizer.
  • step 2 and / or 3 that is, when suspending light silicic anhydride in the solubilizer mixed solution and / or purified water, in step 2, 0.3 to 1 part by weight of light anhydrous silicic acid per 1 part by weight of dutasteride, 3 In the step, it is preferable to suspend 5 to 30 parts by weight of hard anhydrous silicic acid in 100 to 1000 parts by weight of purified water.
  • step 2 when the granules are prepared by directly adding the oil phase in which dutasteride is dissolved in step 2 to the solid excipient such as disintegrant and diluent in step 5 without the emulsification process using step 3 in the water phase, adsorption of dutasteride occurs evenly. There is a possibility that granules of non-uniform content are produced.
  • the "solubilizer” is an organic solvent, solubility in dutasteride at room temperature is preferably 10 mg / g or more. If a solubilizer having low solubility in dutasteride is used, it is not preferable because the amount of solubilizer used to exhibit a sufficient solubilization effect increases, thereby increasing the size of the tablet.
  • solubilizers having a solubility in dutasteride of 10 mg / g or more include propylene glycol monocaprylate, propylene glycol monolaurate, diethylene glycol monoethyl ether, glyceryl monocaprylate, and glyceryl monocaprate. And mixtures thereof, but is not limited thereto.
  • solubilizers are generally oily liquids
  • solubilizers with low solubility in dutasteride should be used in relatively large amounts to achieve sufficient solubilization effects of dutasteride.
  • the amount of the liquid solubilizer added increases, the amount of the adsorbent required for solidification increases, and even if the solubilizer separates from the adsorbent even after solidification. Therefore, it is important to select a solubilizer excellent in solubility in dutasteride.
  • Solid pharmaceutical compositions provided by the present invention may include diluents, binders, glidants or coating bases, etc., in addition to pharmaceutically acceptable excipients such as disintegrants.
  • Disintegrants that can be used in the present invention are generally fast when solid preparations such as tablets, hard capsules, such as crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropylcellulose, It may be selected from the group consisting of materials and mixtures thereof used for the purpose of disintegrating, but is not limited thereto.
  • Diluents that can be used in the present invention are microcrystalline cellulose, powdered cellulose, gelatinized starch, lactose monohydrate, mannitol, sorbitol, formalin-casein, low-substituted hydroxypropyl cellulose (L-HPC), chitin, chitosan, polymerized agar acrylamide , Xylan, smecta, key-jo-clay, crosslinked carboxymethyl guar and modified tapioca starch, alginic acid or alginate, hydroxypropyl cellulose and other cellulose derivatives, polaracryl Potassium chlorine, croscarmellose sodium (Ac-Di-Sol, CLD-2), starch, carboxymethyl starch, gellan gum and the like.
  • Adsorbents that can be used to facilitate solidification of the emulsion in the present invention include calcium silicate, magnesium metasilicate aluminate, and the like.
  • Binders that can be used in the present invention are polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose And so on.
  • Glidants that can be used in the present invention, calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, calendula, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol 4000, polyethylene glycol 6000, liquid paraffin Hydrogenated soybean oil, aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acid, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, acetic acid Sodium, sodium oleate and the like.
  • the preparation method of the present invention does not contain phenolic antioxidants such as butylated hydroxytoluene, which are known to be harmful to humans, including the commercially available product Avorot ® and the previously disclosed dutasteride-containing preparations, and thus have excellent safety in the dutasteride-containing solid preparations. Not only can it be manufactured, but also has a lower storage amount of flexible materials than Avolot ® , a commercial product, and has excellent storage stability, and there is no risk of change of properties during storage.
  • phenolic antioxidants such as butylated hydroxytoluene
  • dutasteride-containing solid preparation prepared by the present invention can improve the content uniformity, thereby minimizing the content variation of the preparation.
  • Figure 2 is the result of evaluating the accelerated four-month flexible material of Example 6.
  • Figure 4 is a photograph showing the appearance after storage 4 months accelerated Example 6 and Comparative Example 4.
  • Table 1 shows the sugar content per tablet.
  • Dootasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer (Korean Science HT-120DX).
  • Dutasteride tablets were prepared in the following manner using propylene glycol monocaprylate and diethylene glycol monoethyl ether as solubilizers and hydroxypropyl cellulose as a binder in the following method.
  • Table 2 shows the sugar content per tablet.
  • Example 8> As a binder Hydroxypropyl cellulose To the water phase of the emulsion Dissolve According to the invention used Dutasteride Manufacture of tablets
  • Dutasteride tablets were prepared by using propylene glycol monocaprylate as a solubilizer and dissolving the hydroxypropyl cellulose as a binder in an aqueous phase and adding the composition of Table 3 in the following manner.
  • Table 3 shows the sugar content per tablet.
  • Dootasteride was added to propylene glycol monocaprylate, a solubilizer, and dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer.
  • Example 6 was prepared in the same manner as in Example 1 6) to 8) to the Example 8.
  • Dutasteride tablets were prepared in the following manner using propylene glycol monocaprylate and diethylene glycol monoethyl ether as solubilizers and adding calcium silicate as adsorbent. Table 4 shows the sugar content per tablet.
  • Example 9 was prepared in the same manner as in Example 6) to 8).
