WO2005030835A1 - Derives de polyethylene glycol et vecteurs de medicament contenant ces derives en tant que constituants membranaires - Google Patents

Derives de polyethylene glycol et vecteurs de medicament contenant ces derives en tant que constituants membranaires Download PDF

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Publication number
WO2005030835A1
WO2005030835A1 PCT/JP2004/014436 JP2004014436W WO2005030835A1 WO 2005030835 A1 WO2005030835 A1 WO 2005030835A1 JP 2004014436 W JP2004014436 W JP 2004014436W WO 2005030835 A1 WO2005030835 A1 WO 2005030835A1
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group
drug carrier
general formula
polyethylene glycol
drug
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PCT/JP2004/014436
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English (en)
Japanese (ja)
Inventor
Masashi Isozaki
Masayo Kondo
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Terumo Kabushiki Kaisha
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Priority to JP2005514292A priority Critical patent/JP4723380B2/ja
Publication of WO2005030835A1 publication Critical patent/WO2005030835A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • 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
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers

Definitions

  • DDS drug delivery system
  • closed vesicles such as ribosomes, emulsions, lipid microspheres, and nanoparticles as drug carriers
  • a method of incorporating or binding a drug to a polymer carrier such as a polymer synthetic polymer micelle or a polysaccharide
  • methods to enhance the target directivity by modifying the surface of these closed vesicles and high molecular carriers with high molecular functional molecules such as antibodies and proteins, and low molecular functional molecules such as specific sugar chains and peptides (Cancer Letters, USA, 1997, Vol.
  • drug carriers include drug carriers, No. 2, p. 153; British Journal of Canada, United Kingdom) , 1997, Vol. 76, No. 1, p. 83).
  • drug carriers also referred to as “drug carriers”
  • problems with avoidance of illness and difficulty in controlling pharmacokinetics In particular, closed vesicles bind to target tissues and cells due to aggregation by interaction with opsonin proteins and plasma proteins in blood, and trapping by reticuloendothelial tissues (RES) such as liver and spleen. Highly selective delivery was difficult.
  • RES reticuloendothelial tissues
  • the surface of polymer carriers such as these closed vesicles is coated with a hydrophilic polymer such as polyethylene glycol (PEG) to adsorb plasma proteins and opsonin proteins.
  • a hydrophilic polymer such as polyethylene glycol (PEG) to adsorb plasma proteins and opsonin proteins.
  • PEG-PE phospholipid derivative
  • the present invention provides a drug carrier which can reliably, efficiently and safely target a drug to a target site, is effective as a DDS preparation, and a novel component constituting a membrane component of the drug carrier.
  • An object is to provide a polyethylene glycol derivative having no charge.
  • the present invention provides the following (1) to (22).
  • A is an aromatic ring
  • R 1 and R 2 are each independently an alkyl or alkenyl group having 10 to 25 carbon atoms.
  • X and Y are each independently 0, S, COO, ⁇ CO, CONH or NHCO, and m represents 0 or a natural number from 1 to 6.
  • n indicates a natural number from 10 to 300.
  • L is OCONH (carbamate bond) or ⁇ CO (ester bond)
  • B is a hydroxyl group, an alkoxy group or a benzyloxy group.
  • A is a benzene ring
  • R 1 and R 2 are an alkyl group having 15 carbon atoms
  • X and Y are ⁇
  • m is 1 (1)
  • a polyethylene glycol derivative according to (4) A polyethylene glycol derivative according to (4).
  • a ′ is an aromatic ring
  • R 3 and R 4 are each independently an alkyl or alkenyl group having 10 to 25 carbon atoms.
  • p represents 0 or a natural number from 1 to 6.
  • q indicates a natural number from 10 to 300.
  • L ' is OCONH (carbamate bond) or OCO (ester bond), and B' is a hydroxyl group, an alkoxy group or a benzyloxy group.
  • R 3 and; 4 are each independently an alkyl or alkenyl group having 12 to 18 carbon atoms, wherein the polyethylene glycol derivative of (6) or (7).
  • a ′ is a benzene ring
  • R 3 and R 4 are an alkyl group having 18 carbon atoms
  • p is 1 in any one of (6) to (8).
  • a drug carrier comprising the polyethylene glycol derivative according to any one of (1) to (9) as one of the constituent components.
  • the drug carrier contains at least one selected from the group consisting of phospholipids and derivatives thereof, lipids and derivatives thereof other than phospholipids, cholesterols, and surface modifiers (10) or (11). ) A drug carrier.
  • Drugs carried are nucleic acids, polynucleotides, genes and their analogs, anticancer agents, antibiotics, enzymatic agents, enzyme inhibitors, antioxidants, lipid uptake inhibitors, hormones, anti-inflammatory agents, steroids Agents, vasodilators, angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, smooth muscle cell proliferation and Z or migration inhibitors, platelet aggregation inhibitors, anticoagulants, chemical media Release inhibitor, vascular endothelial cell proliferation or inhibitor, aldose reductase inhibitor, mesangial cell proliferation inhibitor, reboxygenase inhibitor, immunosuppressant, immunostimulant, antiviral agent, Maillard reaction inhibitor, amyloid Cis inhibitor, NOS inhibitor, AGEs (Advanced 1 ycati on endpr oduc ts; inhibitor, radical callus force ventilator, glycosaminodalican, etc.
  • the drug carried is at least one in-vivo diagnostic selected from the group consisting of X-ray contrast agents, radioisotope-labeled nuclear medicine diagnostics, and diagnostics for nuclear magnetic resonance diagnostics (10) to (14)
  • the drug carrier according to any of (14).
  • a pharmaceutical composition comprising the drug carrier according to any one of (10) to (15).
  • a method for delivering a drug carried on a drug carrier to a target site comprising administering the drug carrier of any of (10) to (15) to a host.
