WO2023282344A1 - 腎毒性軽減剤 - Google Patents
腎毒性軽減剤 Download PDFInfo
- Publication number
- WO2023282344A1 WO2023282344A1 PCT/JP2022/027103 JP2022027103W WO2023282344A1 WO 2023282344 A1 WO2023282344 A1 WO 2023282344A1 JP 2022027103 W JP2022027103 W JP 2022027103W WO 2023282344 A1 WO2023282344 A1 WO 2023282344A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nephrotoxicity
- antisense oligomer
- reducing agent
- sugar alcohol
- pharmaceutical composition
- Prior art date
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
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Images
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P39/00—General protective or antinoxious agents
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/50—Methods for regulating/modulating their activity
- C12N2320/53—Methods for regulating/modulating their activity reducing unwanted side-effects
Definitions
- the present invention relates to a nephrotoxicity-reducing agent for a pharmaceutical composition containing an antisense oligomer, a method for reducing nephrotoxicity of the pharmaceutical composition, a pharmaceutical composition containing an antisense oligomer with reduced nephrotoxicity, and the like.
- Antisense oligomers are nucleic acids that sequence-specifically hybridize to target mRNAs and pre-mRNAs. Antisense oligomers exert their effects through degradation of mRNA and pre-mRNA, exon skipping, exon inclusion, translation inhibition, etc., and are used as therapeutic agents for several diseases.
- Patent Document 1 discloses an antisense nucleic acid capable of treating Fukuyama muscular dystrophy or the like by normalizing aberrant splicing of fukutin gene having an insertion mutation of SVA-type retrotransposon.
- Non-Patent Document 1 morpholino oligomers accumulate in the kidney (Non-Patent Document 1, Figure 2)
- nephrotoxicity occurs due to administration of morpholino oligomers
- Non-Patent Document 2 Figure 3, Table 5
- compositions containing antisense oligomers have nephrotoxicity problems. Under these circumstances, it would be desirable to provide pharmaceutical compositions comprising improved antisense oligomers.
- the present invention provides a nephrotoxicity-reducing agent for a pharmaceutical composition containing an antisense oligomer described below, a method for reducing nephrotoxicity of the pharmaceutical composition, and a medicament with reduced nephrotoxicity containing an antisense oligomer.
- a nephrotoxicity-reducing agent for a pharmaceutical composition containing an antisense oligomer which contains a sugar alcohol and is used in an amount such that the concentration of the sugar alcohol in the pharmaceutical composition is 1 mg/mL to 400 mg/mL , nephrotoxicity-reducing agents.
- the nephrotoxicity-reducing agent according to (1) which is used in an amount such that the sugar alcohol concentration in the pharmaceutical composition is 2.5 mg/mL to 200 mg/mL.
- (4-1) A nephrotoxicity-reducing agent for a pharmaceutical composition containing an antisense oligomer, which contains a sugar alcohol and is used in an amount such that the weight ratio of the sugar alcohol to the weight of the antisense oligomer is 0.05 to 30. , a nephrotoxicity-reducing agent.
- a nephrotoxicity-reducing agent for a pharmaceutical composition containing an antisense oligomer, which contains a sugar alcohol and is used in an amount such that the weight ratio of the sugar alcohol to the weight of the antisense oligomer is 0.05 to 90.
- a nephrotoxicity-reducing agent nephrotoxicity-reducing agent according to (4-1) or (4-2), wherein the pharmaceutical composition and the nephrotoxicity-reducing agent are administered separately.
- the 5' end of the antisense oligomer has the following chemical formulas (1) to (2):
- the nephrotoxicity-reducing agent according to any one of (1) to (8) which is any group of (10) The nephrotoxicity-reducing agent according to any one of (1) to (9), wherein the antisense oligomer contains four consecutive purine bases in its base sequence.
- the nephrotoxicity-reducing agent according to any one of (1) to (11), wherein the antisense oligomer comprises a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-10.
- (15-1) A method for reducing nephrotoxicity of a pharmaceutical composition containing an antisense oligomer, comprising adding a sugar alcohol to a concentration of 1 mg/mL to 400 mg/mL of the sugar alcohol in the pharmaceutical composition.
- a method comprising adding an amount of (15-2) The method according to (15-1), wherein the sugar alcohol is added in an amount such that the sugar alcohol concentration in the pharmaceutical composition is 2.5 mg/mL to 200 mg/mL.
- (15-3) The method according to (15-1) or (15-2), wherein the concentration of the antisense oligomer in the pharmaceutical composition is 0.5 mg/mL to 200 mg/mL.
- (16-1) A method for reducing nephrotoxicity of an antisense oligomer in a subject administered with the antisense oligomer, comprising administering a sugar alcohol to the subject, where the antisense oligomer is 1 is administered in an amount such that the weight ratio of sugar alcohol to sugar alcohol is 0.05-30.
- (16-2) A method for reducing nephrotoxicity of an antisense oligomer in a subject administered with the antisense oligomer, comprising administering a sugar alcohol to the subject, where the antisense oligomer is 1 and sugar alcohol weight ratio of 0.05 to 90.
- (16-3) The method according to (16-1) or (16-2), wherein the antisense oligomer and the sugar alcohol are administered separately.
- (16-4) Any one of (16-1) to (16-3), wherein the sugar alcohol is used in an amount such that the weight ratio of the sugar alcohol to the antisense oligomer is 0.1 to 13.3. described method.
- (17-1) A pharmaceutical composition containing an antisense oligomer and having reduced nephrotoxicity, the pharmaceutical composition containing a nephrotoxicity-reducing agent containing a sugar alcohol at a concentration of 1 mg/mL to 400 mg/mL.
- (17-2) The pharmaceutical composition according to (17-1), which contains a nephrotoxicity-reducing agent containing sugar alcohol at a concentration of 2.5 mg/mL to 200 mg/mL.
- (17-3) The pharmaceutical composition according to (17-1) or (17-2), wherein the concentration of the antisense oligomer in said pharmaceutical composition is 0.5 mg/mL to 200 mg/mL.
- the method or pharmaceutical composition according to any one of (15-1) to (23), wherein the antisense oligomer comprises a base sequence selected from the group consisting of SEQ ID NOS: 1-10.
- the present invention provides a nephrotoxicity-reducing agent for a pharmaceutical composition containing an antisense oligomer and a method for reducing nephrotoxicity of the pharmaceutical composition.
- Absorbance measurements at 620 nm under the conditions shown in Table 11 are shown. Absorbance measurements at 620 nm under the conditions shown in Table 12 are shown. Absorbance measurements at 620 nm under the conditions shown in Table 13 are shown. Absorbance measurements at 620 nm under the conditions shown in Table 14 are shown. Absorbance measurements at 620 nm under the conditions shown in Table 15 are shown. Absorbance measurements at 620 nm under the conditions shown in Table 16 are shown.
- the present invention relates to nephrotoxicity-reducing agents of pharmaceutical compositions comprising antisense oligomers.
- nephrotoxicity-reducing agent means an agent for reducing nephrotoxicity that a pharmaceutical composition containing an antisense oligomer may have or a phenomenon that causes the nephrotoxicity (accumulation of basophilic substances, etc.). do.
- Administration of antisense oligomers distributes and accumulates in the kidney at high concentrations during the excretion process, resulting in the expression of basophils in the kidney.
- Nephrotoxicity means tissue damage or decreased renal function due to higher accumulation of antisense oligomers in the kidney.
