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WO2017018815A1 - Procédé de purification d'un copolymère à blocs amphiphile, copolymère à blocs amphiphile obtenu selon ledit procédé, et composition pharmaceutique contenant ledit copolymère - Google Patents

Procédé de purification d'un copolymère à blocs amphiphile, copolymère à blocs amphiphile obtenu selon ledit procédé, et composition pharmaceutique contenant ledit copolymère Download PDF

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Publication number
WO2017018815A1
WO2017018815A1 PCT/KR2016/008264 KR2016008264W WO2017018815A1 WO 2017018815 A1 WO2017018815 A1 WO 2017018815A1 KR 2016008264 W KR2016008264 W KR 2016008264W WO 2017018815 A1 WO2017018815 A1 WO 2017018815A1
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WO
WIPO (PCT)
Prior art keywords
block copolymer
amphiphilic block
pharmaceutical composition
sublimation
molecular weight
Prior art date
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PCT/KR2016/008264
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English (en)
Inventor
Bong Oh Kim
Ji Yeong Kim
Hye Rim Kim
Bum Chan MIN
Min Hyo Seo
Sa Won Lee
Yil Woong Yi
Joong Woong Cho
In Ja Choi
Original Assignee
Samyang Biopharmaceuticals Corporation
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Publication date
Application filed by Samyang Biopharmaceuticals Corporation filed Critical Samyang Biopharmaceuticals Corporation
Publication of WO2017018815A1 publication Critical patent/WO2017018815A1/fr

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    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/88—Post-polymerisation treatment
    • C08G63/90—Purification; Drying

