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WO2018164513A1 - Stable preparation containing bortezomib and preparation method therefor - Google Patents

Stable preparation containing bortezomib and preparation method therefor 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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Prior art keywords
bortezomib
liquid formulation
formulation
acid
stability
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PCT/KR2018/002782
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French (fr)
Korean (ko)
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이정환
조태근
유재영
조영대
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씨제이헬스케어 주식회사
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Publication of WO2018164513A1 publication Critical patent/WO2018164513A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/69Boron compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable 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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Abstract

The present invention provides a bortezomib liquid preparation comprising: bortezomib or a pharmaceutically acceptable salt thereof; one or more sugar alcohols selected from the group consisting of mannitol, erythritol, sorbitol, isomalt, maltitol, xylitol and trehalose; and a solvent formed by mixing propylene glycol and polar solvents including water. The bortezomib liquid preparation of the present invention can be easily and commercially prepared, can prevent microbial contamination occurring during freeze-drying or reconstitution, exhibits an effect of improved administration convenience and stability, and since a sugar alcohol and propylene glycol are used, the ortezomib liquid preparation has no property abnormalities, such as discoloration or precipitate generation, in comparison with a conventional bortezomib-containing injectable liquid preparation, and meets standards.

Description

보르테조밉을 포함하는 안정한 제제 및 이의 제조방법Stable formulation comprising bortezomib and preparation method thereof
본 발명은 보르테조밉을 포함하는 안정한 제제 및 이의 제조방법에 관한 것으로, 구체적으로 안정성이 매우 우수한 보르테조밉을 포함하는 액상 제제 및 이의 제조방법에 관한 것이다.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.
재발성 다발성 골수종에 사용되는 보르테조밉(Bortezomib)은 화합물의 붕소 원자가 프로테아좀의 촉매 자리에 결합하여, 궁극적으로는 프로테아좀 억제 및 아폽토시스 촉진 인자(pro-apoptotic factor)의 분해 감소를 유도하고, 이는 이어서 치료된 세포의 아폽토시스를 촉발시키는 것으로 여겨진다.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.
현재, 보르테조밉{(N-(2-피라진)카보닐-L-페닐알라닌-L-류신 보론산}은 벨케이드(Velcade)TM로서 개발되어 여러 신생물 질환(neoplastic disease)의 치료, 특히 재발성 다발성 골수종(relapsed multiplemyeloma) 및 외투막 세포 림프종(mantle cell lymphoma)의 치료에서의 사용이 승인된 26S 프로테아좀 억제제이다.Currently, bortezomib {(N- (2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid} has been developed as Velcade 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.
상기 벨케이드TM는 투여 전에 재구성되어야 하는 동결건조 제제의 형태, 즉 환자에게 투여 시 0.9 % 소듐 클로라이드 용액으로 재구성하며, 희석농도는 2.5 mg/ml(i.v.)과 1.0 mg/ml(s.c.)을 최종 농도로 하는 동결건조 분말(3.5mg) 형태의 제형으로 시판되고 있다.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.
그러나, 동결건조 분말 형태의 제형은 제조과정이 복잡하고, 공정 비용이 많이 소요된다. 또한, 동결건조 제제의 재구성 시 미생물에 의한 오염의 위험성이 있으며, 약물의 조제에 관여하는 약사, 의사, 간호사 등이 세포 파괴 물질에 노출될 가능성이 큰 제형이다. 따라서, 보르테조밉과 같은 세포독성 항암제의 경우 동결건조 제형보다는 장기적으로 보관 가능하되 즉시 사용할 수 있는(ready-to-use) 액상 제제의 개발이 필요하다.However, formulations in the form of lyophilized powders are complicated to manufacture and costly to process. In addition, there is a risk of contamination by microorganisms in the reconstitution of the lyophilized formulation, pharmacists, doctors, nurses, etc. involved in the preparation of the drug is a formulation that is likely to be exposed to cell disruption. Therefore, in the case of cytotoxic anticancer agents such as bortezomib, there is a need for the development of ready-to-use liquid formulations that can be stored for a long time rather than lyophilized formulations.
다만, 액상 제제의 가장 큰 문제점은 저장 기간 동안의 안정성이다. 이러한 안정성의 문제로 인해 다수의 주사제가 주사 직전 용해시켜 사용하는 동결건조 제제의 형태로 사용된다. 동결건조 제형으로 제공되기 시작한 보르테조밉 또는 그 약리학적으로 허용되는 염의 경우에도 수용액으로 제조하면 미지의 유연물질이 증가되어 상온에서 장기간 보관할 수 없는 안정성 문제를 갖고 있다. 또한, 보르테조밉은 물(25℃) 에서 용해도가 0.076 mg/ml에 불과하여 액체 상태로 만드는데 장시간이 필요하다. 그런데, 보르테조밉은 액체 상태에서 굉장히 불안정하기 때문에 현재 유통되고 있는 동결건조제형의 경우에도 0.9 % NaCl로 재구성한 후, 8시간 이내에 사용하도록 되어 있다. 이러한 안정성 문제로 인하여 현재 임상에서 계속 동결건조 제형으로 사용되고 있는 실정이다.However, the biggest problem with liquid formulations is their stability during the storage period. Due to this stability problem, many injections are used in the form of lyophilized preparations which are dissolved and used immediately before injection. Bortezomib or its pharmacologically acceptable salts, which have begun to be provided as lyophilized formulations, also have a stability problem in that they can not be stored for a long time at room temperature due to an increase in unknown soft substances when prepared in aqueous solution. Bortezomib also has a long solubility in water (25 ° C.) of only 0.076 mg / ml in liquid form. However, 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.
