WO2017018818A1 - Pharmaceutical composition with improved storage stability and method for preparing the same - Google Patents

Pharmaceutical composition with improved storage stability and method for preparing the same Download PDF

Info

Publication number
WO2017018818A1
WO2017018818A1 PCT/KR2016/008267 KR2016008267W WO2017018818A1 WO 2017018818 A1 WO2017018818 A1 WO 2017018818A1 KR 2016008267 W KR2016008267 W KR 2016008267W WO 2017018818 A1 WO2017018818 A1 WO 2017018818A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
weight
amount
composition according
formula
Prior art date
Application number
PCT/KR2016/008267
Other languages
English (en)
French (fr)
Inventor
Bong Oh Kim
Kyu Jin Kyung
Ji Yeong Kim
Hye Rim Kim
Bum Chan MIN
Yoo Jeong YOON
Min Hyo Seo
Yil Woong Yi
Original Assignee
Samyang Biopharmaceuticals Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP16830851.8A priority Critical patent/EP3328435A4/en
Priority to CA2993925A priority patent/CA2993925A1/en
Priority to RU2018107057A priority patent/RU2018107057A/ru
Priority to CN201680001948.6A priority patent/CN106659681A/zh
Priority to MX2018001221A priority patent/MX2018001221A/es
Priority to AU2016299546A priority patent/AU2016299546B2/en
Application filed by Samyang Biopharmaceuticals Corporation filed Critical Samyang Biopharmaceuticals Corporation
Priority to BR112018001725A priority patent/BR112018001725A2/pt
Priority to JP2018504241A priority patent/JP2018521103A/ja
Publication of WO2017018818A1 publication Critical patent/WO2017018818A1/en
Priority to IL257188A priority patent/IL257188A/en
Priority to ZA2018/01188A priority patent/ZA201801188B/en
Priority to HK18109127.7A priority patent/HK1249442A1/zh

