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WO2018151258A1 - Support d'administration de médicament et système d'administration de médicament - Google Patents

Support d'administration de médicament et système d'administration de médicament Download PDF

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WO2018151258A1
WO2018151258A1 PCT/JP2018/005505 JP2018005505W WO2018151258A1 WO 2018151258 A1 WO2018151258 A1 WO 2018151258A1 JP 2018005505 W JP2018005505 W JP 2018005505W WO 2018151258 A1 WO2018151258 A1 WO 2018151258A1
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drug
drug delivery
formula
delivery system
bond
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PCT/JP2018/005505
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English (en)
Japanese (ja)
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西山　伸宏
宏泰 武元
高徳 稲葉
貴大 野本
誠 松井
敬士郎 友田
暁夢 劉
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国立大学法人東京工業大学
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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 invention relates to a drug delivery carrier and a drug delivery system.
  • This application claims priority based on Japanese Patent Application No. 2017-029264 filed in Japan on February 20, 2017, the contents of which are incorporated herein by reference.
  • antimetabolites such as gemcitabine and doxyfluridine are mainly used as anticancer agents.
  • gemcitabine is treated as a first-line drug for pancreatic cancer.
  • these drugs have a molecular weight as low as 500 or less, they are rapidly eliminated from the blood due to excretion from the kidney or liver when administered to a patient, and the accumulation efficiency in the tumor tissue, which is an affected area, is low. There is a tendency.
  • Non-Patent Document 1 As a method for controlling the pharmacokinetics of a drug, for example, a method such as encapsulating a drug in a polymer micelle or liposome, or binding a drug to a polymer compound has been studied (for example, see Non-Patent Document 1). ).
  • encapsulating drugs in polymer micelles or liposomes is often applicable only to hydrophobic drugs with high encapsulation efficiency, and it may be difficult to apply to highly hydrophilic drugs such as gemcitabine.
  • the structure of the drug itself is modified in order to facilitate the binding of the drug to the polymer compound, or a chemical bond is used to efficiently release the drug in the affected area. Is being considered.
  • problems such as a decrease in the pharmacological activity of the drug may occur due to structural modification of the drug itself.
  • the present invention overcomes the problems of the technology for binding a drug to a polymer compound described above, and provides a drug delivery technology that can efficiently deliver a drug to tumor tissue without reducing the pharmacological activity of the drug.
  • the purpose is to provide.
  • the present invention includes the following aspects.
  • m and n each represent an integer of 0 or 1, and * represents a bond.
  • [In Formula (2), m and n represent the same values as m and n in Formula (1), respectively, and * represents a bond.
  • the drug delivery carrier according to [1], wherein the group capable of forming an acetal bond is a group represented by the following formula (3).
  • R 1 and R 2 each independently represents an alkyl group having 1 to 3 carbon atoms, and * represents a bond. R 1 and R 2 may be linked to form a ring.
  • [3] The drug delivery carrier according to [1] or [2], wherein the biocompatible polymer is biodegradable.
  • [5] The drug delivery carrier according to any one of [1] to [4], wherein 5 to 500 mol of the group capable of forming an acetal bond is bonded to 1 mol of the biocompatible polymer.
  • the drug delivery carrier according to any one of [1] to [5] and the drug having a diol structure represented by the following formula (1) are bound by an acetal bond represented by the following formula (2):
  • Drug delivery system [In the formula (1), m and n each represent an integer of 0 or 1, and * represents a bond. ]
  • [In Formula (2), m and n represent the same values as m and n in Formula (1), respectively, and * represents a bond. ]
  • [7] The method according to [6], wherein the acetal bond is cleaved in an acidic environment, the diol structure represented by the formula (1) of the drug is regenerated, and the drug is released from the drug delivery system. Drug delivery system.
  • the present invention it is possible to provide a drug delivery technique capable of efficiently delivering a drug to a tumor tissue without reducing the pharmacological activity of the drug.
  • FIG. 10 is a graph showing the results of Experimental Example 4.
  • (A) And (b) is a graph which shows the result of Experimental example 5.
  • FIG. (A) And (b) is a graph which shows the result of Experimental example 6.
  • FIG. (A) And (b) is a graph which shows the result of Experimental example 6.
  • FIG. 10 is a graph showing the results of Experimental Example 7.