- Renal tissue damage is known to cause, for example, dilatation and necrosis of renal tubules, and decreased renal function increases, for example, blood urea nitrogen (BUN) and blood creatinine (Cre) levels. It is widely known to Reducing the nephrotoxicity of antisense oligomers may provide pharmaceutical compositions comprising high doses of antisense oligomers, methods for treating disease using such pharmaceutical compositions.
- the presence or absence of nephrotoxicity-reducing effect can be determined, for example, by measuring the blood urea nitrogen (BUN) value and the blood creatinine (Cre) value, for example, by the urease method, the GIDH method, and the enzymatic method, respectively, as described in the Examples. can decide.
- BUN value and/or Cre value when the nephrotoxicity-reducing agent is administered, compared to when the nephrotoxicity-reducing agent is not administered is, for example, 5% or more, 10% or more, 20% or more, 30% or more, A reduction of 40% or more, or 50% or more can be determined to be effective in reducing nephrotoxicity.
- the nephrotoxicity-reducing agent of the present invention may consist of or contain a sugar alcohol.
- sugar alcohols include mannitol, sorbitol, glycerol, xylitol, arabitol, erythritol, galactitol, fucitol, iditol, inositol, boremitol, lactitol.
- the sugar alcohol is selected from the group consisting of mannitol, sorbitol, glycerol and combinations thereof, preferably mannitol, sorbitol and combinations thereof.
- the nephrotoxicity-reducing agent of the present invention contains a component other than sugar alcohol
- the nephrotoxicity-reducing agent contains a sugar alcohol with a pharmaceutically acceptable carrier or additive (and optionally the nephrotoxicity-reducing agent of the present invention). It may be formulated by blending them appropriately. Specifically, oral agents such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, and emulsions; parenteral agents such as injections, infusions, suppositories, ointments, and patches; can do. Parenteral agents are preferred. The injection may be a freeze-dried preparation. The blending ratio of the carrier or additive may be appropriately set based on the range normally employed in the pharmaceutical field.
- the carriers or additives that can be incorporated are not particularly limited, but for example, water, physiological saline, other aqueous solvents, various carriers such as aqueous or oily bases, excipients, binders, pH adjusters, disintegrants, absorption Various additives such as accelerators, lubricants, coloring agents, corrigents, and perfumes are included.
- excipients that can be mixed in tablets, capsules and the like include binders such as gelatin, cornstarch, tragacanth and gum arabic, excipients such as crystalline cellulose, cornstarch, gelatin, alginic acid and the like. Bulking agents, lubricants such as magnesium stearate, sweetening agents such as sucrose, lactose or saccharin, and flavoring agents such as peppermint, redwood oil or cherry may be used. When the dosage unit form is a capsule, the above type of material may further contain a liquid carrier such as oil. Sterile compositions for injection can be prepared according to normal pharmaceutical practice (eg, dissolving or suspending the active ingredient in a solvent such as water for injection, natural vegetable oil, etc.).
- Aqueous solutions for injection include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants (e.g., sodium chloride), and the like. ), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80 TM , HCO-50), and the like.
- the oily liquid for example, sesame oil, soybean oil and the like are used, and they may be used in combination with dissolution aids such as benzyl benzoate and benzyl alcohol.
- buffers e.g., phosphate buffer, sodium acetate buffer
- soothing agents e.g., benzalkonium chloride, procaine hydrochloride, etc.
- stabilizers e.g., human serum albumin, polyethylene glycol, etc.
- preservatives agents eg, benzyl alcohol, phenol, etc.
- antioxidants and the like.
- it may be a freeze-dried preparation.
- antisense oligomers may be either oligonucleotides, morpholino oligomers, or peptide nucleic acid (PNA) oligomers (hereinafter each referred to as “antisense oligos described herein. (also referred to as “nucleotides”, “antisense morpholino oligomers as described herein”, or “antisense peptide nucleic acid oligomers as described herein”).
- PNA peptide nucleic acid
- An antisense oligonucleotide is an antisense oligomer whose constituent units are nucleotides, and such nucleotides may be ribonucleotides, deoxyribonucleotides, or modified nucleotides.
- Modified nucleotides refer to those in which all or part of the nucleobases, sugar moieties, and phosphate-binding moieties that make up ribonucleotides or deoxyribonucleotides have been modified.
- Nucleic acid bases include, for example, adenine, guanine, hypoxanthine, cytosine, thymine, uracil, or modified bases thereof.
- modified bases include pseudouracil, 3-methyluracil, dihydrouracil, 5-alkylcytosine (eg, 5-methylcytosine), 5-alkyluracil (eg, 5-ethyluracil), 5-halouracil (eg, , 5-bromouracil), 6-azapyrimidine, 6-alkylpyrimidine (e.g., 6-methyluracil), 2-thiouracil, 4-thiouracil, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxy methylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluracil, 1-methyladenine, 1-methylhypoxanthine, 2,2-dimethylguanine, 3-methylcytosine, 2-methyladenine, 2-methylguanine, N
- Modifications of the sugar moiety can include, for example, modifications at the 2' position of ribose and modifications at other parts of the sugar.
- Modifications at the 2'-position of ribose include, for example, -OH group at the 2'-position of ribose with -OR, -R, -R'OR, -SH, -SR, -NH 2 , -NHR, -NR 2 , Modifications substituted for -N 3 , -CN, -F, -Cl, -Br, -I can be mentioned.
- R represents alkyl or aryl.
- R' represents alkylene.
- Modifications of other parts of the sugar include, for example, those in which the 4'-position of ribose or deoxyribose is replaced with S, those in which the 2'-position and 4'-position of the sugar are crosslinked, for example, LNA (Locked Nucleic Acid ) or ENA (2′-O,4′-C-Ethylene-bridged Nucleic Acids), but are not limited thereto.
- LNA Locked Nucleic Acid
- ENA (2′-O,4′-C-Ethylene-bridged Nucleic Acids
- Modifications of the phosphate binding moiety include, for example, phosphodiester linkages, phosphorothioate linkages, phosphorodithioate linkages, alkylphosphonate linkages, phosphoramidate linkages, boranophosphate linkages (e.g., Enya et al: Bioorganic & Medicinal Chemistry , 2008, 18, 9154-9160) (see, eg, Republished Patent Publication No. 2006/129594 and Republished Patent Publication No. 2006/038608).
- alkyl is preferably linear or branched alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl and isohexyl. be done.
- the alkyl may be substituted, and examples of such substituents include halogen, alkoxy, cyano, and nitro, and may be substituted with 1 to 3 of these.
- cycloalkyl having 3 to 12 carbon atoms is preferred as cycloalkyl.
- Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl.
- halogen includes fluorine, chlorine, bromine, and iodine.
- alkoxy refers to linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert. -butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy and the like.
- Alkoxy having 1 to 3 carbon atoms is particularly preferred.
- aryl having 6 to 10 carbon atoms is preferred as aryl.
- Specific examples include phenyl, ⁇ -naphthyl, and ⁇ -naphthyl. Phenyl is particularly preferred.
- the aryl may be substituted, and examples of such substituents include alkyl, halogen, alkoxy, cyano, and nitro, which may be substituted 1-3 times.
- alkylene is preferably linear or branched alkylene having 1 to 6 carbon atoms.
- Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 2-(ethyl)trimethylene, and 1-(methyl)tetramethylene.
- acyl includes linear or branched alkanoyl or aroyl.
- Alkanoyl includes, for example, formyl, acetyl, 2-methylacetyl, 2,2-dimethylacetyl, propionyl, butyryl, isobutyryl, pentanoyl, 2,2-dimethylpropionyl, hexanoyl and the like.
