WO2004060404A1 - Vecteur de medicament - Google Patents

Vecteur de medicament Download PDF

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Publication number
WO2004060404A1
WO2004060404A1 PCT/JP2004/000004 JP2004000004W WO2004060404A1 WO 2004060404 A1 WO2004060404 A1 WO 2004060404A1 JP 2004000004 W JP2004000004 W JP 2004000004W WO 2004060404 A1 WO2004060404 A1 WO 2004060404A1
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group
rate
hyaluronic acid
derivative
substituent
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PCT/JP2004/000004
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English (en)
Japanese (ja)
Inventor
Tsuyoshi Shimoboji
Teruo Nakamura
Hajime Miyamoto
Rie Shiokawa
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Chugai Seiyaku Kabushiki Kaisha
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Publication of WO2004060404A1 publication Critical patent/WO2004060404A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present application relates to a hyaluronic acid (HA) derivative drug carrier that can extend and control the blood half-life of a drug and maintain sufficient drug efficacy, conjugation with a drug using the same, and in vivo
  • the present invention relates to a kinetic control technique for the drug.
  • PEG polyethylene glycol
  • Hyaluronic acid is a biomaterial (polysaccharide) isolated from the vitreous of bovine eyes in 1934 by K. Meyer, and has long been known as a major component of fine matrices.
  • HA is a type of darcosamide glycan composed of a disaccharide unit in which D-glucuronic acid and N-acetyltyl glucosamine are linked by a / 3 (1 ⁇ 3) glycosidic bond (formula (II)).
  • HA has no difference in chemical and physical structure, and humans also have a metabolic system. It is the safest biomaterial (Biomateria 1) in terms of immunity and toxicity. In recent years, aspects of bioactive substances such as induction of cell adhesion, proliferation and migration have been reported and attracted attention, and large-scale production of high molecular weight HA by microorganisms has become possible. It has also been put to practical use in the fields of cosmetics and the like.
  • HA as a drug conjugate carrier is safer and can be made larger in size than PEG, which has been widely studied so far. Alternatively, different types of drugs can be carried in one molecule. Therefore, compared to PEG, HA has much greater potential as a drug conjugate carrier for designing and developing conjugates with more advanced pharmacokinetic control functions such as targeting and sustained release. It is thought that. HA is one of the most excellent carriers in terms of safety because it is biodegradable and there is no species difference in its chemical structure.
  • HA has a rapid elimination rate in blood, and its half-life is reported to be 2 minutes when administered intravenously (IV) (J. Intel. Med. Vol. 242, No. 27- 33, 1997).
  • IV intravenously
  • the present inventor has also confirmed that simply conjugating HA to a protein does not extend blood retention and does not lead to improvement in sustained drug efficacy.
  • the main factors controlling the pharmacokinetics of HA, which are important in using HA as a drug carrier are unknown, and increase the kinetics of the HA derivative itself and its retention in blood. There are no reports on the prerequisites required for derivatives to be provided.
  • the main factors for controlling the pharmacokinetics of HA which are important for using HA as a drug carrier, are unknown.
  • there is no report on the kinetics of the modified HA itself or any modification method for increasing the retention in the blood and there is no known method for avoiding the internal metabolic system of HA and controlling the retention in the blood. Absent.
  • the inventor of the present invention has made intensive studies to solve the powerful problem, and by changing the rate of introduction of a substituent into the carboxylic acid of the glucuronic acid moiety in hyaluronic acid (HA), It has been found that the rate of HA disappearance can be adjusted. Furthermore, it has been found that the disappearance rate of HA can be adjusted by changing the molecular weight of HA. That is, the present invention relates to a method for controlling the disappearance rate of HA, and a method for producing a conjugate with a substance having a pharmacological action using the HA.
  • a method for adjusting the rate of disappearance of hyaluronic acid by changing the rate of introduction of a substituent into the carboxylic acid of the dalcuvic acid moiety in the hyaluronic acid derivative by changing the rate of introduction of a substituent into the carboxylic acid of the dalcuvic acid moiety in the hyaluronic acid derivative.
  • the change in the introduction rate of the substituent may be either increase or decrease, and the disappearance rate may be either decrease or increase.
  • the increase in the introduction rate of the substituent may reduce the disappearance rate. It is preferable to reduce the speed.
  • the hyaluronic acid derivative is not particularly limited as long as a substituent of the carboxylic acid of the glucuronic acid moiety is introduced, but is preferably represented by the formula (I):
  • X represents a linear or branched - alkyl group, straight or branched C - alkoxy group, a linear or branched C 2 _ 12 alkenyl, C 6 _ 18 Ariru group, C 3 - 8 cycloalkyl group, or a heterocyclic
  • Each substituent has at least one protecting group-introduced or free hydroxy group, amino group, hydrazide group, mercapto group, maleimide group, olepoxyl group, aldehyde group, or sulfonic acid group. And also includes a polyaddition product or a polycondensate of a substituent having the above functional group,
  • R 2 are each independently a hydrogen atom, a linear or branched alkyl group, a linear or branched Ci-hydroxyalkyl group, an alkylene oxide group or a polyalkylene oxide group.
  • X 0 is _N (-Ri) N (_R 2 ) — or _N (-Ri) N (_R 2 ) CO—
  • X 2 is an amino A linear or branched alkyl group substituted with a hydrazide group or a hydrazide group, and preferably and R 2 is a hydrogen atom.