  • it is a graph which shows the time-dependent change of the body weight of the mouse
  • it is a graph which shows the measurement result of the total food intake of the mouse
  • (A) to (c) are representative photomicrographs showing the results of hematoxylin / eosin (HE) staining of the small intestine specimens of each group of mice in Experimental Example 8.
  • HE hematoxylin / eosin
  • the present invention provides a biocompatible polymer in which the diol structure of a drug having a diol structure represented by the following formula (1) is bonded to a group capable of forming an acetal bond represented by the following formula (2)
  • a drug delivery carrier comprising:
  • n and n each represent an integer of 0 or 1, and * represents a bond.
  • the drug delivery carrier of this embodiment can also form an acetal bond with the diol structure of a drug having a diol structure represented by the following formula (6).
  • the acetal bond represented by the following formula (7) Is formed.
  • n and n each represent an integer of 0 or 1, and * represents a bond.
  • the inventors focused on the fact that most drugs containing antimetabolites have a sugar skeleton and that many of the sugar skeletons have a diol structure, and this diol structure is used as a drug delivery carrier by acetal bonding.
  • the present invention was completed with the idea of combining drugs.
  • the drug bound to the drug delivery carrier of the present embodiment improves in blood retention and tumor accumulation with increasing molecular weight.
  • the acetal structure is cleaved in an acidic organelle environment having a pH of about 4.0 to 6.0, and the drug is released inside the cell.
  • the drug can exhibit its original pharmacological activity.
  • the low molecular weight drug means a drug having a molecular weight of about 1000 or less.
  • the drug bound to the drug delivery carrier of the present embodiment is released from the drug delivery carrier depending on the intracellular environment such as acidic conditions. For this reason, only the accumulation of the drug in the tumor tissue can be improved without inducing the accumulation of the drug in the normal tissue having a high transporter expression level. As a result, according to the drug delivery carrier of this embodiment, high drug efficacy and low side effects can be achieved.
  • examples of the group capable of forming an acetal bond with the diol structure of the drug include a group represented by the following formula (3).
  • R 1 and R 2 each independently represents an alkyl group having 1 to 3 carbon atoms, and * represents a bond. R 1 and R 2 may be linked to form a ring. ]
  • examples of the group represented by the above formula (3) include groups represented by the following formulas (8) to (10).
  • the drug having a diol structure represented by the above formula (1) or the above formula (6) is not particularly limited as long as it is a drug capable of forming an acetal bond with the group represented by the above formula (3),
  • examples include antimetabolites such as gemcitabine, doxyfluridine, cytarabine, fludarabine and pentostatin; antiviral drugs such as ganciclovir, idoxuridine, trifluridine, ribavirin and entecavir.
  • said antiviral agent has an anticancer effect when delivered to tumor tissue.
  • the biocompatible polymer means a polymer that does not easily exert a bad influence such as a strong inflammatory reaction when administered to a living body.
  • the biocompatible polymer is not particularly limited as long as the effect of the present invention is obtained, and examples thereof include polyethylene glycol (PEG), polyamino acid, polyacrylamide, polyether, polyester, polyurethane, polysaccharide, and copolymers thereof. It is done.
  • the biocompatible polymer may have any group introduced in part in the synthesis process. Examples of such a group include a part of a polymerization initiator.
  • the biocompatible polymer is preferably biodegradable.
  • Biodegradability means a property that can be absorbed or decomposed in vivo.
  • the biocompatible polymer that is biodegradable is not particularly limited as long as the effects of the present invention are obtained, and examples thereof include polyamino acids, polyesters, polynucleotides, polysaccharides, and the like.
  • biocompatible polymer being biodegradable means that at least a part of the biocompatible polymer is biodegradable.
  • biodegradable biocompatible polymers that can be used for the drug delivery carrier of the present embodiment include polyamino acids, polyesters, polynucleotides, polysaccharides, PEG, polyacrylamide, polyethers, polyesters, polyurethanes, Block copolymers with polysaccharides and the like can also be suitably used.
  • Conventional polymers sometimes have a problem of accumulation in a living body when administered to a living body.
  • a biodegradable polymer by using a biodegradable polymer, accumulation in the living body can be suppressed, and side effects can be reduced.
  • the drug delivery carrier of this embodiment preferably has a weight average molecular weight of 2,000 to 200,000, for example, 5,000 to 100,000, such as 10,000 to 50,000. There may be.
