WO2012161520A2 - Composition liquide injectable contenant du docétaxel - Google Patents

Composition liquide injectable contenant du docétaxel Download PDF

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Publication number
WO2012161520A2
WO2012161520A2 PCT/KR2012/004087 KR2012004087W WO2012161520A2 WO 2012161520 A2 WO2012161520 A2 WO 2012161520A2 KR 2012004087 W KR2012004087 W KR 2012004087W WO 2012161520 A2 WO2012161520 A2 WO 2012161520A2
Authority
WO
WIPO (PCT)
Prior art keywords
ethanol
docetaxel
composition
solvent
transparency transparency
Prior art date
Application number
PCT/KR2012/004087
Other languages
English (en)
Korean (ko)
Other versions
WO2012161520A3 (fr
Inventor
신동철
박효주
오준교
이봉용
Original Assignee
에스케이케미칼 주식회사
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 에스케이케미칼 주식회사 filed Critical 에스케이케미칼 주식회사
Publication of WO2012161520A2 publication Critical patent/WO2012161520A2/fr
Publication of WO2012161520A3 publication Critical patent/WO2012161520A3/fr

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Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to an injectable composition
  • an injectable composition comprising docetaxel or a pharmaceutically acceptable salt thereof as an active ingredient.
  • This docetaxel is very soluble in water and poorly soluble in water with a solubility of about 6-7 ug / mL. These poorly water-soluble properties make it difficult to prepare injectable compositions for administration to the human body, as well as very poor stability in water.
  • docetaxel preparation In the case of docetaxel preparation, it is currently administered by diluting a specific concentration ratio in the perfusate. Due to the solubility characteristics of the above-mentioned docetaxel, there is a possibility that precipitation may occur when dilution with the perfusate does not mix a large amount with the perfusion solution at a time. There is the inconvenience of diluting and administering at intervals.
  • the problem to be solved by the present invention is to provide a liquid injectable composition of docetaxel or a pharmaceutically acceptable salt thereof that not only has excellent storage stability, but also maintains stability, such as no precipitation is formed when dilution with the perfusate. .
  • the present invention is a transparent liquid injectable composition
  • a transparent liquid injectable composition comprising docetaxel or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD and a solvent, wherein at least 30% by volume of the total solvent is ethanol
  • a transparent liquid injectable composition comprising polyvinylpyrrolidone to promote dissolution of HP- ⁇ -CD.
  • HP- ⁇ -CD which acts as a solubilizer of docetaxel, in particular, plays a role of securing solubility of docetaxel when diluted with perfusion solution, exhibits a very low solubility of about 20 mg / ml or less in anhydrous ethanol. Therefore, in order to add HP- ⁇ -CD in an amount sufficient to guarantee dilution stability, a considerable amount of ethanol should be used, but such a very large volume of injectable compositions is difficult to dilute in perfusate and to administer. .
  • the transparent liquid injectable composition of the present invention comprises docetaxel or a pharmaceutically acceptable salt thereof, preferably docetaxel as an active ingredient, and has a concentration of docetaxel in the composition of 2-30 mg / ml.
  • Anhydrous and trihydrate may be used as the docetaxel.
  • the transparent liquid injectable composition of the present invention uses ethanol as a main solvent to dissolve docetaxel, which is insoluble in water.
  • ethanol a main solvent to dissolve docetaxel, which is insoluble in water.
  • 30-100% by volume of the total solvent is ethanol.
  • an ethanol aqueous solution containing an appropriate amount of water (purified water) is more preferable.
  • the solvent of the composition according to the present invention has a ethanol content of 50-85% by volume Aqueous ethanol solution is preferred, ethanol aqueous solution with 65-80% by volume of ethanol is more preferred, and ethanol aqueous solution with 75-80% by volume of ethanol is most preferred.
  • the specificity of this content range is very exceptional to those of ordinary skill in the art.
  • the present invention is not limited to the above content range. That is, in the present invention, a solvent in which at least 30% by volume of ethanol is ethanol may be used as the solvent, and the concept is more preferable when the ethanol content is in the range of 50-85% by volume. It does not mean to be excluded. That is, when 100% by volume, 99% by volume or 97% by volume of ethanol as a solvent is less stable than the 50-85% by volume range, docetaxel or salt thereof as in the present invention; HP- ⁇ -CD; Polyvinylpyrrolidone; And optionally acidifying agents may achieve some of the objects of the present invention.
  • the transparent liquid injectable composition of the present invention ensures solubility so that docetaxel injectable composition as an active ingredient does not precipitate upon dilution with a perfusate and improves the stability of docetaxel in the perfusate.
  • the content of such HP- ⁇ -CD is preferably 8-100 parts by weight based on 1 part by weight of docetaxel, more preferably 8-50 parts by weight based on 1 part by weight of docetaxel, and 10-25 parts by weight of 1 part by weight of docetaxel. Denial is most desirable. If the content of HP- ⁇ -CD is too low, there is a risk of precipitation when dilution with the perfusate. If the content is too high, ethanol must be added to dissolve it, which increases the total volume of the injectable composition. There is this.
  • the transparent liquid injectable composition of the present invention contains polyvinylpyrrolidone to increase the ethanol solubility of HP- ⁇ -CD without adversely affecting the stability of docetaxel.
  • polyvinylpyrrolidone to increase the ethanol solubility of HP- ⁇ -CD without adversely affecting the stability of docetaxel.
  • the content of the polyvinylpyrrolidone is preferably 0.05-3 parts by weight, more preferably 0.05-1.5 parts by weight with respect to 1 part by weight of HP- ⁇ -CD. If too little polyvinylpyrrolidone is used, the role of improving solubility of HP- ⁇ -CD is weak. If too much polyvinylpyrrolidone is used, there is a concern that the content of the solvent should be increased to dissolve polyvinylpyrrolidone. .