Links

Images

Classifications

    • 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
    • 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
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K47/06—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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—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
    • A61K9/14—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to a pharmaceutical composition with improved storage stability and a method for preparing the same, and more specifically, a pharmaceutical composition of poorly water-soluble drug comprising an amphiphilic block copolymer wherein the content of a specific related compound is kept within a specified limit, and a method for preparing the same.
  • Solubilization of a poorly water-soluble drug is a key technology for delivering the drug into the body via oral or parenteral administration.
  • Such solubilization methods include a method of adding a surfactant to an aqueous solution to form micelles and then entrapping a poorly water-soluble drug therein.
  • An amphiphilic block copolymer used as a surfactant 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
  • 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.
  • US Patent No. 6,322,805 discloses a composition for delivering a poorly water-soluble drug consisting of a polymeric micelle-type drug carrier and a poorly water-soluble drug, wherein the polymeric micelle-type drug carrier is formed from a diblock or triblock copolymer which is not crosslinked by a crosslinking agent and consists of at least one biodegradable hydrophobic polymer selected from the group consisting of polylactide, polyglycolide, poly(lactide-glycolide), polycaprolactone and derivatives thereof and poly(alkylene oxide) as a hydrophilic polymer, wherein the poorly water-soluble drug is physically entrapped in the drug carrier and solubilized, and wherein the polymeric micelle-type drug carrier forms a clear aqueous solution in water and effectively delivers the poorly water-soluble drug into the body.
  • the polymeric micelle-type drug carrier is formed from a diblock or triblock copolymer which is not crosslinked by a crosslinking agent and consists
  • polyethylene glycol-polylactide diblock copolymer is synthesized by removing moisture from monomethoxypolyethylene glycol, adding stannous octoate dissolved in toluene thereto and removing toluene under reduced pressure, adding D,L-lactide to the resulting mixture and conducting a polymerization reaction, adding chloroform to dissolve the produced block copolymer, dropwise adding an excess amount of diethyl ether in small portions with stirring to form precipitant and filtering the formed precipitant, and washing it several times with diethyl ether.
  • this method is difficult to employ in mass-scale production and thus is not commercially available.
  • the ether that has been used for purification may remain in the final polymeric micelle composition.
  • US Patent No. 8,853,351 discloses a method for preparing an amphiphilic block copolymer, comprising (a) dissolving the amphiphilic block copolymer in a water-miscible organic solvent; (b) adding and mixing an aqueous solution of alkali metal salt (sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or lithium carbonate) to the polymeric solution obtained in step (a); (c) separating organic and aqueous phases by salting out for the solution obtained in step (b); and, (d) isolating the organic phase obtained in step (c) and removing the organic solvent therefrom to recover the polymer.
  • the method involves complicated steps, and requires an additional step for removing the alkali metal salt and the salt (sodium chloride or potassium chloride) used for salting out, and may have residual metal salts even after the removal thereof.
  • Impurities of drug must be strictly controlled in various aspects. Particularly, in case of impurities derived from active pharmaceutical ingredient (API), each country sets in its drug approval guideline the upper limit to amount of API-derived, known or unknown impurities (related compounds) in a drug product. In addition, there are some standards used internationally and ICH guideline Q3A is the representative one. In this guideline, at the time of approving a drug, the amount of each related compound in the drug is limited up to 0.1% or 0.2%, etc. and information such as toxicity-related data, etc., which should be provided, is discriminately applied according to the related compound exceeding the limit.
  • API active pharmaceutical ingredient
  • One purpose of the present invention is to provide a polymeric micelle-type pharmaceutical composition of poorly water-soluble drug comprising an amphiphilic block copolymer, which contains a specific related compound in an amount within a specified limit.
  • the other purpose of the present invention is to provide a method for preparing said pharmaceutical composition.
  • One aspect of the present invention provides a polymeric micelle pharmaceutical composition, comprising: a purified amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B), and one or more poorly water-soluble drugs selected from the group consisting of paclitaxel and docetaxel, wherein the pharmaceutical composition contains, when stored at 40°C for 6 months, a related compound represented by the following Formula 1 in an amount of less than 0.17 part by weight, based on 100 parts by weight of the initial amount of the poorly water-soluble drug:
  • R 1 is H or COCH 3
  • R 2 is phenyl or O(CH 3 ) 3 .
  • Another aspect of the present invention provides a method for preparing a polymeric micelle pharmaceutical composition, comprising: (a) purifying an amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B); (b) dissolving one or more poorly water-soluble drugs selected from the group consisting of paclitaxel and docetaxel, and the purified amphiphilic block copolymer in an organic solvent; and (c) adding an aqueous solvent to the solution obtained in step (b) to form polymeric micelles; wherein the pharmaceutical composition contains, when stored at 40°C for 6 months, a related compound represented by the above Formula 1 in an amount of less than 0.17 part by weight, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.
  • a pharmaceutical composition of poorly water-soluble drug which has reduced related compounds and improved storage stability, can be obtained.
  • Figure 1 is the resulting chromatogram of HPLC analysis for the polymeric micelle composition containing paclitaxel used in Experimental Example 1, which had been subjected to the six-month acceleration test.