이러한 액상 상태에서의 보르테조밉의 불안정성은 여러 문헌들에서 보고된 바 있다. 보르테조밉의 경우에도 해당하지만, 아미노알킬보론산을 포함하는 화합물은 유리 알파-아미노 기의 불안정성으로 인해, 자발적 1,3-재배열이 일어나 동종 아민을 제공하며 이들의 분해에 의해 붕산 및 알코올을 생성하게 된다. 이러한 불안정성으로 인하여 C-C 결합보다 더 길고 더 약한 C-B 결합을 용이하게 파괴하는 산화적 반응이 일어나게 된다. 이러한 불안정성은 주사용 수용액 중의 보르테조밉이 본질적으로 불안정하게 되는 원인이 된다. 예를 들어, 에탄올:생리식염액(normal saline solution)(2:98, pH 2.8) 중에서, 보르테조밉(0.5mg/ml)은 25℃에서 저장되는 경우에 6개월 내에 20% 분해되었다. 이외에도, PEG300은 퍼옥사이드를 생성하면서 자가-산화반응을 일으키는 것으로 알려져 있으며, PEG300:EtOH:H2O (40:10:50) 용매에서의 보르테조밉의 분해는 퍼옥사이드에 의한 것으로 추측되어졌다.Instability of bortezomib in this liquid state has been reported in several documents. The same applies to bortezomib, but compounds containing aminoalkylboronic acids, due to the instability of the free alpha-amino groups, cause spontaneous 1,3-rearrangement to give homologous amines, which break down boric acid and alcohols. Will be created. This instability results in an oxidative reaction that readily breaks longer and weaker CB bonds than CC bonds. This instability causes the bortezomib in the aqueous solution for injection to become essentially unstable. For example, in ethanol: normal saline solution (2:98, pH 2.8), Bortezomib (0.5 mg / ml) was 20% degraded within 6 months when stored at 25 ° C. In addition, PEG300 is known to cause a self-oxidation reaction to produce peroxides, and the degradation of Bortezomib in PEG300: EtOH: H 2 O (40:10:50) solvents was assumed to be by peroxides.
그 밖의 연구에서, 보르테조밉은 다수의 실험 조건 하에서 산화적 분해에 취약하며, 알킬 보란의 산화(이는 붕산의 에스테르를 형성함)는 또한 알킬 과산(peracid), 알킬 퍼옥사이드, 또는 산소 라디칼 종과의 반응에 기인할 수 있음이 보고되었다(Brown HC. 1972. Boranes in organic chemistry. Ithaca, NY: Cornell University Press.) 초기 산화는 퍼옥사이드 또는 분자 산소가 원인일 수 있고, 가벼운 금속 이온들, 및 알칼리 조건이 일반적으로 산화를 촉진시킨다. 따라서, 이들 조건은 보르테조밉 또는 어떠한 다른 알킬 보론산 유도체의 안정성에 유리하지 않을 것으로 간주된다(Hussain MA, Knabb R, AungustBJ, Kettner C.1991. Anticoagulant activity of a peptide boronicacid thrombin inhibitor by various routes of administration in rats. Peptide 12:1153-1154).In other studies, 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. (Brown HC. 1972. Boranes in organic chemistry. Ithaca, NY: Cornell University Press.) Initial oxidation may be due to peroxide or molecular oxygen, light metal ions, and Alkali conditions generally promote oxidation. Thus, these conditions are not considered to be beneficial for the stability of bortezomib or any other alkyl boronic acid derivatives (Hussain MA, Knabb R, AungustBJ, Kettner C.1991. Anticoagulant activity of a peptide boronicacid thrombin inhibitor by various routes of administration in rats.Peptide 12: 1153-1154).
미국 등록특허 제7119080호, 제6713446호, 제6958319호, 제6747150호, 및 제6297217호는 동결건조화 후, 보론산 작용기의 만니톨과의 디에스테르 형성을 개시하고 있다. 이와 같이 형성된 에스테르로부터, 주사용 식염수 중에서의 약물 프로덕트(drug product)의 재구성시 활성 보론산이 얻어진다. 유사하게, 벌크화제 및 완충제와 함께 시트르산과 같은 베타-카르복실산 및 알파-하이드록시로 보론산의 에스테르를 형성하려는 시도가 WO 2009/154737에 개시되어 있다.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.
용액 상태의 보르테조밉의 안정성에 대한 문제를 피하기 위해, 화합물이 동결건조되고, 주입 전에 재구성될 수 있다. 그러나, 이러한 방법은 보르테조밉 안정성과 관련된 문제점은 해소하는 경향이 있지만, 재구성된 미사용 용액이 수시간 또는 수일 내에 주입되어야 한다(참조예: 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). 유사하게, 재구성되는 경우, 만니톨의 보르테조밉 에스테르가 실온에서 저장된다면, 8시간 내에 투여되는 것에만 적합하다.To avoid problems with the stability of Bortezomib in solution, the compound can be lyophilized and reconstituted prior to injection. However, 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). Similarly, if reconstituted, the Bortezomib ester of mannitol is only suitable for administration within 8 hours if stored at room temperature.
추가의 공지된 방법은 WO2008075376A1에 개시된 바와 같이 개선된 안정성을 갖는 특이적 다형체 형태의 분리, 및 WO2010089768A2에 개시된 바와 같이 트로메타민과의 동결건조된 형태를 포함한다. 선택된 유기 용매 및 그 밖의 성분을 지닌 또 다른 포뮬레이션이 WO2010039762A2에 개시되어 있다. 불행히도, 이러한 공지된 조성물 전부 또는 거의 전부는 특히 포뮬레이션이 액체 포뮬레이션인 경우, 보르테조밉에 상당한 안정성을 제공하지 못한다.Further known methods include isolation of specific polymorphic forms with improved stability as disclosed in WO2008075376A1, and lyophilized forms with tromethamine as disclosed in WO2010089768A2. Another formulation with selected organic solvents and other components is disclosed in WO2010039762A2. Unfortunately, all or almost all of these known compositions do not provide significant stability to Bortezomib, especially when the formulation is a liquid formulation.
