[go: up one dir, main page]

WO2010058669A1 - Nouveau dérivé de prostaglandine e1 et nanoparticules dans lesquelles est encapsulé ce dérivé - Google Patents

Nouveau dérivé de prostaglandine e1 et nanoparticules dans lesquelles est encapsulé ce dérivé Download PDF

Info

Publication number
WO2010058669A1
WO2010058669A1 PCT/JP2009/067885 JP2009067885W WO2010058669A1 WO 2010058669 A1 WO2010058669 A1 WO 2010058669A1 JP 2009067885 W JP2009067885 W JP 2009067885W WO 2010058669 A1 WO2010058669 A1 WO 2010058669A1
Authority
WO
WIPO (PCT)
Prior art keywords
derivative
pge1
prostaglandin
lactic acid
poly
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2009/067885
Other languages
English (en)
Japanese (ja)
Inventor
水島　徹
雅巳 大塚
良成 岡本
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LTT Bio Pharma Co Ltd
Original Assignee
LTT Bio Pharma Co Ltd
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
Application filed by LTT Bio Pharma Co Ltd filed Critical LTT Bio Pharma Co Ltd
Priority to JP2010539189A priority Critical patent/JPWO2010058669A1/ja
Priority to EP09827450A priority patent/EP2361918A1/fr
Priority to US13/129,729 priority patent/US20110262548A1/en
Priority to CN2009801457967A priority patent/CN102216310A/zh
Publication of WO2010058669A1 publication Critical patent/WO2010058669A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