  • a homogeneous emulsion was prepared by adding the suspension prepared above to emulsified water.
  • Example 4 it was prepared in the same manner as in Example 6) to 8) and was set to Example 10, respectively.
  • the dutasteride tablet was prepared by including hard silicic anhydride only in the aqueous phase, and adding the light silicic anhydride to the oil phase.
  • Dootasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and the mixture was stirred for 30 minutes at 300 to 500 rpm using a mechanical stirrer to dissolve.
  • the prepared emulsion was added to a mixture of diluent mannitol, microcrystalline cellulose and a disintegrant low-substituted hydroxypropyl cellulose, and a binder hydroxypropyl cellulose. Drying at 12 °C for 12 hours to prepare a granule by a wet granulation method.
  • Example 11 was prepared in the same manner as in Example 6) to 8).
  • Dootasteride was added to propylene glycol monocaprylate and diethylene glycol monoethyl ether as solubilizers, and dissolved by stirring at 300 to 500 rpm using a mechanical stirrer.
  • dutasteride tablets were prepared with the composition of Table 8 not including hard silicic anhydride.
  • Dootasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and the mixture was stirred for 30 minutes at 300 to 500 rpm using a mechanical stirrer to dissolve.
  • Example 1 was prepared in the same manner as 6) to 8) of Example 1 to be Comparative Example 1.
  • Dootasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and the mixture was stirred for 30 minutes at 300 to 500 rpm using a mechanical stirrer to dissolve.
  • step 5) Using the suspension prepared in step 4) as a binding liquid, the mixture is added to a powder mixture of diluent mannitol, microcrystalline cellulose, a disintegrant low-substituted hydroxypropyl cellulose and a binder hydroxypropyl cellulose. It was dried at 60 °C for 12 hours to prepare a granule by a wet granulation method.
  • Example 1 was manufactured in the same manner as in 6) to 8) of Example 1 to be Comparative Example 2.
  • Dootasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether as a solubilizer, and the mixture was stirred for 30 minutes at 300 to 500 rpm using a mechanical stirrer to dissolve.
  • a commercial product Avorot (AVODART ® , GlaxoSmithKline, Lot No. 064481A) was used as Comparative Example 4 for the comparative evaluation of the accelerated stability with the tablet-type dutasteride composition provided by the present invention.
  • the soft matter content of dutasteride was evaluated using Examples 1 to 5, Example 7, Example 10, and Example 11 and Comparative Examples 1 to 3.
  • the total amount of lead material was evaluated as a percentage (%) of the sum of the peak areas of dutasteride lead material among the sum of all peak areas. At this time, peaks derived from excipients other than dutasteride were excluded.
  • the results by HPLC analysis are shown in FIG. 1. As a test method for evaluation of analogues of dutasteride, the following HPLC conditions were used.
  • UV absorbance photometer (wavelength 210 nm)
  • Mobile phase A 1.3609 g of potassium dihydrogen phosphate was dissolved in 1,000 mL ultrapure water, adjusted to pH 3.0 using 10% phosphoric acid solution, and degassed.
  • Mobile phase B mixed with acetonitrile and water in a ratio of 9: 1, and then degassed for use
  • Example 1 to the present invention comprising a hard anhydrous silicic acid as a stabilizer on any one of the oil agent
  • emulsion emulsion
  • Example 1 to the present invention comprising a hard anhydrous silicic acid as a stabilizer on any one of the oil agent
  • Comparative Example 1 including hard silicic anhydride as a stabilizer
  • Comparative Example 2 tabletted using the light stabilizer hard silicic anhydride in powder form
  • 0.89%, 0.72% and 0.97 It shows a high lead content in%.
  • the present invention can suppress the generation of soft substances of dutasteride by using hard silicic anhydride as a stabilizer during the manufacturing process. That is, the reference to the flexible material of the commercial product Avobot ® is controlled to 0.5% or less of the total flexible material, the results shown in Figure 1 will be said to have a very excellent effect.
  • Avorate ® is a soft capsule containing dutasteride, and is prepared by dissolving dutasteride and butylated hydroxytoluene as a stabilizer in mono-diglycerides of capric acid / caprylic acid and then filling the soft capsule. It is very unlikely that a non-uniformity in the content of individual capsules will be produced in the case of a product prepared by such a manufacturing method.
  • Examples 1 to 7 and Comparative Example 1 are tablets prepared by adding an emulsion obtained by uniformly dispersing an oil phase obtained by dissolving dutasteride in a solubilizer in an aqueous phase, to a solid excipient
  • Comparative Example 2 is an emulsion. It is a tablet prepared by diluting an oil phase in which dutasteride is dissolved with about 5 to 10 times 50% ethanol without forming it, and adding it to a solid excipient.
  • Example 6 The stability of Example 6 manufactured by the present invention and Comparative Example 4 commercially available Avobot ® was evaluated.
  • silica gel as an absorbent was packed into a HDPE bottle for general medicine packaging, and Abolot ® was stored in PVC-aluminum foil PTP packaged product for 4 months under accelerated conditions (40 ° C 75% RH) and the softness of dutasteride To evaluate the change in the material is shown in Figures 2 to 4 below .
  • Avobot ® contains 0.035 mg of butylated hydroxytoluene per capsule as a stabilizer
  • Example 6 provided by the present invention is commercially available in Comparative Example 4, although it does not contain any antioxidant. It showed the same stability of lead material as phosphorous aboat ® .
  • Comparative Example 4 was a soft capsule under soft acceleration and degeneration of the soft film under the accelerated stability evaluation conditions appeared capsules sticking to each other or the capsule attached to the packaging material.
  • Example 6 according to the present invention did not show any change in the properties it can be seen that shows excellent stability.