  • the drug delivery carrier is produced by combining the drug with the weight average molecular weight of the drug delivery carrier within the above range, the retention of the drug in the blood and the accumulation in the tumor tissue are appropriately improved, In addition, accumulation in normal tissues such as the liver can be prevented. As a result, the drug can be efficiently delivered to the tumor tissue.
  • the weight average molecular weight of the drug delivery carrier a value measured by size exclusion chromatography (SEC) analysis can be used. Specifically, after dissolving or dispersing a drug delivery carrier in a solvent, the drug delivery carrier is passed through a column using a filler having many pores, and the molecular weight is increased or decreased in the column. It is detected by using a differential refractometer, an ultraviolet-visible spectrophotometer, a viscometer, a light scattering detector or the like as a detector. SEC-dedicated devices are widely available on the market and are generally measured by standard polyethylene glycol conversion. The weight average molecular weight in this specification is measured by this standard polyethylene glycol conversion.
  • the drug delivery carrier of this embodiment it is preferable that 5 to 500 mol of the group capable of forming the acetal bond is bonded to 1 mol of the biocompatible polymer described above, for example, 12 to 250 mol. For example, it may be 25 to 125 mol.
  • the present invention provides a drug delivery system in which the above-described drug delivery carrier and a drug having a diol structure represented by the following formula (1) are bound by an acetal bond represented by the following formula (2). I will provide a.
  • n and n each represent an integer of 0 or 1, and * represents a bond.
  • the drug delivery system of the present embodiment is a drug delivery system in which the above-mentioned drug delivery carrier and a drug having a diol structure represented by the following formula (4) are bound by an acetal bond represented by the following formula (5). It may be.
  • the drug delivery system of the present embodiment stably holds a drug at pH 7.4 corresponding to pH in blood, and has a pH of about 4. corresponding to an intracellular acidic organelle environment. In the range of 0 to 6.0, the drug can be released efficiently.
  • the retention of the drug in the blood and the accumulation in the tumor tissue can be improved moderately, and the accumulation in the normal tissue such as the liver can be prevented.
  • the dose of the drug can be reduced, and furthermore, higher pharmacological activity can be exhibited than when the drug is administered with a carrier.
  • the toxicity of the drug can be reduced.
  • the drug having a diol structure represented by the formula (1) or the formula (6) can form an acetal bond with the group represented by the formula (3). If it is a drug, it will not specifically limit, The drug similar to what was mentioned above is mentioned.
  • the drug having the diol structure may be an antimetabolite.
  • Many antimetabolite drugs have a sugar skeleton and often have a diol structure. For this reason, it is easy to apply to the drug delivery system of this embodiment.
  • the acetal bond is cleaved in an acidic environment and the diol structure represented by the formula (1) or the formula (4) of the drug is regenerated.
  • the drug is released.
  • “In an acidic environment” means an intracellular acidic organelle environment, and is an environment having a pH of about 4.0 to 6.0.
  • the drug delivery system according to the present embodiment releases a drug when taken into a cell and placed in an acidic environment. At this time, since the original diol structure of the drug is regenerated, the drug can exhibit its original pharmacological activity.
  • the invention comprises a method of treating a disease comprising administering an effective amount of a drug delivery system to a patient in need of treatment, said drug delivery system comprising a biocompatible polymer,
  • a therapeutic method comprising a drug having a diol structure represented by the following formula (1), wherein the biocompatible polymer and the drug are bonded by an acetal bond represented by the following formula (2).
  • n and n each represent an integer of 0 or 1, and * represents a bond.
  • the disease includes cancer.
  • the biocompatible polymer and the drug having a diol structure represented by the formula (1) are the same as those described above.
  • the invention comprises a method of treating a disease comprising administering an effective amount of a drug delivery system to a patient in need of treatment, said drug delivery system comprising a biocompatible polymer,
  • a therapeutic method comprising a drug having a diol structure represented by the following formula (4), wherein the biocompatible polymer and the drug are bonded by an acetal bond represented by the following formula (5).
  • the disease includes cancer.
  • the biocompatible polymer and the drug having a diol structure represented by the formula (1) are the same as those described above.
  • the present invention is a drug delivery system for treatment of a disease, the drug delivery system comprising a biocompatible polymer and a drug having a diol structure represented by the following formula (1).
  • a drug delivery system is provided in which the biocompatible polymer and the drug are bound by an acetal bond represented by the following formula (2).
  • n and n each represent an integer of 0 or 1, and * represents a bond.