  • Figure 2 shows the results of LC/MS/MS analysis for the related compound (RRT 0.87 ⁇ 0.02 (0.85 ⁇ 0.89), with which RRT 0.87 is interchangeably used hereinafter) obtained in Experimental Example 1.
  • Figure 3 shows the results of LC/MS/MS analysis for the material obtained at RRT 0.87 in the mixture obtained by treating paclitaxel with acid in Experimental Example 3.
  • Figure 4 shows the results of product ion scan in the LC/MS/MS analysis for the material obtained at RRT 0.87 in the mixture obtained by treating paclitaxel with acid in Experimental Example 3, together with the results of the six-month acceleration tested sample of the polymeric micelle pharmaceutical composition containing paclitaxel:
  • Figure 5 shows the results of 1 H NMR analysis in the NMR analysis for the material obtained at RRT 0.87 in the mixture obtained by treating paclitaxel with acid in Experimental Example 3.
  • Figure 6 shows the results of 13 C NMR analysis in the NMR analysis for the material obtained at RRT 0.87 in the mixture obtained by treating paclitaxel with acid in Experimental Example 3.
  • Figure 7 shows the results of COSY (Correlation Spectroscopy) analysis in the NMR analysis for the material obtained at RRT 0.87 in the mixture obtained by treating paclitaxel with acid in Experimental Example 3.
  • Figure 8 shows the results of HMBC (Heteronuclear Multiple Bond Correlation Spectroscopy) analysis in the NMR analysis for the material obtained at RRT 0.87 in the mixture obtained by treating paclitaxel with acid in Experimental Example 3.
  • HMBC Heteronuclear Multiple Bond Correlation Spectroscopy
  • Figure 9 is the resulting chromatogram of HPLC analysis conducted in Experimental Example 5.
  • the pharmaceutical composition of an embodiment of the present invention comprises a purified amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B).
  • 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.
  • amphiphilic block copolymer a purified one is used.
  • the amphiphilic block copolymer is one that has been purified by sublimation.
  • the purification by sublimation may be conducted at a temperature of preferably 80°C or higher and lower than 120°C and more preferably 80 to 100°C, and under a pressure of a vacuum degree of preferably 10 torr or less, more preferably 5 torr or less and even more preferably 1 torr or less, for a time of preferably 10 to 74 hours, more preferably 10 to 48 hours and even more preferably 24 to 48 hours. Conducting the purification by sublimation under such conditions can minimize the change in molecular weight of the copolymer and remove impurities therefrom.
  • the pharmaceutical composition of the present invention comprises, as active ingredient, one or more poorly water-soluble drugs selected from the group consisting of paclitaxel and docetaxel.
  • the pharmaceutical composition may further comprise, as additional active ingredient, one or more poorly water-soluble drugs other than paclitaxel and docetaxel.
  • one or more taxane anticancer agents selected from the group consisting of 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, may be used.
  • the pharmaceutical composition of 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 "initial" amount of the poorly water-soluble drug means the weight of the poorly water-soluble drug incorporated when the pharmaceutical composition was prepared.
  • the pharmaceutical composition contains, when stored at the accelerated condition (40°C) for 6 months, a related compound represented by the following Formula 1 in an amount of less than 0.17 part by weight, based on 100 parts by weight of the initial amount of the poorly water-soluble drug:
  • R 1 is H or COCH 3
  • R 2 is phenyl or O(CH 3 ) 3 .
  • the poorly water-soluble drug is paclitaxel
  • the related compound(s) may include the compound represented by the following Formula 1a:
  • the pharmaceutical composition of an embodiment of the present invention may contain, when stored at the accelerated condition (40°C) for 6 months, a related compound of Formula 1 (particularly, Formula 1a) in an amount of less than 0.17 part by weight, preferably 0.15 part by weight or less, more preferably 0.1 part by weight or less, even more preferably 0.08 part by weight or less, and most preferably 0.04 part by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.
  • a related compound of Formula 1 particularly, Formula 1a in an amount of less than 0.17 part by weight, preferably 0.15 part by weight or less, more preferably 0.1 part by weight or less, even more preferably 0.08 part by weight or less, and most preferably 0.04 part by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.
  • the pharmaceutical composition of an embodiment of the present invention may contain, when stored at the severe condition (80°C) for 3 weeks, a related compound of Formula 1 (particularly, Formula 1a) in an amount of less than 0.76 part by weight, preferably 0.5 part by weight or less, more preferably 0.4 part by weight or less, even more preferably 0.2 part by weight or less, and most preferably 0.15 part by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.
  • a related compound of Formula 1 particularly, Formula 1a in an amount of less than 0.76 part by weight, preferably 0.5 part by weight or less, more preferably 0.4 part by weight or less, even more preferably 0.2 part by weight or less, and most preferably 0.15 part by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.
  • the pharmaceutical composition which contains a specific related compound in an amount within a specified limit, is a commercially available composition since it can be produced on a large scale.
  • the pharmaceutical composition of the present invention does not have ether, for example, diethyl ether, at all.
  • the pharmaceutical composition of the present invention does not have metal salt, for example, alkali metal salt and/or salt for salting out, for example, NaCl or KCl, at all.
  • metal salt for example, alkali metal salt and/or salt for salting out, for example, NaCl or KCl, at all.
  • the pharmaceutical composition of an embodiment of the present invention can be prepared by a method comprising (a) purifying an amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B); (b) dissolving one or more poorly water-soluble drugs selected from the group consisting of paclitaxel and docetaxel, and the purified amphiphilic block copolymer in an organic solvent; and (c) adding an aqueous solvent to the solution obtained in step (b) to form polymeric micelles.
  • amphiphilic block copolymer The purification of the amphiphilic block copolymer is explained above, and a conventional method can be used for the formation of the polymeric micelles.