  • the transparent liquid injectable composition according to the present invention preferably contains a pH adjuster which is an acidifying agent in order to further secure stability, particularly when the transparent liquid injectable composition contains purified water as part of a solvent. More preferably, the pH of the composition is 5 or less, and more preferably 3 to 5, containing a pH adjuster.
  • acidifiers include maleic, fumaric, benzoic, ascorbic, succinic, methanesulphonic, benzenesulphonic, toluenesulphonic, acetic, oxalic, trifluoroacetic, trifluoro Methinesulphonic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, formic, glycolic, glutamic, benzene Organic acids such as sulfonic acids or inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, hydroiodic, sulfuric, phosphoric, nitric acid may be used, citric acid, fumaric acid, lactic acid, tartaric acid. , Succinic acid, maleic acid, acetic acid, tartaric acid, oxalic acid, phosphoric acid, hydrochloric acid and the like are preferred, and citric acid is
  • the transparent liquid injectable composition containing docetaxel or a pharmaceutically acceptable salt thereof according to the present invention not only has excellent storage stability, but also has excellent stability of dilution of perfusate, such as no precipitation occurs when dilution with perfusion liquid, It can be diluted directly in the perfusion solution without use.
  • HP- ⁇ -CD is well soluble in water but very poorly soluble in ethanol.
  • PVP was used to test the increase of HP- ⁇ -CD solubility in ethanol solvent.
  • HP- ⁇ -CD and PVP were put together in 1 ml of absolute ethanol and vortexed and shaken for 10 minutes. After 24 hours, dissolution and precipitation were confirmed. The results are shown in Table 1 below.
  • Table 1 Unit mg HP- ⁇ -CD PVP Liquid phase One 20 0 Dissolution 2 30 0 Sedimentation 3 20 30 Dissolution 4 40 30 Dissolution 5 50 60 Dissolution 6 70 60 Dissolution 7 100 60 Dissolution 8 200 100 Dissolution 9 200 150 Dissolution 10 200 200 Dissolution 11 300 120 Dissolution 12 300 150 Dissolution 13 300 200 Dissolution 14 400 120 Dissolution 15 400 150 Dissolution 16 400 200 Dissolution
  • Taxotere TM is diluted in 0.9% saline or 5% dextrose solution to make docetaxel at a concentration of 0.74 mg / mL or less and is then injected within 4 hours. Therefore, at least docetaxel should not precipitate for 4 hours at concentrations below 0.74 mg / mL in the perfusate.
  • the dilution stability test was tested by varying the amount of HP- ⁇ -CD and the amount of PVP. Specifically, after dissolving HP- ⁇ -CD and PVP, docetaxel and citric acid were dissolved.
  • HP- ⁇ -CD Hydroxylpropyl-beta-cyclodextrin
  • PVP Polyvinylpyrrolidone
  • Dilution stability was evaluated as follows and the results are shown in Table 3 below.
  • the injectable compositions of F0 to F8 and Taxotere (one vial) were diluted in a 5% dextrose solution at a concentration of 0.74mg / ml and observed for precipitation for 4 hours. According to the degree of precipitation production of the final administration composition, it was measured by dividing into more (3), moderate (2), less (1) and none (0).
  • HP- ⁇ -CD The amount of HP- ⁇ -CD was about 7.7 parts by weight based on 1 part by weight of docetaxel, but precipitation started at 4 hours in F6, but no precipitation occurred by F4 (about 10 parts or more). It was found to be about 8 parts by weight or more relative to 1 part by weight.
  • HP- ⁇ -CD which acts as a solubilizer for docetaxel in the present invention, exhibits a very low solubility of about 20 mg / ml or less in anhydrous ethanol. Therefore, in order to add HP- ⁇ -CD in an amount sufficient to ensure dilution stability, a considerable amount of ethanol should be used, but such a bulky injectable composition is practically very difficult to be diluted in perfusion solution. . As a result, a means for increasing the solubility of HP- ⁇ -CD in an ethanol solvent system is essential. In the present invention, PVP is used together with an injectable composition including docetaxel and HP- ⁇ -CD under an ethanol solvent system. Can solve the problem.
  • ethanol is preferred to water as a solvent, considering the storage stability of the docetaxel injectable composition.However, as mentioned above, ethanol is a stabilizer of HP- ⁇ -CD that acts as a stabilizer when distillate is perfused. Negatively affect solubility.
  • Purified water has a negative effect on the storage stability of docetaxel by reducing the solubility of docetaxel and increasing the amount of the flexible substance.
  • the pH control agent may improve the stability to some extent, and since such purified water may help to improve the solubility of other excipients such as HP- ⁇ -CD, ethanol is used as the main solvent and Co using purified water as a cosolvent.
  • ethanol is used as the main solvent and Co using purified water as a cosolvent.
  • stabilization was attempted using an appropriate ratio of ethanol and water.
  • Docetaxel-containing injectable compositions were prepared according to the formulations in Table 7 below, and the accelerated (40 ° C., 75%) stability of the composition was evaluated for 1 month. The results are shown in Table 8-10.
  • Table 8 shows the results of the increase of Epi-docetaxel (RRT 1.31)
  • Table 9 shows the results of the increase of the flexible material (RRT 0.74) whose structure is not confirmed
  • Table 10 shows the results of appearance observation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne une composition injectable contenant du docétaxel, ladite composition injectable comprenant : du docétaxel ou des sels pharmaceutiquement acceptables de celui-ci ; une HP-β-CD ; et un solvant, 30 % en volume ou plus dudit solvant total étant constitué d'éthanol et la composition injectable comprenant, en outre, une polyvinylpyrrolidone pour faciliter la dissolution de la HP-β-CD. La composition liquide transparente injectable selon l'invention a non seulement une stabilité à la conservation supérieure mais aussi une stabilité très supérieure à la dilution dans un perfusat, de sorte que la composition ne précipite pas quand elle est diluée avec un perfusat.
PCT/KR2012/004087 2011-05-23 2012-05-23 Composition liquide injectable contenant du docétaxel WO2012161520A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20110048225 2011-05-23
KR10-2011-0048225 2011-05-23