  • a method for transporting a drug carrier to a target site comprising administering the drug carrier according to any one of (10) to (15) to a host.
  • a method for preventing and / or treating a disease comprising administering to a host a prophylactically and / or therapeutically effective amount of the drug carrier of any of (10) to (15).
  • a method for diagnosing a disease which comprises administering an effective amount of the drug carrier of any of (10) to (13) or (15) to a host.
  • composition for delivering a drug carried on a drug carrier to a target site comprising an effective amount of the drug carrier according to any of (10) to (15).
  • composition for transporting a drug carrier to a target site which comprises an effective amount of the drug carrier according to any of (10) to (15).
  • a novel non-charged polyethylene glycol derivative usable as a membrane component of a drug carrier is provided.
  • the drug carrier containing the polyethylene glycol derivative of the present invention as one of the membrane components has excellent blood retention. Further, the drug carrier containing the polyethylene glycol derivative of the present invention and a cationized lipid as constituents has good binding properties to target cells as shown in Examples and Test Examples described later. From the characteristics as described above, the drug carrier containing the polyethylene dalicol derivative of the present invention as an S3 ⁇ 4i component and a pharmaceutical composition containing the drug carrier have excellent effects in treating and / or diagnosing diseases. Brief description of
  • Figure 1 is a graph comparing the amounts of ribosomes (modification rate (ratio of PEG derivative amount to total lipid amount) 1%) prepared in Example 2 and Reference Example 1 to cells in Test Example 1. .
  • FIG. 2 shows a comparison of the amount of ribosome (modification ratio (ratio of PEG derivative amount to total lipid amount) 1%) prepared in Example 4 and Reference Example 2 to cells in Test Example 2.
  • PEG derivative polyethylene glycol derivative
  • drug carrier containing the PEG derivative as one of the membrane components
  • PEG derivative (A) represented by the following general formula (1) is provided.
  • A is an aromatic ring.
  • aromatic ring in addition to the ring, indene, naphthalene, tetralin, anthracene, It may be a combined ring. However, it is preferably a benzene ring.
  • R 1 and R 2 are each independently an alkyl group or alkenyl group having 10 to 25 carbon atoms, and preferably each independently an alkyl group or alkenyl group having 12 to 18 carbon atoms.
  • X and Y are each independently 0, S, COO, OCO, CONH or NHCO, preferably both X and Y are O.
  • n is 0 or a natural number from 1 to 6, preferably 1 to 3.
  • n represents a natural number from 10 to 300, preferably n is a natural number from 20 to 200, and more preferably a natural number from 30 to 150.
  • L is OCONH 2 (capillate bond) or ⁇ C ⁇ (ester bond), and is preferably a cal ⁇ mate bond.
  • B is a hydroxyl group, an alkoxy group or a benzyloxy group, and is preferably a methoxy group.
  • A is a benzene ring
  • B is a methoxy group
  • X and Y are both 0, and m is 1.
  • Specific examples of such a PEG derivative (A) include monomethoxypolyethylene dalicol dialkoxybenzyl carbamate.
  • PEG derivative (A) represented by the general formula (1) A is a benzene ring, R 1 and R 2 are both alkyl groups having 15 carbon atoms, and X and Y are both 0. , M is preferably 1.
  • PEG derivative (A) Specific examples thereof include monomethoxypolyethylene glycol 3,5-phosphate represented by the following structural formula.
  • the PEG derivative (A) represented by the general formula (1) is, for example, a compound represented by the following general formula (4) (App 1. Bi) ochem. Biotec. 11, 141)
  • A is an aromatic ring
  • R 1 and R 2 are each independently an alkyl or alkenyl group having 10 to 25 carbon atoms.
  • X and Y are each independently 0, S, COO, ⁇ C0, C ⁇ NH or NHCO, and 1 represents 0 or a natural number from 1 to 6.
  • n represents a natural number from 10 to 300.
  • B is a hydroxyl group, an alkoxy group or a benzyloxy group.
  • the compound of the general formula (3) can be synthesized by a general synthesis method.
  • it can be synthesized by introducing an alkenyl group with an ether bond, further reducing the ester moiety to a hydroxyl group, and then converting the ⁇ acid group to an amino group.
  • A is an aromatic ring, and m represents 0 or a natural number from 1 to 5.
  • R 1 and R 2 are each independently an alkyl or alkenyl group having 10 to 25 carbon atoms, and m represents a natural number of 0 or 1 to 5 .
  • R 1 and R 2 are each independently an alkyl or alkenyl group having 10 to 25 carbon atoms, and 1 represents 0 or a natural number from 1 to 6.
  • the compound of the general formula (4) can be synthesized by a general method. For example, it can be synthesized by the method of Veronese et al.
  • n is a natural number from 10 to 30; therefore, the number average molecular weight of the polyethylene glycol Is about 500 to about 13000.
  • the term “average molecular weight” refers to the number average molecular weight.
  • the number-average molecular weight refers to the average molecular weight of each component molecule based on the mole fraction.
  • the PEG derivative (A) of the general formula (1) synthesized by the above procedure is It can be isolated and collected by ordinary purification means such as recrystallization.
  • the production method and purification method of the PEG derivative (A) of the general formula (1) are not limited to the above.
  • the PEG derivative (A) of the general formula (1) is suitably used as a membrane component of a drug carrier since it has no charge.
  • the present invention provides a polyethylene glycol derivative represented by the following general formula (2) (hereinafter, also referred to as “PEG derivative (B)”).
  • PEG derivative (B) a polyethylene glycol derivative represented by the following general formula (2)
  • a ′ is an aromatic ring.
  • the aromatic ring may be a condensed ring such as indene, naphthalene, tetralin, anthracene, and phenanthrene in addition to the benzene ring. However, it is preferably a benzene ring.