  • a water-miscible organic solvent for example, selected from the group consisting of alcohol (for example, ethanol), 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, physiological 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 method may further comprise lyophilizing the micelle composition with addition of a lyophilization aid.
  • the lyophilization aid may be added for the lyophilized composition to maintain a cake form.
  • the lyophilization aid may be one or more selected from the group consisting of sugar and sugar alcohol.
  • the sugar may be one or more selected from lactose, maltose, sucrose or trehalose.
  • the sugar alcohol may be one or more selected from mannitol, sorbitol, maltitol, xylitol and lactitol.
  • the lyophilization aid may also function to facilitate homogeneous dissolution of the lyophilized polymeric micelle composition upon reconstitution.
  • the lyophilization aid may be contained at an amount of 1 to 90 weight%, particularly, 1 to 60 weight%, more particularly 10 to 60 weight%, based in a total weight of the lyophilized composition.
  • Preparation Example 1 Synthesis of diblock copolymer consisting of monomethoxypolyethylene glycol and D,L - lactide (mPEG- PDLLA ) and purification by sublimation method
  • mPEG monomethoxypolyethylene glycol
  • the reactor was tightly sealed and the polymerization reaction was conducted at 120°C for 10 hours. After the reaction was terminated, under agitation with a magnetic bar, 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.
  • the molecular weight (Mn: ⁇ 3740) was calculated by analyzing with 1 H-NMR obtaining relative intensities of appropriate peaks with reference to -OCH 3 which is the terminal group of monomethoxypolyethylene glycol.
  • Preparation Example 5 Purification of diblock copolymer (mPEG- PDLLA ) by adsorption method using aluminum oxide (Al 2 O 3 )
  • a lyophilization aid 2.5 g of anhydrous lactose was added thereto and dissolved completely, filtered using a filter with a pore size of 200 nm, and freeze-dried to obtain a polymeric micelle composition containing paclitaxel in powder form.
  • Example 1 Preparation of polymeric micelle composition containing paclitaxel
  • a polymeric micelle composition containing paclitaxel was prepared by the same method as in Comparative Example 1.
  • a polymeric micelle composition containing paclitaxel was prepared by the same method as in Comparative Example 1.
  • Nebulizer gas pressure: Nitrogen (35 psi)
  • the substance for analysis which was isolated and came out of the detection stage, was set to flow in the mass spectrometer, and at that time the detected ion of related compound was qualitatively analyzed selecting the characteristic ion of mass spectrum [M+Na].
  • the material obtained at RRT 0.87 by treating paclitaxel with acid showed an HPLC peak at exactly the same position as that of the related compound (RRT: 0.87 ⁇ 0.02 (0.85 ⁇ 0.89)) in the polymeric micelle composition containing paclitaxel of the present invention which had been subjected to the six-month acceleration test.
  • the MS product ion scan of these peaks showed the same pattern, it could be confirmed that the two materials have the same structure.
  • the compound prepared by adding 1N HCl to paclitaxel was isolated and fractionally collected at RRT 0.87, and its structure was analyzed by NMR.
  • NMR analysis the results of 1 H NMR analysis are shown in Figure 5, the results of 13 C NMR analysis are shown in Figure 6, the results of COSY (Correlation Spectroscopy) analysis are shown in Figure 7, and the results of HMBC (Heteronuclear Multiple Bond Correlation Spectroscopy) analysis are shown in Figure 8.
  • the material obtained at RRT 0.87 by treating paclitaxel with acid i.e., the related compound (RRT: 0.87 ⁇ 0.02 (0.85 ⁇ 0.89)) in the polymeric micelle composition containing paclitaxel of an embodiment of the present invention which had been subjected to the six-month acceleration test
  • the related compound (RRT: 0.87 ⁇ 0.02 (0.85 ⁇ 0.89) in the polymeric micelle composition containing paclitaxel of an embodiment of the present invention which had been subjected to the six-month acceleration test was the compound of the following form of the combination of paclitaxel and water.
  • NMR equipment Brucker DRX-300, AVANCE-400 equipped with a temperature controller
  • Probehead Brucker 5 mm QNP or C-H dual probe
  • Probehead Brucker 5 mm QNP or C-H dual probe
  • Probehead Brucker 5 mm inverse probe
  • the polymeric micelle compositions of paclitaxel prepared in Comparative Example 1 and Examples 1 and 2 were kept in an oven at 80°C for 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 9 and the change in the amount of related compound (%) according to the severe test time is shown in the following Table 2.
  • Amount of each related compound (%) 100(Ri/Ru)
  • the above test result shows an average value of the amounts of each related compound and paclitaxel in the test conducted for 3 or more polymeric micelle compositions of different batches.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/KR2016/008267 2015-07-28 2016-07-28 Pharmaceutical composition with improved storage stability and method for preparing the same WO2017018818A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
CA2993925A CA2993925A1 (en) 2015-07-28 2016-07-28 Pharmaceutical composition with improved storage stability and method for preparing the same
RU2018107057A RU2018107057A (ru) 2015-07-28 2016-07-28 Фрамацевтическая композиция с улучшенной устройчивостью при хранении и способ ее получения
CN201680001948.6A CN106659681A (zh) 2015-07-28 2016-07-28 具有改善的储存稳定性的药物组合物及其制备方法
MX2018001221A MX2018001221A (es) 2015-07-28 2016-07-28 Composicion farmaceutica con estabilidad de almacenamiento mejorada y metodo para prepararla.
AU2016299546A AU2016299546B2 (en) 2015-07-28 2016-07-28 Pharmaceutical composition with improved storage stability and method for preparing the same
EP16830851.8A EP3328435A4 (en) 2015-07-28 2016-07-28 PHARMACEUTICAL COMPOSITION WITH IMPROVED STORAGE STABILITY AND METHOD FOR THE MANUFACTURE THEREOF
BR112018001725A BR112018001725A2 (pt) 2015-07-28 2016-07-28 composição farmacêutica com micela polimérica.
JP2018504241A JP2018521103A (ja) 2015-07-28 2016-07-28 保存安定性が向上した医薬組成物及びその製造方法
IL257188A IL257188A (en) 2015-07-28 2018-01-28 Pharmaceutical composition with improved storage stability and method for preparing the same
ZA2018/01188A ZA201801188B (en) 2015-07-28 2018-02-21 Pharmaceutical composition with improved storage stability and method for preparing the same
HK18109127.7A HK1249442A1 (zh) 2015-07-28 2018-07-13 具有改善的儲存穩定性的藥物組合物及其製備方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20150106627 2015-07-28
KR10-2015-0106627 2015-07-28