Definitions

  • the present disclosure relates to purification of an amphiphilic block copolymer, and more specifically, a method for purifying an amphiphilic block copolymer effectively by sublimation method with suppressing the molecular weight reduction, an amphiphilic block copolymer composition obtained by the purification method, and a pharmaceutical composition comprising the amphiphilic block copolymer composition.
  • An amphiphilic block copolymer comprises a hydrophilic polymer block and a hydrophobic polymer block. Since the hydrophilic polymer block directly contacts blood proteins and cell membranes in vivo , polyethylene glycol or monomethoxypolyethylene glycol, etc. having biocompatibility has been used.
  • the hydrophobic polymer block improves affinity to a hydrophobic drug, and polylactide, polyglycolide, poly(lactic-glycolide), polycaprolactone, polyamino acid or polyorthoester, etc. having biodegradability has been used.
  • polylactide derivatives have been applied to drug carriers in various forms because they have excellent biocompatibility and are hydrolyzed into harmless lactic acid in vivo . Polylactide derivatives have various physical properties depending on their molecular weights, and have been developed in various forms such as microsphere, nanoparticle, polymeric gel and implant agent.
  • the release rate of drug can be controlled by adjusting the composition ratio and each molecular weight, etc. of the hydrophilic and hydrophobic blocks.
  • the purity of the amphiphilic block copolymer is important. Monomers are used to synthesize the hydrophobic biodegradable polymer block. If the final amphiphilic block copolymer contains unreacted monomers, the storage stability of the drug decreases. In addition, if the remaining monomers are decomposed to lower the pH, the decomposition rate of the polymer increases and the stability of drug decreases due to the low pH, resulting in acceleration of the generation of related compounds. That is, impurities such as monomers, etc. contained in the amphiphilic polymer can be a cause of reducing the storage period during which the stability of the drug composition can be guaranteed.
  • a technology for purifying an amphiphilic block copolymer comprising polylactide derivative as a hydrophobic block by a solvent/non-solvent method has been known.
  • methylene chloride/ether are used as solvent/non-solvent to remove D,L-lactide monomer.
  • Such a method is effective in removing D,L-lactide.
  • ether used as a non-solvent has a very low boiling point, there are many problems in its application to a commercial process.
  • Another purification method is a method of removing the monomers without using a solvent.
  • this method after synthesizing an amphiphilic copolymer comprising polylactide derivative, unreacted lactide monomer is removed by a sublimation method using its sublimating property.
  • This method can be advantageously applied for commercialization.
  • it is difficult to control the molecular weight as desired due to the thermal decomposition of the synthesized polymer under high temperature and vacuum conditions for a long time.
  • International Publication No. WO 2009/091150 discloses a method for purifying an amphiphilic block copolymer by dissolving the amphiphilic block copolymer in a water-miscible organic solvent, adding water or an aqueous solution of alkali metal salt to the polymer solution and mixing, salting out the resulting solution to separate it into an organic layer and an aqueous layer, and removing the organic solvent from the obtained organic layer to recover the polymer.
  • this method requires a complicated process and increased production cost, and thus is difficult to practically apply in a commercial process, and there is a problem of residual organic solvent, etc.
  • One purpose of the present invention is to provide a method for purifying an amphiphilic block copolymer effectively by sublimation method with suppressing the molecular weight reduction.
  • Another purpose of the present invention is to provide an amphiphilic block copolymer composition obtained by the above purification method.
  • Yet another purpose of the present invention is to provide a pharmaceutical composition comprising the above amphiphilic block copolymer composition.
  • One aspect of the present invention provides a method for purifying an amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B) by sublimation, wherein the sublimation is conducted at a temperature of 80°C or higher and lower than 120°C and under a pressure of a vacuum degree of 10 torr or less.
  • Another aspect of the present invention provides an amphiphilic block copolymer composition which is purified by the above purification method and shows 3.0% or less of reduction in number average molecular weight (Mn), as compared with the initial number average molecular weight of the amphiphilic block copolymer composition.
  • Still another aspect of the present invention provides a polymeric micelle pharmaceutical composition comprising the above amphiphilic block copolymer composition.
  • an amphiphilic block copolymer can be purified effectively without thermal decomposition of the polymer, which is advantageous in application to commercialization. If a pharmaceutical composition is prepared by using the amphiphilic block copolymer composition purified as above, the amount of impurity contained in the polymer composition is reduced and the generation of related compounds is suppressed even under severe condition or in long-term storage, and thus a pharmaceutical composition having excellent storage stability can be provided.
  • Figure 1 is the resulting chromatogram of HPLC analysis conducted in Experimental Example 1.
  • amphiphilic block copolymer composition refers to a composition including amphiphilic block copolymer and impurities such as unreacted monomer, e.g., unreacted lactide monomer.
  • amphiphilic block copolymer composition can be interchangeably used with “amphiphilic block copolymer.”
  • an amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B) is conducted by sublimation.
  • the sublimation is characterized by being conducted at a temperature of 80°C or higher and lower than 120°C and under a pressure of a vacuum degree of 10 torr or less.
  • the sublimation may be conducted at a temperature condition of preferably 80 to 100°C, more preferably 90 to 100°C and most preferably 100°C, and under a pressure of a vacuum degree of preferably 7 torr or less, more preferably 5 torr or less and even more preferably 1 torr or less, for a period of time of preferably 10 hours to 74 hours, more preferably 10 hours to 48 hours and even more preferably 24 hours to 48 hours. Conducting the sublimation under such conditions can minimize the change in molecular weight of the copolymer and remove impurities therefrom effectively.
  • a process for preparing an amphiphilic polymer by a conventional commercial method comprises the steps of reactant feeding (initiator, monomer, catalyst), polymerization and purification.
  • a conventional purification step is conducted under a high temperature/vacuum condition in order to remove the unreacted monomer, and the temperature is 120 to 130°C which is the same as the polymerization temperature. If the synthesized amphiphilic polymer is exposed to such a high temperature under vacuum condition for a long time, thermal decomposition occurs and impurities are generated continuously, and as a result thereof, the purification efficiency decreases and it becomes difficult to remove impurities below a certain level (for example, 1% by weight or less of the total weight of the polymer).
  • a certain level for example, 1% by weight or less of the total weight of the polymer.
  • the molecular weight of the amphiphilic polymer decreases too much as a result of thermal decomposition, it becomes difficult to constantly maintain the commercial production properties.
  • impurities can be effectively removed therefrom while minimizing the change in properties such as molecular weight, etc. of the amphiphilic block copolymer.
  • the amphiphilic block copolymer comprises an A-B type diblock copolymer consisting of a hydrophilic block (A) and a hydrophobic block (B), or a B-A-B type triblock copolymer.
  • the amphiphilic block copolymer may comprise the hydrophilic block in an amount of 20 to 95% by weight, and more concretely 40 to 95% by weight, based on the total weight of the copolymer.