  • R 3 and R 4 are each independently an alkyl group or alkenyl group having 10 to 25 carbon atoms, and preferably each independently an alkyl group or alkenyl group having 12 to 18 carbon atoms.
  • P is 0 or a natural number from 1 to 6, preferably 1 to 3.
  • Q represents a natural number from 10 to 300, preferably n is a natural number from 20 to 200, more preferably a natural number from 30 to 150.
  • L ′ is OC ⁇ NH 2 (a olebamate bond) or OCO (an ester bond), preferably a olebamate bond.
  • B ′ is a hydroxyl group, an alkoxy group or a benzyloxy group, and is preferably a methoxy group.
  • a ′ is a benzene ring
  • B ′ is a methoxy group
  • R 3 and R 4 are alkyl groups independent of each other
  • p is 1.
  • Specific examples of such an amide compound include 4- (N ′ — (methoxypolyethyleneglycolcarbonyl) 2-aminoethyl) N, N-dialkylbenzamide.
  • a ′ is a benzene ring
  • R 3 and R 4 are both an alkyl group having 18 carbon atoms
  • p is 1.
  • a specific example of such an amide compound is 4- (N′-chololeponyl) 2-aminoethyl) N, N-doca S represented by the following structural formula.
  • the PEG derivative (B) represented by the general formula (2) can be obtained, for example, by introducing a compound represented by the following general formula (9) into an amino group of a compound represented by the following general formula (8). Can be manufactured.
  • a ′ is an aromatic ring
  • R 3 and R 4 are each independently an alkyl or alkenyl group having 10 to 25 carbon atoms.
  • p represents 0 or a natural number from 1 to 6.
  • Q represents a natural number from 10 to 300.
  • B ′ is a hydroxyl group, an alkoxy group or a benzyloxy group.
  • the compound of the general formula (8) can be synthesized by a general synthesis method.
  • an amino compound may be formed by protecting an amino group of an aminoalkyl aromatic ring carboxylic acid derivative with an appropriate protecting group (Prote tec ti group s n by The odora W.Greene, PeterG.M.Wuts).
  • a ′ is an aromatic ring, and p represents 0 or a natural number from 1 to 5.
  • a ′ is an aromatic ring, p is 0 or a natural number from 1 to 5, and P represents a protecting group.
  • R 3 and R 4 independently represent an alkyl group or an alkenyl group having 10 to 25 carbon atoms.
  • a ′ is an aromatic ring, R 3 and R 4 are each independently an alkyl or alkenyl group having 10 to 25 carbon atoms, and p represents 0 or a natural number from 1 to 5.
  • examples of the carboxylic acid activator include, for example, thionyl chloride, phosphorus pentachloride, chloroformate (methyl chloroformate and ethyl ethyl chloroformate), oxalyl chloride, and carpoimides (eg, N , N'-Dicyclohexylcarposimide (DCC), 1-Ethyl_3- (3-dimethylaminopropyl) carposimide (WSC)), Benzotriazol-1-yl
  • the compound of the general formula (9) can be synthesized by a general method. For example, it can be synthesized by the method of Veronese et al. (Applied Biochemistry and BioChno loggy 11, 141, 1985). Polyethylene glycol used as a raw material for synthesizing the compound of the general formula (9) can be purchased commercially, and in formula (9), Q is a natural number from 10 to 30.
  • the molecular weight is from about 500 to about 13000.
  • the term “average molecular weight” refers to the number average molecular weight.
  • the number-average molecular weight refers to the average molecular weight of each component molecule based on the mole fraction.
  • the PEG derivative (B) of the general formula (2) synthesized by the above procedure can be isolated and collected by ordinary purification means such as chromatography and recrystallization.
  • the production method and purification method of the PEG derivative (B) of the general formula (2) are not limited to the above.
  • the PEG derivative (B) represented by the general formula (2) has no charge and is therefore suitably used as a Fujinari component of a drug carrier.
  • the drug carrier of the present invention contains the PEG derivative (A) represented by the general formula (1) or the PEG derivative (B) represented by the general formula (2) as one of the membrane components.
  • the drug carrier refers to a small spherical structure having lipid as a basic constituent material of a membrane and capable of carrying a drug for diagnosing a disease and for Z or treatment.
  • the content of the PEG derivative (A) of the formula (1) or the PEG derivative (B) of the formula (2) in the drug carrier of the present invention is usually 0.1 in terms of the ratio to the total lipid amount constituting the drug carrier. 22 Omo 1% can be present, preferably 0.1-5 mol%, more preferably 0.5-5 mol%.
  • the total lipid amount is the amount of all lipids constituting the drug carrier, and the amount of the surface modifier described later is also included in the total lipid amount.
  • the total lipid means a membrane component of the drug carrier excluding the PEG derivative (A) of the formula (1) or the PEG derivative (B) of the formula (2), and is expressed in molar concentration (mM).
  • the drug carrier of the present invention contains the PEG derivative (A) of the above formula (1) or the PEG derivative (B) of the formula (2) as one of the components, and other components are not limited.
  • Other constituents may include lipids and their derivatives as membrane basic constituents as described below, and may further include a surface modifier, and may further include other components such as a stabilizer and an antioxidant. .
  • the drug carrier of the present invention may contain only the PEG derivative (A) of the formula (1) or the PEG derivative (B) of the formula (2) as a constituent. Further, only the PEG derivative (A) or (B) and the membrane basic constituent material can be contained as constituent components. In this case, the membrane basic constituent material may contain only phospholipids, only lipids other than phospholipids, or only cholesterols, or may contain only a combination thereof.
  • the form of the drug carrier of the present invention is not particularly limited as long as it has a structure capable of supporting a drug, and can take various forms. Specifically, it is desirably made of at least one selected from ribosomes, lipid microspheres and polymer microspheres, which has a potential function of encapsulating a drug in a high concentration therein.