  • the disease includes cancer.
  • the biocompatible polymer and the drug having a diol structure represented by the formula (1) are the same as those described above.
  • the present invention is a drug delivery system for treatment of a disease, the drug delivery system comprising a biocompatible polymer and a drug having a diol structure represented by the following formula (4).
  • a drug delivery system is provided in which the biocompatible polymer and the drug are bound by an acetal bond represented by the following formula (5).
  • the disease includes cancer.
  • the biocompatible polymer and the drug having a diol structure represented by the formula (1) are the same as those described above.
  • the present invention is the use of a drug delivery system for producing a therapeutic agent for a disease, wherein the drug delivery system comprises a biocompatible polymer and a diol structure represented by the following formula (1): The biocompatible polymer and the drug are combined with an acetal bond represented by the following formula (2).
  • n and n each represent an integer of 0 or 1, and * represents a bond.
  • the disease includes cancer.
  • the biocompatible polymer and the drug having a diol structure represented by the formula (1) are the same as those described above.
  • the present invention is the use of a drug delivery system for producing a therapeutic agent for a disease, wherein the drug delivery system comprises a biocompatible polymer and a diol structure represented by the following formula (4): The biocompatible polymer and the drug are bound by an acetal bond represented by the following formula (5).
  • the disease includes cancer.
  • the biocompatible polymer and the drug having a diol structure represented by the formula (1) are the same as those described above.
  • MeO-PEG-poly ( ⁇ -benzyl L-aspartate) (MeO-PEG-PBLA), which is a diblock copolymer of PEG-polyamino acids, was synthesized. Specifically, first, 720 mg of BLA-N-carbohydrate (BLA-NCA) was dissolved in 10 mL of dimethylformamide (DMF). Subsequently, 600 mg of MeO-PEG-NH 2 dissolved in 40 mL of dichloromethane (DCM) was added as a polymerization initiator to the obtained solution, and the mixture was stirred at 35 ° C. for 2 days. All the above operations were performed in an argon atmosphere.
  • BLA-NCA BLA-N-carbohydrate
  • DCM dichloromethane
  • reaction solution was added dropwise to an excess amount (about 30 times volume) of diethyl ether, and the precipitate was suction filtered and dried under reduced pressure to obtain PEG-PBLA as a white solid (1. 02g, 83.8%).
  • the resulting white solid was analyzed by 1 H NMR and gel filtration chromatography to confirm the chemical structure and molecular weight distribution of the product.
  • Mw weight average molecular weight
  • Mn number average molecular weight
  • the polymerization degree of PBLA calculated by 1 H NMR measurement was about 44.
  • MeO-PEG-PAsp (dimethyl acetate), which is a drug delivery carrier represented by the following formula (11), was synthesized by utilizing an aminolysis reaction of the side chain of MeO-PEG-PBLA to the benzyl group. Specifically, first, 500 mg of PEG-PBLA was dissolved in 8 mL of N-methylpyrrolidone (NMP), and 50-fold molar amount of aminoacetaldehydrate dimethylacetal was transferred to another container with respect to the benzyl group of PEG-PBLA. It was. Subsequently, the aminoacetaldehydrate dimethylacetal solution was added dropwise to the PEG-PBLA solution and allowed to react overnight at room temperature. All the above operations were performed in an argon atmosphere.
  • NMP N-methylpyrrolidone
  • MeO-PEG-PAsp (dimethylacetal) has a dimethylylacetal group possessed by dimethylethylacetal and a diol group possessed by gemcitabine, and is represented by the following formula (13).
  • MeO-PEG-PAsp (dimethylacetal)
  • gemcitabine hydrochloride relative to the dimethylacetal group of MeO-PEG-PAsp (dimethylacetal)
  • MeO-PEG- as a reaction catalyst
  • a 1-fold molar amount of paratoluenesulfonic acid monohydrate with respect to the dimethylacetal group of PAsp (dimethylacetal) was dissolved in 10 mL of NMP and reacted at 50 ° C. overnight.
  • MeO-PEG-PAsp (dimethyl ocetal) is a drug delivery system represented by the following formula (13) by a transacetalization reaction between the dimethylacetal group possessed by dimethylacetal and the diol group possessed by gemcitabine. dimethyl (acetal-gemcitabine) was generated. All the above operations were performed in an argon atmosphere.
