WO2014041825A1 - Amide derivative and use of the same as stability index of a luliconazole pharmaceutical formulation - Google Patents

Amide derivative and use of the same as stability index of a luliconazole pharmaceutical formulation Download PDF

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Publication number
WO2014041825A1
WO2014041825A1 PCT/JP2013/055025 JP2013055025W WO2014041825A1 WO 2014041825 A1 WO2014041825 A1 WO 2014041825A1 JP 2013055025 W JP2013055025 W JP 2013055025W WO 2014041825 A1 WO2014041825 A1 WO 2014041825A1
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WO
WIPO (PCT)
Prior art keywords
luliconazole
pharmaceutical formulation
amide derivative
production
component
Prior art date
Application number
PCT/JP2013/055025
Other languages
English (en)
French (fr)
Inventor
Takaaki Masuda
Hiroshi Yamaguchi
Original Assignee
Pola Pharma Inc.
Nihon Nohyaku Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pola Pharma Inc., Nihon Nohyaku Co., Ltd. filed Critical Pola Pharma Inc.
Priority to IN2930DEN2015 priority Critical patent/IN2015DN02930A/en
Priority to CN201380047770.5A priority patent/CN104662017A/zh
Priority to US14/347,939 priority patent/US9145401B2/en
Priority to EP13709572.5A priority patent/EP2895480A1/en
Priority to RU2015113587A priority patent/RU2612557C2/ru
Publication of WO2014041825A1 publication Critical patent/WO2014041825A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to an amide
  • Luliconazole is an antifungal agent which is excellent in the action on fungi.
  • luliconazole is widely used as a pharmaceutical or medicine for tinea pedis and tinea corporis, and it is going to be applied also for the action on tinea unguium as well.
  • problems which should be solved such that the luliconazole is converted to the stereoisomers such as the SE form or the Z form, and that the crystallization of luliconazole is caused immediately after the application (see, for example, Patent Documents 1 to 6) .
  • Patent Document 1 WO2007/102241
  • Patent Document 2 WO2007/102242 ;
  • Patent Document 3 WO2007/102243;
  • Patent Document 4 WO2009/031642 ;
  • Patent Document 5 WO2009/031643 ;
  • Patent Document 6 O2009/031644.
  • luliconazole is to specify the related substance and clarify. the relationship with respect to the pharmaceutical formulation component.
  • the present invention has been made in the circumstances as described above, an object of which is to establish an index to prepare a stable pharmaceutical formulation by specifying a related substance which appears depending on the type of a selected solvent in the
  • a method for evaluating stability of a luliconazole pharmaceutical formulation comprising:
  • condition at 40°C or 60°C is larger.
  • ⁇ production amount of the amide derivative as defined in ⁇ 1> is not more than 10% by mass with respect to a total amount of luliconazole under a storage condition at 40°C for 6 months or at 60°C for 3 weeks .
  • luliconazole wherein a content of the amide derivative as defined in ⁇ 1> is used as an index to evaluate a quality of the produced pharmaceutical composition.
  • a method for selecting a pharmaceutical formulation component for a luliconazole pharmaceutical formulation comprising:
  • a high temperature storage condition is a condition at 40°C for 6 months or at 60°C for 3 weeks.
  • composition containing luliconazole comprising a step of dissolving luliconazole in the pharmaceutical formulation components, at least one of which is selected by the method for selecting the pharmaceutical formulation component as defined in ⁇ 9> or ⁇ 10>.
  • the structure of the new related substance is clarified and the index to prepare the stable pharmaceutical formulation of
  • the amide derivative of luliconazole which is the indicator (index substance) of the present invention, is a related substance of luliconazole which appears when a specified solvent (s) is selected for the luliconazole pharmaceutical formulation.
  • the amide derivative of luliconazole appears especially when the luliconazole pharmaceutical formulation is stored under a high
  • the substance of the present invention is the amide derivative (amide form) ( [R- (E) ] -a- [4- (2, 4-dichlorophenyl ) - 1, 3-dithiolan-2-ylidene] -lH-imidazole-l-acetamide)
  • the amide derivative (amide form) thus obtained is purified by means of, for example, the chromatography such as silica gel column chromatography, octadecyl modified silica gel column chromatography or the like and/or the recrystallization from a mixture solution of ethyl acetate and normal hexane, ethanol, isopropanol or the like, and the amide derivative (amide form) is provided as the indicator or index
  • the purity is not less than 90%.
  • Such a component can be confirmed by means of HPLC.
  • a chiral normal phase column is used in many cases in order to distinguish the isomer such as the SE form or the Z form.