- Aroyl includes, for example, benzoyl, toluoyl and naphthoyl. Such aroyl may be optionally substituted at any substitutable position or may be substituted with alkyl.
- the antisense oligonucleotides described herein can be easily synthesized using various automated synthesizers (e.g., AKTA oligopilot plus 10/100 (GE Healthcare)), or can be synthesized by a third party ( For example, it can be produced by entrusting to Promega or Takara) or the like.
- automated synthesizers e.g., AKTA oligopilot plus 10/100 (GE Healthcare)
- a third party For example, it can be produced by entrusting to Promega or Takara
- the antisense morpholino oligomer described in this specification is an antisense oligomer having a group represented by the following general formula as a structural unit.
- Base represents a nucleobase
- W represents a group represented by any one of the following formulas.
- the morpholino oligomer is preferably an oligomer (phosphorodiamidate morpholino oligomer (hereinafter referred to as "PMO")) having a group represented by the following formula as a constituent unit.
- PMO phosphorodiamidate morpholino oligomer
- Morpholino oligomers can be produced, for example, according to the method described in WO 1991/009033 or WO 2009/064471.
- PMO can be produced according to the method described in WO2009/064471 or WO2013/100190.
- the antisense peptide nucleic acid oligomer described in this specification is an antisense oligomer having a group represented by the following general formula as a structural unit.
- Peptide nucleic acid oligomers can be produced, for example, according to the following literature. 1) P. E. Nielsen, M. Egholm, R. H. Berg, O. Buchardt, Science, 254, 1497 (1991) 2) M. Egholm, O. Buchardt, P. E. Nielsen, R. H. Berg, JACS, 114, 1895 (1992) 3) K. L. Dueholm, M. Egholm, C. Behrens, L. Christensen, H. F. Hansen, T. Vulpius, K. H. Petersen, R. H. Berg, P. E. Nielsen, O. Buchardt, J. Org.
- the antisense oligomers described herein may be in a pharmaceutically acceptable salt form, a hydrate form, or a hydrate form of a pharmaceutically acceptable salt thereof.
- Examples of pharmaceutically acceptable salts of the antisense oligomers described herein include alkali metal salts such as sodium, potassium and lithium salts, alkaline earth metal salts such as calcium and magnesium salts. metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts; ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salts, organic amine salts such as tetramethylammonium salts
- inorganic acid salts such as nitrates, perchlorates, sulfates and phosphates; lower alkanesulfonates such as methanesulfonates, trifluoromethanesulfonates and ethanesulfonates; benzenesulfonates, p - arylsulfonates such as toluenesulfonates; organic acid salts such as acetates, malate, fumarates, succinates, citrates, tartrates, oxalates, maleates; glycinates. , lysine salts, arginine salts, ornithine salts, glutamates, and amino acid salts such as aspartates.
- these salts can be produced by known methods.
- the antisense oligomers described herein may be in their hydrate form.
- the 5' end of the antisense oligomer described herein may be any group represented by the following chemical formulas (1) to (3). Preferably, it is the group (1) or (2).
- group (1) groups represented by (1), (2), and (3) above are referred to as “group (1),” “group (2),” and “group (3),” respectively.
- the base sequence of the antisense oligomer described herein is not limited, it may contain, for example, four consecutive purine bases in the base sequence. Also, at least two of the four consecutive purine bases may be guanine.
- the antisense oligomers described herein have (i) a base sequence selected from the group consisting of SEQ ID NOs: 1-10, (ii) a base selected from the group consisting of SEQ ID NOs: 1-10 80% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more of sequence identity, or (iii) one or several nucleotide sequences selected from the group consisting of SEQ ID NOS: 1 to 10 contains or consists of a base sequence in which the bases of are added, deleted, or substituted.
- the antisense oligomer described herein is the genome of an insertion mutant fukutin gene in which an SVA-type retrotransposon sequence (GenBank ACCESSION: AB185332) is inserted into the genome sequence of the fukutin gene (GenBank ACCESSION: AB038490).
- the target sequence is the range from position 115937 to position 115981 of the sequence (SEQ ID NO: 11), or this range is not the target sequence.
- Examples of antisense oligomers targeting the range of positions 115937 to 115981 of SEQ ID NO: 11 include antisense oligomers containing a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1-7.
- Examples of antisense oligomers that do not target the range of positions 115937 to 115981 of SEQ ID NO: 11 include antisense oligomers containing a base sequence selected from the group consisting of SEQ ID NOS: 8-10.
- the antisense oligomers described herein are conjugates with attached functional peptides, such as cell penetrating peptides (CPPs).
- functional peptides such as cell penetrating peptides (CPPs).
- Known functional peptides or commercially available functional peptides can be used herein.
- Functional peptides that can be used herein include, for example, arginine-rich peptides disclosed in WO2008/036127; or organs disclosed in WO2009/005793.
- Targeting peptides such as RXR, RBR, etc.; or peptides comprising amino acid subunits disclosed in WO2012/150960 are included.
- CPPs Cell-penetrating peptides
- Known CPPs or commercially available CPPs can be used herein.
- CPPs that can be used herein are, for example, Pharmacology & Therapeutics 154 (2015) 78-86, Table 1 on page 80, for example TAT(48-60), penetratin, polyarginine, Oct4, WT1-pTj, DPV3, transportan, MAP , VP22, Rep1, KW, KFGF, FGF12, Intefrin ⁇ 3 peptide, C105Y, TP2; Paragraph [0085] of Japanese Patent Publication No. 2017-500856 (International Publication No.
- CPPs listed in Table 1 Examples include DPV10/6, DPV15b, YM-3, Tat, LR11, C45D18, Lyp-1, Lyp-2, BMV GAG, hLF1-22, C45D18, LR20 and the like.
- CPPs are available from Funakoshi, Co., for example. , Ltd. It is commercially available from Commercially available CPPs such as TAT (Funakoshi, Co., Ltd.), penetratin (Funakoshi, Co., Ltd.), or known CPPs, such as R8, can be used herein.
- Preferred CPPs that can be used herein include, for example, hLIMK, TAT, penetratin, R8, etc.
- the CPP can be directly attached to the antisense oligomers herein or can be attached via a linker that can attach the CPP to the antisense oligomer.
- linkers can be used herein. Such linkers include, for example, Japanese Patent Publication No. 2017-500856 (International Publication No. 2015/089487), International Publication No. 2015/089487, International Publication No. 2009/073809, International Publication No. 2013/ 075035 pamphlet, International Publication No. 2015/105083 pamphlet, International Publication No.
- linkers that can be used herein include, for example, 4-maleimidobutyric acid, linkers that can bind to the functional peptides or antisense oligomers herein via disulfide bonds, and the like.
- the conjugates herein can be prepared by methods known to those skilled in the art.
- composition described herein may be formulated by appropriately blending a pharmaceutically acceptable carrier or additive (and optionally the sugar alcohol of the present invention).
- Pharmaceutical compositions, pharmaceutically acceptable carriers or additives, and formulations are the same as those described for the nephrotoxicity-reducing agent of the present invention, except that the antisense nucleic acid is the active ingredient.
- the nephrotoxicity-reducing agent of the present invention is used in an amount such that the concentration of sugar alcohol in the pharmaceutical composition described herein is between 1 mg/mL and 400 mg/mL, such as between 2.5 mg/mL and 200 mg/mL. and/or added to pharmaceutical compositions.