  • a preferred embodiment is a closed vesicle having a structure that forms a space separated from the outside by a membrane generated based on the polarities of the hydrophobic group and the hydrophilic group of the lipid molecule.
  • No. Ribosomes are closed vesicles composed of a lipid bilayer based on phospholipids.
  • Lipid microspheres are closed vesicles made by emulsifying one of water and oil in the other.
  • Polymer microspheres are closed vesicles formed by emulsifying a polymer and then solidifying it by denaturation, chemical crosslinking, radiation polymerization, drying in liquid, and other operations.
  • a ribosome is a particularly preferred embodiment of the drug carrier.
  • the size of the drug carrier of the present invention is not particularly limited, but when the drug carrier has a spherical shape or a shape close thereto, the outer diameter of the particle is from 0.22 to 250 m, preferably from 0.03 to 0. 4 m, more preferably 0.05 to 0.2 zm.
  • the diameter of the particle outer diameter is an average value of the diameters of all the drug carrier particles measured by the light scattering method.
  • Other components constituting the drug carrier together with the PEG derivative (A) of the above formula (1) or the PEG derivative (B) of the formula (2) are those which can stably form the above-mentioned form.
  • the drug carrier contains at least one selected from lipids, derivatives thereof, and surface modifiers as membrane constituents.
  • lipids include phospholipids, lipids other than phospholipids, and cholesterols, and derivatives thereof.
  • Cholesterols include, but are not limited to, cholesterol and cholestano. And the like.
  • lipids other than phospholipids include lipids containing no phosphoric acid, and include, but are not particularly limited to, glycerol glycolipids, glycosphingolipids, and the like.
  • a surface modifier is used to change the structure and physical properties of lipids, which are membrane components of a drug carrier, and to impart desired properties to the drug carrier membrane. Therefore, the surface modifier can be used as one of the membrane components of the drug carrier.
  • the surface modifier include, but are not particularly limited to, a substance composed of lipid and a compound bonded to lipid.
  • the “compound that binds to lipid” is not particularly limited, and examples thereof include a hydrophilic polymer, a derivative of a water-soluble polysaccharide, and a compound having a basic functional group.
  • hydrophilic polymer examples include, but are not particularly limited to, polyethylene glycol, polyester, polyvinyl alcohol, styrene / maleic anhydride alternating copolymer, divinyl ether / maleic anhydride alternating copolymer, and synthetic polyamino acids. It is.
  • derivative of the water-soluble polysaccharide include, but are not particularly limited to, glyceronic acid, sialic acid, dextran, pullulan, amylose, amylopectin, chitosan, mannan, cyclodextrin, pectin, and carrageenan.
  • the lipid to which the hydrophilic polymer or the water-soluble polysaccharide binds is not particularly limited, but a compound having a hydrophobic region (hydrophobic compound) may be used.
  • a compound having a hydrophobic region include, but are not particularly limited to, long-chain fatty alcohol, sterol, polyoxypropylene alkyl, and glycerin fatty acid ester.
  • the hydrophilic polymer is polyethylene dalicol and the hydrophobic compound is distearoyl phosphatidylethanolamine
  • the surface modifier is polyethylene glycol.
  • the drug carrier is ribosome
  • a surface modifier containing a hydrophobic compound when used, at least the hydrophobic region of the hydrophobic compound is stable in the lipid bilayer membrane of the liposome. Be transformed into As a result, a hydrophilic polymer or a water-soluble polysaccharide bonded to a hydrophobic compound can be present on the membrane surface of the lipid bilayer (on the outer surface and on the Z or inner surface of the drug carrier). By doing so, it becomes possible to modify the film of the drug carrier, and as a result, there are effects such as enhancing the blood stability of the drug carrier.
  • Examples of the “basic functional group” include, but are not particularly limited to, an amino group, an amidino group, and a guadinino group.
  • Compounds having a basic functional group include DOTMA (Japanese Patent No. 61161246), DOTAP (Japanese Patent No. 5508626), Tran sfect am (Japanese Patent No. 2292246), TMAG (Japanese Patent No. 4108391), Known compounds such as 3,5-dipentyldecyloxybenzamidine hydrochloride (International Publication No. 97Z42166 pamphlet), DOSPA, TfxTM-50, DDAB, DC-CHOL, DMRIE, and the like can be mentioned.
  • the surface modifying agent contains a basic functional group
  • the surface modifying agent is a substance in which a compound having a basic functional group is bonded to lipid
  • this is called a cationized lipid.
  • the drug carrier is a ribosome
  • the lipid portion of the cationized lipid is stabilized in the membrane of the lipid bilayer of the liposome, and the basic functional group portion is attached to the membrane surface of the lipid bilayer.
  • the carrier is a ribosome
  • the lipid portion of the cationized lipid is stabilized in the membrane of the lipid bilayer of the liposome, and the basic functional group portion is attached to the membrane surface of the lipid bilayer.
  • On the outer surface and / or on the inner surface of the carrier it becomes possible to modify the film of the drug carrier, and as a result, it is possible to enhance the adhesion to the target cells and the like.
  • the drug carrier of the present invention comprises the non-charged PEG derivative (A) or (B) of the present invention as a component, when a cationic lipid is used as a surface modifier, the modifying effect of the cationic lipid is inhibited. Not done.
  • the drug carrier of the present invention can be used by carrying a drug for diagnosis and / or treatment of a disease.
  • the “loading” refers to a state in which the drug is sealed in the enclosed space of the drug carrier, in a membrane of the drug carrier, for example, in a lipid bilayer in the case of ribosome, a part or all of the drug. Or the state where the drug is attached to the outer surface of the drug carrier.
  • the “loading ratio” refers to the ratio between the mixed drug and the loaded drug when the drug carrier is mixed with the drug material of the drug carrier to form the drug carrier.
