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WO2018164513A1 - Préparation stable contenant du bortézomib et son procédé de préparation - Google Patents

Préparation stable contenant du bortézomib et son procédé de préparation Download PDF

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Publication number
WO2018164513A1
WO2018164513A1 PCT/KR2018/002782 KR2018002782W WO2018164513A1 WO 2018164513 A1 WO2018164513 A1 WO 2018164513A1 KR 2018002782 W KR2018002782 W KR 2018002782W WO 2018164513 A1 WO2018164513 A1 WO 2018164513A1
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WO
WIPO (PCT)
Prior art keywords
bortezomib
liquid formulation
formulation
acid
stability
Prior art date
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PCT/KR2018/002782
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English (en)
Korean (ko)
Inventor
이정환
조태근
유재영
조영대
Original Assignee
씨제이헬스케어 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.)
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Application filed by 씨제이헬스케어 주식회사 filed Critical 씨제이헬스케어 주식회사
Publication of WO2018164513A1 publication Critical patent/WO2018164513A1/fr

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Classifications

    • 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
    • A61K9/08—Solutions
    • 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
    • A61K31/69—Boron compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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 a stable formulation containing bortezomib and a method for preparing the same, and more particularly to a liquid formulation containing bortezomib having excellent stability and a method for preparing the same.
  • Bortezomib used in relapsing multiple myeloma binds the boron atoms of the compound to the catalytic sites of the proteasome, ultimately inducing proteasome inhibition and reduced degradation of the pro-apoptotic factor. It is then believed to trigger apoptosis of the treated cells.
  • bortezomib (N- (2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid ⁇ has been developed as Velcade TM to treat several neoplastic diseases, in particular relapsing multiple It is a 26S proteasome inhibitor approved for use in the treatment of relapsed multiplemyeloma and mantle cell lymphoma.
  • the Belcade TM is reconstituted in the form of a lyophilized formulation that must be reconstituted prior to administration, i.e., 0.9% sodium chloride solution upon administration to the patient, with dilution concentrations of 2.5 mg / ml (iv) and 1.0 mg / ml (sc). It is commercially available in the form of a lyophilized powder (3.5 mg) form.
  • Bortezomib is very unstable in liquid state, so even in the case of the currently lyophilized formulation, it is to be used within 8 hours after reconstitution with 0.9% NaCl. Due to this stability problem, it is currently being used as a lyophilized formulation in clinical practice.
  • bortezomib is susceptible to oxidative degradation under a number of experimental conditions, and oxidation of alkyl boranes, which form esters of boric acid, can also be combined with alkyl peracids, alkyl peroxides, or oxygen radical species.
  • alkyl peracids alkyl peroxides
  • oxygen radical species oxygen radical species
  • U.S. Pat.Nos.7119080,6713446,6958319,6747150, and 6297217 disclose diester formation with mannitol of boronic acid functional groups after lyophilization. From the ester thus formed, active boronic acid is obtained upon reconstitution of the drug product in saline for injection. Similarly, attempts to form esters of boronic acid with beta-carboxylic acids such as citric acid and alpha-hydroxy with bulking agents and buffers are disclosed in WO 2009/154737.
  • the compound can be lyophilized and reconstituted prior to injection.
  • this method tends to solve the problems associated with Bortezomib stability, but the reconstituted unused solution should be injected within hours or days (see, eg, Stability of unused reconstituted bortezomib in original manufacturer vials; J Oncol Pharm Pract. 2010 Oct 6, or Stability of bortezomib 1-mg / mL solution in plastic syringe and glass vial; Ann Pharmacother. 2005 Sep; 39 (9): 1462-6).
  • the Bortezomib ester of mannitol is only suitable for administration within 8 hours if stored at room temperature.
  • the present inventors have conducted extensive research, and have prepared a bortezomib liquid formulation having excellent stability while using a mixed solvent having a high biocompatibility with a high proportion of polar solvents.
  • the present invention is a solvent, mannitol, erythritol, sorbitol, isomalt composed of a polar solvent comprising bortezomib or a pharmaceutically acceptable salt thereof, propylene glycol and water as an active ingredient
  • a bortezomib liquid formulation comprising at least one sugar alcohol selected from the group consisting of, maltitol, ziritol, and trehalose.
  • the ratio of bortezomib or its pharmaceutically acceptable salt to sugar alcohol may be 1: 10 to 60, preferably 1: 20 to 60.
  • the solvent system of the present invention may be 40 vol% or more, more specifically 40 vol% to 60 vol% of a polar solvent comprising water, and even in the case of containing a polar solvent, more specifically water in such a content,
  • the degradation rate of bortezomib can be reduced to a total of 2.5% or less, preferably 2% or less.