  • the compound of the chemical formula (1) is hardly detected under the elution condition for the chiral normal phase column. Therefore, it is preferable to perform the investigation under such a condition that a reverse phase column, which is based on the use of cation- capturing counterion such as alkylsulfonate or the like, is used.
  • Such an analysis condition is preferably exemplified by the following. Under this condition, it is also possible to detect main related substances such as the SE form, the Z form and the like together with luliconazole .
  • the amide form (amide derivative) represented by the chemical formula (1) is produced during the storage at a high temperature of 40 to 60°C depending on the type of the selected solvent.
  • the antifungal activity of the amide form itself is low. Therefore, the production of the amide form results in the decrease in the activity of the
  • the amide form represented by the chemical formula (1) may be contained by about 10% by mass in the luliconazole pharmaceutical formulation, depending on, for example, the content of luliconazole, the type of the solvent, and the amount of the solvent.
  • the stability of the luliconazole pharmaceutical formulation can be evaluated by using, as the indicator (index substance) , the amide form represented by the chemical formula (1) in accordance with the method for evaluating the pharmaceutical formulation of the present invention. It is possible to judge that the stability of the pharmaceutical formulation is more lower if the amount of production of the amide form represented by the chemical formula (1) is larger in the pharmaceutical formulation. Thus, it is possible to secure the stability of the
  • the amount of production of the amide form is preferably not more than 10% by mass, more preferably not more than 5% by mass, much more preferably not more than 1% by mass, still much more preferably not more than 0.5% by mass/ and most preferably not more than 0.1% by mass with respect to the total amount of
  • any active pharmaceutical ingredient-related substance which has a production amount of not more than 0.2% by mass, is not classified into the related substance according to the Pharmaceutical Affairs Law in Japan.
  • the content of the compound represented by the chemical formula (1) as described above is measured to evaluate the product, which can be also used to guarantee the quality of the product.
  • the operation for measuring the content of the compound represented by the chemical formula (1) is incorporated into the production step concerning the quality of the product.
  • the production step concerning the quality of the product is preferably exemplified, for example, by the step of dissolving
  • the luliconazole pharmaceutical formulation can be designed by using, as the index, the amide form represented by the chemical formula (1) of the present invention.
  • the index is whether the amount of production of the amide form represented by the chemical formula (1) is large or small during the storage at a high temperature in a coexisting state together with luliconazole. If the amount of production of the amide derivative is large, the concerning component is not selected as the pharmaceutical formulation component. If the amount of production is small, the concerning component is selected as the
  • the basis or standard (reference) which is usable to judge whether the amount of production of the amide derivative is large or small, can be appropriately set depending on, for example, the objective pharmaceutical formulation and the method of use.
  • polyhydric alcohol such as 1 , 3-butanediol or the like
  • polyhydric alcohol such as 1 , 3-butanediol or the like
  • aromatic alcohol such as benzyl alcohol or the like
  • heterocyclic compound-based solvent such as N- methyl-2-pyrrolidone or the like as the solvent with which the amide form may be produced. If such an indicator (index substance) is increased in the prepared
  • the amount of production of the amide form as described above can be changed by
  • polyhydric alcohol is exemplified as the solvent which acts to produce the amide form.
  • 3-butanediol has an intense tendency thereof.
  • polyhydric alcohol for example, polyethylene glycol and polypropylene glycol have a weak tendency thereof. Therefore, when the amide form is considerably produced in a pharmaceutical formulation containing 1, 3-butanediol, the production of the amide form can be suppressed by substituting 1,3- butanediol with polyethylene glycol and/or polypropylene glycol.
  • polyethylene glycol it is possible to exemplify that polyethylene glycol is contained
  • polyethylene glycol is contained more preferably by 20 to 35% by mass with respect to the total amount of the pharmaceutical formulation.
  • polypropylene glycol is contained
  • polypropylene glycol is contained more preferably by 17 to 25% by mass, for the following reason. That is, if the content is excessively large, the compatibility with respect to luliconazole is deteriorated in some cases. If the content is excessively small, the effect to suppress the amide form is not