  • retention in blood means a property of a drug-administered host in which blood is present in the blood in a state of being carried by the drug carrier.
  • anticancer drug examples include, but are not limited to, nedaplatin, docetaxel, gemushibin hydrochloride, cyclophosphamide, diphosphamide, nitrodiene mustard hydrochloride-N-oxide, zotepa, brusuan, kypopocon, dimustine hydrochloride, ramustine hydrochloride, and mermel Phalan, improsulfan tosylate, dacarbazine, procarbazine hydrochloride, cysteine rabin, cysteine rabine oxfat, enosinopine, mercaptopurine, thioinosine, fluorouracil, doxyfluridine, tegafur, methotrexate, carmofur, hydroxycarbamide, vincristine sulfate, Vinblastine sulfate, vindesine sulfate, etoposide, chromomycin A3,
  • antibiotics include, but are not limited to, benzylpenicillin potassium, benzylpenicillin benzathine, phenoxymethyl penicillin potassium, and pheneticillin. , Flux mouth Xacillin sodium, Ampicillin, Sulphomycin tosylate, Pa'campicillin hydrochloride, Hydrochloric acid
  • antioxidants examples include, but are not limited to, tocopherol, ascorbic acid, and uric acid.
  • anti-inflammatory agents include, but are not limited to, choline salicylate, sazapyrine, sodium salicylate, aspirin, difludisal, flufenamic acid, mefenamic acid, floctafenin, tolfenamic acid, diclofenacnatrim, tolmetinnat Lium, sulindac, fenbufen, fuerbinacethyl, indomethacin, indomethacin fuarnesyl, acamethasin, progourmet maleic maleate, fenfenac sodium, nabumetone, ibuprofen, flurbiprofen, flurbiprofen axetile, Ketoprofen, Naproxen, Protidic acid, Pranoprofen, Fenoprofen calcium, Thiaprofenic acid, Oxaprozin, Loxoprofen sodium, Aluminoprofen, Zaltoprofen, Phen
  • steroids examples include, but are not limited to, cortisone acetate, hydrocortisone (phosphate ester, acetate salt), hydrocortisone butyrate, hydrocortisone sodium succinate, and prednisolone (acetate, succinate, tertiary butyl acetate, phosphate).
  • vasodilator examples include, but are not limited to, theophylline, diprofylline, proxifylline, aminophylline, choline theophylline, prostaglandin, Prostaglandin derivatives, alprosyl Jil alfadex, alprostadil, limaprost alfadex, papaverine, cyclandelato, cinnaridin, bencyclane fumarate, cinepazide maleate, dilazep hydrochloride, trapidil, difenidol hydrochloride, nicotinic acid, inositol Hexanicotinate, dicanoic acid dicametate, nicotinic tartrate alcohol, tocopherol nicotinate, topronicat, isoxsuprine hydrochloride, bamethane sulfate, trarizone hydrochloride, dihydroergotoxine mesylate, ifenpro
  • angiotensin converting enzyme inhibitor examples include, but are not particularly limited to, aracepril, imidabril hydrochloride, temocapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, force butopril, cilazapril, enalapril maleate, ricinoburil and the like.
  • angiotensin receptor antagonist examples include, but are not particularly limited to, oral monkey and the like.
  • Smooth muscle cell migration and Z or growth inhibitors include, but are not limited to, sodium heparin, sodium dareleteparin (low molecular weight heparin), heparin calcium And dextran sulfate.
  • Examples of the platelet aggregation inhibitor include, but are not particularly limited to, ticlopidine hydrochloride, syros perazole, ethyl icosapentate, beraprost sodium, sarpgrelat hydrochloride, batroxobin, dipyridamole, and the like.
  • anticoagulant examples include, but are not limited to, heparin sodium, dalteparin sodium (low molecular weight heparin), heparin calcium, dextran sulfate, perfarin potassium, argatroban and the like.
  • Examples of the chemical mediator release inhibitor include, but are not limited to, tranilast, ketophetin fumarate, azelastine hydrochloride, oxatomide, amlexanox, and repirinast.
  • immunosuppressant examples include, but are not particularly limited to, cyclosporine and the like.
  • antiviral agent examples include, but are not limited to, acyclovir, ganciclovir, didanosine, zidovudine, sorivudine, and vidarabine.
  • the type of the diagnostic drug that can be carried on the drug carrier is not particularly limited as long as the formation of the drug carrier is not impaired.
  • Specific examples include in-vivo diagnostic agents such as X-ray contrast agents, ultrasonic diagnostic agents, radioisotope-labeled nuclear medicine diagnostic agents, and diagnostic agents for nuclear magnetic resonance diagnosis.
  • X-ray contrast agents include, for example, amidotriso-medalmine, sodium iodilate, medalmine iotalamate, gastrografin, iodamide medalmine, lipiodol ultrafluid, adipiodon medalmin, ixoxagulic acid, medalmin thiotroxate, and iodrolan Iopanic acid, iopamidol, iohexol, ioversol, iopodate sodium, iomeprol, isobek, eodoxamic acid and the like.
  • the ultrasonic diagnostic agent include, but are not particularly limited to, gas and liquid.
  • the gas include air, carbon dioxide, oxygen, nitrogen, helium, and argon.
  • the liquid include water, physiological saline, a buffer, and an aqueous suspension containing metal powder.
  • the drug carrier of the present invention may further contain a pharmaceutically acceptable stabilizer and Z or an antioxidant depending on the administration route.
  • stabilizer include, but are not particularly limited to, sterols such as cholesterol that reduce membrane fluidity, and saccharides such as glycerol and sucrose.
  • Antioxidants include, but are not limited to, ascorbic acid, uric acid, or tocopherol homologs such as vitamin E. Tocopherol has four isomers of ⁇ , ⁇ , and ⁇ , and any of them can be used in the present invention.
