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WO2024122467A1 - Suppression d'un trouble rénal induit par la cyclodextrine - Google Patents

Suppression d'un trouble rénal induit par la cyclodextrine Download PDF

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Publication number
WO2024122467A1
WO2024122467A1 PCT/JP2023/043142 JP2023043142W WO2024122467A1 WO 2024122467 A1 WO2024122467 A1 WO 2024122467A1 JP 2023043142 W JP2023043142 W JP 2023043142W WO 2024122467 A1 WO2024122467 A1 WO 2024122467A1
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WO
WIPO (PCT)
Prior art keywords
cyclodextrin
cilastatin
renal
derivatives
derivative
Prior art date
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Ceased
Application number
PCT/JP2023/043142
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English (en)
Japanese (ja)
Inventor
亮彦 齋藤
佐和子 後藤
康宏 細島
秀門 蒲澤
▲吉▼朗 平山
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Denka Co Ltd
Niigata University NUC
Original Assignee
Denka Co Ltd
Niigata University NUC
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Publication of WO2024122467A1 publication Critical patent/WO2024122467A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention relates to the suppression of renal damage induced by cyclodextrin or its derivatives.
  • cyclodextrins are cyclic oligosaccharides consisting of 6, 7, and 8 glucopyranose molecules, and are usually called ⁇ -CD, ⁇ -CD, and ⁇ -CD, respectively. They have a doughnut-shaped three-dimensional structure, but the hydrogen bonds between the C2- and C3-hydroxyl groups of adjacent glucopyranose molecules in the molecule are located at the large opening, and the C6-hydroxyl group is located at the small opening, so that the oxygen bonds are close to each other inside the cavity, making the inside electron-rich and hydrophobic.
  • CDs can take in hydrophobic compounds of a size that matches the size of the cavity as guest molecules and form inclusion complexes with the guest molecules. The size of this hydrophobic cavity is determined by the number of glucopyranose molecules that form the CD.
  • CDs and their derivatives are used in a variety of fields, including food, pharmaceuticals, cosmetics, and industry, for purposes such as improving solubility, stabilization, powdering oily and low-melting substances, preventing evaporation, masking flavors and odors, reducing local irritation, and improving bioavailability.
  • Patent Document 1 describes a technique for improving the pharmacokinetics or bioavailability of drugs using cyclodextrin derivatives such as sulfobutyl ether ⁇ -cyclodextrin
  • Patent Documents 2 and 3 use cyclodextrin derivatives such as hydroxypropyl- ⁇ -cyclodextrin to solubilize or stabilize drugs.
  • Non-Patent Document 1 the package insert for a medicine containing a cyclodextrin derivative (Non-Patent Document 1) states that the derivative may accumulate in patients with renal dysfunction, causing deterioration of renal function, etc.
  • Cilastatin has been reported to be able to suppress renal damage caused by several drugs by antagonizing drugs that bind to megalin expressed in proximal tubule cells at the megalin receptor (Non-Patent Document 2, Patent Document 4).
  • the objective of the present invention is to provide a new means for suppressing renal damage induced by cyclodextrin or its derivatives.
  • an object of the present invention is to provide a new means for inhibiting the uptake of cyclodextrin or its derivatives into renal tissue.
  • cilastatin is effective in suppressing renal damage induced by cyclodextrin or its derivatives. They also discovered that cilastatin suppresses the uptake of cyclodextrin or its derivatives into renal tissue.
  • the present invention includes, but is not limited to, the following aspects.
  • ⁇ -cyclodextrin or a derivative thereof is selected from the group consisting of methyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, trimethyl- ⁇ -cyclodextrin, partially methylated ⁇ -cyclodextrin, ethyl- ⁇ -cyclodextrin, diethyl- ⁇ -cyclodextrin, triethyl- ⁇ -cyclodextrin, (2-hydroxyethyl)- ⁇ -cyclodextrin, (2-hydroxypropyl)- ⁇ -cyclodextrin, (3-hydroxypropyl)- ⁇ -cyclodextrin, (2,3-dihydroxypropyl)- ⁇ -cyclodextrin, (2-hydroxyisobutyl)- ⁇ -cyclodextrin, sulfobutyl ether ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, and maltosy
  • a pharmaceutical composition comprising cilastatin or a pharma- ceutically acceptable salt thereof and cyclodextrin or a derivative thereof.