  • reaction solution was dropped into an excess amount of an aqueous sodium hydrogen carbonate solution to neutralize paratoluenesulfonic acid monohydrate in the system.
  • unreacted gemcitabine hydrochloride in the aqueous solution was removed by ultrafiltration, and lyophilized to obtain a product, MeO-PEG-PAsp (dimethyl acetate-gemcitabine) as a white yellow solid ( 187 mg, 87.4%).
  • the amount of gemcitabine introduced into the product was confirmed by 1 H NMR measurement and calculated to be about 10% by mass.
  • MeO-PEG-PAsp dimethylacetal
  • dimethylacetal which is the drug delivery carrier synthesized in Experimental Example 1
  • the diol group of doxyfluridine the following formula ( The drug delivery system shown in 15), MeO-PEG-PAsp (dimethyl acetic-doxifluridine), was obtained.
  • MeO-PEG-PAsp dimethylacetal
  • MeO-PEG-PAsp dimethylethyl
  • a 1-fold molar amount of paratoluenesulfonic acid monohydrate was dissolved in 4 mL of NMP and reacted at 50 ° C. overnight. All the above operations were performed in an argon atmosphere.
  • reaction solution was dropped into an excess amount of an aqueous sodium hydrogen carbonate solution to neutralize paratoluenesulfonic acid monohydrate in the system.
  • unreacted doxyfluridine in the aqueous solution was removed by ultrafiltration, and lyophilized to obtain MeO-PEG-PAsp (dimethyl acetate-doxifluridine) as a white solid (20.5 mg, 98.4%).
  • the amount of doxyfluridine introduced into the product was confirmed by 1 H NMR measurement and calculated to be about 4% by mass.
  • Example 4 (Drug release test) A drug release test was performed using the drug delivery system synthesized in Experimental Example 2. Specifically, the drug delivery system synthesized in Experimental Example 2 was added to a buffer solution adjusted to pH 7.4 corresponding to blood pH, pH 5.5 corresponding to intracellular acidic organelle environment, and pH 4.2. And incubated at 37 ° C. Subsequently, sampling was performed over time, and gemcitabine released by high performance liquid chromatography (HPLC) was quantified.
  • HPLC high performance liquid chromatography
  • FIG. 1 is a graph showing the results of measuring the amount of gemcitabine released. As a result, it was revealed that the drug delivery system synthesized in Experimental Example 2 is stable at pH 7.4 corresponding to the pH in blood. On the other hand, it was revealed that gemcitabine was efficiently released from the drug delivery system synthesized in Experimental Example 2 at pH 5.5 and pH 4.2 corresponding to the intracellular acidic organelle environment.
  • FIG. 2A is a graph showing the measurement results of the tumor growth rate.
  • “*” indicates that there is a significant difference when the correlation coefficient (p value) is less than 0.05
  • “**” indicates that there is a significant difference when the p value is less than 0.005.
  • "***” indicates that there is a significant difference when the p value is less than 0.001
  • “***” indicates that there is a significant difference when the p value is less than 0.0001.
  • FIG.2 (b) is a graph which shows the measurement result of a weight change rate. In FIG. 2 (a) and (b), the arrow shows the time when the drug was administered.
  • gemcitabine hydrochloride and the drug delivery system were dissolved in 10 mM phosphate buffer so as to be 1 mg / mL and 10 mg / mL, respectively.
  • 5 ⁇ L of Iodine-125 (Perkin Elmer) and 100 ⁇ L of chloramine T aqueous solution (10 mg / mL) were added to 100 ⁇ L of gemcitabine aqueous solution or 100 ⁇ L of drug delivery system aqueous solution and allowed to stand at room temperature for reaction.
  • the reaction time of gemcitabine was 30 minutes, and the reaction time of the drug delivery system was 1 hour.
  • reaction was terminated by adding 100 ⁇ L of a sodium disulfite aqueous solution (20 mg / mL) to each reaction solution.
  • a sodium disulfite aqueous solution (20 mg / mL)
  • 125 I-labeled gemcitabine was purified by an anion exchange column
  • 125 I-labeled drug delivery system was purified by a PD-10 column (manufactured by GE Healthcare).
  • 125 I-labeled gemcitabine and a drug delivery system were each administered to a tumor-bearing model mouse by tail vein injection.
  • the dose of 125 I-labeled gemcitabine was 80 mg / kg, which is the amount used for treatment.