  • the drug carrier of the present invention may further contain a pharmaceutically acceptable additive depending on the administration route.
  • a pharmaceutically acceptable additive include water, saline, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxypinyl polymer, carboxymethylcellulose sodium, sodium polyacrylate, alginic acid Sodium, water-soluble dextran, carboxymethylsuccinic acid, pectin, methylcellulose, ethylcellulose, xanthan gum, acacia, casein, gelatin, agar, diglycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl Acceptable as alcohol, stearic acid, human serum albumin (HSA), mannitol, sorbitol, lactose, PBS, biodegradable polymer, serum-free medium, pharmaceutical additive Surfactants or physiologically acceptable physiological pH Impact liquid and the like.
  • HSA human serum albumin
  • the additive is selected from the above according to the dosage form, or is used in combination, but is not limited thereto.
  • a drug composition in which the above-mentioned drug is supported on a drug carrier and the above-mentioned stabilizer and an optional additive such as an antioxidant are contained can be provided as a pharmaceutical composition.
  • the above-exemplified therapeutic drug carried on a drug carrier can be used as a medical composition for treating a disease.
  • the above-exemplified diagnostic drug carried on a drug carrier can be used as a pharmaceutical composition for diagnosing a disease.
  • the drug carried on the drug carrier may be one kind or a plurality of kinds.
  • the additive When an additive is contained in the drug carrier, the additive may be of one type or a plurality of types.
  • the pharmaceutical composition of the present invention can be stored according to a usual method, for example, can be refrigerated at 0 to 8 ° C or stored at room temperature of 15 to 25 ° C.
  • the drug carrier of the present invention can be obtained by a conventional method.
  • a method for producing liposomes is shown below as an example of a drug carrier, but is not limited thereto.
  • the PEG derivative (A) or (B) of the present invention and another membrane component such as a phospholipid are mixed with an organic solvent such as chloroform, and the organic solvent is distilled off. By drying, a thin film is formed on the inner wall of the flask.
  • a drug is added to the flask and stirred vigorously to obtain a ribosome dispersion.
  • the obtained ribosome dispersion can be purified by a commonly used method such as gel filtration, dialysis, membrane separation and Z or centrifugation to remove the drug not carried on the liposome.
  • the obtained ribosome dispersion is prepared by a French press,
  • the outer diameter of the ribosome particles can be adjusted by a commonly used method such as a pressure filter or an extruder.
  • a liposome is formed by a conventional method using a mixed lipid obtained by mixing a liposome-forming lipid not containing the PEG derivative (A) or (B) of the present invention, and then the PEG derivative (A ) Or (B) may be added.
  • the ribosome can also be obtained by mixing the above-mentioned components and discharging the mixture by a high-pressure discharge emulsifier.
  • the method for preparing the liposome is specifically described in “Ribosomes in Life Science” (Terada, Yoshimura et al .; Springer Fairmark Tokyo (1992)), and this description is described herein using a bow. It is assumed that A pH gradient method can be used to support the drug on the carrier. This method is described in G. Gregori ad is, edited by L. i.
  • the drug carrier of the present invention transports a drug to a target site while carrying the drug.
  • the resulting drug is delivered to the target site.
  • the transportability of the drug to the target site means that the drug carrier carrying the drug reaches the target site. This means that the drug to be carried is taken into the target site, and in this case, the effect of the drug is exerted on the target site or its vicinity without being taken into the target site.
  • the “target site” of the drug carrier means that the drug to be carried is delivered. Specific cells, tissues, organs or organs specified for each site, and their interiors.
  • the drug carrier comprising the PEG derivative (A) or (B) of the present invention as one of the membrane components can maintain stability in blood and has transportability to a target site.
  • the loaded drug can be delivered to the target site.
  • Target sites such as cells, tissues, organs or organs, and the inside thereof are sites to be treated and / or diagnosed, and include, but are not particularly limited to, tumors and inflammatory sites. Therefore, target sites include cells, tissues, organs, or internal organs of tumors and inflammation sites, and the insides thereof.
  • the drug carrier is excellent in blood retention.
  • the non-charged PEG derivative (A) or (B) of the present invention is used as a membrane component.
  • the drug carrier of the present invention is used to transport and / or deliver a drug to a desired target site.
  • the drug carrier of the present invention is useful for preventing and treating or treating a disease, diagnosing a disease, transporting a drug carrier to a target site, or delivering a drug encapsulated in a drug carrier to a target site. Therefore, it can be administered parenterally, systemically or locally to a host (patient).
  • Hosts to be administered include B-breast animals, preferably humans, monkeys, rats, livestock, and the like.
  • Parenteral administration routes include intravenous injection (intravenous injection) such as infusion, intramuscular injection, intraperitoneal injection, and subcutaneous injection, depending on the patient's age and symptoms.
  • the method of administration can be selected.
  • the drug carrier of the present invention is administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease.
  • the effective dose of a drug supported on a substance carrier is selected in the range of 0.0 lmg to 10 Omg / kg body weight per day.
  • the drug carrier of the present invention is not limited to these doses.
  • the administration may be carried out after the occurrence of the disease, or may be administered prophylactically when the onset of the disease is predicted to relieve symptoms at the onset.
  • the administration period can be selected according to the patient's age and symptoms.
  • the pharmaceutical composition can be administered by syringe IV.
  • a catheter is inserted into the body of a patient or a host, for example, into a lumen, for example, into a blood vessel, and the tip is guided to the vicinity of a target site.
  • the catheter is passed through the catheter to a desired target site or its vicinity or a target site. It is also possible to administer from the site where blood flow is expected.
  • a ribosome containing —3,5′-one of the membrane components was prepared as follows.