Definitions

  • the present invention relates to a novel prostaglandin E1 (PGE1) derivative and nanoparticles encapsulating the same.
  • Prostaglandins are a group of physiologically active substances having a prostanoic acid skeleton, and are one of the eicosanoids biosynthesized from arachidonic acid and have various strong physiological activities.
  • Various prostaglandin derivatives have been known so far.
  • PGE1 prostaglandin E1
  • PGE1 has a strong vasodilatory action, platelet aggregation action, and therapeutic action for chronic arterial occlusion based on these actions.
  • the present applicant has also synthesized several PGE1 derivatives and studied their pharmacological actions. For example, as one of them, development of a prodrug of PGE1 in which PGE1 is esterified to increase fat solubility.
  • a PGE1 derivative represented by code number AS013 is provided (Patent Document 1).
  • This AS103 is a compound designed to be efficiently converted into PGE1 in vivo, and is a prodrug of PGE1, so that vascular expansion action, platelet aggregation action, and chronic arterial occlusion possessed by PGE1 It is known to have an action and the like. It is also known that AS013 has an angiogenesis promoting action.
  • a lipoformation preparation in which AS013 is embedded in fat particles is also provided, and such lipoformation preparation has excellent affinity and accumulation of AS013 locally. Since it is gradually converted to PGE1, it is a preparation excellent in sustaining action (Patent Document 2).
  • the present invention provides a PGE1 derivative excellent in the sustained action and sustained release of the action of PGE1, and further nanoparticulates the PGE1 derivative to efficiently target the affected area, and has excellent drug sustained release, and It is an object of the present invention to provide PGE1 derivative-containing nanoparticles with reduced side effects.
  • n an integer of 1 to 12
  • a more preferred present invention is a prostaglandin E1 derivative represented by the formula (I) wherein n is 2 in the above formula.
  • the present invention also provides a nanoparticle containing a prostaglandin E1 derivative represented by the above formula (I) as a second basic embodiment, and more specifically, a prosthesis represented by the formula (I).
  • the glandin E1 derivative is hydrophobized with a metal ion, and this is converted into a poly L-lactic acid or poly (L-lactic acid / glycolic acid) copolymer, and a poly DL- or L-lactic acid-polyethylene glycol block copolymer or poly (DL Prostaglandin E1 derivative-containing nanoparticles obtained by reacting with-or L-lactic acid / glycolic acid) -polyethylene glycol block copolymer.
  • the present invention is the above-mentioned prostaglandin E1 derivative-containing nanoparticle comprising further mixing a basic low molecular compound and further incorporating a surfactant, and the metal ion is a zinc ion , Iron ions, copper ions, nickel ions, beryllium ions, manganese ions or cobalt ions, or a prostaglandin E1 derivative-containing nanoparticle.
  • the polyDL- or L-lactic acid-polyethylene glycol block copolymer or the poly (DL- or L-lactic acid / glycolic acid) -polyethylene glycol block copolymer has a weight average molecular weight of 3, Prostaglandin E1 derivative-containing nanoparticles having a molecular weight of 000 to 30,000.
  • the basic low-molecular compound is (dimethylamino) pyridine, pyridine, piperidine, pyrimidine, pyrazine, pyridazine, quinoline, quinuclidine, isoquinoline, bis (dimethylamino) naphthalene, naphthylamine, morpholine, amantadine, aniline, spermine.
  • the surfactant may be phosphatidylcholine, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20 ) Sorbitan monopalmitate, polyoxyethylene (20) sorbitan trioleate, polyoxyethylene (80) octylphenyl ether, polyoxyethylene (20) cholesterol ester, lipid-polyethylene glycol, polyoxyethylene hydrogenated castor oil and fatty acid-polyethylene Prostaglandin E1 derivative-containing nanoparticles that are one or more selected from glycol copolymers.
  • the most preferred present invention is a prostaglandin E1 derivative-containing nanoparticle having a particle diameter of 20 to 300 nm.
  • a PGE1 derivative as a prodrug which is excellent in sustaining the action of PGE1 and is effectively converted to PGE1.
  • the PGE1 derivative provided by the present invention can be synthesized by a simpler means than PGE1, the conversion to PGE1 is easy, the conversion is sustained, and the storage stability is excellent. Therefore, it is extremely specific in that it exhibits a sustained-release PGE1 action.
  • the PGE1 derivative provided by the present invention can be easily converted into a hydrophobic metal salt, poly L-lactic acid or poly (L-lactic acid / glycolic acid) copolymer, and poly DL- or L -It is possible to form nanoparticles using a lactic acid-polyethylene glycol block copolymer or a poly (DL- or L-lactic acid / glycolic acid) -polyethylene glycol block copolymer.
  • the obtained nanoparticles are extremely stable, and the PGE1 derivative remains in the particles for a long period of time. Therefore, the nanoparticles provided by the present invention are extremely effective in that they are excellent in sustained drug release, and as a result, the action of PGE1 can be sustained.
  • C2, C3, C4, C6, C8 and C12 are PGE1 (C2) PONa, PGE1 (C3) PONa, PGE1 (C4) PONa, PGE1 (C6) PONa, PGE1 (C8) PONa and PGE1, respectively.
  • (C12) represents PONa.
  • PGE1 phosphate ester derivative of PGE1 represented by the above formula (I).
  • PGE1 derivatives have been provided so far, but the present invention is the first to provide them as phosphate ester derivatives. Therefore, these PGE1 derivatives are also novel compounds.