  • the bortezomib liquid formulation may include any one or more selected from the group consisting of butylated hydroxyanisole, sodium hydrogen carbonate, and acetylcysteine as an antioxidant, and preferably butylated hydroxyanisole, and It may include any one or more selected from the group consisting of acetylcysteine. Most preferably, acetylcysteine.
  • the pH range of the Bortezomib liquid formulation is preferably 4.0 to 6.0, most preferably 4.0 to 5.0.
  • the preparation is more preferably in a ready-to-use sealed container as a liquid preparation that can be stored in solution.
  • the concentration of the ready-to-use injection is preferably 1 mg / ml to 5 mg / ml.
  • the amount of oxygen in the headspace in the container is preferably 3 v / v% or less with respect to the volume of the headspace, the oxygen amount can be adjusted by replacing the oxygen in the headspace with an inert gas.
  • the inert gas may be nitrogen or argon.
  • Bortezomib formulations such as above can maintain up to 2% total degradation of bortezomib when stored at 25 ° C./RH 60% for 3 months.
  • Bortezomib formulations of the invention comprise Bortezomib or a pharmaceutically acceptable salt thereof as the active ingredient.
  • the Bortezomib according to the present invention includes a pharmacologically effective drug or a pharmacologically effective drug by a chemical or enzymatic method in the body, and specifically, the Bortezomib drug itself or a pharmaceutically acceptable salt thereof may be used. .
  • bortezomib is a compound having the name "(N- (2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid", specifically, Denotes a 26S proteasome inhibitor approved for use in the treatment of recurrent multiple myeloma and mantle cell lymphoma.
  • the term "pharmaceutically acceptable salts” refers to salts prepared according to methods conventional in the art, and such methods are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric acid, bromic acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfuric acid Phonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like.
  • Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium or potassium, alkaline earth metals such as magnesium.
  • sucrose alcohol includes excipients such as erthritol, mannitol, maltitol, isomalt, sorbitol, xylitol, trehalose and the like, and is an excipient commonly used in injection formulation research.
  • Excipients conventionally used in injectable preparations include mannitol, sorbitol, sucrose, trehalose, lactose, glucose, erthritol, maltitol, maltose, xylitol, sodium gluconate, magnesium gluconate, calcium gluconate, iron gluconate, White sugar, starch, corn starch, potato starch, sodium carboxymethylcellulose, ethylcellulose, cyclodextrin, dextrose, hydroxypropyl beta cyclodextrin and the like.
  • an excipient may include a sugar alcohol selected from the group consisting of mannitol, erthritol, sorbitol, isomalt, trehalose, maltitol, xylitol, and mixtures thereof. More preferably, it may include a sugar alcohol selected from the group consisting of mannitol, erythritol, isomalt and maltitol. Most preferably, it may include mannitol.
  • Bortezomib formulations of the present invention using the above “sugar alcohol”, it is possible to stably store Bortezomib or a pharmaceutically acceptable salt thereof for a pharmaceutically long term.
  • the Bortezomib formulation is preferably when the concentration ratio of Bortezomib or its pharmaceutically acceptable salt: sugar alcohol is 1: 10 ⁇ 60 (w / w), in particular, the concentration ratio is 1: 20 ⁇ 60 More preferred.
  • the unit of each concentration may be mg / mL.
  • stabilizers and antioxidants conventionally used in injectable preparations include beta carotene, glycine, gallic acid, thimerosal, EDTA, parahydroxybenzoic acid ester derivatives, phenol derivatives ( phenol derivatives, alcohols, retinol, tocopherol, TPGS, acetic anhydride, sodium carboxylate, lauryl sulfate, cysteamine ), Cystine, cysteine, amino acids, organic acids such as ascorbic acid, sulfide compounds, sulfite, sulfite, butylated hydroxyani Butylated hydroxyanisole, butylated hydroxytoluene, and the like.
  • the antioxidant may include any one or more selected from the group consisting of butylated hydroxyanisole, sodium hydrogen carbonate, and acetylcysteine. More preferably, at least one selected from the group consisting of butylated hydroxyanisole, and acetylcysteine. Most preferably, acetylcysteine.
  • acetylcysteine is a compound having the name of N-acetyl-L-Cysteine (N-Acetyl-L-Cysteine, NAC, C5H9NO3S, CAS number616-91-1), Borte of the present invention By compound used as an antioxidant in zomib formulations.
  • N-acetyl-L-Cysteine N-Acetyl-L-Cysteine, NAC, C5H9NO3S, CAS number616-91-1
  • Borte of the present invention By compound used as an antioxidant in zomib formulations.
  • “acetylcysteine” and “N-acetyl-L-cysteine” are used interchangeably.
  • the Bortezomib formulation may preferably be a liquid formulation that can be stored in solution, and more preferably, may be a liquid formulation for injection in a sealed container ready-to-use. .
  • the Bortezomib formulation may include a pharmaceutically acceptable carrier and pH adjusting agent.
  • Bortezomib formulations of the present invention may further include pharmaceutically acceptable excipients, and examples thereof include lactose, dextrose, cyclodextrin and derivatives thereof, sucrose, glycerol, sodium carbonate, citric acid, mannitol and the like.