Publications (1)

Publication Number Publication Date
WO2017018818A1 true WO2017018818A1 (en) 2017-02-02

Family

ID=57885186

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2016/008267 WO2017018818A1 (en) 2015-07-28 2016-07-28 Pharmaceutical composition with improved storage stability and method for preparing the same

Country Status (13)

Country Link
EP (1) EP3328435A4 (zh)
JP (1) JP2018521103A (zh)
KR (1) KR101787451B1 (zh)
CN (1) CN106659681A (zh)
AU (1) AU2016299546B2 (zh)
BR (1) BR112018001725A2 (zh)
CA (1) CA2993925A1 (zh)
HK (1) HK1249442A1 (zh)
IL (1) IL257188A (zh)
MX (1) MX2018001221A (zh)
RU (1) RU2018107057A (zh)
WO (1) WO2017018818A1 (zh)
ZA (1) ZA201801188B (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102144479B1 (ko) * 2018-05-24 2020-08-13 주식회사 덱스레보 조직 수복용 조성물 및 이의 제조방법
KR102251192B1 (ko) * 2020-08-07 2021-05-13 주식회사 덱스레보 조직 수복용 조성물 및 이의 제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003033592A1 (en) * 2001-10-18 2003-04-24 Samyang Corporation Polymeric micelle composition with improved stability
US20110251269A1 (en) * 2008-12-26 2011-10-13 Samyang Corporation Preparation method of polymeric micelles composition containing a poorly water-soluble drug
US8853351B2 (en) * 2007-12-31 2014-10-07 Samyang Biopharmaceuticals Corporation Highly pure amphiphilic copolymer comprising hydrophobic block from alpha-hydroxy acid and process for the preparation thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4049588B2 (ja) * 2000-05-12 2008-02-20 サムヤン コーポレイション ブロック共重合体の相分離による高分子ミセルの製造方法
US7217770B2 (en) * 2000-05-17 2007-05-15 Samyang Corporation Stable polymeric micelle-type drug composition and method for the preparation thereof
ATE487134T1 (de) 2007-03-06 2010-11-15 Cell Therapeutics Europe Srl Verfahren zur bestimmung der menge konjugierten taxans in polyglutaminsäure-taxan-konjugaten
US9801818B2 (en) * 2007-12-31 2017-10-31 Samyang Biopharmaceuticals Corporation Method for stabilizing amphiphilic block copolymer micelle composition containing poorly water-soluble drug
KR101024742B1 (ko) * 2007-12-31 2011-03-24 주식회사 삼양사 탁산 함유 양친성 블록 공중합체 미셀 조성물 및 그 제조방법
CN102218027B (zh) * 2011-04-22 2014-07-02 上海谊众生物技术有限公司 一种包载难溶性抗肿瘤药物的聚合物胶束冻干制剂
CN103768013A (zh) * 2014-01-17 2014-05-07 丽珠医药集团股份有限公司 以精制两亲性嵌段共聚物为载体的紫杉醇聚合物胶束