  • the PGE1 derivative provided by the present invention that is, the phosphate ester derivative of PGE1 can be prepared by the following production method. If the preparation method is described by a chemical reaction formula, it can be summarized by the following chemical formula.
  • n an integer of 1 to 12
  • THP represents a tetrahydropyranyl group
  • Bn represents a benzyl group. Also, (a) to (f) represent each step.
  • one hydroxyl group (OH group) of the corresponding alkanediol compound (II) is reacted with 3,4-dihydro-2H-pyran and aluminum chloride and protected with a tetrahydropyranyl group (THP group).
  • THP group tetrahydropyranyl group
  • the thus obtained compound (V) is used to esterify PGE1 and induce it to the desired phosphate ester derivative of PGE1 of the present invention.
  • Such induction is performed as follows. That is, the compound (V) and the PGE1 compound (VI) are used using, for example, EDC [1-ethyl-3- (3-dimethylaminopropyl) carbodiimide] hydrochloride as the condensing agent and using 4-dimethylaminopyridine as the base. And condensed to give compound (VII) [step d].
  • the tetrahydropyranyl group of the obtained compound (VII) is deprotected with acetic acid in a suitable solvent, for example, a tetrahydrofuran-water mixture to obtain a compound (VIII) [step e], and finally the compound ( The reductive deprotection of the benzyl group of VIII) is followed by conversion to sodium phosphate with sodium acetate leading to the desired PGE1 derivative (I) of the present invention [step f].
  • a suitable solvent for example, a tetrahydrofuran-water mixture
  • the debenzylation of compound (VIII) to the PGE1 derivative of formula (I), which is the target compound of the present invention is, for example, catalytic reduction in 1,4-cyclohexene / acetic acid using 10% palladium-carbon. Can be performed.
  • reaction conditions of steps (a) to (f) in the preparation method of the PGE1 derivative represented by the formula (I) of the present invention described above apply various conditions described in general textbooks of various chemistry. Can be done.
  • Examples of the PGE1 derivative of the present invention thus prepared include the following.
  • the PGE1 derivative of the present invention prepared as described above was easily converted into PGE1 itself in the body and effectively exhibited the vasodilatory action, platelet aggregation action, etc. possessed by PGE1 (implementation to be described later) See example).
  • the present invention is also nanoparticles encapsulating the PGE1 derivative prepared above.
  • such nanoparticles are prepared as follows. That is, conventionally, a drug is applied to microparticles or nanoparticles of a lactic acid / glycolic acid copolymer (hereinafter sometimes referred to as “PLGA”) or a lactic acid polymer (hereinafter sometimes referred to as “PLA”).
  • PLGA lactic acid / glycolic acid copolymer
  • PLA lactic acid polymer
  • biodegradable polymers are also preferably used in the preparation of the nanoparticles of the present invention. Among these, poly DL- or L-lactic acid-polyethylene glycol block copolymers (DL-forms are referred to as PDLLA).
  • L-isomer may be referred to as PLLA-PEG) or poly (DL- or L-lactic acid / glycolic acid) -polyethylene glycol block copolymer (DL-isomer is PDLLGA-PEG, L-isomer is PLLGA- PEG) may also be poly DL-lactic acid (sometimes called PDLLA) or poly L-lactic acid (sometimes called PLLA) or poly (DL-lactic acid / glycolic acid) copolymer (PDLLGA).
  • PDLLA poly DL-lactic acid
  • PLLA poly L-lactic acid
  • PDLLGA poly (DL-lactic acid / glycolic acid) copolymer
  • poly (L-lactic acid / glycolic acid) copolymer also referred to as PLLGA
  • PLLGA poly (L-lactic acid / glycolic acid) copolymer
  • a copolymer obtained by reacting block A) and polyethylene glycol (sometimes called PEG) (also called block B) under a condensing agent such as ethylenedimethylaminopropylcarbodiimide it is preferable to form particles.
  • these copolymers can be synthesize
  • the object of the present invention can be achieved regardless of whether the block copolymer is of the AB type, ABA type, or BAB type.
  • the weight average molecular weight of these block copolymers is preferably 3,000 to 30,000.
  • the nanoparticle provided by the present invention is prepared by hydrophobizing a PGE1 derivative represented by the formula (I) with a metal ion, and converting the hydrophobized PGE1 derivative to poly (L-lactic acid) or poly (L-lactic acid / Glycolic acid) copolymer, and poly DL- or L-lactic acid-polyethylene glycol block copolymer or poly (DL- or L-lactic acid / glycolic acid) -polyethylene glycol block copolymer. it can.
  • the PGE1 derivative represented by the formula (I) and a metal ion are mixed in an organic solvent or a water-containing organic solvent to form a hydrophobic drug, and poly L-lactic acid or poly ( L-lactic acid / glycolic acid) copolymer, and further added with poly DL- or L-lactic acid-polyethylene glycol block copolymer or poly (DL- or L-lactic acid / glycolic acid) -polyethylene glycol block copolymer and stirred. It can be prepared by adding and diffusing this solution in water.
  • poly L-lactic acid or poly (L-lactic acid / glycolic acid) copolymer poly DL- or L-lactic acid-polyethylene glycol block copolymer or poly (DL- or L-lactic acid / glycolic acid) -polyethylene Similar nanoparticles can be prepared by simultaneously adding and mixing a solution in which a glycol block copolymer is dissolved in a solvent, an aqueous solution of the PGE1 derivative represented by the formula (I), and an aqueous metal ion solution.