  • the bortezomib formulation may include a solvent composed by mixing a polar solvent such as propylene glycol and water. It is preferable that the said polar solvent corresponds to the solvent of the injection approved by FDA.
  • the pH of the Bortezomib injectable liquid formulation may preferably be about 4.0 to 6.0, more preferably about 4.0 to 5.0.
  • the pH of the solution can be adjusted using an acid such as hydrochloric acid or a base such as sodium hydroxide.
  • Bortezomib formulation of the present invention may be prepared by purging with an inert gas such as nitrogen or argon and then filtered.
  • suitable containers may be glass vials, vials, cartridges, pre-filled injections and the like, preferably glass vials. More preferably, it may be a light shielding glass vial.
  • the liquid formulation for injection of bortezomib of the present invention is dispensed in a pre-washed sterilized container, and the surface of the cap suitable for the container is sealed with a teflon plug which is inert to the liquid formulation for injection of bortezomib.
  • the space between the injectable liquid formulation and the stopper is filled with an inert gas.
  • the vial filled with the liquid for injection is sterilized if necessary.
  • the inventors of the present invention used a solvent containing propylene glycol as a solvent and a sugar alcohol as an excipient, the total softening material was maintained at 2% or less and discolored for 3 months at 25 ° C / RH60% stability conditions. Or it was found that no sediment will occur to have stability that meets the criteria.
  • both propylene glycol and sugar alcohols are generally used, and there is also an advantage of low commercial unit price.
  • the present invention can provide a Bortezomib formulation which is easy to manufacture commercially, can prevent microbial contamination accompanying freeze-drying or reconstitution, and has improved dosage convenience and stability.
  • sugar alcohol and propylene glycol it is possible to provide a stabilized bortezomib formulation that meets the criteria without abnormalities such as discoloration or deposit generation as compared to conventional bortezomib-containing injectable liquid formulations.
  • liquid formulations were prepared according to the formulations set forth in Table 2 below.
  • a solvent the composition ratio of propylene glycol and acetate buffer solution was used in a mixture of 60:40 (%) to 40:60 (%), and as excipients, mannitol, erythritol, maltitol, trehalose, sorbitol, isomalt or Prepared by dissolving xylitol. Nitrogen substitution was performed, and a light shielding vial was used as a container for storing the sample.
  • Table 3 shows the results of the stability evaluation for Formulation Examples 1 to 6. Stability test conditions are 1 5 ° C and 2 25 ° C / RH60%. After storage for 21 days in the chamber (closed), the total cast material was evaluated.
  • the stability evaluation results for Formulation Examples 7 to 24 are shown in Table 4.
  • the stability test conditions were 1 40 ° C./RH75%, 2 60 ° C./RH 80%, and were stored in the stability chamber for 10 days and then evaluated for the total flexible material.
  • Stability test conditions are 1 5 °C, 2 25 °C / RH60%. 1 and 2 were stored in the chamber (closed) for 21 days (# 007 ⁇ 011) or 33 days (# 012 ⁇ 019), and then evaluated for the total flexible material.
  • Stability test results for the above described compositions are shown in Table 8. Stability test conditions are 1 5 °C, 2 25 °C / RH60%. For # 036 to # 063, total lead was assessed after 30 days of storage in a stable chamber.
  • butylated hydroxyanisole, sodium hydrogen carbonate, or acetylcysteine as the antioxidant, more preferably, butylated hydroxyanisole or acetylcysteine.
  • # 064 is made of a Velcade r state (Janssen Korea ( ⁇ )) and # 065 is Velcade r main reconstruct (Janssen Korea ( ⁇ )) (reconstitution) ready-to-use type injection (ready-to-use) by the freeze-dried formulation It is.
  • Stability test results for the above described compositions are shown in Table 10.
  • Stability test conditions are 1 5 °C, 2 25 °C / RH60%. 1 and 2 were stored in a stable chamber for 3 months, and then evaluated for total flexible substances.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une préparation liquide de bortézomib comprenant : du bortézomib ou un sel pharmaceutiquement acceptable de celui-ci; un ou plusieurs alcools de sucre choisis dans le groupe constitué par le mannitol, l'érythritol, le sorbitol, l'isomalt, le maltitol, le xylitol et le tréhalose; et un solvant formé par mélange de propylène glycol et de solvants polaires comprenant de l'eau. La préparation liquide de bortézomib de la présente invention peut être préparée facilement et commercialement, peut prévenir la contamination microbienne se produisant pendant le lyophilisation ou la reconstitution, présente un effet de commodité d'administration et de stabilité améliorées, et étant donné qu'un alcool de sucre et du propylène glycol sont utilisés, la préparation liquide de zomib n'a pas d'anomalies de propriété, telles que la décoloration ou la génération de précipité, par comparaison avec une préparation liquide injectable classique contenant du bortézomib, et répond aux normes.
PCT/KR2018/002782 2017-03-09 2018-03-08 Préparation stable contenant du bortézomib et son procédé de préparation WO2018164513A1 (fr)