  • the present invention can suppress renal damage induced by cyclodextrin or its derivatives.
  • cyclodextrin or its derivatives are taken up into renal tissue via megalin, causing renal damage.
  • cilastatin inhibits the binding between megalin and cyclodextrin or its derivatives, inhibits the uptake of cyclodextrin or its derivatives into renal tissue, and thus inhibits renal damage.
  • suppress as used herein in relation to renal disorders means that symptoms do not appear at all, that the symptoms are alleviated, etc.
  • the “alleviation” includes reducing the amount of the symptoms that appear, reducing symptoms that have already appeared, and completely eliminating symptoms that have already appeared.
  • prevention preventing disease symptoms from appearing at all or reducing the amount of symptoms that appear.
  • inhibitor medicines for “suppressing” are referred to as “inhibitors.”
  • renal damage caused by cyclodextrin or its derivatives may limit the amount of cyclodextrin or its derivatives.
  • cilastatin in combination, it is possible to incorporate a larger amount of cyclodextrin or its derivatives while avoiding renal damage. Therefore, the present invention is expected to have an effect of promoting pharmaceutical development.
  • the present invention reduces concerns about kidney damage, it will be possible to ensure that all patients, including those with concerns about renal function, have the opportunity to receive drug treatment with medicines containing cyclodextrin or its derivatives.
  • FIG. 1 is a set of fluorescence microscopy images showing megalin-dependent uptake of HP ⁇ CD into renal proximal tubule epithelial cells.
  • FIG. 2 is a set of fluorescence microscopy images showing megalin-dependent uptake of SBECD into renal proximal tubule epithelial cells.
  • FIG. 3 is a set of fluorescence microscopy images showing the inhibitory effect of cilastatin on the uptake of HP ⁇ CD into renal proximal tubule epithelial cells.
  • FIG. 4 is a set of fluorescence microscopy images showing the inhibitory effect of cilastatin on the uptake of SBECD into renal proximal tubule epithelial cells.
  • FIG. 1 is a set of fluorescence microscopy images showing megalin-dependent uptake of HP ⁇ CD into renal proximal tubule epithelial cells.
  • FIG. 3 is a set of fluorescence microscopy images showing the inhibitor
  • FIG. 5 is a graph showing the inhibitory effect (quantitative evaluation) of cilastatin on renal uptake of HP ⁇ CD (inner layer of renal cortex).
  • FIG. 6 is a graph showing the inhibitory effect (quantitative evaluation) of cilastatin on renal uptake of SBECD (in the inner layer of the renal cortex).
  • FIG. 7 shows PAS staining images showing the inhibitory effect of cilastatin on HP ⁇ CD-induced renal damage.
  • FIG. 8 shows PAS staining images showing the inhibitory effect of cilastatin on renal damage induced by SBECD.
  • FIG. 9 is a graph showing the inhibitory effect of cilastatin on HP ⁇ CD-induced renal damage (quantitative evaluation of PAS stained images).
  • FIG. 10 is a graph showing the inhibitory effect of cilastatin on SBECD-induced renal damage (quantitative evaluation of PAS stained images).
  • FIG. 11 is a graph showing the inhibitory effect of cilastatin on HP ⁇ CD-induced renal injury (quantitative evaluation of biochemical renal injury markers).
  • FIG. 12 is a graph showing the inhibitory effect of cilastatin on SBECD-induced renal injury (quantitative evaluation of biochemical renal injury markers).
  • cilastatin In the present invention, cilastatin or a pharma- ceutically acceptable salt thereof is used.
  • Cilastatin is (Z)-7-[[(R)-2-amino-2-carboxyethyl]thio]-2-[[[(S)-2,2-dimethylcyclopropyl]carbonyl]amino]-2-heptenoic acid.
  • cilastatin forms a hydrate, the use of the hydrate is also within the scope of the present invention.
  • Examples of pharma- ceutically acceptable salts of cilastatin include alkali metal salts, such as lithium salt, sodium salt, and potassium salt; alkaline earth metal salts, such as magnesium salt and calcium salt; zinc salt and aluminum salt; organic amine salts, such as choline salt, ethanolamine salt, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, dibenzylamine salt, phenethylbenzylamine salt, procaine salt, morpholine salt, pyridine salt, piperidine salt, piperazine salt, and N-ethylpiperidine salt; ammonium salts; basic amino acid salts, such as lysine salt and arginine salt; and the like.