  • Hydrogenated soybeans (HSPC, Lioid) 0.225 mmol, cholesterol (Solvay) 0.189 mmol, 3,5-dipentine hydrochloride (WO 97/42166)
  • PEG—PE phosphatidylethanolamine
  • the PEG-PE solution (0.75 mM) was obtained by dissolving in 4 ml of a closed mouth form, and 4 ml of the mixed lipid solution was transferred to an eggplant flask, and the PEG-PE solution was added to the lm 1 (PEG-PE modification rate).
  • Mouse melanoma B 16F1 (Tohoku University Institute of Aging and Medicine, TKG0347) was prepared in a medium at a concentration of 2 ⁇ 10 5 ce 11 s / ml, and the medium was 12 we 1 1 late lmlZwe l 1 (3 we l 1 per sample) ) Sown.
  • 202 lZwe11 of Example 2 or Reference Example 1 paste at a lipid concentration of 10 mM was added to Pate containing a cell culture medium. After 24 hours, the medium was removed and washed twice with PBS.
  • RI PA bu ffer 5 OmM Tr is, 15 OmM NaC 1, 0.5% Sodium um Deoxycho late, 1% I GEPAL CA-630, 0.1% Sodi urn Laury l Su lfate
  • the cells were lysed by adding / we11.
  • the cell lysate was transferred to 0.2 weZl of 96 we11pi ⁇ 76 for fluorescence measurement.
  • a calibration curve was prepared using a solution obtained by diluting rhodamine-labeled dani ribosome with RIPA buffer.
  • the fluorescence intensity of rhodamine (Ex. 544 nm, Em.
  • the absorbance (540 nm) was measured using i EMS Reader MF (Dainippon Pharmaceutical). Calibration curve was created in BS A. The amount of ribosome bound to cells (lipid / protein) was calculated from the ratio of lipid concentration to protein.
  • FIG. 1 is a graph showing the amount of the liposome bound to the target cell when the polyethylene glycol-modified liposome (modification rate: 1%) prepared in Example 2 and Reference Example 1 was used.
  • the “modification ratio” means the ratio of the amount of PEG derivative to the total amount of lipid.
  • the ribosome modified with the uncharged PEG derivative (A) of the present invention was transferred to the B16F1 cell.
  • the amount bound was greater than the amount of negatively charged PEG-PE-modified ribosome bound to cells.
  • the binding amount of the liposome to the target cells at the modification rates of 2% and 3% was as follows. Amount of ribosome bound to target cells (mo11ipidsZmgroteine)
  • the liposome containing the PEG derivative (A) of the present invention as a component has a high drug delivery efficiency to PEG-PE-modified liposome tumor cells.
  • the PEG derivative (A) of the present invention does not reduce the interaction of the cationized lipid with cells as compared with the conventional PEG-PE when the cationized lipid is blended. It became clear that. That is, it was shown that the liposome containing the PEG derivative (A) of the present invention as a membrane component has a higher drug delivery efficiency to tumor cells than the PEG-PE modified liposome.
  • a 1 Oml solution of 1.07 g of carbonate and 22 mg of trieduramine (Wako Pure Chemical Industries, Ltd.) in dry form was stirred at room temperature for 12 hours.
  • the reaction solvent was diluted with Kuroguchi-form (Kokusan Chemical), washed with saturated sodium bicarbonate solution, water, and saturated saline, dried over anhydrous sodium sulfate (Kanto Chemical), and concentrated under reduced pressure.
  • One containing ribosome was prepared as follows.
  • Hydrogenated soybeans (HSPC, Lioid) 0.225mmo1, cholesterol (Solvay) 0.189mmo1, 3, 5-dipen
  • z hydrochloride (WO 97/42166. 0.036mmo1 was weighed into a 25 ml volumetric flask, and the fluorescent dye Rhod am in—DHPE (Liss amine TM, rhoda mine B 1,2—di he zadec) anoy l— sn— gl yc ero 3— phos phoe thano 1 ami ne, triethy 1 ammo ni urn salt, Mo le cu lar Probes) Add 12 ml of Z-cloth form solution (0.1 mg / m 1) After dissolving, the sample was made up with a black hole form to obtain a mixed lipid solution (total lipid concentration 18 mM). 4.5 mo 1 of the compound synthesized in Example 3 was dissolved in 6 ml of black hole form to obtain a compound solution (0.75 mM).
  • Polyethylene glycol (molecular weight: 5,000)-phosphatidyl phenol nolamine (PEG-PE, Nippon Oil & Fats) 4.5 mo 1 was dissolved in 6 ml of black-mouthed form to obtain a PEG-PE solution (0.75 mM). Transfer 4 ml of the mixed lipid solution to an eggplant flask, and transfer the PEG-PE solution to lm 1 (PEG-PE modification rate 1 mo 1%) or 2 ml (PEG-PE modification rate 2mo 1%) or 3 ml (PEG-PE Modification rate 3 mo 1%) was added. The solvent was removed by evaporation from the mixed lipid solution containing PEG-PE.
  • a mouse melanoma B 16F 1 (Tohoku University Institute of Aging Medicine, TKG0347) was prepared in a medium to a concentration of 2 ⁇ 10 5 ce 11 sZml, and 12we 1 plate was prepared. To lmlZwe 1 1 (3we 1 1 per sample). On the next day, the ribosome of Example 4 or Reference Example 2 having a lipid concentration of 10 mM was added to Zate 11 containing P21 containing a cell culture medium. After 24 hours, the medium was removed and washed twice with PBS.
  • RI PA bu ffer 5 OmM Tris, 15 OmM NaCl, 0.5% Sodium Deoxycho late, 1% I GEPAL CA-- 6 30, 0.1 Sodi urn Laury l Su lfate
  • the cells were lysed by adding we11.
  • the cell lysate was transferred to a 96-well piate for fluorescence measurement in an amount of 0.2 ml.