  • the metal ion used is any one of zinc ion, iron ion, copper ion, nickel ion, beryllium ion, manganese ion and cobalt ion, and one or more of these water-soluble metal salts are used.
  • zinc ions and iron ions are preferable, and zinc chloride, iron chloride and the like can be preferably used.
  • Solvents used in the above reaction include organic solvents such as acetone, acetonitrile, ethanol, methanol, propanol, dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, and water-containing solvents thereof, acetone, dimethylformamide, dioxane, Tetrahydrofuran is preferred.
  • the encapsulation rate of the PGE1 derivative in the nanoparticles is increased, and it can be encapsulated to about 10%. it can.
  • Such basic low molecular weight compounds include (dimethylamino) pyridine, pyridine, piperidine, pyrimidine, pyrazine, pyridazine, quinoline, quinuclidine, isoquinoline, bis (dimethylamino) naphthalene, naphthylamine, morpholine, amantadine, aniline, spermine, spermidine , Hexamethylenediamine, putrescine, cadaverine, phenethylamine, histamine, diazabicyclooctane, diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, ethylamine, diethylamine, triethylamine, methylamine, dimethylamine, trimethylamine, triethylenediamine, diethylenetriamine, Examples include ethylenediamine and trimethylenediamine. Details, a secondary or tertiary amine, diethanolamine being particularly preferred.
  • a surfactant may be further added to the nanoparticles containing the PGE1 derivative represented by the formula (I) thus prepared.
  • a surfactant By adding a surfactant, the generated nanoparticles are stabilized, and the interparticle Aggregation can be suppressed. Therefore, it becomes a preferable thing for the formulation process of the formulation containing nanoparticles.
  • Surfactants used include phosphatidylcholine, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan Monopalmitate, polyoxyethylene (20) sorbitan trioleate, polyoxyethylene (80) octylphenyl ether, polyoxyethylene (20) cholesterol ester, lipid-polyethylene glycol, polyoxyethylene hydrogenated castor oil and fatty acid-polyethylene glycol A polymer etc. can be mention
  • the particle diameter of the particle is in the range of 20 to 300 nm, preferably 50 to 200 nm, and each drug is applied to the target target affected area. Depending on the particle size can be determined.
  • the nanoparticle containing the PGE1 derivative represented by the formula (I) of the present invention thus prepared is prepared by operating a solution or suspension of the nanoparticle by centrifugation, ultrafiltration, gel filtration, filter filtration, fiber dialysis, etc. After being appropriately purified by lyophilization, it is obtained and stored by lyophilization.
  • a stabilizer and / or a dispersing agent in order to resuspend the lyophilized preparation so that it can be administered, and then lyophilized.
  • a stabilizer and / or a dispersing agent are preferably used.
  • Nanoparticles containing the PGE1 derivative represented by the formula (I) provided by the present invention are preparations for parenteral administration such as intravenous injection preparations, topical injection preparations, nasal drops, eye drops, inhalants, sprays and the like.
  • parenteral administration such as intravenous injection preparations, topical injection preparations, nasal drops, eye drops, inhalants, sprays and the like.
  • the characteristics and effects of the nanoparticles can be better exhibited.
  • Examples of the base and other additive components used for the preparation of these parenteral preparations include various bases and additive components that are pharmaceutically acceptable and used. Specifically, saccharides such as physiological saline, monosaccharides, disaccharides, sugar alcohols, polysaccharides; polymer additives such as hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose; ionic or nonionic surfactants; Etc. can be appropriately selected and used depending on the dosage form.
  • saccharides such as physiological saline, monosaccharides, disaccharides, sugar alcohols, polysaccharides
  • polymer additives such as hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose
  • ionic or nonionic surfactants Etc.
  • Example 2 Conversion of various PGE1 derivatives to PGE1 by enzyme and serum treatment
  • the various PGE1 derivatives synthesized in Example 1 were treated with porcine liver-derived esterase (PLE), human placenta-derived alkaline phosphatase (ALP), and human serum.
  • the conversion rate to PGE1 and intermediates was measured using HPLC.
  • AS103 which is an ester derivative of PGE1, was also carried out as a control.
  • the conversion rate was set to 100% when the PGE1 derivative before the reaction was completely converted to PGE1.
  • the specific method is as follows.
  • the solution was loaded onto a C18 reverse phase cartridge column (SepPack C-18), washed with 6 mL of ultrapure water, and then eluted with 3 mL of acetonitrile.
  • the eluate was mixed with an equal volume of 0.2 mg / mL 9-anthryldiazomethane (ADAM) in acetone and incubated at 37 ° C. for 18 hours in the dark. After the incubation, the amount of PGE1 contained in the sample was changed to Super- Measurement was performed using an ODS column and a fluorescence detector.
  • ADAM 9-anthryldiazomethane
  • PGE1 derivative was mixed with 1 ⁇ L of 100 mM ethanol solution, 0.75 ⁇ L of porcine liver-derived esterase (PLE) solution, and 98.25 ⁇ L of 0.1 M Tris-HCl (pH 7.4), and incubated at 37 ° C. Thereafter, an equal amount of methanol was added, and protein removal was performed on ice for 30 minutes. Subsequently, centrifugation was performed at 4 ° C., 13200 rpm for 10 minutes, and 150 ⁇ L of the supernatant was dried with a centrifugal concentrator.