  • a particularly preferred salt is cilastatin sodium. It should be noted that the scope of pharma- ceutically acceptable salts also includes salt hydrates.
  • Cilastatin or a pharma- ceutical acceptable salt thereof can be, for example, a commercially available product, or can be produced or obtained by a method known per se or a method similar to a known method.
  • cyclodextrin refers to unmodified cyclic oligosaccharides composed of ( ⁇ -1,4)-linked ⁇ -D-glucopyranose units, examples of which are ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • cyclodextrin derivative means a compound in which one or more of the hydroxyl groups present at the 2nd, 3rd, and 6th positions of the ⁇ -D-glucopyranose unit in the cyclodextrin molecule have been chemically modified. Such derivatives also include derivatives in the form of pharma- ceutically acceptable salts.
  • the cyclodextrin or derivative thereof used in the present invention is preferably ⁇ -cyclodextrin or a derivative thereof, and more preferably methyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, trimethyl- ⁇ -cyclodextrin, partially methylated ⁇ -cyclodextrin (RM- ⁇ -CD: randomly methylated beta-cyclodextrin), ethyl- ⁇ -cyclodextrin, diethyl- ⁇ -cyclodextrin, triethyl- ⁇ -cyclodextrin, (2-hydroxyethyl)- ⁇ -cyclodextrin, It is selected from the group consisting of cyclodextrin, (2-hydroxypropyl)- ⁇ -cyclodextrin, (3-hydroxypropyl)- ⁇ -cyclodextrin, (2,3-dihydroxypropyl)- ⁇ -cyclodextrin, (2-hydroxyisobutyl)- ⁇ -cycl
  • Cyclodextrin or its derivatives can be obtained, for example, from commercially available products or by a method known per se or a method similar to a known method.
  • the present invention relates to an agent for suppressing renal damage induced by cyclodextrin or a derivative thereof, comprising cilastatin or a pharma- ceutical acceptable salt thereof as an active ingredient.
  • cilastatin or a pharma- ceutical acceptable salt thereof, and the cyclodextrin or a derivative thereof, as well as preferred examples and specific examples thereof, are as described above.
  • the inhibitor of the present invention contains cilastatin or a pharma- ceutically acceptable salt thereof in an amount effective for inhibiting renal damage induced by cyclodextrin or a derivative thereof.
  • An example of the daily dose of cilastatin or a salt thereof for an adult is 1.0 to 2.0 g, or 1.0 to 1.5 g.
  • the inhibitor can be administered once or in several divided doses so that the dose falls within the range. Intermittent administration, such as every other day or every other day, can also be used.
  • the kidney damage can be induced by cyclodextrin or its derivatives via megalin. Since the main site of expression of megalin in the body is thought to be renal proximal tubular epithelial cells (mainly the luminal membrane), the present invention is particularly useful for suppressing proximal tubular epithelial cell damage and the kidney damage that derives from it.
  • kidney disorders include osmotic nephropathy, osmotic nephropathy, nephropathy, kidney disorder, nephritis, renal failure, kidney disease, acute nephropathy, acute kidney injury, acute nephritis, acute renal failure, acute kidney disease, chronic nephropathy, chronic kidney injury, chronic nephritis, chronic renal failure, chronic kidney disease, tubular nephropathy, tubular kidney injury, tubular nephritis, tubular renal failure, tubular kidney disease, tubular interstitial nephropathy, tubular interstitial kidney injury, tubular interstitial nephritis, tubular interstitial renal failure, tubular interstitial kidney disease, obstructive nephropathy, obstructive kidney injury, obstructive nephritis, obstructive renal failure, obstructive kidney disease, acute nephritic syndrome, rapidly progressive nephritic syndrome,
  • Cyclodextrin or its derivatives are incorporated into pharmaceuticals due to the poor solubility of the physiologically active ingredients in the drug, but the true nature of cyclodextrin or its derivatives is the formation of inclusion complexes.
  • the properties brought about by inclusion complexes also include improved stability of the inclusion complexes. Therefore, it is reasonably expected that cyclodextrin or its derivatives will be incorporated in pharmaceuticals containing various physiologically active substances, either now or in the future.
  • the present invention can also act as an inhibitor of kidney damage in such pharmaceuticals.