따라서, 당 분야에 공지된 보르테조밉에 대한 포뮬레이션이 다수 존재함에도 불구하고, 모든 또는 거의 모든 그러한 포뮬레이션은 보르테조밉이 용액 상태로 존재하는 경우에 제한된 안정성을 갖는다. 결과적으로, 최근에 사용되는 프로덕트는 투여 융통성(flexibility of dosing)을 제공하지 못하며, 특히 연장된 안정성을 지닌 다회용(multi-dose) 포뮬레이션을 허용하지 못한다. 또한 프로필렌글리콜과 같은 용해보조제를 과량 포함하고 있어 신체에 대한 부작용이 발생할 가능성도 있다. 따라서, 보다 안정성이 높으면서 동시에 생체안정성이 높은 성분을 함유하는 개선된 대안적인 보르테조밉 포뮬레이션을 제공하는 것이 여전히 필요하다.Thus, despite the large number of formulations for Bortezomib known in the art, all or almost all such formulations have limited stability when Bortezomib is in solution. As a result, recently used products do not provide flexibility of dosing, and in particular do not allow for multi-dose formulations with extended stability. It also contains an excess of dissolution aids such as propylene glycol, which can cause side effects on the body. Thus, there is still a need to provide improved alternative bortezomib formulations containing more stable and at the same time highly biostable components.
이러한 배경 하에서, 본 발명자들은 연구를 거듭한 결과, 극성 용매의 비율이 높아 생체 적합도가 높은 혼합용매를 사용하면서도 안정성이 우수한 보르테조밉 액상제제를 제조하였다.Under these circumstances, 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.
본 발명의 목적은 안정화된 보르테조밉 제제를 제공하는 것이다.It is an object of the present invention to provide a stabilized bortezomib formulation.
특히, 본 발명의 목적은 보르테조밉 제제를 즉시 사용형 주사용액(ready-to-use)으로 제공하는 것이다.In particular, it is an object of the present invention to provide bortezomib formulations in ready-to-use solutions.
상기 과제를 해결하기 위하여, 본 발명은 유효성분으로 보르테조밉 또는 이의 약제학적으로 허용가능한 염, 프로필렌글리콜 및 물을 포함하는 극성용매를 혼합하여 구성되는 용매, 만니톨, 에리쓰리톨, 솔비톨, 이소말트, 말티톨, 자이리톨, 및 트레할로스로 이루어진 군으로부터 선택된 하나 이상의 당 알코올을 포함하는 보르테조밉 액상제제를 제공한다.In order to solve the above problems, 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 To provide a bortezomib liquid formulation comprising at least one sugar alcohol selected from the group consisting of, maltitol, ziritol, and trehalose.
본 발명에 있어서, 보르테조밉 또는 이의 약제학적으로 허용가능한 염 : 당 알코올의 비율(w/w)은 1 : 10 ~ 60일 수 있으며, 바람직하게는 1 : 20 ~ 60 일 수 있다.In the present invention, the ratio of bortezomib or its pharmaceutically acceptable salt to sugar alcohol (w / w) may be 1: 10 to 60, preferably 1: 20 to 60.
본 발명의 용매 시스템은 물을 포함하는 극성 용매를 40 vol% 이상, 보다 구체적으로 40 vol% 내지 60 vol% 일 수 있으며, 이와 같은 함량으로 극성 용매, 보다 구체적으로 물을 함유하는 경우에도, 본 발명에 따른 제제는 25℃/RH60%에서 3개월 동안 저장되는 경우, 보르테조밉의 분해율을 총 2.5% 이하, 바람직하게는 2% 이하로 줄일 수 있다.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, When the formulation according to the invention is stored for 3 months at 25 ° C./RH 60%, the degradation rate of bortezomib can be reduced to a total of 2.5% or less, preferably 2% or less.
상기 보르테조밉 액상제제는 항산화제로서 부틸레이티드히드록시아니솔, 탄산수소나트륨, 및 아세틸시스테인으로 이루어진 군으로부터 선택된 어느 하나 이상을 포함할 수 있으며, 바람직하게는 부틸레이티드히드록시아니솔, 및 아세틸시스테인으로 이루어진 군으로부터 선택된 어느 하나 이상을 포함할 수 있다. 가장 바람직하게는 아세틸시스테인을 포함할 수 있다.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.
또한, 상기 보르테조밉 액상제제의 pH 범위는 4.0 ~ 6.0 인 것이 바람직하며, 가장 바람직하게는 4.0 ~ 5.0인 것이 바람직하다. In addition, the pH range of the Bortezomib liquid formulation is preferably 4.0 to 6.0, most preferably 4.0 to 5.0.
본 발명의 일 실시양태에 따르면, 상기 제제는 용액 상태로 저장 가능한 액상 제제로서 즉시 사용형(ready-to-use)으로 밀봉된 용기에 담긴 것이 더욱 바람직하다.According to one embodiment of the invention, the preparation is more preferably in a ready-to-use sealed container as a liquid preparation that can be stored in solution.
상기 즉시 사용형 주사의 농도는 1 mg/ml ~ 5 mg/ml 인 것이 바람직하다.The concentration of the ready-to-use injection is preferably 1 mg / ml to 5 mg / ml.