  • PLE porcine liver-derived esterase
  • the PGE1 derivative was mixed with 1 ⁇ L of a 100 mM ethanol solution, 1 ⁇ L of human placenta-derived alkaline phosphatase (ALP) solution, and 98 ⁇ L of 0.1 M Tris-HCl (pH 7.4), and incubated at 37 ° C. Thereafter, an equal amount of methanol was added, and protein removal was performed on ice for 30 minutes. Subsequently, the mixture was centrifuged at 4 ° C., 13200 rpm for 10 minutes, and the supernatant was analyzed by HPLC.
  • HPLC conditions The conditions of HPLC analysis in the above are as follows [HPLC conditions]
  • the HPLC used the Waters Alliance HPLS system and the software used Empower.
  • the pump and autosampler used 2795 Separation module, the detector used 2996 Photodiode Array detector, and the column used 4.6 ⁇ 100-mm (2-um) TSKgel super-ODS column.
  • Mobile phase A was acetonitrile
  • mobile phase B was a 5 mM ammonium acetate solution.
  • the sample was separated under conditions where mobile phase A was ramped to 1 minute at 25%, then 25-60% in 7 minutes, then 60-100% in 5 minutes, and held at 100% for 7 minutes.
  • the flow rate was 0.5 mL / min, the sample injection amount was 10 ⁇ L, and the detection wavelength was 195 nm.
  • FIG. 1 shows the conversion rate to PGE1 and intermediate when treated with porcine liver-derived esterase (PLE)
  • FIG. 2 shows the conversion rate to PGE1 and intermediate when treated with human placenta-derived alkaline phosphatase (ALP).
  • FIG. 3 shows the conversion rate to PGE1 and intermediates when treated with human serum.
  • Example 3 Effect of PGE1 Derivatives on Platelet Aggregation Induced by ADP (Adenosine Diphosphate)
  • ADP adenosine diphosphate
  • PRP platelet-rich fraction
  • ADP adenosine diphosphate
  • the concentration of PGE1 derivative that inhibits aggregation by 50% was determined by setting the aggregation induced when physiological saline was used as 100%.
  • AS103 which is an ester derivative of PGE1
  • the specific method is as follows. [Platelet treatment] Blood was obtained from healthy individuals who had not taken the drug for more than a week using 3.8% sodium citrate (1/9 volume of blood) as an anticoagulant. The blood was centrifuged at 1000 rpm for 15 minutes to obtain platelet-rich plasma (PRP). The remaining blood was centrifuged at 3000 rpm for 10 minutes to obtain platelet-poor plasma (PPP). Incubation of 215 ⁇ L of PRP at 37 ° C. for 1 minute and addition of 10 ⁇ L of sample followed by addition of 25 ⁇ L of 20 ⁇ L ADP induced aggregation.
  • PRP platelet-rich plasma
  • PPP platelet-poor plasma
  • the specific method is as follows. [Measurement of blood flow] Under the anesthesia of Wister male rats, the footpad skin blood flow was measured by the laser Doppler method, and the PGE1 derivative was administered from the tail vein. The sample dose was 10 nmol / kg. The change in blood flow was observed at 0 minutes after sample administration.
  • FIG. 5 shows changes in blood flow in the rat.
  • the blood flow is sustained in the PGE1 derivative represented by the formula (I) of the present invention.
  • FIG. 6 shows the conversion rate of PGE1 derivatives into PGE1 over time in rat plasma and human serum. The above results are also understood from the fact that the conversion to PGE1 is sustained. Is.
  • Example 5 Synthesis of PLA-PEG used for preparation of nanoparticles 2 g of PEG, 2 to 6 g of dl-Lactide and tin octylate (0.5% by weight) were placed in a polymerization tube, mixed well, and then hydraulically pumped. I was degassed. The mixture was dissolved by heating at 125 ° C. in an oil bath, heated to 160 ° C. and reacted for 3 to 5 hours. The reaction product was cooled and dissolved in about 20 mL of dichloromethane.
  • Example 6 Preparation method of nanoparticles Particles were prepared by an oil-in-water solvent diffusion method.
  • PLLA was used in 1,4-dioxane
  • PEG-PLA and DEA diethanolamine
  • zinc chloride and PGE1 derivative were used in ultrapure water.
  • the total amount of PLLA and PEG-PLA was 25 mg. 22.5 ⁇ L of PLLA solution, 27.5 ⁇ L of PEG-PLA solution, 20.3 ⁇ L of 1M zinc chloride aqueous solution, and 14.3 ⁇ L of PGE1 derivative aqueous solution were mixed in this order and incubated at room temperature for 10 minutes.
  • the mixture obtained while stirring 25 mL of ultrapure water at 1000 rpm was added dropwise at a rate of 48 mL / hour through a 26 G syringe needle.
  • 500 ⁇ L of 0.5 M aqueous sodium citrate (pH 7.4) and 12.5 ⁇ L of 200 mg / mL Tween 80 aqueous solution were added to chelate excess zinc ions and stabilize the diffusion of particles.
  • the suspension of particles was concentrated by ultrafiltration using Centriprep YM-50, and concentrated by adding 50 mM EDTA (pH 7) and ultrapure water to purify the particles.
  • the amount of PGE1 derivative encapsulated in the particles was measured by reacting with ADAM using a Super-ODS column and a fluorescence detector.
  • the encapsulation rate of the PGE1 derivative in the particles was defined as the weight ratio of the PGE1 derivative to the total weight of the particles.
  • the particle size and its distribution were measured by a dynamic light diffusion method. The results are shown in Table 3 below.
  • the measurement of the encapsulation amount of the PGE1 derivative in the nanoparticles is as follows.
  • Method for measuring the amount of PGE1 in particles The amount of PGE1 in the particles was measured as follows. 50 ⁇ L of the particle suspension was dried with a centrifugal concentrator. The dried particles were dissolved in 150 ⁇ L of 1,4-dioxane. Subsequently, 150 ⁇ L of 60 ⁇ g / mL 3-phenylpropionate was added as an internal standard material, and 1.7 mL of 50 mM EDTA (pH 3.6) was added. After 20 minutes, the solution was loaded onto a C18 reverse phase cartridge column (SepPack C-18).