  • the production of the amide form is varied depending on the type and the amount of the pharmaceutical formulation component. Therefore in order to obtain the stable antifungal activity, it is necessary to precisely judge or discriminate whether or not the pharmaceutical formulation is adequate for luliconazole by using, as the index, the time-dependent amount of production of the amide form.
  • the amount of production of the amide form can be used as the index for the judgment or discrimination. That is, it is possible to discriminate that the pharmaceutical formulation, which provides a larger amount of production of the amide form in the time- dependent change caused by the storage, is not adequate as the pharmaceutical formulation of luliconazole .
  • the pharmaceutical formulation which provides a smaller amount of production of the amide form
  • the pharmaceutical formulation adequate for luliconazole. It is affirmed that the use of the amide form for the discrimination as described above is the use of the amide form as the indicator (index
  • Such a mode of use can be preferably exemplified by the following mode of use. That is, the amide form of the present invention is
  • the pharmaceutical formulation of the medicine which accompanies the appended document as described above, also belongs to the technical scope of the present invention.
  • the behavior of production of the amide form is the index of the stability of the pharmaceutical formulation, and the evaluation, which is performed by utilizing the index as described above, falls under the use as the indicator (index substance) .
  • the content of luliconazole is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and much more preferably 1 to 10% by mass.
  • the formulation for external use which includes, for example, liquid (solution) , cream, gel, foam, spray, and ointment, can be preferably exemplified as the
  • the components for preparing the pharmaceutical formulation are differentiated or distinguished to select the component which easily produces the amide form and the component which suppresses the production of amide form, followed by being classified into groups.
  • the component, which suppresses the production of the amide form is contained therein.
  • invention can contain any arbitrary component to be contained in an ordinary pharmaceutical composition, other than luliconazole and the pharmaceutical formulation component selected by the method for selecting the
  • Such an arbitrary component can be preferably exemplified, for example, by hydrocarbons including, for example, vaseline, microcrystalline wax, and liquid
  • paraffin paraffin
  • silicones including, for example, dimethicone and cyclomethicone
  • esters including, for example, spermaceti and Japan tallow
  • triglycerides including, for example, olive oil, beef tallow, and coconut oil
  • nonionic nonionic
  • surfactants including, for example, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, and
  • polyoxyethylene sorbitan fatty acid polyoxyethylene sorbitan fatty acid
  • anionic surfactants including, for example, sodium lauryl sulfonate and sodium POE lauryl sulfonate
  • fatty acids including, for example, stearic acid, oleic acid, lauric acid, palmitic acid, and myristic acid
  • antioxidants including, for example, BHT, BHA, and tocopherol
  • coloring agents lubricants
  • taste/odor-correcting agents The pharmaceutical
  • composition (pharmaceutical formulation) can be produced by treating the foregoing components in accordance with an ordinary method.
  • the pharmaceutical medicament formulation or the pharmaceutical composition of the present invention is preferably used to treat or cure the disease caused by any fungus or prevent the deterioration of the disease by utilizing the characteristic of luliconazole .
  • the disease caused by any fungus can be exemplified by tinea pedis such as athlete's foot, tinea corporis such as candidiasis and tinea versicolor, and trichophytosis of hard keratin portion such as tinea unguium. It is especially preferable to use the pharmaceutical medicament formulation or the pharmaceutical composition of the present invention for treating the disease of the hard keratin portion such as tinea unguium, because the effect thereof is remarkable.
  • the effect of the pharmaceutical composition of the present invention is expressed on the nail especially preferably. However, the effect is also exerted on any ordinary
  • the pharmaceutical composition which is directed to the dermatomycosis and which fulfills the construction of the present invention, also belongs to the technical scope of the present invention.
  • dermatomycosis as described above can be exemplified, for example, by the tinea pedis and the trichophytosis of the propagation in horny substance type, the trichophytosis of the propagation in horny substance type appearing, for example, in the heel and being included in the tinea pedis.