또한, 상기 용기 내의 헤드스페이스 내 산소량이 상기 헤드스페이스 부피에 대하여 3 v/v% 이하인 것이 바람직하며, 상기 산소량은 상기 헤드스페이스 내 산소를 비활성기체로 치환하여 조절할 수 있다. 상기 비활성기체는 질소 또는 아르곤을 사용할 수 있다.In addition, 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.
위와 같은 보르테조밉 제제는 25℃/RH60% 에서 3개월 동안 저장되는 경우, 보르테조밉의 분해를 총 2% 이하로 유지할 수 있다.Bortezomib formulations such as above can maintain up to 2% total degradation of bortezomib when stored at 25 ° C./RH 60% for 3 months.
이하에서 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 보르테조밉 제제는 활성성분으로 보르테조밉 또는 이의 약제학적으로 허용가능한 염을 포함한다. 본 발명에 따른 상기 보르테조밉은 약리학적으로 유효하거나, 또는 체내 화학적 또는 효소적 방법에 의해 약리적으로 유효한 약물을 포함하며, 구체적으로 상기 보르테조밉 약물 자체, 이의 약제학적으로 허용가능한 염이 사용될 수 있다.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. .
본 발명에서 사용된 용어, "보르테조밉(bortezomib)"은 "(N-(2-피라진) 카보닐-L-페닐알라닌-L-류신 보론산"의 명칭을 가지는 화합물로서, 구체적으로 하기 화학식 1로 표시되며, 재발성 다발성 골수종 및 외투막 세포 림프종의 치료에 사용이 승인된 26S 프로테아좀 억제제를 의미한다.As used herein, the term "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.
Figure PCTKR2018002782-appb-C000001
Figure PCTKR2018002782-appb-C000001
본 발명에서 사용된 용어, "약제학적으로 허용가능한 염"은 당해 기술분야에서 통상적인 방법에 따라 제조된 염을 의미하며, 이러한 제조방법은 당업자에게 공지되어 있다. 구체적으로, 상기 약제학적으로 허용가능한 염은 약리학적 또는 생리학적으로 허용되는 하기 무기산과 유기산 및 염기로부터 유도된 염을 포함하지만 이것으로 한정되지는 않는다. 적합한 산의 예로는 염산, 브롬산, 브롬화수소산, 황산, 질산, 과염소산, 푸마르산, 말레산, 인산, 글리콜산, 락트산, 살리실산, 숙신산, 톨루엔-p-설폰산, 타르타르산, 아세트산, 시트르산, 메탄설폰산, 포름산, 벤조산, 말론산, 나프탈렌-2-설폰산, 벤젠설폰산 등을 포함할 수 있다. 적합한 염기로부터 유도된 염은 알칼리 금속, 예를 들어, 소듐 또는 포타슘, 알칼리 토금속, 예를 들어, 마그네슘을 포함할 수 있으며 이에 제한되지 않는다.As used herein, 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. Examples of 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.
본 발명에서 사용된 용어, "당 알코올"은 부형제로서, 에르스리톨, 만니톨, 말티톨, 이소말트, 소르비톨, 자일리톨, 트레할로스 등이 있으며, 주사제 제형연구에서 흔하게 사용하는 부형제이다. As used herein, the term “sugar 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.
종래에 주사용 제제에 사용되는 부형제로는, 만니톨, 소르비톨, 수크로오스, 트레할로스, 락토오스, 글루코오스, 에르스리톨, 말티톨, 말토오스, 자일리톨, 글루콘산 나트륨, 글루콘산 마그네슘, 글루콘산 칼슘, 글루콘산 철, 백당, 전분, 옥수수 전분, 감자 전분, 나트륨 카르복시메틸셀룰로오스, 에틸셀룰로오스, 시클로덱스트린, 덱스트로오스, 히드록시프로필 베타 시클로덱스트린 등이 있다.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.
본 발명에서는 부형제로서 만니톨, 에르스리톨, 소르비톨, 이소말트, 트레할로스, 말티톨, 자일리톨 및 이의 혼합물로 이루어진 군으로부터 선택된 당 알코올을 포함할 수 있다. 더욱 바람직하게는, 만니톨, 에리쓰리톨, 이소말트 및 말티톨로 이루어진 군으로부터 선택된 당 알코올을 포함할 수 있다. 가장 바람직하게는, 만니톨을 포함할 수 있다.In the present invention, 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.
본 발명의 보르테조밉 제제는 위 "당 알코올"을 사용하여, 보르테조밉 또는 이의 약제학적으로 허용가능한 염을 약제학적으로 장기간 동안 안정하게 보관하는 것이 가능하다.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.
본 발명에서, 상기 보르테조밉 제제는 보르테조밉 또는 이의 약제학적으로 허용가능한 염: 당 알코올의 농도비가 1 : 10~60 (w/w)일 경우에 바람직하며, 특히 상기 농도비가 1 : 20~60일 경우에 더욱 바람직하다. 이때 각각의 농도의 단위는 mg/mL일 수 있다.In the present invention, 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. In this case, the unit of each concentration may be mg / mL.
또한, 종래에 주사용 제제에 사용되는 안정화제 및 항산화제로는 베타 카로테인, 글리신, 갈릭산, 티메로살(thimerosal), EDTA, 파라히드록시벤조산 에스테르 유도체(parahydroxybenzoic acid ester derivatives), 페놀 유도체(phenol derivatives), 알코올(alcohols), 레티놀(retinol), 토코페롤(tocopherol), TPGS, 아세트산 무수물(acetic anhydride), 소듐 카르복실레이트(sodium carboxylate), 라우릴 설페이트(lauryl sulfate),시스테아민(cysteamine), 시스틴(cystine), 시스테인(cystein), 아미노산(amino acids), 아스코르브산(ascorbic acid) 등의 유기산(organic acids), 설파이드 화합물(sulfide compounds), 아황산염(sulfite), 부틸레이티드히드록시아니솔(butylated hydroxyanisole), 부틸레이티드히드록시톨루엔(butylated hydroxytoluene ) 등이 있다.In addition, 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.