- the nephrotoxicity-reducing agent of the present invention has a sugar alcohol concentration of 1 mg/mL or higher, 2.5 mg/mL or higher, 3 mg/mL or higher, 4 mg/mL or higher, or 5 mg/mL or higher in the pharmaceutical composition.
- the concentration of sugar alcohol in the pharmaceutical composition is 400 mg/mL or less, 350 mg/mL or less, 300 mg/mL or less, 250 mg/mL or less, or 200 mg/mL or less. used in amounts and/or added to pharmaceutical compositions.
- the concentration of antisense oligomer in the pharmaceutical composition described herein is 0.5 mg/mL to 200 mg/mL, such as 6 mg/mL to 200 mg/mL. In one embodiment, the concentration of antisense oligomer in the pharmaceutical composition described herein is 0.5 mg/mL or greater, 1 mg/mL or greater, 2 mg/mL or greater, 3 mg/mL or greater, 4 mg/mL or greater, 5 mg /mL or more, or 6 mg/mL or more, and may be 200 mg/mL or less, 180 mg/mL or less, 150 mg/mL or less, 140 mg/mL or less, or 130 mg/mL or less.
- the present invention provides a nephrotoxicity-reducing agent for a pharmaceutical composition comprising an antisense oligomer, which comprises a sugar alcohol, wherein the weight ratio of the sugar alcohol to the antisense oligomer is 0.05 to 90, It relates to nephrotoxicity-reducing agents used in an amount of 0.05 to 30, such as 0.1 to 13.3. Pharmaceutical compositions and sugar alcohols containing antisense oligomers are described above.
- the nephrotoxicity-reducing agent of the present invention has a sugar alcohol weight ratio of 0.05 or higher, 0.1 or higher, 0.15 or higher, 0.2 or higher, 0.3 or higher, 0.4 or higher, 0.5 or higher, to 1 for the antisense oligomer.
- the nephrotoxicity-reducing agent of the present invention has a sugar alcohol weight ratio of 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, to 1 for the antisense oligomer. It is used in an amount that is 25 or less, 20 or less, 15 or less, 13.3 or less, or 10 or less.
- the nephrotoxicity-reducing agent of the present invention is contained in a pharmaceutical composition described herein and administered with the pharmaceutical composition described herein.
- a pharmaceutical composition in which the antisense oligomer described herein is optionally lyophilized with a carrier such as glucose and dissolved in a solvent such as water for injection is mixed with the nephrotoxicity-reducing agent described herein. and then optionally adjusting the amount with a solvent and administering to the subject.
- the antisense oligomer described herein is freeze-dried together with the nephrotoxicity-reducing agent of the present invention, dissolved in a solvent such as water for injection to form a pharmaceutical composition, and then the amount is arbitrarily adjusted with the solvent. may be administered to the subject.
- nephrotoxicity-reducing agents of the invention are not included in the pharmaceutical compositions described herein and are administered separately (simultaneously or sequentially) from the pharmaceutical compositions described herein. be done.
- a pharmaceutical composition in which a lyophilized antisense oligomer described herein is dissolved in a solvent such as water for injection and the nephrotoxicity-reducing agent described herein may be administered to a subject separately.
- administering the nephrotoxicity-mitigating agent and the pharmaceutical composition "at the same time” means administering the nephrotoxicity-mitigating agent and the pharmaceutical composition at the same time.
- administering the nephrotoxicity-reducing agent and the pharmaceutical composition means administering at different times. Specifically, it can be administered before or after the nephrotoxicity-reducing agent, and in this case, the administration interval between the nephrotoxicity-reducing agent and the pharmaceutical composition is not limited, but for example, several minutes, several hours, or about one day. can be up to
- subjects to which the pharmaceutical composition and/or nephrotoxicity-reducing agent are administered include, but are not limited to, mammals, such as primates such as humans, experimental animals such as rats, mice, and rats, pigs, Livestock animals such as cattle, horses, and sheep are included, and humans are preferred.
- the dosage for administration of the pharmaceutical composition and/or nephrotoxicity-reducing agent includes the type of sugar alcohol contained in the antisense oligomer and nephrotoxicity-reducing agent contained in the pharmaceutical composition, and the amount of the pharmaceutical composition and nephrotoxicity-reducing agent. It can be adjusted in consideration of the dosage form, the condition of the subject such as age and weight, the route of administration, and the nature and symptoms of the disease. For example, it can be in the range of 1 mg to 1 g/person, such as 10 mg to 100 mg/person, and the amount of sugar alcohol is, for example, in the range of 0.1 mg to 200 g/person, such as 1 mg to 100 g/person per day.
- the number of administrations and the administration frequency are not limited, but for example, the administration can be performed once a day or two or three times at an interval of one day to two or three days. Also, for example, it can be administered only once, and can be administered again several days later for a total of two administrations.
- the invention is a method for reducing nephrotoxicity of a pharmaceutical composition comprising an antisense oligomer, or a method for producing a pharmaceutical composition with reduced nephrotoxicity comprising an antisense oligomer. and adding sugar alcohol in an amount such that the concentration of sugar alcohol in said pharmaceutical composition is between 1 mg/mL and 400 mg/mL.
- the antisense oligomer, the pharmaceutical composition, the sugar alcohol, the concentration of the sugar alcohol in the pharmaceutical composition, etc. are as described herein.
- the present invention provides a method for reducing nephrotoxicity of an antisense oligomer in a subject administered an antisense oligomer or a pharmaceutical composition comprising an antisense oligomer comprising: a sugar alcohol or a nephrotoxicity-reducing agent; to the subject, in an amount such that the weight ratio of sugar alcohol to 1 is 0.05-90 or 0.05-30.
- the weight ratio of the antisense oligomer, the pharmaceutical composition, the sugar alcohol, the nephrotoxicity-reducing agent, the sugar alcohol to the antisense oligomer and the like are as described in this specification.
- the present invention provides a reduced nephrotoxicity pharmaceutical composition
- a reduced nephrotoxicity pharmaceutical composition comprising an antisense oligomer, the pharmaceutical composition comprising a nephrotoxicity reducing agent comprising a sugar alcohol at a concentration of 1 mg/mL to 400 mg/mL. about things.
- the antisense oligomer, the pharmaceutical composition, the sugar alcohol, the concentration of the sugar alcohol in the pharmaceutical composition, etc. are as described herein.
- Antisense oligomers (PMO Nos. 1 to 10 (SEQ ID NOS: 1 to 10)) shown in Table 1 were synthesized according to the method described in International Publication WO2013/100190. The theoretical and ESI-TOF-MS molecular weights of each antisense oligomer are also shown.
- Example 2 Evaluation of nephrotoxicity-reducing effect of D-mannitol
- PMO No. 1, 2, 3, 4, 6, 7, and 10 SEQ ID NOS: 1, 2, 3, 4, 6, 7, and 10.
- SEQ ID NOS: 1, 2, 3, 4, 6, 7, and 10 were evaluated for safety in the kidney in order to verify their usefulness for pharmaceutical use. rice field.
- Each antisense oligomer of 1, 2, 6, 7 and 10 was dissolved in water for injection containing 0.9% sodium chloride (manufactured by Otsuka Pharmaceutical Co., Ltd.), and A control dosing solution containing D-mannitol without D-mannitol was prepared.
- Each antisense oligomer of 3 and 4 was dissolved in 5% glucose (manufactured by Otsuka Pharmaceutical Co., Ltd.) to prepare a control dosing solution containing each antisense oligomer at the concentration shown in Tables 4 and 5 and containing no D-mannitol.