  • elution was performed with 4.5 mL of acetonitrile.
  • the eluate was mixed with an equal volume of 0.2 mg / mL 9-anthryldiazomethane (ADAM) in acetone and incubated at 37 ° C. for 18 hours in the dark. After incubation, the amount of PGE1 was measured using a Super-ODS column and a fluorescence detector.
  • the encapsulation rate of PGE1 in the particles was defined as the ratio of the weight of PGE1 to the total weight of the particles.
  • the HPLC measurement of PGE1-ADAM was performed as follows.
  • the HLPC used the Waters Alliance HPLS system and the software used Empower.
  • the pump and autosampler used 2795 Separation module, the detector used 2996 Photodiode Array detector and 2475 Multi ⁇ Fluorescence Detector, and the column used 4.6 ⁇ 100-mm (2 um) TSKgel super-ODS column.
  • Mobile phase A was acetonitrile
  • mobile phase B was ultrapure water.
  • the sample was separated under the condition that the mobile phase A was gradient at 65% for 25 minutes and then 65-100% in 10 minutes and kept at 100% for 10 minutes.
  • the flow rate was 0.3 mL / min, the sample injection amount was 5 ⁇ L, the excitation wavelength was 365 nm, and the detection wavelength was 412 nm.
  • FIG. 7 shows the particle diameter when PLA (molecular weight 5000: PLA05), PLLA (molecular weight 5000: PLLA05) and PLLA (molecular weight 20000: PLLA20) is used as a base
  • FIG. 8 shows the encapsulation rate of the PGE1 derivative
  • FIG. 9 shows the results of an in vivo release test. As can be seen from the results, when PLLA is used as a base, the obtained nanoparticles are found to exhibit a good particle size, drug encapsulation rate, and sustained release.
  • FIG. 10 shows pH at the time of particle production under various conditions
  • FIG. 11 shows the particle diameter of the produced particle
  • FIG. 12 shows the encapsulation rate of the PGE1 derivative.
  • FIG. 13 shows the particle diameters of the various nanoparticles obtained
  • FIG. 14 shows the encapsulation rate of the PGE1 derivative
  • FIG. 15 shows the results of the in vitro release test.
  • the release test of PGE1 from the particles was specifically performed by the following method.
  • the nanoparticles encapsulating PGE1 were dispersed in a mixture (50% v / v) of bovine serum albumin (FBS) and phosphate buffer (PBS). After incubation at 37 ° C. for each time, 100 ⁇ L of each solution, 900 ⁇ L of 50 mM EDTA (pH 7) was added, and centrifugation was performed at 4 ° C., 50,000 ⁇ g, for 30 minutes. The supernatant was removed, 1 mL of ultrapure water was added, and the mixture was further centrifuged. The supernatant was removed, and the amount of PGE1 contained in the precipitate was measured by HPLC.
  • FIG. 16 shows the stability results when incubated at 37 ° C.
  • FIG. 17 shows the results of stability when incubated at 4 ° C., but it is understood that the stability is even better under such conditions.
  • a PGE1 derivative as a prodrug which is excellent in sustaining the action of PGE1 and is effectively converted into PGE1.
  • the PGE1 derivative provided by the present invention is easy to convert into PGE1, and the conversion is continuous. Further, the PGE1 derivative is excellent in storage stability and exhibits sustained-release PGE1 action. It is very specific.
  • the PGE1 derivative provided by the present invention can be made into nanoparticles, the obtained nanoparticles are extremely stable, and the PGE1 derivative remains in the particles for a long period of time. It is. Therefore, the nanoparticle provided by the present invention is excellent in sustained release of the drug, and as a result, is extremely effective in that the action of PGE1 can be sustained, and has a great industrial applicability. It is.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention a pour but de proposer un dérivé de PGE1 qui présente une excellente durée d'action de la PGE1 et d'excellentes propriétés de libération lente, et de préparer des nanoparticules du dérivé de PGE1 pour fournir des nanoparticules contenant un dérivé de PGE1 qui peuvent cibler une surface touchée de façon efficace, qui présentent d'excellentes propriétés de libération lente de médicament et des effets secondaires réduits. L'invention concerne donc un dérivé de prostaglandine E1 représenté par la formule (I) [dans laquelle n représente un entier de 1 à 12]. L'invention concerne également des nanoparticules contenant le dérivé de prostaglandine E1 que l'on obtient en rendant hydrophobe le dérivé de prostaglandine E1 avec un ion métallique et en faisant réagir le produit résultant avec un poly (acide L-lactique) ou un copolymère poly (acide L-lactique/acide glycolique) et un copolymère bloc poly (acide DL- ou L-lactique)-(polyéthylène glycol) ou un copolymère bloc poly(acide DL- ou L-lactique/acide glycolique)-(polyéthylène glycol).
PCT/JP2009/067885 2008-11-18 2009-10-16 Nouveau dérivé de prostaglandine e1 et nanoparticules dans lesquelles est encapsulé ce dérivé Ceased WO2010058669A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2010539189A JPWO2010058669A1 (ja) 2008-11-18 2009-10-16 新規プロスタグランジンｅ１誘導体及びそれを封入するナノ粒子
EP09827450A EP2361918A1 (fr) 2008-11-18 2009-10-16 Nouveau dérivé de prostaglandine e1 et nanoparticules dans lesquelles est encapsulé ce dérivé
US13/129,729 US20110262548A1 (en) 2008-11-18 2009-10-16 Novel prostaglandin e1 derivative and nanoparticle having the same encapsulated therein
CN2009801457967A CN102216310A (zh) 2008-11-18 2009-10-16 新型前列腺素e1衍生物以及包封了该前列腺素e1衍生物的纳米粒子