  • the amphiphilic block copolymer may comprise the hydrophobic block in an amount of 5 to 80% by weight, and more concretely 5 to 60% by weight, based on the total weight of the copolymer.
  • the amphiphilic block copolymer may have a number average molecular weight of 1,000 to 50,000 Daltons, and more concretely 1,500 to 20,000 Daltons.
  • the hydrophilic block is a polymer having biocompatibility and may comprise one or more selected from the group consisting of polyethylene glycol or derivatives thereof, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide and combinations thereof, and more concretely, it may comprise one or more selected from the group consisting of polyethylene glycol, monomethoxypolyethylene glycol and combinations thereof.
  • the hydrophilic block may have a number average molecular weight of 200 to 20,000 Daltons, and more concretely 200 to 10,000 Daltons.
  • the hydrophobic block is a polymer having biodegradability and may be a polymer of monomers derived from alpha ( ⁇ )-hydroxy acid. Concretely, it may comprise one or more selected from the group consisting of polylactide, polyglycolide, polymandelic acid, polycaprolactone, polydioxan-2-one, polyamino acid, polyorthoester, polyanhydride, polycarbonate and combinations thereof, and more concretely, it may comprise one or more selected from the group consisting of polylactide, polyglycolide, polycaprolactone, polydioxan-2-one and combinations thereof.
  • the hydrophobic block may have a number average molecular weight of 200 to 20,000 Daltons, and more concretely 200 to 10,000 Daltons.
  • an amphiphilic block copolymer comprising a hydrophobic polymer block of poly(alpha ( ⁇ )-hydroxy acid) may be synthesized by a known ring-opening polymerization method using a hydrophilic polymer having hydroxyl group as an initiator, and a lactone monomer of alpha ( ⁇ )-hydroxy acid.
  • L-lactide or D,L-lactide may be polymerized with hydrophilic polyethylene glycol or monomethoxypolyethylene glycol having hydroxyl group as an initiator by ring opening. Synthesis of diblock or triblock copolymer is possible according to the number of hydroxyl group existing in the hydrophilic block which is the initiator.
  • an organometallic catalyst such as tin oxide, lead oxide, tin octoate, antimony octoate, etc. may be used, and tin octoate having biocompatibility is preferably used in preparing polymer for medical use.
  • An amphiphilic block copolymer purified by the purification method according to an embodiment of the present invention shows 3.0% or less, preferably 2.5% or less and more preferably 2.0% or less, of reduction in number average molecular weight (Mn), as compared with the initial number average molecular weight of the amphiphilic block copolymer.
  • An amphiphilic block copolymer composition purified according to an embodiment of the present invention can be used as a drug carrier to prepare a pharmaceutical composition ⁇ for example, a polymeric micelle pharmaceutical composition.
  • a pharmaceutical composition according to an embodiment of the present invention can comprise poorly water-soluble drug as active ingredient.
  • the poorly water-soluble drug can be selected from drugs having a solubility in water (25°C) of 100 mg/mL or less.
  • it can be selected from antineoplastic agents, antifungal agents, immunosuppressants, analgesics, anti-inflammatory agents, antiviral agents, anxiolytic sedatives, contrasting agents, corticosteroids, diagnostic agents, diagnostic imaging agents, diuretics, prostaglandins, radiopharmaceuticals, sex hormones including steroids and combinations thereof, but it is not limited thereto.
  • the poorly water-soluble drug can be selected from anticancer agents, and concretely, it can be a taxane anticancer agent.
  • the taxane anticancer agent can be one or more selected from the group consisting of paclitaxel, docetaxel, 7-epipaclitaxel, t-acetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel and cabazitaxel, and more concretely, it can be paclitaxel, docetaxel or a combination thereof.
  • the method for preparing a pharmaceutical composition of an embodiment of the present invention may comprise (a) dissolving poorly water-soluble drug and the purified amphiphilic block copolymer in an organic solvent; and (b) adding an aqueous solvent to the solution obtained in step (a) to form polymeric micelles.
  • a water-miscible organic solvent for example, selected from the group consisting of alcohol, acetone, tetrahydrofuran, acetic acid, acetonitrile and dioxane and combinations thereof can be used, but it is not limited thereto.
  • aqueous solvent one selected from the group consisting of conventional water, distilled water, distilled water for injection, saline, 5% glucose, buffer and combinations thereof can be used, but it is not limited thereto.
  • the method for preparing a pharmaceutical composition of an embodiment of the present invention may further comprise removing an organic solvent after said step (a).
  • the pharmaceutical composition according to an embodiment of the present invention may comprise the poorly water-soluble drug in an amount of 0.1 to 50 parts by weight, and more concretely 0.5 to 30 parts by weight, based on 100 parts by weight of the amphiphilic block copolymer. If the amount of the poorly water-soluble drug is too small as compared with that of the amphiphilic block copolymer, the weight ratio of the amphiphilic copolymer used per drug is high and thus the time for reconstitution may increase. On the other hand, if the amount of the poorly water-soluble drug is too large, there may be a problem of rapid precipitation of the poorly water-soluble drug.
  • the pharmaceutical composition according to an embodiment of the present invention may contain, when stored at the severe condition (80°C) for 3 weeks, the related compounds derived from the poorly water-soluble drug in the amounts shown in the following Table 1, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.
  • Preparation Example 1 Synthesis of diblock copolymer consisting of monomethoxypolyethylene glycol and D,L - lactide (mPEG- PDLLA )
  • mPEG monomethoxypolyethylene glycol
  • Example 1 Purification of diblock copolymer (mPEG- PDLLA ) by sublimation method
  • Example 2 Purification of diblock copolymer (mPEG- PDLLA ) by sublimation method
  • Comparative Example 1 Purification of diblock copolymer (mPEG- PDLLA ) by sublimation method
  • Comparative Example 2 Preparation of polymeric micelle composition containing paclitaxel by using the polymer purified at 120°C
  • Preparation Example 1 after completing the polymerization reaction, under continuous agitation with an agitator the reactor was connected to a vacuum pump and the product was purified under a pressure of 1 torr or less by a sublimation method for 7 hours to obtain 262 g of mPEG-PDLLA in molten state. 1 g of paclitaxel and 5 g of the obtained mPEG-PDLLA were weighed, and 4 ml of ethanol was added thereto and agitated at 60°C until the mixture was completely dissolved to form a clear solution. Ethanol was then removed by distillation under reduced pressure using a rotary evaporator equipped with a round-bottom flask at 60°C for 3 hours.
  • Example 3 Preparation of polymeric micelle composition containing paclitaxel by using the polymer purified at 100°C
  • Example 2 Except that mPEG-PDLLA purified for 24 hours in Example 2 was used, a polymeric micelle composition containing paclitaxel was prepared by the same method as in Comparative Example 2.
  • the polymeric micelle composition of paclitaxel prepared in Comparative Example 2 (using the polymer purified at 120°C) and that prepared in Example 3 (using the polymer purified at 100°C) were kept in an oven at 80°C for 2 weeks and 3 weeks, and the compositions were then analyzed with HPLC to compare the amounts of related compound.
  • the test solution was prepared by dissolving the micelle composition in 80% acetonitrile aqueous solution and diluting to 600 ppm concentration of paclitaxel.
  • the resulting chromatogram of HPLC analysis is shown in Figure 1, and the change in the amount of related compound (%) according to the severe test time is shown in the following Table 3.
  • Amount of each related compound (%) 100(Ri/Ru)
  • Example 3 prepared according to an embodiment of the present invention showed improved stability and smaller reduction of paclitaxel amount, as compared with the composition of Comparative Example 2, whereby the efficacy of the drug contained in the composition can be maintained more stably.