- PMO No. No. 2 antisense oligomer was dissolved in a solution of D-sorbitol (manufactured by Maruishi Seiyaku Co., Ltd.) dissolved in physiological saline to prepare a dosing solution containing the antisense oligomer and D-sorbitol at the concentrations shown in Table 9.
- PMO No. The antisense oligomer of No. 3 was dissolved in a solution of D-sorbitol dissolved in water for injection to prepare an administration solution containing the antisense oligomer and D-sorbitol at the concentrations shown in Table 10.
- Example 4 Evaluation of precipitation inhibitory action by D-mannitol
- Test method Among the antisense oligomers shown in Table 1, PMO No. 1, 2, 3, 5, 6, 7 (SEQ ID NOS: 1, 2, 3, 5, 6, 7) were tested in the presence of ions assuming urine in order to further verify their usefulness for pharmaceutical applications. The precipitation amount and the precipitation suppressing effect of D-mannitol were evaluated.
- Each antisense oligomer was dissolved in physiological saline or an aqueous solution of D-mannitol and mixed with an aqueous solution containing potassium chloride and sodium chloride, which was assumed to be urine.
- Tables 11 to 16 show the evaluated conditions (solution composition).
- the absorbance of the mixed solution at 620 nm was measured under heating conditions of 37°C using a plate reader Infinite F200 Pro (manufactured by TECAN). Assuming precipitation of antisense oligomers in urine, the concentrations of antisense oligomers, potassium chloride, and sodium chloride will vary depending on the dose of antisense oligomers and urine volume. was used to set the conditions under which precipitation was observed.
- the measurement was performed under the conditions in which only the medium was changed to an aqueous solution of D-mannitol from the obtained conditions, and the absorbance obtained under both conditions was compared.
- the absorbance increased, it was determined that precipitation was observed, and the time until precipitation was observed and the absorbance increase value were evaluated.
- the D-mannitol aqueous solution was used as a medium, it was determined that the precipitation suppressing effect was present when the time until precipitation was observed was slower than when the medium was water for injection, or when the absorbance increase value was small.
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Abstract
Description
(1)アンチセンスオリゴマーを含む医薬組成物の腎毒性軽減剤であって、糖アルコールを含み、前記医薬組成物中の糖アルコールの濃度が1mg/mL~400mg/mLになる量で使用される、腎毒性軽減剤。
(2)前記医薬組成物中の糖アルコールの濃度が2.5mg/mL~200mg/mLになる量で使用される、(1)に記載の腎毒性軽減剤。
(3)前記医薬組成物中のアンチセンスオリゴマーの濃度が、0.5mg/mL~200mg/mLである、(1)又は(2)に記載の腎毒性軽減剤。
(4-1)アンチセンスオリゴマーを含む医薬組成物の腎毒性軽減剤であって、糖アルコールを含み、アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.05~30となる量で使用される、腎毒性軽減剤。
(4-2)アンチセンスオリゴマーを含む医薬組成物の腎毒性軽減剤であって、糖アルコールを含み、アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.05~90となる量で使用される、腎毒性軽減剤。
(4-3)前記医薬組成物と腎毒性軽減剤が別々に投与される、(4-1)又は(4-2)に記載の腎毒性軽減剤。
(5)アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.1~13.3となる量で使用される、(4-1)~(4-3)のいずれかに記載の腎毒性軽減剤。
(6)糖アルコールが、マンニトール、ソルビトール、及びそれらの組み合わせからなる群から選択される、(1)~(5)のいずれかに記載の腎毒性軽減剤。
(7)アンチセンスオリゴマーがモルホリノオリゴマーである、(1)~(6)のいずれかに記載の腎毒性軽減剤。
(8)アンチセンスオリゴマーがホスホロジアミデートモルホリノオリゴマーである、(1)~(7)のいずれかに記載の腎毒性軽減剤。
(9)アンチセンスオリゴマーの5'末端が、下記化学式(1)~(2):
(10)前記アンチセンスオリゴマーが、その塩基配列中に4つの連続するプリン塩基を含む、(1)~(9)のいずれかに記載の腎毒性軽減剤。
(11)前記4つの連続するプリン塩基のうちの少なくとも2つがグアニンである、(10)に記載の腎毒性軽減剤。
(12)前記アンチセンスオリゴマーが、配列番号1~10からなる群から選択される塩基配列を含む、(1)~(11)のいずれかに記載の腎毒性軽減剤。
(13)前記アンチセンスオリゴマーが、配列番号11で示される塩基配列の第115937位~第115981位の範囲を標的配列とする、(1)~(12)のいずれか記載の腎毒性軽減剤。
(14)前記アンチセンスオリゴマーが、配列番号11で示される塩基配列の第115937位~第115981位の範囲を標的配列とするものではない、(1)~(12)のいずれかに記載の腎毒性軽減剤。
(15-1)アンチセンスオリゴマーを含む医薬組成物の腎毒性を軽減するための方法であって、糖アルコールを、前記医薬組成物中の糖アルコールの濃度が1mg/mL~400mg/mLになる量で添加することを含む、方法。
(15-2)糖アルコールを、前記医薬組成物中の糖アルコールの濃度が2.5mg/mL~200mg/mLになる量で添加する、(15-1)に記載の方法。
(15-3)前記医薬組成物中のアンチセンスオリゴマーの濃度が、0.5mg/mL~200mg/mLである、(15-1)又は(15-2)に記載の方法。
(16-1)アンチセンスオリゴマーを投与した対象において、アンチセンスオリゴマーの腎毒性を軽減するための方法であって、糖アルコールを前記対象に投与することを含み、アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.05~30となる量で投与される、方法。
(16-2)アンチセンスオリゴマーを投与した対象において、アンチセンスオリゴマーの腎毒性を軽減するための方法であって、糖アルコールを前記対象に投与することを含み、アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.05~90となる量で投与される、方法。
(16-3)前記アンチセンスオリゴマーと前記糖アルコールが別々に投与される、(16-1)又は(16-2)に記載の方法。
(16-4)糖アルコールが、アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.1~13.3となる量で使用される、(16-1)~(16-3)のいずれかに記載の方法。
(17-1)アンチセンスオリゴマーを含む腎毒性が軽減された医薬組成物であって、糖アルコールを含む腎毒性軽減剤を1mg/mL~400mg/mLの濃度で含む、医薬組成物。
(17-2)糖アルコールを含む腎毒性軽減剤を2.5mg/mL~200mg/mLの濃度で含む、(17-1)に記載の医薬組成物。
(17-3)前記医薬組成物中のアンチセンスオリゴマーの濃度が、0.5mg/mL~200mg/mLである、(17-1)又は(17-2)に記載の医薬組成物。