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008-294167 2008-11-18
JP2008294167 2008-11-18

Publications (1)

Publication Number Publication Date
WO2010058669A1 true WO2010058669A1 (fr) 2010-05-27

Family

ID=42198108

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/067885 Ceased WO2010058669A1 (fr) 2008-11-18 2009-10-16 Nouveau dérivé de prostaglandine e1 et nanoparticules dans lesquelles est encapsulé ce dérivé

Country Status (6)

Country Link
US (1) US20110262548A1 (fr)
EP (1) EP2361918A1 (fr)
JP (1) JPWO2010058669A1 (fr)
KR (1) KR20110095887A (fr)
CN (1) CN102216310A (fr)
WO (1) WO2010058669A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012111627A1 (fr) * 2011-02-18 2012-08-23 株式会社Ｌｔｔバイオファーマ Nanoparticule contenant un dérivé de prostaglandine i2
WO2019102606A1 (fr) 2017-11-27 2019-05-31 国立大学法人大阪大学 Formulation liposomale spécifique à un site de maladie

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007074604A1 (fr) * 2005-12-26 2007-07-05 Ltt Bio-Pharma Co., Ltd. Nanoparticule contenant une substance hydrosoluble, non peptidique, de faible poids moleculaire
EP2156848A4 (fr) * 2007-05-14 2012-11-28 Ltt Bio Pharma Co Ltd Nanoparticule contenant un médicament de bas poids moléculaire ayant un groupe chargé négativement à libération prolongée
CN105777601A (zh) * 2014-12-26 2016-07-20 中国人民解放军第二军医大学 一种前列地尔衍生物及其药物制剂

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3746728A (en) * 1971-09-10 1973-07-17 Smith Kline French Lab Phosphatide derivatives of prostaglandins
JPS532457A (en) * 1976-06-29 1978-01-11 Nattermann A & Cie Novel phsphor lipid derivative of prostagladine and process for preparing same
JPH09110828A (ja) * 1995-08-16 1997-04-28 Ono Pharmaceut Co Ltd プロスタグランジンｅ１エステル、それらを含有するリポソーム製剤、およびそれらを含有する医薬
JPH09124593A (ja) * 1995-08-25 1997-05-13 Ono Pharmaceut Co Ltd プロスタグランジンｅ１エステル、それらを含有するリポソーム製剤、およびそれらを含有する医薬
JP2849608B2 (ja) 1990-10-12 1999-01-20 裕 水島 プロスタグランジン類縁体
WO1999009992A1 (fr) 1997-08-27 1999-03-04 Yoshitomi Pharmaceutical Industries, Ltd. Promoteurs de neovascularisation
JPH11279184A (ja) * 1998-03-25 1999-10-12 Asahi Glass Co Ltd エノールホスフェート誘導体およびその製造方法
JP2003506454A (ja) * 1999-08-04 2003-02-18 ザ プロクター アンド ギャンブル カンパニー 新規な２−デカルボキシ−２−ホスフィニコプロスタグランジンｆ類似体
JP2006248992A (ja) * 2005-03-10 2006-09-21 Tokyo Institute Of Technology ホスホリルコリン類の製造方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW367324B (en) * 1995-08-16 1999-08-21 Ono Pharmaceutical Co Prostaglandin derivatives