본 발명에서는 항산화제로서 부틸레이티드히드록시아니솔, 탄산수소나트륨, 및 아세틸시스테인으로 이루어진 군으로부터 선택된 어느 하나 이상을 포함할 수 있다. 더욱 바람직하게는 부틸레이티드히드록시아니솔, 및 아세틸시스테인으로 이루어진 군으로부터 선택된 어느 하나 이상을 포함할 수 있다. 가장 바람직하게는 아세틸시스테인을 포함할 수 있다.In the present invention, 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.
본 발명에서 사용된 용어, "아세틸시스테인"은 N-아세틸-L-시스테인(N-Acetyl-L-Cysteine, NAC, C5H9NO3S, CAS number616-91-1)의 명칭을 가지는 화합물로서, 본 발명의 보르테조밉 제제에서 항산화제로서 사용되는 화합물을 의미한다. 본 발명에서는 "아세틸시스테인"과 "N-아세틸-L-시스테인"이 서로 혼용되어 사용된다.As used herein, the term "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. In the present invention, "acetylcysteine" and "N-acetyl-L-cysteine" are used interchangeably.
본 발명에서, 상기 보르테조밉 제제는 바람직하기로 용액 상태로 저장 가능한 액상 제제일 수 있으며, 더욱 바람직하기로 즉시 사용 가능하도록(ready-to-use) 밀봉된 용기에 담긴 주사용 액상 제제일 수 있다.In the present invention, 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. .
본 발명에서, 상기 보르테조밉 제제는 약제학적으로 허용 가능한 담체 및 pH 조절제를 포함할 수 있다.In the present invention, the Bortezomib formulation may include a pharmaceutically acceptable carrier and pH adjusting agent.
본 발명의 보르테조밉 제제는 약제학적으로 허용가능한 부형제를 추가적으로 포함할 수 있으며, 락토오스, 덱스트로오스, 시클로덱스트린 및 그의 유도체, 수크로오스, 글리세롤, 소디움 카보네이트, 시트르산, 만니톨 등을 예로 들 수 있다.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.
본 발명에서, 상기 보르테조밉 제제는 프로필렌글리콜 및 물 등의 극성 용매를 혼합하여 구성된 용매를 포함할 수 있다. 상기 극성 용매는, FDA에서 승인된 주사제의 용매에 해당하는 것이 바람직하다.In the present invention, 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.
본 발명에서, 보르테조밉 주사용 액상 제제의 pH는 바람직하기로 약 4.0 내지 6.0, 더욱 바람직하기로 약 4.0 내지 5.0일 수 있다. 용액의 pH는 염산 등의 산, 또는 수산화 나트륨과 같은 염기를 이용해 조절하는 것이 가능하다. In the present invention, 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.
본 발명의 보르테조밉 제제는 질소 또는 아르곤 등의 불활성 기체를 이용하여 퍼징한 후 여과시켜 제조된 것일 수 있다.Bortezomib formulation of the present invention may be prepared by purging with an inert gas such as nitrogen or argon and then filtered.
또한, 본 발명의 보르테조밉 제제는 이 기술 분야에 알려진 적절한 용기에 포장될 수 있다. 예를 들면, 적절한 용기는 유리 바이알, 유리병, 카트리지, 사전-충전 주사 및 이와 유사한 것들일 수 있으며, 바람직하게는 유리 바이알일 수 있다. 더욱 바람직하게는 차광 유리 바이알일 수 있다.In addition, the Bortezomib formulations of the invention may be packaged in suitable containers known in the art. For example, 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.
본 발명 보르테조밉 주사용 액상 제제는 미리 세척 멸균한 용기에 담아 분배하고, 상기 용기에 적합한 마개의 표면이 보르테조밉 주사용 액상 제제에 비활성인 테프론 마개로 밀봉한다. 이때, 필요한 경우 상기 주사용 액상 제제 및 마개 사이의 공간을 비활성 기체로 채운다. 크림퍼를 이용하여 마개를 부착시킨 후, 필요 시 주사용 액상 제제가 충전된 바이알은 가열 멸균시킨다.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. At this time, if necessary, the space between the injectable liquid formulation and the stopper is filled with an inert gas. After the stopper is attached using a crimper, the vial filled with the liquid for injection is sterilized if necessary.
본 발명에서는 다양한 첨가제 또는 부형제를 대상으로 주사 제형의 보르테조밉 제제의 안정화 시험을 수행하였다. 그 결과, 대다수의 첨가제 또는 부형제의 경우 안정성이 향상되지 않을 뿐 아니라 오히려 침전이나 변색을 일으키는 등 문제를 나타냄을 확인하였다.In the present invention, stabilization tests of Bortezomib formulations of injectable formulations were carried out on various additives or excipients. As a result, in the case of the majority of additives or excipients, not only the stability was improved but also the problem of precipitation or discoloration was confirmed.
그러나, 놀랍게도, 본 발명의 발명자들은 용매로서 프로필렌글리콜을 포함한 용매를 사용하고, 부형제로서 당 알코올을 사용한 경우, 25℃/RH60% 안정성 조건에서 3개월 동안 총 유연물질이 2% 이하로 유지되고 변색 또는 침전물이 발생하지 않아 기준에 적합한 안정성을 갖게 됨을 발견하였다. 또한 프로필렌글리콜과 당 알코올은 모두 일반적으로 사용되며 단가가 저렴하여 상업성이 우수한 장점 또한 있다.Surprisingly, however, 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. In addition, both propylene glycol and sugar alcohols are generally used, and there is also an advantage of low commercial unit price.