(18)糖アルコールが、マンニトール、ソルビトール、及びそれらの組み合わせからなる群から選択される、(15-1)~(17-3)のいずれかに記載の方法又は医薬組成物。
(19)アンチセンスオリゴマーがモルホリノオリゴマーである、(15-1)~(18)のいずれかに記載の方法又は医薬組成物。
(20)アンチセンスオリゴマーがホスホロジアミデートモルホリノオリゴマーである、(15-1)~(19)のいずれかに記載の方法又は医薬組成物。
(21)アンチセンスオリゴマーの5'末端が、下記化学式(1)~(2):
(22)前記アンチセンスオリゴマーが、その塩基配列中に4つの連続するプリン塩基を含む、(15-1)~(21)のいずれかに記載の方法又は医薬組成物。
(23)前記4つの連続するプリン塩基のうちの少なくとも2つがグアニンである、(22)に記載の方法又は医薬組成物。
(24)前記アンチセンスオリゴマーが、配列番号1~10からなる群から選択される塩基配列を含む、(15-1)~(23)のいずれかに記載の方法又は医薬組成物。
(25)前記アンチセンスオリゴマーが、配列番号11で示される塩基配列の第115937位~第115981位の範囲を標的配列とする、(15-1)~(24)のいずれか記載の腎毒性軽減剤。
(26)前記アンチセンスオリゴマーが、配列番号11で示される塩基配列の第115937位~第115981位の範囲を標的配列とするものではない、(15-1)~(24)のいずれかに記載の腎毒性軽減剤。
Wは、以下のいずれかの式で表わされる基を表す。
R1は、H、アルキルを表し;
R2及びR3は、同一又は異なって、H、アルキル、シクロアルキル、又はアリールを表し;
Y1は、O、S、CH2、又はNR1を表し;
Y2は、O、S、又はNR1を表し;
Zは、O又はSを表す。))
本明細書において、モルホリノオリゴマーは、好ましくは、以下の式で表わされる基を構成単位とするオリゴマー(ホスホロジアミデートモルホリノオリゴマー(以下、「PMO」という))である。
モルホリノオリゴマーは、例えば、国際公開公報第1991/009033号、又は国際公開公報第2009/064471号に記載の方法に従って製造することができる。特に、PMOは、国際公開公報第2009/064471号、又は国際公開公報第2013/100190号に記載の方法に従って製造することができる。
ペプチド核酸オリゴマーは、例えば、以下の文献に従って製造することができる。
1)P. E. Nielsen, M. Egholm, R. H. Berg, O. Buchardt,Science, 254, 1497 (1991)2)M. Egholm, O. Buchardt, P. E. Nielsen, R. H. Berg,JACS, 114, 1895 (1992)
3)K. L. Dueholm, M. Egholm, C. Behrens, L. Christensen, H. F. Hansen, T. Vulpius, K. H. Petersen, R. H. Berg, P. E. Nielsen, O. Buchardt,J. Org. Chem., 59, 5767 (1994)
4)L. Christensen, R. Fitzpatrick, B. Gildea, K. H. Petersen, H. F. Hansen, T. Koch, M. Egholm,O. Buchardt, P. E. Nielsen, J. Coull, R. H. Berg, J. Pept. Sci., 1, 175 (1995)5)T. Koch, H. F. Hansen, P. Andersen, T. Larsen, H. G. Batz, K. Otteson, H. Orum, J. Pept. Res., 49, 80 (1997)
本明細書に記載のアンチセンスオリゴマーは、その医薬的に許容可能な塩の形態、水和物の形態、又は医薬的に許容可能な塩の水和物の形態であってもよい。
& Therapeutics 154 (2015) 78-86の80頁の表1に列挙されたCPPが含まれ、例えば、TAT(48-60)、ペネトラチン、ポリアルギニン、Oct4、WT1-pTj、DPV3、トランスポータン、MAP、VP22、Rep1、KW、KFGF、FGF12、インテフリンβ3ペプチド、C105Y、TP2;特表2017-500856明細書(国際公開第2015/089487号パンフレット)の段落[0085]、表1に列挙されるCPP、例えばDPV10/6、DPV15b、YM-3、Tat、LR11、C45D18、Lyp-1、Lyp-2、BMV GAG、hLF1-22、C45D18、LR20などが挙げられる。CPPは、例えば、Funakoshi,Co.,Ltd.から市販されている。TAT(Funakoshi,Co.,Ltd.)、ペネトラチン(Funakoshi,Co.,Ltd.)などの市販のCPP、又は公知のCPP、例えばR8などを本明細書において使用することができる。本明細書において用いることができる好ましいCPPは、例えば、hLIMK、TAT、ペネトラチン、R8などを含む(国際公開第2016/187425号パンフレット、国際公開第2018/118662号パンフレット、国際公開第2018/118599号パンフレット、国際公開第2018/118627号パンフレット、EBioMedicine 45 (2019) 630-645などを参照されたい)。CPPは、本明細書のアンチセンスオリゴマーに直接結合することができ、又はCPPをアンチセンスオリゴマーに結合することができるリンカーを介して結合することができる。公知のリンカーを本明細書において使用することができる。このようなリンカーには、例えば、特表2017-500856明細書(国際公開第2015/089487号パンフレット)、国際公開第2015/089487号パンフレット、国際公開第2009/073809号パンフレット、国際公開第2013/075035号パンフレット、国際公開第2015/105083号パンフレット、国際公開第2014/179620号パンフレット、国際公開第2015/006740号パンフレット、国際公開第2017/010575号パンフレットなどに記載されるものが含まれる。本明細書において使用することができる好ましいリンカーは、例えば、4-マレイミド酪酸、ジスルフィド結合を介して本明細書の機能性ペプチド又はアンチセンスオリゴマーに結合することができるリンカーなどを含む。本明細書のコンジュゲートは、当業者に公知の方法によって調製することができる。
国際公開公報WO2013/100190に記載の方法に従い、表1に示すアンチセンスオリゴマー(PMO No.1~10(配列番号1~10))を合成した。各アンチセンスオリゴマーの分子量の理論値及びESI-TOF-MSによる実測値も示す。
表1に示すアンチセンスオリゴマーのうち、PMO No.1、2、3、4、6、7、10(配列番号1、2、3、4、6、7、10)について、医薬用途への有用性を検証するため、腎臓における安全性評価を行った。
(1)評価方法
PMO No.1、2、6、7、10の各アンチセンスオリゴマーを0.9%の塩化ナトリウムを含む注射用水(大塚製薬製)に溶解し、各アンチセンスオリゴマーを表2、3、6、7、8に記載の濃度で含みD-マンニトールを含まない対照の投与液を作製した。また、PMO No.3、4の各アンチセンスオリゴマーを5%グルコース(大塚製薬製)に溶解し、各アンチセンスオリゴマーを表4、5に記載の濃度で含みD-マンニトールを含まない対照の投与液を作製した。
(2)評価結果
試験した各アンチセンスオリゴマーは、D-マンニトールを含む投与液を投与したマウスにおいて、BUN値及びCre値の両方の値で低下傾向が認められたため、D-マンニトールが腎毒性を軽減することを確認した。結果を表2、3、4、5、6、7、8に示す。
[実施例3:D-ソルビトールによる腎毒性軽減作用の評価]
表1に示すアンチセンスオリゴマーのうち、PMO No.2、3(配列番号2、3)について、医薬用途への有用性を検証するため、腎臓における安全性評価を行った。
(1)評価方法
PMO No.2のアンチセンスオリゴマーを生理食塩水に溶解し、アンチセンスオリゴマーを表9に記載の濃度で含みD-ソルビトールを含まない対照の投与液を作製した。また、PMO No.3のアンチセンスオリゴマーをダルベッコPBS(-)(ニッスイ製)に溶解し、アンチセンスオリゴマーを表10に記載の濃度で含みD-ソルビトールを含まない対照の投与液を作製した。
(2)評価結果
試験した各アンチセンスオリゴマーは、D-ソルビトールを含む投与液を投与したマウスにおいて、BUN値及びCre値の両方の値で低下傾向が認められたため、D-ソルビトールが腎毒性を軽減することを確認した。結果を表9、10に示す。
試験方法
表1に示すアンチセンスオリゴマーのうち、PMO No.1、2、3、5、6、7(配列番号1、2、3、5、6、7)について、医薬用途への有用性をさらに検証するため、尿中を想定したイオン存在下での析出量及びD-マンニトールによる析出抑制作用を評価した。
試験した各アンチセンスオリゴマーは、全てD-マンニトール水溶液を媒体とした場合に、析出がみられるまでの時間が遅延し、吸光度の上昇を抑制したことから、D-マンニトールはアンチセンスオリゴマーの析出を抑制することが示された。それぞれの結果を、図1~6に示す。
Claims (17)
- アンチセンスオリゴマーを含む医薬組成物の腎毒性軽減剤であって、糖アルコールを含み、前記医薬組成物中の糖アルコールの濃度が1mg/mL~400mg/mLになる量で使用される、腎毒性軽減剤。
- 前記医薬組成物中の糖アルコールの濃度が2.5mg/mL~200mg/mLになる量で使用される、請求項1に記載の腎毒性軽減剤。
- 前記医薬組成物中のアンチセンスオリゴマーの濃度が、0.5mg/mL~200mg/mLである、請求項1又は2に記載の腎毒性軽減剤。
- アンチセンスオリゴマーを含む医薬組成物の腎毒性軽減剤であって、糖アルコールを含み、アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.05~30となる量で使用される、腎毒性軽減剤。
- アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.1~13.3となる量で使用される、請求項4に記載の腎毒性軽減剤。
- 糖アルコールが、マンニトール、ソルビトール、及びそれらの組み合わせからなる群から選択される、請求項1~5のいずれか一項に記載の腎毒性軽減剤。