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KR1020170030225A KR101807462B1 (ko) 2017-03-09 2017-03-09 보르테조밉을 포함하는 안정한 제제 및 이의 제조방법
KR10-2017-0030225 2017-03-09

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3908258A4 (fr) * 2019-01-11 2022-09-28 Intas Pharmaceuticals Ltd. Procédé de préparation d'une composition pharmaceutique stable de bortézomib
EP4134083A1 (fr) 2021-08-12 2023-02-15 Extrovis AG Compositions pharmaceutiques de bortézomib
WO2024097387A1 (fr) * 2022-11-03 2024-05-10 Astrocyte Pharmaceuticals, Inc. Compositions pour administration intraveineuse
US11986486B2 (en) 2020-11-02 2024-05-21 Spes Pharmaceuticals Inc. Aqueous compositions of bortezomib

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101807462B1 (ko) * 2017-03-09 2017-12-08 씨제이헬스케어 주식회사 보르테조밉을 포함하는 안정한 제제 및 이의 제조방법

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JP2012514633A (ja) * 2009-01-09 2012-06-28 サン・ファーマ・アドバンスド・リサーチ・カンパニー・リミテッド 非経口用医薬組成物及びその非経口用医薬組成物の製造方法
KR101530942B1 (ko) * 2010-03-18 2015-06-23 이노파르마, 인코포레이티드 안정한 보르테조밉 포뮬레이션
WO2016059587A1 (fr) * 2014-10-16 2016-04-21 Piramal Enterprises Limited Composition injectable stable d'agents pharmaceutiquement actifs et procédé de préparation associé
WO2016166653A1 (fr) * 2015-04-13 2016-10-20 Leiutis Pharmaceuticals Pvt Ltd Compositions pharmaceutiques liquides stables de bortézomib
KR101807462B1 (ko) * 2017-03-09 2017-12-08 씨제이헬스케어 주식회사 보르테조밉을 포함하는 안정한 제제 및 이의 제조방법

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CA2784240C (fr) 2012-03-27 2014-07-08 Innopharma, Inc. Formulations stables a base de bortezomib

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
JP2012514633A (ja) * 2009-01-09 2012-06-28 サン・ファーマ・アドバンスド・リサーチ・カンパニー・リミテッド 非経口用医薬組成物及びその非経口用医薬組成物の製造方法
KR101530942B1 (ko) * 2010-03-18 2015-06-23 이노파르마, 인코포레이티드 안정한 보르테조밉 포뮬레이션
WO2016059587A1 (fr) * 2014-10-16 2016-04-21 Piramal Enterprises Limited Composition injectable stable d'agents pharmaceutiquement actifs et procédé de préparation associé
WO2016166653A1 (fr) * 2015-04-13 2016-10-20 Leiutis Pharmaceuticals Pvt Ltd Compositions pharmaceutiques liquides stables de bortézomib
KR101807462B1 (ko) * 2017-03-09 2017-12-08 씨제이헬스케어 주식회사 보르테조밉을 포함하는 안정한 제제 및 이의 제조방법

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3908258A4 (fr) * 2019-01-11 2022-09-28 Intas Pharmaceuticals Ltd. Procédé de préparation d'une composition pharmaceutique stable de bortézomib
US11986486B2 (en) 2020-11-02 2024-05-21 Spes Pharmaceuticals Inc. Aqueous compositions of bortezomib
EP4134083A1 (fr) 2021-08-12 2023-02-15 Extrovis AG Compositions pharmaceutiques de bortézomib
WO2024097387A1 (fr) * 2022-11-03 2024-05-10 Astrocyte Pharmaceuticals, Inc. Compositions pour administration intraveineuse

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TW201836609A (zh) 2018-10-16
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