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WO2012161520A2 true WO2012161520A2 (fr) 2012-11-29
WO2012161520A3 WO2012161520A3 (fr) 2013-03-21

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016149162A1 (fr) * 2015-03-16 2016-09-22 Meridian Lab Compositions pharmaceutique contenant du des complexes de taxane-cyclodextrine, procédé de production et procédés d'utilisation
CN110755371A (zh) * 2018-07-25 2020-02-07 比卡生物科技（广州）有限公司 一种注射用多西他赛组合物及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090093581A (ko) * 2008-02-29 2009-09-02 동아제약주식회사 도세탁셀을 함유하는 단일액상의 안정한 약제학적 조성물
KR20090101145A (ko) * 2006-05-22 2009-09-24 에스케이케미칼주식회사 우수한 저장안정성을 갖는 도세탁셀 함유 주사제 조성물의 제조방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090101145A (ko) * 2006-05-22 2009-09-24 에스케이케미칼주식회사 우수한 저장안정성을 갖는 도세탁셀 함유 주사제 조성물의 제조방법
KR20090093581A (ko) * 2008-02-29 2009-09-02 동아제약주식회사 도세탁셀을 함유하는 단일액상의 안정한 약제학적 조성물

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016149162A1 (fr) * 2015-03-16 2016-09-22 Meridian Lab Compositions pharmaceutique contenant du des complexes de taxane-cyclodextrine, procédé de production et procédés d'utilisation
US20180050116A1 (en) * 2015-03-16 2018-02-22 Meridian Lab Pharmaceutical compositions containing taxane-cyclodextrin complexes, method of making and methods of use
JP2018512395A (ja) * 2015-03-16 2018-05-17 メリディアン ラボＭｅｒｉｄｉａｎｌａｂ タキサン−シクロデキストリン複合体を含む医薬組成物、作成方法、および使用方法
US10398785B2 (en) 2015-03-16 2019-09-03 Meridian Lab Pharmaceutical compositions containing taxane-cyclodextrin complexes, method of making and methods of use
CN110755371A (zh) * 2018-07-25 2020-02-07 比卡生物科技（广州）有限公司 一种注射用多西他赛组合物及其制备方法
CN110755371B (zh) * 2018-07-25 2021-08-31 比卡生物科技（广州）有限公司 一种注射用多西他赛组合物及其制备方法

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