  • the dermatomycosis described above it is preferable to make the application to the trichophytosis of the propagation in horny substance type on which any ordinary agent or drug hardly exerts the effect, because the effect of the present invention remarkably arises.
  • the mode of use can be appropriately selected while considering, for example, the body weight, the age, the sexuality, and the symptoms or condition of the
  • luliconazole preferable to administer luliconazole in an amount of 0.01 to 1 g per day in ordinary cases. Reference can be made to the amount of use of luliconazole ordinarily used for the disease caused by any fungus.
  • the application in an appropriate amount to the disease portion once or several times a day. It is preferable that the treatment as described above is performed every day.
  • the tinea unguium luliconazole as the active ingredient, which is in an amount that cannot be brought about by any ordinary pharmaceutical formulation, can be transferred into the nail. Accordingly, the tinea unguium can be cured by means of only the external
  • the pharmaceutical composition of the present invention is administered without taking any antifungal agent for a long period of time. Further, the recurrence and the reinfection cause great problems in relation to the tinea unguium. However, it is possible to avoid the recurrence and the reinfection as described above by administering the pharmaceutical composition of the present invention for 1 week to 2 weeks after the quietness of symptoms. In such a mode, the pharmaceutical composition of the present
  • luliconazole pharmaceutical preparation was manufactured in accordance with a formulation shown below. That is, formulation components were heated, stirred, and solubilized, followed by being stirred and cooled to room temperature to obtain the luliconazole pharmaceutical preparation.
  • the luliconazole pharmaceutical preparation was stored under a temperature condition at 60°C for 3 weeks, and produced related substances were confirmed by means of the HPLC method. As a result, three peaks were confirmed other than the peak of luliconazole.
  • the amide form was also the index to be considered to judge the stability together with the SE form and the Z form. That is, according to this fact, it is confirmed that the amide form is the important related substance depending on the system.
  • HPLC condition column: Inertsil ODS-2 4.6 x 150 mm, column temperature: 40°C, mobile phase: solution of 0.15% sodium undecan-l-sulfonate in a mixture
  • Luliconazole pharmaceutical preparations 2 to 4 were manufactured in the same manner as in Example 2 in
  • the condition, under which the amide form is hardly produced even under the accelerated condition and/or the severe condition is found out by using the amide form as the index of the stability as described above, and thus it is " possible to design the stable pharmaceutical formulation.
  • the solvent component in the pharmaceutical formulation is the factor of the production of the amide form. Therefore, it is confirmed that the pharmaceutical formulation having the high stability can be manufactured by selecting the solvent which does not accelerate the production of the amide form in a time- dependent manner or which suppresses the production of the amide form.
  • Amount of production of 0.86 0.32 amide form (with respect (% by mass) (% by mass) to luliconazole)
  • composition 7 was manufactured in accordance with a formulation shown below. Also in this case, it is confirmed that the production of the amide form is suppressed under a storage condition at 60°C for 3 weeks. In relation thereto, it is considered that the addition of polyethylene glycol 400 may exert any
  • the effect of polyethylene glycol to facilitate the production of the amide form is lower than that of 1 , 3-butanediol .
  • the amide form can be used as the index for evaluating the effect of addition of the
  • the present invention can be applied, for example, to the design of the pharmaceutical formulation luliconazole and the evaluation of the pharmaceutical formulation .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
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  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)
PCT/JP2013/055025 2012-09-14 2013-02-19 Amide derivative and use of the same as stability index of a luliconazole pharmaceutical formulation WO2014041825A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
IN2930DEN2015 IN2015DN02930A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2012-09-14 2013-02-19
CN201380047770.5A CN104662017A (zh) 2012-09-14 2013-02-19 酰胺衍生物及其作为卢立康唑药物制剂的稳定性指标的用途
US14/347,939 US9145401B2 (en) 2012-09-14 2013-02-19 Amide derivative and use of the same as stability index of a luliconazole pharmaceutical formulation
EP13709572.5A EP2895480A1 (en) 2012-09-14 2013-02-19 Amide derivative and use of the same as stability index of a luliconazole pharmaceutical formulation
RU2015113587A RU2612557C2 (ru) 2012-09-14 2013-02-19 Амидное производное и его применение в качестве критерия стабильности фармацевтической композиции луликоназола