  • a calibration curve was prepared using a solution in which rhodamine-labeled ribosome was diluted with RIPA buffer.
  • the fluorescence intensity of rhodamine (Ex. 544 nm, Em.
  • FIG. 2 is a graph showing the amount of ribosome bound to the target cell when the polyethylene glycol-modified liposome (modification rate: 1%) prepared in Example 4 and Reference Example 2 was used.
  • the “modification rate” refers to the PEG induction relative to the total lipid content. It means the ratio of the amount of conductor.
  • binding of the ribosome modified with the uncharged PEG derivative (B) of the present invention to cells in the liposome modified with the polyethylenedaricol derivative to B16F1 cells The amount was greater than the amount of negatively charged PEG-PE-modified ribosome bound to the cells.
  • the amounts of ribosomes bound to target cells at the modification rates of 2% and 3% were as follows. Amount of ribosome bound to target cells mo l l i p i ds Zmg p r o t e i n;
  • the liposome containing the PEG derivative (B) of the present invention as a component of the liposome has a higher drug delivery efficiency to tumor cells than the PEG-PE modified liposome.
  • the PEG derivative (B) of the present invention did not reduce the interaction of the cationized lipid with cells as compared with conventional PEG-PE when the cationized lipid was added. That is, it was shown that the ribosome containing the PEG derivative (B) of the present invention as a membrane component has a higher drug delivery efficiency to tumor cells than the PEG-PE-modified liposome.
  • Acute toxicity test was performed by oral administration using ICR male mice (5 weeks old) As a result, the LD50 of each of the liposomes of Example 4 was 32 OmgZkg or more. The safety of the drug carrier containing the PEG derivative (B) was confirmed.

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Abstract

L'invention concerne des vecteurs de médicament permettant une administration sécurisée, efficace et sure de médicaments au niveau de zones cibles et qui sont utilisés dans des préparations DDS. L'invention concerne également des dérivés de polyéthylène glycol non chargés servant de constituant membranaire aux vecteurs de médicament. Les dérivés de polyéthylène glycol sont notamment représentés par les formules générales (1) et (2); et les vecteurs de médicament contenant ces dérivés en tant qu'un de leurs constituants. Dans les formules (1), (2), A et A' représentent chacun un anneau aromatique; R1, R2, R3 et R4 représentent chacun de façon indépendante un alkyle en C10-25 ou un alcényle; X, X', Y et Y' représentent chacun de façon indépendante O, S, COO, OCO, CONH ou NHCO; m et p représentent chacun 0 ou un nombre naturel compris entre 1 et 6; n et q représentent chacun un nombre naturel compris entre 10 et 30; L et L' représentent chacun OCONH (liaison carbamate) ou OCO (liaison ester); et B et B' représentent chacun un hydroxy, un alcoxy, ou un benzyloxy.
PCT/JP2004/014436 2003-09-25 2004-09-24 Derives de polyethylene glycol et vecteurs de medicament contenant ces derives en tant que constituants membranaires WO2005030835A1 (fr)

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WO2008096690A1 (fr) * 2007-02-05 2008-08-14 Nippon Shinyaku Co., Ltd. Dérivé de polyéthylène glycol
JP5000512B2 (ja) * 2005-05-11 2012-08-15 日本化薬株式会社 シチジン系代謝拮抗剤の高分子誘導体
JP2014504649A (ja) * 2011-02-08 2014-02-24 ウ，ニアン ポリマー−炭水化物−脂質複合体
JP2014505145A (ja) * 2011-01-11 2014-02-27 アルニラム・ファーマシューティカルズ・インコーポレーテッド Ｐｅｇ化脂質および薬剤送達のためのそれらの使用
WO2014148378A1 (fr) * 2013-03-19 2014-09-25 公立大学法人首都大学東京 Composé de type tensio-actif
CN104262613A (zh) * 2014-10-13 2015-01-07 辽宁奥克医药辅料有限公司 一种含有环氧乙烷杂质的聚乙二醇的精制方法
CN114099705A (zh) * 2021-11-18 2022-03-01 浙江大学杭州国际科创中心 一种基于肼屈嗪改善肿瘤微环境的纳米药物及其制备和应用

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5000512B2 (ja) * 2005-05-11 2012-08-15 日本化薬株式会社 シチジン系代謝拮抗剤の高分子誘導体
WO2008096690A1 (fr) * 2007-02-05 2008-08-14 Nippon Shinyaku Co., Ltd. Dérivé de polyéthylène glycol
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JP5347510B2 (ja) * 2007-02-05 2013-11-20 日本新薬株式会社 ポリエチレングリコール誘導体
JP2014505145A (ja) * 2011-01-11 2014-02-27 アルニラム・ファーマシューティカルズ・インコーポレーテッド Ｐｅｇ化脂質および薬剤送達のためのそれらの使用
JP2014504649A (ja) * 2011-02-08 2014-02-24 ウ，ニアン ポリマー−炭水化物−脂質複合体
WO2014148378A1 (fr) * 2013-03-19 2014-09-25 公立大学法人首都大学東京 Composé de type tensio-actif
JPWO2014148378A1 (ja) * 2013-03-19 2017-02-16 公立大学法人首都大学東京 界面活性剤様化合物
CN104262613A (zh) * 2014-10-13 2015-01-07 辽宁奥克医药辅料有限公司 一种含有环氧乙烷杂质的聚乙二醇的精制方法
CN114099705A (zh) * 2021-11-18 2022-03-01 浙江大学杭州国际科创中心 一种基于肼屈嗪改善肿瘤微环境的纳米药物及其制备和应用
CN114099705B (zh) * 2021-11-18 2023-06-13 浙江大学杭州国际科创中心 一种基于肼屈嗪改善肿瘤微环境的纳米药物及其制备和应用

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