  • cyclodextrin or its derivatives not as an additive but as an active ingredient in the treatment of lysosomal diseases and Alzheimer's disease caused by lipid metabolism disorders in the body is also in the development stage (Ory et al., Lancet, 2017, Vol. 390, pp. 1758-1768; www.ClinicalTrials.gov NCT03624842 https://clinicaltrials.gov/ct2/show/NCT05607615).
  • the present invention can also be used as an inhibitor of kidney damage caused by the administration of cyclodextrin or its derivatives for therapeutic purposes.
  • the present invention is a pharmaceutical composition, which comprises cilastatin or a pharma- ceutically acceptable salt thereof, and a cyclodextrin or a derivative thereof.
  • composition contains cilastatin or a pharma- ceutically acceptable salt thereof, and cyclodextrin or a derivative thereof, as well as specific and preferred examples thereof, as described above.
  • cilastatin or a pharma- ceutically acceptable salt thereof in the composition are the same as those described above for the inhibitor.
  • Cyclodextrin or its derivatives are used for a wide range of purposes, such as solubilizing or stabilizing drugs and exerting specific medicinal effects. Therefore, the content of cyclodextrin or its derivatives in the composition of the present invention and the dosage can be appropriately determined by a person skilled in the art based on publicly known information depending on the purpose of use.
  • An example of the daily dosage of cyclodextrin or its derivatives for an adult is 0.1 to 5000 mg/kg, or 0.1 to 3000 mg/kg.
  • the pharmaceutical composition of the present invention can be administered once a day or in several divided doses. Intermittent administration, such as every other day or every other day, can also be used.
  • the pharmaceutical composition of the present invention may contain other active ingredients.
  • active ingredients include, but are not limited to, posaconazole, voriconazole, remdesivir, itraconazole, letermovir, and carfilzomib.
  • NPC Niemann-Pick disease type C
  • AD Alzheimer's disease
  • a preferred example of the pharmaceutical composition of the present invention is a pharmaceutical composition for treating NPC.
  • Another preferred example of the pharmaceutical composition of the present invention is a pharmaceutical composition for treating AD.
  • the present invention relates to an inhibitor of the uptake of cyclodextrin or a derivative thereof into renal tissue, which comprises cilastatin or a pharma- ceutical acceptable salt thereof as an active ingredient.
  • Cilastatin is thought to directly or indirectly inhibit the binding of cyclodextrin or its derivatives to megalin. This inhibitory effect is thought to suppress the uptake of cyclodextrin or its derivatives into renal tissue, and thus suppress renal damage.
  • the inhibitor of the present invention contains an effective amount of cilastatin or a pharma- ceutically acceptable salt thereof.
  • the effective amount can be determined by referring to the amounts described above for the inhibitor of renal dysfunction of the present invention.
  • the form of the inhibitor and composition of the present invention is not particularly limited, and may be in the form of a solid preparation such as a powder, granules, capsules, tablets, or chewable agent, a liquid preparation such as a solution or syrup, an injection, or a spray, etc.
  • a solid preparation such as a powder, granules, capsules, tablets, or chewable agent
  • a liquid preparation such as a solution or syrup
  • an injection or a spray, etc.
  • the preferred form is an injection.
  • the inhibitor and composition of the present invention may contain a pharma- ceutically acceptable carrier according to the need for formulation.
  • the carrier include excipients and solvents.
  • additional components that may be contained in the inhibitor of the present invention include binders, pH adjusters, disintegrants, chelating agents, solubilizing agents, suspending agents, emulsifiers, isotonicity agents, stabilizers, soothing agents, preservatives, antioxidants, lubricants, flavoring agents, and coloring agents.
  • the excipients include sugars such as lactose, glucose, D-mannitol, etc.; organic excipients such as starches; celluloses such as crystalline cellulose; and inorganic excipients such as dicalcium phosphate, calcium carbonate, kaolin, etc.
  • Solvents include purified water, physiological saline, etc.
  • Binders include pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.
  • pH adjusters include hydrochloric acid, sodium hydroxide, etc.
  • Disintegrants include low-substituted hydroxypropylcellulose, chemically modified cellulose and starches, alginic acid, etc.
  • Chelating agents include calcium disodium edetate hydrate, calcium sodium edetate hydrate, etc.
  • solubilizing agents include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.
  • suspending agents or emulsifying agents include celluloses such as sodium lauryl sulfate, gum arabic, gelatin, lecithin, glycerin monostearate, polyvinyl alcohol, polyvinylpyrrolidone, and sodium carboxymethylcellulose; polysorbates; and polyoxyethylene hydrogenated castor oil.