본 발명은 상업적으로 제조가 용이하고, 동결 건조 또는 재구성 시 수반되는 미생물 오염을 방지할 수 있으며, 투약 편이성 및 안정성이 향상된 보르테조밉 제제를 제공할 수 있다. 또한, 당 알코올 및 프로필렌글리콜을 사용함으로써 종래의 보르테조밉 함유 주사용 액상 제제에 비교하여 변색 또는 침전물 발생 등의 성상의 이상이 없고 기준에 적합한 안정화된 보르테조밉 제제를 제공할 수 있다.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. In addition, by using 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.
이하, 실시예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들 실시예에 의해 제한되는 것은 아니다.Hereinafter, the configuration and effects of the present invention through the embodiments will be described in more detail. These examples are only for illustrating the present invention, but the scope of the present invention is not limited by these examples.
[[ 제제예Formulation example 1 내지 24] 1 to 24]
아래 표 1에 제시된 처방에 따라 액상제제를 제조하였다. 아세테이트 완충액을 준비한 후, 프로필렌글리콜과 아세테이트완충액의 조성비를 60:40(%) 내지 40:60(%)로 혼합하여 용매로 사용하였다. 부형제로는 만니톨을 용해시켜 제조하였다. 단, 제제예 4에서는 아세테이트 완충액을 주사용수(WFI)로 대체하여 프로필렌글리콜을 포함하는 혼합용매를 제조하였다. 제제예 1, 2, 5 및 6에 대하여 질소치환을 실시하였다. To prepare a liquid formulation according to the prescription shown in Table 1 below. After preparing an acetate buffer, the composition ratio of propylene glycol and acetate buffer solution was mixed at 60:40 (%) to 40:60 (%) and used as a solvent. An excipient was prepared by dissolving mannitol. However, in Preparation Example 4, a mixed solvent including propylene glycol was prepared by replacing acetate buffer with water for injection (WFI). Nitrogen substitution was performed about Formulation Examples 1, 2, 5, and 6.
Figure PCTKR2018002782-appb-T000001
Figure PCTKR2018002782-appb-T000001
또한, 다음 표 2에 제시된 처방에 따라 액상 제제를 제조하였다. 용매로서 프로필렌글리콜과 아세테이트완충액의 조성비를 60:40(%) 내지 40:60(%)로 혼합하여 사용하였고, 부형제로는 만니톨, 에르스리톨, 말티톨, 트레할로오스, 소르비톨, 이소말트 또는 자일리톨을 용해시켜 제조하였다. 질소치환을 실시하였으며, 검체를 보관하는 용기로는 차광 바이알을 사용하였다.In addition, liquid formulations were prepared according to the formulations set forth in Table 2 below. As 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.
Figure PCTKR2018002782-appb-T000002
Figure PCTKR2018002782-appb-T000002
제제예 1 내지 6에 대한 안정성 평가 결과를 표 3에 나타내었다. 안정성 시험 조건은 ① 5℃, ② 25℃/RH60%이다. 21일 동안 챔버(closed)에 보관 후, 총 유연물질에 대해 평가하였다.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.
Figure PCTKR2018002782-appb-T000003
Figure PCTKR2018002782-appb-T000003
만니톨을 첨가하지 않은 #002에 비해, 만니톨을 첨가한 #001의 총 유연물질(%)이 약 50% 감소되었다. Compared to # 002 without the addition of mannitol, the total% of%% of 001 added mannitol was reduced by about 50%.
#005와 #006을 비교할 때, 만니톨을 3배 더 첨가한 #005의 총 유연물질(%)이 #006보다 약 50% 감소 되었다.Compared with # 005 and # 006, the total% of the% related soft substance of # 005 with 3 times more mannitol was reduced by about 50% than # 006.
#001과 #003을 비교할 때, 용기내 헤드스페이스를 질소치환한 #003이 질소치환을 하지 않은 #001 보다 총 유연물질(%)이 현저하게 낮아짐을 확인할 수 있었다.When comparing # 001 and # 003, it was confirmed that # 003, which was nitrogen-substituted in headspace, was significantly lower in total lead (%) than # 001 which was not nitrogen-substituted.
#003과 #004에서, 아세테이트완충액을 사용한 #003의 총 유연물질이 주사용수를 사용한 #004의 경우보다 낮았다.In # 003 and # 004, the total analog of # 003 with acetate buffer was lower than that of # 004 with water for injection.
제제예 7 내지 24에 대한 안정성 평가 결과는 표 4에 나타내었다. 안정성 시험 조건은 ① 40℃/RH75%, ② 60℃/RH80%이며, 10일 동안 안정성 챔버(closed)에 보관 후 총 유연물질에 대해 평가하였다. 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.
Figure PCTKR2018002782-appb-T000004
Figure PCTKR2018002782-appb-T000004
표 4의 안정성 결과를 보면, 당 알코올을 포함할 경우 전반적으로 안정성이 우수하게 구현됨을 알 수 있다(#002의 안정성 평가결과와 대조적임).Looking at the stability results of Table 4, it can be seen that the overall stability is excellent when the sugar alcohol is included (as opposed to the stability evaluation results of # 002).