  • the dose of the 125 I-labeled drug delivery system was 20 mg / kg in terms of gemcitabine.
  • each mouse was killed 30 minutes, 2 hours, and 24 hours after administration of the drug.
  • blood and each organ (heart, lung, liver, kidney, spleen, pancreas, stomach, intestine, tumor) were collected.
  • the radioactivity of the collected blood was quantified with a gamma counter to evaluate the retention of gemcitabine in the blood.
  • the radioactivity of each collected organ was quantified with a gamma counter, and the amount of gemcitabine accumulated in each organ was evaluated.
  • FIG. 3 (a) is a graph showing the measurement results of the remaining amount of gemcitabine in the blood.
  • 95% disappeared from the blood in 2 hours after the administration and only 5% remained whereas in the administration of the drug delivery system synthesized in Experimental Example 2, it was about 4 times. It was revealed that 20% of gemcitabine remained in the blood.
  • FIG. 3 (b) is a graph showing the measurement results of the amount of gemcitabine tumor tissue accumulated. As a result, it was revealed that about 3 times as much gemcitabine was accumulated in the tumor tissue as compared with the administration of gemcitabine by administration of the drug delivery system synthesized in Experimental Example 2 at 2 hours after administration. On the other hand, in the administration of the drug delivery system synthesized in Experimental Example 2, no noticeable accumulation of gemcitabine in the liver or the like was confirmed.
  • FIG. 4 (a) is a graph showing the results of measuring the amount of gemcitabine accumulated in each organ when gemcitabine is administered alone.
  • FIG.4 (b) is a graph which shows the result of having measured the accumulation amount to each organ of the gemcitabine administered with the form of the drug delivery system.
  • Example 7 (Toxicity test 1) 4-week-old BALB / c mice were bred for 1 week, then gemcitabine and the drug delivery system synthesized in Experimental Example 2 were administered, and toxicity was evaluated.
  • the dose of gemcitabine was 80 mg / kg.
  • the dose of the drug delivery system synthesized in Experimental Example 2 was 20 mg / kg in terms of gemcitabine.
  • Each drug was administered by daily tail vein administration once a day after the start of the experiment, and changes in the body weight of the mice were observed. Weight loss is one indicator of toxicity.
  • FIG. 5 is a graph showing the results of measuring the weight change rate of each group of mice.
  • the arrow indicates the time when the drug was administered.
  • the weights of all the mice (3 animals) were decreased, and all mice died on the third day from the start of the experiment.
  • weight loss was not confirmed, and no dead mice were confirmed.
  • Example 8 (Toxicity test 2) 4-week-old BALB / c mice were bred for 1 week, then gemcitabine and the drug delivery system synthesized in Experimental Example 2 were administered, and toxicity was evaluated.
  • the concentration of the gemcitabine aqueous solution was 2 mg / mL.
  • the concentration of the aqueous solution in the drug delivery system was 20 mg / mL.
  • the dose of drug in each group was 200 ⁇ L per dose. As a result, the dose per administration was 20 mg / kg body weight in terms of gemcitabine in both the gemcitabine administration group and the drug delivery system administration group.
  • mouth which administered physiological saline was made into the control group.
  • mice After the start of the experiment, the body weight was measured with an electronic balance every time the drug was administered. In addition, the total food intake of mice was measured. Subsequently, the small intestine and spleen were collected on the 3rd day, starting on the 0th day. The collected small intestine was prepared as a specimen by the paraffin embedding method and observed with a microscope after staining with hematoxylin / eosin (HE). In addition, the mass of the spleen was measured.
  • HE hematoxylin / eosin
  • FIG. 6 is a graph showing changes in body weight of mice in each group over time. Statistical significance was calculated by one-way ANOVA (Tukey's multiple comparisons test). As a result, weight loss was not observed in the mice of the control group and the drug delivery system administration group. In contrast, significant weight loss was observed in the mice in the gemcitabine administration group.
  • FIG. 7 is a graph showing the measurement results of the total food intake of mice in each group. Statistical significance was calculated by one-way ANOVA (Tukey's multiple comparisons test). As a result, it was clarified that the total food intake of the mice in the gemcitabine administration group was significantly reduced as compared with the mice in the other groups.
  • FIGS. 8A to 8C are representative photomicrographs showing the results of staining the small intestine of each group of mice with hematoxylin / eosin (HE).