  • isotonic agents include sodium chloride, potassium chloride, sugars, glycerin, and urea.
  • stabilizers include polyethylene glycol, sodium dextran sulfate, and other amino acids.
  • soothing agents include glucose, calcium gluconate, and procaine hydrochloride.
  • preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • antioxidants include sulfites and ascorbic acid.
  • the injection may be in a form in which the active ingredient is pre-dissolved, or in a solid form that is dissolved when used.
  • These injection solutions preferably contain, for example, 0.001 to 10 mass%, 0.01 to 5 mass%, or 0.1 to 1 mass% of cilastatin or a pharma- ceutically acceptable salt thereof as the active ingredient, based on the mass of the entire solution.
  • examples of the content of cilastatin or a pharma- ceutically acceptable salt thereof in the inhibitor are 0.001 to 100 mass%, 0.001 to 99.9 mass%, or 0.01 to 90 mass%.
  • Suitable solvents or diluents for injections may be those commonly used, including aqueous media such as physiological saline, distilled water for injection, glucose solution, lidocaine hydrochloride solution (for intramuscular injection), intravenous injection liquid (e.g., aqueous solutions of citric acid and sodium citrate), electrolyte solutions (for intravenous drip infusion and intravenous injection), organic media such as ethanol, polyethylene glycol, and propylene glycol, or mixtures of these.
  • aqueous media such as physiological saline, distilled water for injection, glucose solution, lidocaine hydrochloride solution (for intramuscular injection)
  • intravenous injection liquid e.g., aqueous solutions of citric acid and sodium citrate
  • electrolyte solutions for intravenous drip infusion and intravenous injection
  • organic media such as ethanol, polyethylene glycol, and propylene glycol, or mixtures of these.
  • the inhibitors and compositions of the present invention do not contain imipenem.
  • the inhibitor and composition of the present invention do not contain a bicarbonate such as sodium bicarbonate.
  • Another aspect of the inhibitor of the present invention is the use of cilastatin or a pharma- ceutically acceptable salt thereof in suppressing renal damage induced by cyclodextrin or a derivative thereof, or in suppressing the uptake of cyclodextrin or a derivative thereof into renal tissue.
  • Cilastatin or a pharma- ceutically acceptable salt thereof, cyclodextrin or a derivative thereof, and renal damage, as well as specific and preferred examples thereof, are as described above.
  • the use may be further combined with the administration of cyclodextrin or a derivative thereof.
  • Cyclodextrin or a derivative thereof may be administered simultaneously with cilastatin or a pharma- ceutically acceptable salt thereof, separately, or at an interval.
  • cyclodextrin or a derivative thereof may be administered simultaneously with, before, or after the administration of cilastatin or a pharma- ceutical acceptable salt thereof, or two or more of them may be combined.
  • the inhibitor of the present invention is a method for suppressing renal damage induced by cyclodextrin or a derivative thereof, or suppressing the uptake of cyclodextrin or a derivative thereof into renal tissue, the method comprising administering an effective amount of cilastatin or a pharma- ceutically acceptable salt thereof to a subject in need thereof.
  • Cilastatin or a pharma- ceutically acceptable salt thereof, cyclodextrin or a derivative thereof, and renal damage, as well as specific and preferred examples thereof, are as described above.
  • the method may further comprise administering an effective amount of cyclodextrin or a derivative thereof to the subject.
  • the cyclodextrin or a derivative thereof may be administered simultaneously with cilastatin or a pharma- ceutically acceptable salt thereof, separately, or at a time interval.
  • the cyclodextrin or a derivative thereof may be administered simultaneously with, before, or after the administration of cilastatin or a pharma- ceutical acceptable salt thereof, or two or more of them may be combined.
  • the individual components or agents may be administered in separate or single formulations.
  • the effective amount or dosage of cilastatin or a pharma- ceutically acceptable salt thereof and cyclodextrin or a derivative thereof can be determined based on the above description of the inhibitor and pharmaceutical composition of the present invention.
  • subjects requiring various inhibitions are, for example, subjects who have or are at risk of having symptoms of renal impairment, and subjects in whom the symptoms are present prior to administration of cyclodextrin or a derivative thereof and for whom administration of cyclodextrin or a derivative thereof is contraindicated.