Applications Claiming Priority (2)

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JP2012-202696 2012-09-14
JP2012202696A JP5460797B1 (ja) 2012-09-14 2012-09-14 アミド誘導体及び安定性指標としてのその使用

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WO2014041825A1 true WO2014041825A1 (en) 2014-03-20

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US (1) US9145401B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
EP (1) EP2895480A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
JP (1) JP5460797B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
CN (1) CN104662017A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
IN (1) IN2015DN02930A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
RU (1) RU2612557C2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO2014041825A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

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US8952044B2 (en) 2009-08-25 2015-02-10 Pola Pharma Inc. Antimycotic pharmaceutical composition
US8962669B2 (en) 2010-06-11 2015-02-24 Pola Pharma Inc. Antimycotic pharmaceutical composition
US9012484B2 (en) 2012-09-14 2015-04-21 Pola Pharma Inc. Crystal and pharmaceutical preparation containing the same crystal
US9050271B2 (en) 2009-04-09 2015-06-09 Pola Pharma Inc. Antimycotic pharmaceutical composition
US20150168357A1 (en) * 2013-12-12 2015-06-18 Pola Pharma Inc. Method of evaluating pharmaceutical preparation containing luliconazole and index substance
US9068958B1 (en) 2012-09-14 2015-06-30 Pola Pharma Inc. Use of surface free energy for differential evaluation of crystal, crystal evaluated on basis of surface free energy as index, and pharmaceutical composition prepared by containing the crystal
US9199977B2 (en) 2012-09-14 2015-12-01 Pola Pharma Inc. Crystal having crystal habits and pharmaceutical composition obtained by processing the crystal
US9453006B2 (en) 2013-03-08 2016-09-27 Pola Pharma Inc. Crystalline form having specific crystal habit and pharmaceutical composition containing this crystalline form as active ingredient
US9527836B2 (en) 2013-09-06 2016-12-27 Pola Pharma Inc. Crystal having specific crystal habit and pharmaceutical composition containing the crystal as active ingredient
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JP5623671B1 (ja) * 2014-07-23 2014-11-12 株式会社ポーラファルマ ルリコナゾールを含有する製剤の評価方法及び指標物質
WO2020161849A1 (ja) * 2019-02-07 2020-08-13 株式会社島津製作所 分析方法、分析装置およびプログラム

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US20150191456A1 (en) 2015-07-09
JP2014058449A (ja) 2014-04-03
US9145401B2 (en) 2015-09-29
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JP5460797B1 (ja) 2014-04-02

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