- アンチセンスオリゴマーがモルホリノオリゴマーである、請求項1~6のいずれか一項に記載の腎毒性軽減剤。
- アンチセンスオリゴマーがホスホロジアミデートモルホリノオリゴマーである、請求項1~7のいずれか一項に記載の腎毒性軽減剤。
- 前記アンチセンスオリゴマーが、その塩基配列中に4つの連続するプリン塩基を含む、請求項1~9のいずれか一項に記載の腎毒性軽減剤。
- 前記4つの連続するプリン塩基のうちの少なくとも2つがグアニンである、請求項10に記載の腎毒性軽減剤。
- 前記アンチセンスオリゴマーが、配列番号1~10からなる群から選択される塩基配列を含む、請求項1~11のいずれか一項に記載の腎毒性軽減剤。
- 前記アンチセンスオリゴマーが、配列番号11で示される塩基配列の第115937位~第115981位の範囲を標的配列とする、請求項1~12のいずれか一項に記載の腎毒性軽減剤。
- 前記アンチセンスオリゴマーが、配列番号11で示される塩基配列の第115937位~第115981位の範囲を標的配列とするものではない、請求項1~12のいずれか一項に記載の腎毒性軽減剤。
- アンチセンスオリゴマーを含む医薬組成物の腎毒性を軽減するための方法であって、糖アルコールを、前記医薬組成物中の糖アルコールの濃度が1mg/mL~400mg/mLになる量で添加することを含む、方法。
- アンチセンスオリゴマーを投与した対象において、アンチセンスオリゴマーの腎毒性を軽減するための方法であって、糖アルコールを前記対象に投与することを含み、アンチセンスオリゴマーを1としたときの糖アルコールの重量比が0.05~30となる量で投与される、方法。
- アンチセンスオリゴマーを含む腎毒性が軽減された医薬組成物であって、糖アルコールを含む腎毒性軽減剤を1mg/mL~400mg/mLの濃度で含む、医薬組成物。
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Citations (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991009033A1 (en) | 1989-12-20 | 1991-06-27 | Anti-Gene Development Group | Uncharged morpholino-based polymers having phosphorous-containing chiral intersubunit linkages |
US20020036767A1 (en) | 2000-09-22 | 2002-03-28 | Alcatel | Method for monitoring an optical waveguide, as well as monitoring system and monitoring unit for said method |
JP2004512383A (ja) * | 2000-11-02 | 2004-04-22 | アイネックス ファーマシューティカルズ コーポレイション | 毒性の減少した治療用オリゴヌクレオチド |
JP2006038608A (ja) | 2004-07-27 | 2006-02-09 | Tokyo Electric Power Co Inc:The | 超音波検査装置及び方法 |
JP2006129594A (ja) | 2004-10-28 | 2006-05-18 | Hitachi Ltd | 船舶用電気推進装置の制御方法及びその装置 |
WO2008036127A2 (en) | 2006-05-10 | 2008-03-27 | Avi Biopharma, Inc. | Oligonucleotide analogs having cationic intersubunit linkages |
WO2009005793A2 (en) | 2007-06-29 | 2009-01-08 | Avi Biopharma, Inc. | Tissue specific peptide conjugates and methods |
WO2009064471A1 (en) | 2007-11-15 | 2009-05-22 | Avi Biopharma, Inc. | Method of synthesis of morpholino oligomers |
WO2009073809A2 (en) | 2007-12-04 | 2009-06-11 | Alnylam Pharmaceuticals, Inc. | Carbohydrate conjugates as delivery agents for oligonucleotides |
WO2010009038A2 (en) | 2008-07-18 | 2010-01-21 | Oncogenex Technologies Inc. | Antisense formulation |
WO2012150960A1 (en) | 2011-05-05 | 2012-11-08 | Avi Biopharma, Inc. | Peptide oligonucleotide conjugates |
WO2013075035A1 (en) | 2011-11-18 | 2013-05-23 | Alnylam Pharmaceuticals | Rnai agents, compositions and methods of use thereof for treating transthyretin (ttr) associated diseases |
WO2013100190A1 (ja) | 2011-12-28 | 2013-07-04 | 日本新薬株式会社 | アンチセンス核酸 |
WO2014179620A1 (en) | 2013-05-01 | 2014-11-06 | Isis Pharmaceuticals, Inc. | Conjugated antisense compounds and their use |
WO2015006740A2 (en) | 2013-07-11 | 2015-01-15 | Alnylam Pharmaceuticals, Inc. | Oligonucleotide-ligand conjugates and process for their preparation |
JP2015091229A (ja) | 2013-10-04 | 2015-05-14 | 国立大学法人神戸大学 | 福山型筋ジストロフィー治療用アンチセンス核酸 |
WO2015089487A1 (en) | 2013-12-12 | 2015-06-18 | Life Technologies Corporation | Membrane-penetrating peptides to enhance transfection and compositions and methods for using same |
WO2015105083A1 (ja) | 2014-01-07 | 2015-07-16 | 塩野義製薬株式会社 | アンチセンスオリゴヌクレオチド及び糖誘導体を含む二本鎖オリゴヌクレオチド |
WO2016187425A1 (en) | 2015-05-19 | 2016-11-24 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
WO2017010575A1 (ja) | 2015-07-16 | 2017-01-19 | 協和発酵キリン株式会社 | β2GPI遺伝子発現抑制核酸複合体 |
WO2018118662A1 (en) | 2016-12-19 | 2018-06-28 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
WO2018118599A1 (en) | 2016-12-19 | 2018-06-28 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
WO2018118627A1 (en) | 2016-12-19 | 2018-06-28 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060159737A1 (en) | 2004-11-19 | 2006-07-20 | Steffen Panzner | Pharmaceutical compositions for local administration |
CN1868456A (zh) | 2006-06-25 | 2006-11-29 | 沈阳药科大学 | 反义脱氧寡核苷酸isis23665脂质体制剂及制备方法 |
CN102989007B (zh) | 2011-06-29 | 2015-12-16 | 湖州市中心医院 | 大规模制备注射用中期因子反义寡核苷酸纳米脂质体的方法 |
-
2022
- 2022-07-08 EP EP22837758.6A patent/EP4368176A1/en active Pending
- 2022-07-08 CN CN202280047615.2A patent/CN118201606A/zh active Pending
- 2022-07-08 TW TW111125776A patent/TW202308664A/zh unknown
- 2022-07-08 US US18/577,111 patent/US20240285547A1/en active Pending
- 2022-07-08 WO PCT/JP2022/027103 patent/WO2023282344A1/ja active Application Filing
- 2022-07-08 JP JP2022555690A patent/JPWO2023282344A1/ja active Pending
- 2022-11-07 JP JP2022178039A patent/JP7471613B2/ja active Active
Patent Citations (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991009033A1 (en) | 1989-12-20 | 1991-06-27 | Anti-Gene Development Group | Uncharged morpholino-based polymers having phosphorous-containing chiral intersubunit linkages |