  • the subject is preferably a mammal, for example, a human; domestic animals such as mice, rats, rabbits, guinea pigs, hamsters, monkeys, sheep, horses, cows, pigs, donkeys, dogs, and cats; or other laboratory animals, and humans are particularly preferred.
  • Wild-type mice used were C57BL/6J (Charles River Laboratories Japan, Yokohama, Japan).
  • Fluorescently labeled CDs were also purchased. Specifically, fluorescein-labeled HP ⁇ CD was purchased from CycloLab, Hungary (6-deoxy-6-[(5/6)-fluoresceinylthioureido]-HPBCD, CY-F-2005.1), and rhodamine-labeled SBECD was purchased from CycloLab, Hungary (rhodamine labeled sulfobutylated-BCD sodium salt, CY-RL-2041.2).
  • cilastatin we purchased the product (CILASTATIN SODIUM (sterile)) from ACS DOBFAR, an Italian company.
  • Method 100 ⁇ L of a saline solution of fluoresceinated HP ⁇ CD (1 mg/2 mL) or a saline solution of rhodamine-conjugated SBECD (1 g/2 mL) was administered via the tail vein to kidney-specific conditional megalin KO mice and littermate control mice (both male, 12-14 weeks old).
  • the area ratio of the CD-incorporated area was also measured using the hybrid cell counter (BZ-H4C) of the BZ-X800Analyzer (BZ-H4A).
  • FIG. 5 shows the results of the test using fluorescein-conjugated HP ⁇ CD
  • FIG. 6 shows the results of the test using rhodamine-conjugated SBECD.
  • CD uptake was quantitatively evaluated in the S2-3 region as described above, CD uptake was significantly suppressed in the cilastatin-administered group compared to the control group. This demonstrated that cilastatin inhibits the uptake of CD into renal tissue.
  • Method 1 Animal Medication, Sample Preparation
  • the left kidney was removed from wild-type mice (male, 10-12 weeks old) by a conventional method.
  • mice Two weeks later, the mice were intraperitoneally administered with one of the following drugs for seven consecutive days (food and water intake).
  • Method 3 Quantitative assessment using biochemical markers of renal injury
  • Urine was collected using a metabolic cage, and each animal was dissected before the removal of the right kidney. Blood was collected from the inferior vena cava during dissection. The collected blood was centrifuged at room temperature at 800 g for 30 minutes to separate and collect serum. The urine and serum obtained were stored at -80°C until analysis. Measurements of urinary NAG and Cr were requested from SRL Co., Ltd., and blood urea nitrogen (BUN) and serum Cr were requested from Oriental Yeast Co., Ltd., to evaluate the renal damage suppression effect of cilastatin.
  • Results-2 The results of quantitative evaluation of PAS stained images in the test using HP ⁇ CD are shown in Figure 9, and in the test using SEBCD are shown in Figure 10. Compared to the control group, the proportion of renal tubules containing vacuoles was significantly suppressed in the cilastatin administration group.
  • Figure 12 shows the results of quantitative evaluation using biochemical markers of kidney damage in a study using SBECD. Compared to the control group, the increase in urinary NAG, a marker of damage, was significantly suppressed in the cilastatin-administered group.
  • the present invention makes it possible to suppress kidney damage in pharmaceuticals that contain cyclodextrin or its derivatives as an additive or active ingredient, and ensures opportunities for drug treatment with pharmaceuticals that contain cyclodextrin or its derivatives.
  • the present invention avoids the effects of cyclodextrin or its derivatives on the kidneys, thereby facilitating the development of pharmaceuticals.

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Abstract

La présente invention aborde un problème consistant à fournir un moyen pour supprimer des troubles rénaux induits par la cyclodextrine ou un dérivé de celle-ci.　La présente invention utilise de la cilastatine et un sel pharmaceutiquement acceptable de celle-ci.
PCT/JP2023/043142 2022-12-06 2023-12-01 Suppression d'un trouble rénal induit par la cyclodextrine Ceased WO2024122467A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015111666A1 (fr) * 2014-01-24 2015-07-30 味の素株式会社 Antagoniste de la mégaline
WO2020069138A1 (fr) * 2018-09-28 2020-04-02 Axsome Therapeutics, Inc. Formes posologiques comprenant des principes pharmaceutiques actifs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015111666A1 (fr) * 2014-01-24 2015-07-30 味の素株式会社 Antagoniste de la mégaline
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