  • 8 (a) is a histological image of the small intestine of the control group
  • FIG. 8 (b) is a histological image of the small intestine of the mouse of the drug delivery system administration group
  • FIG. 8 (c) is a mouse of the gemcitabine administration group. It is a histological image of the small intestine.
  • the scale bar indicates 100 ⁇ m.
  • the part enclosed with a square shows the intestinal crypt of the villi bottom.
  • the intestinal crypt is known as the intestinal gland that contributes to the secretion of various enzymes.
  • FIG. 9 is a graph showing the results of measuring villi length in the small intestine of each group of mice. Statistical significance was calculated by one-way ANOVA (Tukey's multiple comparisons test). As a result, it was revealed that the villi length was significantly decreased in the small intestine of the mice in the gemcitabine administration group compared with the mice in the other groups.
  • mice in the gemcitabine administration group were damaged in the small intestine.
  • the digestive organs especially in the small intestine
  • FIG. 10 is a graph showing the measurement results of the spleen mass of each group of mice. Statistical significance was calculated by one-way ANOVA (Tukey's multiple comparisons test).
  • mice of the gemcitabine administration group had a significantly reduced spleen mass compared to the mice of the other groups.
  • the mass of the spleen is one index for evaluating immunotoxicity. Therefore, this result indicates that immunotoxicity is observed in mice in the gemcitabine administration group.
  • the concentration of the gemcitabine aqueous solution was 2 mg / mL.
  • the concentration of the aqueous solution in the drug delivery system was 20 mg / mL.
  • the dose of drug in each group was 200 ⁇ L per dose. As a result, the dose per administration was 20 mg / kg body weight in terms of gemcitabine in both the gemcitabine administration group and the drug delivery system administration group.
  • mouth which administered physiological saline was made into the control group.
  • the blood was collected on the third day, starting from the experiment start day.
  • the concentration of the gemcitabine aqueous solution was 2 mg / mL.
  • the concentration of the aqueous solution in the drug delivery system was 20 mg / mL.
  • the dose of drug in each group was 200 ⁇ L per dose. As a result, the dose per administration was 20 mg / kg body weight in terms of gemcitabine in both the gemcitabine administration group and the drug delivery system administration group.
  • mouth which administered physiological saline was made into the control group.
  • MeO-PEG-PAsp is a drug delivery system represented by the above formula (13) by a transacetalization reaction between a dimethylacetal group of MeO-PEG-PAsp (dimethylacetal) and a diol group of gemcitabine. dimethyl (acetal-gemcitabine) was generated. All the above operations were performed in an argon atmosphere.
  • reaction solution was added dropwise to 900 mL of a 0.1 M aqueous sodium hydrogen carbonate solution under ice cooling to neutralize paratoluenesulfonic acid monohydrate in the system.
  • unreacted gemcitabine hydrochloride in the aqueous solution was removed by ultrafiltration, and lyophilized to obtain a product, MeO-PEG-PAsp (dimethyl acetate-gemcitabine) as a white yellow solid ( 1400 mg, 55.3%).
  • the amount of gemcitabine introduced into the product was confirmed by 1 H NMR measurement and calculated to be about 27% by mass.
  • MeO-PEG-poly ( ⁇ -benzyl L-aspartate) (MeO-PEG-PBLA), which is a diblock copolymer of PEG-polyamino acids, was synthesized. Specifically, first, 1500 mg of BLA-N-carbohydrate (BLA-NCA) was dissolved in 10 mL of dimethylformamide (DMF). Subsequently, 600 mg of MeO-PEG-NH 2 dissolved in 40 mL of dichloromethane (DCM) was added as a polymerization initiator to the obtained solution, and the mixture was stirred at 35 ° C. for 3 days. All the above operations were performed in an argon atmosphere.
  • BLA-NCA BLA-N-carbohydrate
  • DCM dichloromethane
  • reaction solution was added dropwise to an excess amount (about 30 times volume) of diethyl ether, and the precipitate was suction filtered and dried under reduced pressure to obtain PEG-PBLA as a white solid (1. 42g, 78.8%).
  • the resulting white solid was analyzed by 1 H NMR and gel filtration chromatography to confirm the chemical structure and molecular weight distribution of the product.
  • Mw weight average molecular weight
  • Mn number average molecular weight
  • the polymerization degree of PBLA calculated by 1 H NMR measurement was about 98.