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3746728A (en) * 1971-09-10 1973-07-17 Smith Kline French Lab Phosphatide derivatives of prostaglandins
JPS532457A (en) * 1976-06-29 1978-01-11 Nattermann A & Cie Novel phsphor lipid derivative of prostagladine and process for preparing same
JP2849608B2 (ja) 1990-10-12 1999-01-20 裕 水島 プロスタグランジン類縁体
JPH09110828A (ja) * 1995-08-16 1997-04-28 Ono Pharmaceut Co Ltd プロスタグランジンｅ１エステル、それらを含有するリポソーム製剤、およびそれらを含有する医薬
JPH09124593A (ja) * 1995-08-25 1997-05-13 Ono Pharmaceut Co Ltd プロスタグランジンｅ１エステル、それらを含有するリポソーム製剤、およびそれらを含有する医薬
WO1999009992A1 (fr) 1997-08-27 1999-03-04 Yoshitomi Pharmaceutical Industries, Ltd. Promoteurs de neovascularisation
JPH11279184A (ja) * 1998-03-25 1999-10-12 Asahi Glass Co Ltd エノールホスフェート誘導体およびその製造方法
JP2003506454A (ja) * 1999-08-04 2003-02-18 ザ プロクター アンド ギャンブル カンパニー 新規な２−デカルボキシ−２−ホスフィニコプロスタグランジンｆ類似体
JP2006248992A (ja) * 2005-03-10 2006-09-21 Tokyo Institute Of Technology ホスホリルコリン類の製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MANAMI SHIZUKA ET AL.: "Synthesis of Isoprostanyl Phosphatidylcholine and Isoprostanyl Phosphatidylethanolamine", JOURNAL OF ORGANIC CHEMISTRY, vol. 71, no. 4, 2006, pages 1330 - 1334 *
MIHO TAKEDA ET AL.: "Synthesis of Prostaglandin El Phosphate Derivatives and Their Encapsulation in Biodegradable Nanoparticles", PHARMACEUTICAL RESEARCH, vol. 26, no. 7, July 2009 (2009-07-01), pages 1792 - 1800, XP019686227 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012111627A1 (fr) * 2011-02-18 2012-08-23 株式会社Ｌｔｔバイオファーマ Nanoparticule contenant un dérivé de prostaglandine i2
JP2012171883A (ja) * 2011-02-18 2012-09-10 Ltt Bio-Pharma Co Ltd プロスタグランジンｉ２誘導体を含有するナノ粒子
US9161986B2 (en) 2011-02-18 2015-10-20 Ltt Bio-Pharma Co., Ltd. Nanoparticle containing prostaglandin I2 derivative
WO2019102606A1 (fr) 2017-11-27 2019-05-31 国立大学法人大阪大学 Formulation liposomale spécifique à un site de maladie

Also Published As

Publication number Publication date
KR20110095887A (ko) 2011-08-25
JPWO2010058669A1 (ja) 2012-04-19
US20110262548A1 (en) 2011-10-27
EP2361918A1 (fr) 2011-08-31
CN102216310A (zh) 2011-10-12

Similar Documents

Publication Publication Date Title
CA2867323C (fr) Lipides cationiques biodegradables a base de diether pour l'administration de petit arni
EP2206502B1 (fr) Conjugué polymère-stéroïde
JP6592458B2 (ja) カチオン性脂質
JP5131971B2 (ja) 水溶性非ペプチド性低分子薬物含有ナノ粒子
CN102037058B (zh) 多西紫杉醇高分子衍生物、及其制造方法及其用途
JP2024505327A (ja) 炭酸塩を含むナノ材料
JP2011173908A (ja) 新規ブロック共重合体、ミセル調製物及びそれを有効成分とする抗癌剤
EP2679227B1 (fr) Nanoparticule contenant un dérivé de prostaglandine i2
WO2010058669A1 (fr) Nouveau dérivé de prostaglandine e1 et nanoparticules dans lesquelles est encapsulé ce dérivé
BG65501B1 (bg) Приложение на естери на l-карнитин или алканоилови l-карнитини като катионни липиди за интрацелуларен пренос на фармакологично активни вещества
US11034708B2 (en) Lipid derivative for nucleic acid introduction
CN117534585B (zh) 一种可电离阳离子脂质化合物及其制备方法与应用
JP2018012694A (ja) ラパマイシン類結合ブロック共重合体
JPH08217787A (ja) 脂溶性アントラサイクリン誘導体
KR20240110610A (ko) 조성물의 순화 방법
WO2025161942A1 (fr) Composé lipidique et nanoparticules lipidiques pour administration
WO2024214013A1 (fr) Nanoparticules de promédicaments d'acide mycophénolique et leur utilisation thérapeutique
JP5021899B2 (ja) 水溶性カンプトテシン製剤

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200980145796.7

Country of ref document: CN

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

Ref document number: 09827450

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2010539189

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2009827450

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20117013566

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 13129729

Country of ref document: US