[[ 제제예Formulation example 25 내지 35] 25 to 35]
다음 표 5에 제시된 처방과 같이 액상 제제를 제조하였다. 프로필렌글리콜과 아세테이트완충액 또는 주사용수를 조성비 60:40(%)로 혼합하여 용매로 사용하였으며, 부형제로 만니톨을 용해시켜 제조하였다. pH 2.0 ~ 8.0 범위 내에서 각 제제예별로 pH를 달리 설정하였다.To prepare a liquid formulation as prescribed in the following Table 5. Propylene glycol and acetate buffer or water for injection were mixed in a composition ratio of 60:40 (%) and used as a solvent, and prepared by dissolving mannitol as an excipient. The pH was set differently for each formulation within the range of pH 2.0 to 8.0.
Figure PCTKR2018002782-appb-T000005
Figure PCTKR2018002782-appb-T000005
안정성 평가 결과를 다음 표 6에 나타내었다. 안정성 시험 조건은 ① 5℃, ② 25℃/RH60% 이다. ①과 ②는 21일(#007~011) 또는 33일(#012~019) 동안 챔버(closed)에 보관 후, 총 유연물질에 대해 평가하였다.The stability evaluation results are shown in Table 6 below. Stability test conditions are ① 5 ℃, ② 25 ℃ / 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.
Figure PCTKR2018002782-appb-T000006
Figure PCTKR2018002782-appb-T000006
안정성 결과를 보면, pH 4.0 ~ 6.0 범위의 제제에서 총 유연물질(%)이 낮아 안정함을 확인할 수 있었다. In the stability results, it was confirmed that the total flexible material (%) in the formulation of the pH range 4.0 to 6.0 is low.
#033 ~ #035의 결과를 통해, 아세테이트완충액을 사용하면 총 유연물질(%) 측면에서 주사용수를 사용할 때보다 유리함을 알 수 있다. The results of # 033 ~ # 035 show that the use of acetate buffer is more advantageous than the use of water for injection in terms of the total% flexible.
[[ 제제예Formulation example 36 내지 63] 36 to 63]
다음 표 7에 제시된 처방과 같이 액상 제제를 제조하였다. 용매로서 프로필렌글리콜과 아세테이트완충액을 조성비 40:60(%)으로 혼합하여 사용하였고, 부형제로 만니톨, 말티톨 또는 이소말트를 용해시켜 제조하였다. 추가적으로, 아스코르브산, 아황산수소나트륨, 부틸레이티드히드록시아니솔, 탄산수소나트륨, 피로아황산나트륨 또는 N-아세틸-L-시스테인을 첨가하였다. 질소치환을 실시하였고, 보관하는 용기로는 차광 바이알을 사용하였다. To prepare a liquid formulation as shown in the following Table 7. Propylene glycol and acetate buffer were used as a solvent in a composition ratio of 40:60 (%) and prepared by dissolving mannitol, maltitol or isomalt as excipients. In addition, ascorbic acid, sodium bisulfite, butylated hydroxyanisole, sodium bicarbonate, sodium pyrosulfite or N-acetyl-L-cysteine was added. Nitrogen substitution was performed, and a light-shielding vial was used as a container for storing.
Figure PCTKR2018002782-appb-T000007
Figure PCTKR2018002782-appb-T000007
상기 설명된 조성에 대한 안정성 시험 결과는 표 8에 나타내었다. 안정성 시험 조건은 ① 5℃, ② 25℃/RH60% 이다. #036~#063에 대해서는 안정성 챔버(closed)에 30일 동안 보관한 후에 총 유연물질에 대해 평가하였다.The stability test results for the above described compositions are shown in Table 8. Stability test conditions are ① 5 ℃, ② 25 ℃ / RH60%. For # 036 to # 063, total lead was assessed after 30 days of storage in a stable chamber.
Figure PCTKR2018002782-appb-T000008
Figure PCTKR2018002782-appb-T000008
상기 표 8의 안정성 결과를 보면, 모든 당 알코올 처방에서 항산화제로서 아스코르브산(#036, #043, #050, #057)을 사용한 검체는 가장 높은 총 유연물질 수준(%)을 나타내는 것으로 확인되었다. 또한 아황산수소나트륨(#037, #044, #051, #058)과 피로아황산나트륨(#040, #047, #054, #061)을 사용한 경우 모든 검체에서 피크 정량화를 할 수 없었다. 이것은 활성물질인 보르테조밉과 화학적인 반응에 의한 것으로 보인다. From the stability results of Table 8, it was confirmed that the sample using ascorbic acid (# 036, # 043, # 050, # 057) as the antioxidant in all sugar alcohol formulations showed the highest total level of analog (%). . In addition, peak quantification was not possible in all samples when sodium bisulfite (# 037, # 044, # 051, # 058) and sodium pyrosulfite (# 040, # 047, # 054, # 061) were used. This may be due to a chemical reaction with the active ingredient bortezomib.
하지만, 부틸레이티드히드록시아니솔, 탄산수소나트륨, 또는 아세틸시스테인을 사용한 검체는 장기조건인 25℃/RH60% 에서 대략 1% 이하의 총 유연물질을 나타내었다. However, samples using butylated hydroxyanisole, sodium hydrogen carbonate, or acetylcysteine showed a total softening material of approximately 1% or less at 25 ° C / RH60%, which is a long term condition.
결론적으로, 항산화제로서 부틸레이티드히드록시아니솔, 탄산수소나트륨, 또는 아세틸시스테인을 사용하는 것이 바람직하며, 더 바람직하게는 부틸레이티드히드록시아니솔 또는 아세틸시스테인을 사용하는 것이 바람직하다.In conclusion, it is preferable to use butylated hydroxyanisole, sodium hydrogen carbonate, or acetylcysteine as the antioxidant, more preferably, butylated hydroxyanisole or acetylcysteine.