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003033592A1 (en) * 2001-10-18 2003-04-24 Samyang Corporation Polymeric micelle composition with improved stability
US8853351B2 (en) * 2007-12-31 2014-10-07 Samyang Biopharmaceuticals Corporation Highly pure amphiphilic copolymer comprising hydrophobic block from alpha-hydroxy acid and process for the preparation thereof
US20110251269A1 (en) * 2008-12-26 2011-10-13 Samyang Corporation Preparation method of polymeric micelles composition containing a poorly water-soluble drug

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CIUTARU, D. ET AL.: "A HPLC validated assay of paclitaxel's related impurities in pharmaceutical forms containing Cremophor EL.", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 34, 2004, pages 493 - 499, XP055350129 *
KUMAR, D. ET AL.: "Isolation and characterization of degradation impurities in docetaxel drug substance and its formulation.", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 43, 2007, pages 1228 - 1235, XP005901637 *
See also references of EP3328435A4 *

Also Published As

Publication number Publication date
EP3328435A4 (en) 2019-03-13
AU2016299546A1 (en) 2018-03-08
CA2993925A1 (en) 2017-02-02
HK1249442A1 (zh) 2018-11-02
AU2016299546B2 (en) 2019-05-02
JP2018521103A (ja) 2018-08-02
ZA201801188B (en) 2018-12-19
EP3328435A1 (en) 2018-06-06
IL257188A (en) 2018-03-29
RU2018107057A3 (zh) 2019-08-28
BR112018001725A2 (pt) 2018-09-18
KR20170015199A (ko) 2017-02-08
MX2018001221A (es) 2018-04-24
CN106659681A (zh) 2017-05-10
KR101787451B1 (ko) 2017-10-19
RU2018107057A (ru) 2019-08-28

Similar Documents

Publication Publication Date Title
WO2018110870A1 (ko) 미셀 안정성이 향상된 양친성 블록 공중합체 조성물 및 이를 포함하는 약학 조성물
WO2010074380A1 (en) Preparation method of polymeric micellar nanoparticles composition containing a poorly water-soluble drug
WO2011081406A2 (ko) 단백질, 폴리펩타이드 또는 펩타이드 약물 전달용 고분자 및 그 제조방법, 및 단백질, 폴리펩타이드 또는 펩타이드 약물의 서방형 조성물 및 그 제조 방법
WO2010053242A1 (en) Highly purified polylactic acid or a derivative thereof, a salt of the same, and purification method thereof
WO2017018818A1 (en) Pharmaceutical composition with improved storage stability and method for preparing the same
WO2017018814A1 (en) Method for analyzing related substances of a pharmaceutical composition containing a polymeric carrier
WO2017018816A1 (en) Pharmaceutical composition with improved storage stability and method for preparing the same
US11464861B2 (en) Pharmaceutical composition with improved storage stability and method for preparing the same
WO2017018819A1 (en) Pharmaceutical composition with improved storage stability and method for preparing the same
WO2017018820A1 (en) Pharmaceutical composition with improved storage stability and method for preparing the same
US20170028066A1 (en) Pharmaceutical composition with improved storage stability and method for preparing the same
US20170028067A1 (en) Pharmaceutical composition with improved storage stability and method for preparing the same
WO2023038202A1 (ko) 생분해성 고분자를 이용한 서방형 미립구 및 이의 제조방법
US20170027866A1 (en) Pharmaceutical composition with improved storage stability and method for preparing the same
WO2017018815A1 (en) Process for purifying an amphiphilic block copolymer, amphiphilic block copolymer obtained therefrom, and pharmaceutical composition containing the same
WO2024039187A1 (ko) 피리미딘-4-카복사마이드 화합물의 결정형 및 이를 포함하는 경구용 약학 제제
WO2023249464A1 (ko) 약물과 파모산을 함유하는 서방성 미립구

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16830851

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2993925

Country of ref document: CA

Ref document number: 2018504241

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2018/001221

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 257188

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 11201800767Q

Country of ref document: SG

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2018107057

Country of ref document: RU

Ref document number: 2016830851

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2016299546

Country of ref document: AU

Date of ref document: 20160728

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112018001725

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112018001725

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20180126