US20020036767A1 (en) | 2000-09-22 | 2002-03-28 | Alcatel | Method for monitoring an optical waveguide, as well as monitoring system and monitoring unit for said method |
JP2004512383A (ja) * | 2000-11-02 | 2004-04-22 | アイネックス ファーマシューティカルズ コーポレイション | 毒性の減少した治療用オリゴヌクレオチド |
JP2006038608A (ja) | 2004-07-27 | 2006-02-09 | Tokyo Electric Power Co Inc:The | 超音波検査装置及び方法 |
JP2006129594A (ja) | 2004-10-28 | 2006-05-18 | Hitachi Ltd | 船舶用電気推進装置の制御方法及びその装置 |
WO2008036127A2 (en) | 2006-05-10 | 2008-03-27 | Avi Biopharma, Inc. | Oligonucleotide analogs having cationic intersubunit linkages |
WO2009005793A2 (en) | 2007-06-29 | 2009-01-08 | Avi Biopharma, Inc. | Tissue specific peptide conjugates and methods |
WO2009064471A1 (en) | 2007-11-15 | 2009-05-22 | Avi Biopharma, Inc. | Method of synthesis of morpholino oligomers |
WO2009073809A2 (en) | 2007-12-04 | 2009-06-11 | Alnylam Pharmaceuticals, Inc. | Carbohydrate conjugates as delivery agents for oligonucleotides |
WO2010009038A2 (en) | 2008-07-18 | 2010-01-21 | Oncogenex Technologies Inc. | Antisense formulation |
JP2011528657A (ja) * | 2008-07-18 | 2011-11-24 | オンコジェネックス・テクノロジーズ・インコーポレーテッド | アンチセンス製剤 |
WO2012150960A1 (en) | 2011-05-05 | 2012-11-08 | Avi Biopharma, Inc. | Peptide oligonucleotide conjugates |
WO2013075035A1 (en) | 2011-11-18 | 2013-05-23 | Alnylam Pharmaceuticals | Rnai agents, compositions and methods of use thereof for treating transthyretin (ttr) associated diseases |
WO2013100190A1 (ja) | 2011-12-28 | 2013-07-04 | 日本新薬株式会社 | アンチセンス核酸 |
WO2014179620A1 (en) | 2013-05-01 | 2014-11-06 | Isis Pharmaceuticals, Inc. | Conjugated antisense compounds and their use |
WO2015006740A2 (en) | 2013-07-11 | 2015-01-15 | Alnylam Pharmaceuticals, Inc. | Oligonucleotide-ligand conjugates and process for their preparation |
JP2015091229A (ja) | 2013-10-04 | 2015-05-14 | 国立大学法人神戸大学 | 福山型筋ジストロフィー治療用アンチセンス核酸 |
WO2015089487A1 (en) | 2013-12-12 | 2015-06-18 | Life Technologies Corporation | Membrane-penetrating peptides to enhance transfection and compositions and methods for using same |
WO2015105083A1 (ja) | 2014-01-07 | 2015-07-16 | 塩野義製薬株式会社 | アンチセンスオリゴヌクレオチド及び糖誘導体を含む二本鎖オリゴヌクレオチド |
WO2016187425A1 (en) | 2015-05-19 | 2016-11-24 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
WO2017010575A1 (ja) | 2015-07-16 | 2017-01-19 | 協和発酵キリン株式会社 | β2GPI遺伝子発現抑制核酸複合体 |
WO2018118662A1 (en) | 2016-12-19 | 2018-06-28 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
WO2018118599A1 (en) | 2016-12-19 | 2018-06-28 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
WO2018118627A1 (en) | 2016-12-19 | 2018-06-28 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
Non-Patent Citations (16)
Title |
---|
"GenBank", Database accession no. AB038490 |
ALTSCHUL SF ET AL., J MOL BIOL, vol. 215, 1990, pages 403 |
ALTSCHUL: "BLAST (Basic Local Alignment Search Tool", PROC. NATL. ACAD. SCI. USA, 1990, pages 872264 - 2268 |
CARVER MPCHARLESTON JSSHANKS CZHANG JMENSE MSHARMA AKKAUR HSAZANI P: "Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates", J NEUROMUSCUL DIS, vol. 3, no. 3, 30 August 2016 (2016-08-30), pages 361 - 393, XP009510433, DOI: 10.3233/JND-160157 |
EBIOMEDICINE, vol. 45, 2019, pages 630 - 645 |
ENYA ET AL., BIOORGANIC MEDICINAL CHEMISTRY, vol. 18, 2008, pages 9154 - 9160 |
H. F. HANSENT. KOCHM. EGHOLMO. BUCHARDTP. E. NIELSENJ. COULLR. H. BERG, J. PEPT. SCI., vol. 1, 1995, pages 175 |
HEEMSKERK HADE WINTER CLDE KIMPE SJVAN KUIK-ROMEIJN PHEUVELMANS NPLATENBURG GJVAN OMMEN GJVAN DEUTEKOM JCAARTSMA-RUS A: "In vivo comparison of 2'-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping", J GENE MED., vol. 11, no. 3, March 2009 (2009-03-01), pages 257 - 66 |
HUM MOL GENET, vol. 20, no. 16, 15 August 2011 (2011-08-15), pages 3151 - 3160 |
M. EGHOLMO. BUCHARDTP. E. NIELSENR. H. BERG, JACS, vol. 114, 1992, pages 1895 |
O. BUCHARDT, J. ORG. CHEM., vol. 59, 1994, pages 5767 |
P. E. NIELSENM. EGHOLMR. H. BERGO. BUCHARDT, SCIENCE, vol. 254, 1991, pages 1497 |
PHARMACOLOGY & THERAPEUTICS, vol. 154, 2015, pages 78 - 86 |
PROC NATL ACAD SCI USA, vol. 90, 1993, pages 5873 |
SAZANI PNESS KPWELLER DLPOAGE DNELSON KSHREWSBURY AS: "Chemical and mechanistic toxicology evaluation of exon skipping phosphorodiamidate morpholino oligomers in mdx mice", INT J TOXICOL, vol. 30, no. 3, May 2011 (2011-05-01), pages 322 - 33, XP009510407, DOI: 10.1177/1091581811403504 |
T. KOCHH. F. HANSENP. ANDERSENT. LARSENH. G. BATZK. OTTESONH. ORUM, J. PEPT. RES., vol. 49, 1997, pages 80 |
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