[[ 대조예Control 64 및 65]  64 and 65]
표 9에서, #064는 동결건조 제형의 벨케이드주(한국얀센㈜)이고 #065는 벨케이드ⓡ주(한국얀센㈜)를 재구성(reconstitution)하여 즉시 사용형 주사제(ready-to-use)로 제조한 것이다. In Table 9, # 064 is made of a Velcade state (Janssen Korea ㈜) and # 065 is Velcade ⓡ main reconstruct (Janssen Korea ㈜) (reconstitution) ready-to-use type injection (ready-to-use) by the freeze-dried formulation It is.
Figure PCTKR2018002782-appb-T000009
Figure PCTKR2018002782-appb-T000009
상기 설명된 조성에 대한 안정성 시험 결과는 표 10에 나타내었다. 안정성 시험 조건은 ① 5℃, ② 25℃/RH60% 이다. ①, ②는 3개월 동안 안정성 챔버(closed)에 보관 후, 총 유연물질에 대해 평가하였다. The stability test results for the above described compositions are shown in Table 10. Stability test conditions are ① 5 ℃, ② 25 ℃ / RH60%. ① and ② were stored in a stable chamber for 3 months, and then evaluated for total flexible substances.
Figure PCTKR2018002782-appb-T000010
Figure PCTKR2018002782-appb-T000010

Claims (12)

  1. 보르테조밉 또는 이의 약제학적으로 허용가능한 염;Bortezomib or a pharmaceutically acceptable salt thereof;
    만니톨, 에리쓰리톨, 솔비톨, 이소말트, 말티톨, 자이리톨, 및 트레할로스로 이루어진 군으로부터 선택된 하나 이상의 당 알코올; 및 One or more sugar alcohols selected from the group consisting of mannitol, erythritol, sorbitol, isomalt, maltitol, xyitol, and trehalose; And
    프로필렌글리콜 및 물을 포함하는 극성용매를 혼합하여 구성되는 용매를 포함하는 보르테조밉 액상제제.Bortezomib liquid formulation containing a solvent comprising a polar solvent containing propylene glycol and water.
  2. 제 1 항에 있어서, 보르테조밉 또는 이의 약제학적으로 허용가능한 염 : 당 알코올의 비율(w/w)이 1 : 10 ~ 60 인 보르테조밉 액상제제.The bortezomib liquid formulation according to claim 1, wherein the bortezomib or a pharmaceutically acceptable salt thereof: sugar alcohol has a ratio of 1 to 10 to 60.
  3. 제 2 항에 있어서, 상기 비율(w/w)이 1 : 20 ~ 60 인 보르테조밉 액상제제.The bortezomib liquid formulation according to claim 2, wherein the ratio (w / w) is 1:20 to 60.
  4. 제 1 항에 있어서, 상기 당 알코올은 만니톨, 에리쓰리톨, 이소말트, 및 말티톨 중 선택된 어느 하나인 보르테조밉 액상제제.The bortezomib liquid formulation of claim 1, wherein the sugar alcohol is any one selected from mannitol, erythritol, isomalt, and maltitol.
  5. 제 1 항에 있어서, 상기 혼합용매 중 프로필렌글리콜이 전체 용매의 40 ~ 60 % vol 로 포함되는 보르테조밉 액상제제.According to claim 1, Bortezomib liquid formulation of the mixed solvent containing propylene glycol 40 to 60% vol of the total solvent.
  6. 제 1 항에 있어서, 상기 보르테조밉 액상제제의 pH 범위는 4.0 ~ 6.0 인 보르테조밉 액상제제.The bortezomib liquid formulation of claim 1, wherein the pH of the bortezomib liquid formulation is 4.0 to 6.0.
  7. 제 1 항에 있어서, 상기 보르테조밉 액상제제는 항산화제로서 부틸레이티드히드록시아니솔, 탄산수소나트륨, 및 아세틸시스테인으로 이루어진 군으로부터 선택된 어느 하나 이상을 포함하는 보르테조밉 액상제제. The bortezomib liquid formulation of claim 1, wherein the bortezomib liquid formulation comprises at least one selected from the group consisting of butylated hydroxyanisole, sodium hydrogen carbonate, and acetylcysteine as an antioxidant.
  8. 제 1 항에 있어서, 상기 제제는 즉시 사용형(ready-to-use)으로 밀봉된 용기에 담긴 보르테조밉 액상제제.The formulation of Bortezomib according to claim 1, wherein the formulation is in a sealed container ready-to-use.
  9. 제 8 항에 있어서, 상기 즉시 사용형 주사의 농도는 1 mg/ml ~ 5 mg/ml 인보르테조밉 액상제제.10. The liquid formulation of claim 8, wherein the concentration of the ready-to-use injection is 1 mg / ml-5 mg / ml.
  10. 제 8 항에 있어서, 상기 용기 내의 헤드스페이스 내 산소량이 상기 헤드스페이스 부피에 대하여 3 v/v% 이하인 보르테조밉 액상제제.9. The Bortezomib liquid formulation according to claim 8, wherein the amount of oxygen in the headspace in the container is 3 v / v% or less with respect to the headspace volume.
  11. 제 10 항에 있어서, 상기 산소량은 상기 헤드스페이스 내 산소를 비활성기체로 치환하여 조절하는 것인 보르테조밉 액상제제.11. The bortezomib liquid formulation of claim 10, wherein the amount of oxygen is controlled by replacing oxygen in the headspace with an inert gas.
  12. 제 11 항에 있어서, 상기 비활성 기체는 질소 또는 아르곤인 보르테조밉 액상제제.12. The bortezomib liquid formulation of claim 11, wherein the inert gas is nitrogen or argon.
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