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Abstract

La présente invention concerne une composition de dutastéride sous forme de comprimé présentant une stabilité améliorée, et plus particulièrement, un comprimé de dutastéride dans lequel la composition de dutastéride sous forme de comprimé selon la présente invention comprend de l'acide silicique anhydre de faible masse moléculaire utilisé comme stabilisant de manière à supprimer la production d'impuretés pendant un processus de préparation de formulation de dutastéride, présentant ainsi une excellente stabilité.
PCT/KR2016/000069 2015-01-14 2016-01-05 Composition de dutastéride sous forme de comprimé présentant une stabilité améliorée WO2016114521A1 (fr)

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Cited By (4)

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WO2018102526A1 (fr) * 2016-12-01 2018-06-07 Glaxosmithkline Llc Forme posologique pharmaceutique
WO2018230504A1 (fr) * 2017-06-12 2018-12-20 富士化学工業株式会社 Granules, comprimés et leur procédé de production
JP2021501195A (ja) * 2017-11-21 2021-01-14 コリア プライム ファーム カンパニー リミテッドＫｏｒｅａ Ｐｒｉｍｅ Ｐｈａｒｍ Ｃｏ．， Ｌｔｄ． デュタステリドの固体分散体、その製造方法、及びこれを含む薬学的組成物
JP2021511371A (ja) * 2018-01-10 2021-05-06 シャンハイ ダブリュディー ファーマシューティカル カンパニー，リミティド 固体微粒子およびその製造方法とそれを含む薬物組成物

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Publication number Priority date Publication date Assignee Title
KR101835506B1 (ko) * 2016-10-25 2018-03-07 주식회사 에스텍파마 두타스테리드와 타다라필을 함유하는 속효성 복합정제
KR101978747B1 (ko) * 2017-06-02 2019-05-16 (주)인벤티지랩 두타스테라이드 함유 고형 경구 제형 및 이의 제조 방법
WO2020066392A1 (fr) * 2018-09-25 2020-04-02 日新製薬株式会社 Préparation solide destinée à être administrée par voie orale et procédé de production s'y rapportant

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