  • MeO-PEG-PAsp (dimethyl acetal), which is a drug delivery carrier represented by the above formula (11), was utilized in Experimental Example 1 by utilizing an aminolysis reaction to the benzyl group of the side chain of MeO-PEG-PBLA. It was synthesized by the same method. Specifically, first, 200 mg of PEG-PBLA was dissolved in 4 mL of N-methylpyrrolidone (NMP), and 50-fold molar amount of aminoacetaldehydrate dimethylacetal was transferred to another container with respect to the benzyl group of PEG-PBLA. It was. Subsequently, the aminoacetaldehydrate dimethylacetal solution was added dropwise to the PEG-PBLA solution and allowed to react overnight at room temperature. All the above operations were performed in an argon atmosphere.
  • NMP N-methylpyrrolidone
  • MeO-PEG-PAsp (dimethylacetal)
  • 10 times molar amount of gemcitabine hydrochloride with respect to the dimethylacetal group of MeO-PEG-PAsp (dimethylacetal)
  • MeO-PEG- as a reaction catalyst
  • a 1-fold molar amount of paratoluenesulfonic acid monohydrate with respect to the dimethylacetal group of PAsp (dimethylacetal) was dissolved in 8 mL of DMF and reacted at 50 ° C. overnight.
  • MeO-PEG-PAsp (dimethyl) is a drug delivery system represented by formula (13) by transacetalization reaction between the dimethylacetal group of MeO-PEG-PAsp (dimethylacetal) and the diol group of gemcitabine. acetal-gemcitabine) was generated. All the above operations were performed in an argon atmosphere.
  • reaction solution was dropped into an excess amount of an aqueous sodium hydrogen carbonate solution to neutralize paratoluenesulfonic acid monohydrate in the system.
  • unreacted gemcitabine hydrochloride in the aqueous solution was removed by ultrafiltration, and lyophilized to obtain a product, MeO-PEG-PAsp (dimethyl acetate-gemcitabine) as a white yellow solid ( 82 mg, 72.5%).
  • the amount of gemcitabine introduced into the product was confirmed by 1 H NMR measurement and calculated to be about 14% by mass.
  • the present invention it is possible to provide a drug delivery technique capable of efficiently delivering a drug to a tumor tissue without reducing the pharmacological activity of the drug.

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Abstract

La présente invention concerne un support d'administration de médicament comprenant un polymère biocompatible auquel est lié un groupe apte à former une liaison acétal représentée par la formule (2) (dans la formule 2, m et n représentent chacun un nombre entier de 0 ou 1, et * représente une liaison) avec une structure diol d'un médicament ayant une structure diol représentée par la formule (1) (dans la formule (1), m et n représentent chacun les mêmes valeurs que m et n dans la formule (2), et * représente une liaison).
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WO2019163942A1 (fr) * 2018-02-22 2019-08-29 公益財団法人川崎市産業振興財団 Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle

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WO2011010714A1 (fr) * 2009-07-23 2011-01-27 国立大学法人東京大学 Polymère anionique, complexe polyions utilisant un polymère anionique, composite de polymère ternaire, et composition pharmaceutique
US20160022824A1 (en) * 2014-07-24 2016-01-28 University-Industry Foundation, Yonsei University Nanoparticle comprising hydrophobic drug conjugated to cationic polymer and hydrophilic drug conjugated to anionic polymer
US20160250245A1 (en) * 2013-10-21 2016-09-01 INSERM (Institut National de la Santé et de la Recherche Médicale Methods and Pharmaceutical Composition for the Treatment of Polyomavirus Infections
JP2016531921A (ja) * 2013-09-06 2016-10-13 バイオコンパティブルズ ユーケー リミテッド 放射線不透過性ポリマー

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WO2011010714A1 (fr) * 2009-07-23 2011-01-27 国立大学法人東京大学 Polymère anionique, complexe polyions utilisant un polymère anionique, composite de polymère ternaire, et composition pharmaceutique
JP2016531921A (ja) * 2013-09-06 2016-10-13 バイオコンパティブルズ ユーケー リミテッド 放射線不透過性ポリマー
US20160250245A1 (en) * 2013-10-21 2016-09-01 INSERM (Institut National de la Santé et de la Recherche Médicale Methods and Pharmaceutical Composition for the Treatment of Polyomavirus Infections
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WO2019163942A1 (fr) * 2018-02-22 2019-08-29 公益財団法人川崎市産業振興財団 Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle

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