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Abstract

L'invention concerne un procédé de purification d'un copolymère à blocs amphiphile par sublimation avec maîtrise de la diminution de sa masse moléculaire, une composition de copolymère à blocs amphiphile obtenue par ce procédé de purification, et une composition pharmaceutique comprenant ladite composition de copolymère à blocs amphiphile.
PCT/KR2016/008264 2015-07-28 2016-07-28 Procédé de purification d'un copolymère à blocs amphiphile, copolymère à blocs amphiphile obtenu selon ledit procédé, et composition pharmaceutique contenant ledit copolymère WO2017018815A1 (fr)

Applications Claiming Priority (2)

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KR1020150106625A KR101745429B1 (ko) 2015-07-28 2015-07-28 양친성 블록 공중합체의 정제방법, 이로부터 얻어지는 양친성 블록 공중합체, 및 이를 포함하는 약학 조성물
KR10-2015-0106625 2015-07-28

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Cited By (1)

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CN115209879A (zh) * 2019-12-31 2022-10-18 三养控股公司 制备包含低分子量的两亲性嵌段共聚物的纳米颗粒的方法

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US20190231689A1 (en) * 2018-01-29 2019-08-01 Samyang Biopharmaceuticals Corporation Amphiphilic Block Copolymer Composition With Enhanced Micelle Stability

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WO2003033592A1 (fr) * 2001-10-18 2003-04-24 Samyang Corporation Composition de micelle polymere a la stabilite amelioree
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WO2003033592A1 (fr) * 2001-10-18 2003-04-24 Samyang Corporation Composition de micelle polymere a la stabilite amelioree
KR20100097144A (ko) * 2007-12-31 2010-09-02 주식회사 삼양사 고순도의 폴리 알파(α)-히드록시산의 소수성 고분자 블록을 포함하는 양친성 블록 공중합체 및 그의 제조방법
US20140335194A1 (en) * 2011-12-16 2014-11-13 Samyang Biopharmaceuticals Corporation Polymeric nanoparticle solution composition and its manufacturing process

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ROBB, M. J. ET AL.: "Functional block copolymer nanoparticles: toward the next generation of delivery vehicles", POLYM CHEM., vol. 3, no. 6, 2012, pages 1618 - 1628, XP055350956 *

Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN115209879A (zh) * 2019-12-31 2022-10-18 三养控股公司 制备包含低分子量的两亲性嵌段共聚物的纳米颗粒的方法

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