  • the hyaluronic acid derivative may form a conjugate with a substance having a pharmacological action.
  • the rate of disappearance is not particularly limited, but is preferably a rate of disappearance in blood.
  • a conjugate wherein a substance having a pharmacological action is bound to a hyaluronic acid derivative whose disappearance rate has been adjusted or reduced by the above method.
  • the substance having a pharmacological action is not particularly limited, but is preferably a protein or a peptide.
  • X 2 is linear or branched. 12 alkyl group, straight or branched ( ⁇ - 12 alkoxy group, linear or branched C 2 _ 12 alkenyl group, (6 _ 18 Ariru group, C 3 - is 8 cycloalkyl group or a heterocyclic group, Each substituent is a protecting group-introduced or free hydroxyl group, amino group, hydrazide group, mercapto group, maleimide group, hepoxyl group
  • An aldehyde group or a sulfonic acid group and also includes a polyadduct or a polycondensate of a substituent having the above functional group,
  • R 2 are each independently a hydrogen atom, a straight-chain or branched C-alkyl group, a straight-chain or branched- ⁇ hydroxyalkyl group, an alkylene oxide group or a polyalkylene oxide group.
  • hyaluronic acid derivative in the preparation of a conjugate in which a substance having a pharmacological action is bound to a hyaluronic acid derivative having one or more repeating structures represented by the following formulas in the molecule is provided.
  • X 0 is preferably —N (-R x ) N (—R 2 ) — or one N ( ⁇ R X ) N (—R 2 ) CO—, preferably X 2 is a straight-chain or branched alkylene group substituted with an amino group or a hydrazide group, and preferably and R 2 is a hydrogen atom.
  • the following steps (a) binding a substance having a pharmacological action to two or more hyaluonic acid derivatives having different introduction ratios of the substituents to the carboxylic acid in the darcnic acid moiety,
  • a method for preparing a conjugate of a hyaluronic acid derivative and a substance having a pharmacological action comprising: a step of preparing a hyaluronic acid derivative having an introduction rate calculated in (c).
  • the method for preparing the conjugate comprises the following steps:
  • the elimination rate is not particularly limited, but is preferably a blood elimination rate. According to yet another aspect of the invention, the following steps are provided:
  • the present invention provides a method for predicting the disappearance rate of a hyaluronic acid derivative containing:
  • the rate of disappearance is not particularly limited, but is preferably the rate of disappearance in blood.
  • the adjustment of the molecular weight of the hyaluronic acid derivative and the adjustment of the rate of introduction of a substituent into the carboxylic acid of the glucuronic acid portion of the hyaluronic acid derivative are combined to provide the hyaluronic acid derivative.
  • a method is provided for adjusting the rate of disappearance.
  • FIG. 1 is a graph showing the time-dependent change in the concentration of the HA derivative (a0-a3) in a plasma sample collected from a rat to which the HA derivative (a0-a3) was administered.
  • FIG. 2 is a graph showing a time-dependent change in the concentration of the HA derivative (b 0 -b 3) in a plasma sample collected from a rat to which the HA derivative was administered.
  • FIG. 3 is a graph showing a time-dependent change in the concentration of the HA derivative in a plasma sample collected from a rat to which the HA derivative (c 0 -c 3) was administered.
  • HA hyaluronic acid
  • the main sites of metabolism of HA are the liver and lymph glands, and its metabolism is mainly mediated through receptor membrane-mediated receptors such as CD44, RHAMM, and HARE (Receptor Mediated) cells. It is due to internal uptake and subsequent degradation by hyaluronidase. Both of these molecules have been reported to use the continuous free carboxylic acid (hexasaccharide) of HA as the main recognition site (Exp. Cell Res., Vol. 228, No. 16). — See page 228, 1996.) The present inventors have paid attention here, and have found that by modifying a carboxylic acid to ⁇ t so as to be hardly recognized by metabolic molecules, the blood retention can be controlled and prolonged. The modification rate of the carboxylic acid is determined by proton NMR.
  • the molecular weight of the HA derivative of the present invention is also an important factor for its pharmacokinetics.
  • the blood retention of the HA derivative of the present invention also depends on the molecular weight of HA, and the higher the molecular weight of HA, the longer its half-life in blood. Therefore, the half-life in blood of the HA derivative can be controlled by changing the molecular weight of HA and the modification rate of the carboxylic acid of HA.
  • various known methods such as a light scattering method and a viscosity method can be used.
  • the adjustment of the disappearance rate of HA refers to changing the disappearance rate of HA by increasing or decreasing the disappearance rate of HA, and is usually changed so as to have a target disappearance rate.
  • the change in the introduction ratio of the substituent is usually changed in the range of 0.001% to 99.999%, preferably in the range of 1% to 99%, More preferably, it is varied between 10% and 90%.
  • the substituent to be introduced into the carboxylic acid of dalc carboxylic acid in HA is not particularly limited, and any substituent that can be introduced can be used.
  • the introduced functional group is hydrophobic, the solubility of the HA derivative is reduced, so that a hydrophilic functional group is preferable.
  • the method for introducing the substituent is not particularly limited as long as a person skilled in the art can usually carry out the method.
  • a propyloxyl group is converted into an amide group, an ester group, or a hydrazide group, and the amide group and the hydrazide group are converted. It can be introduced as a substituent on a nitrogen atom or as a substituent on an oxygen atom of an ester group.
  • Specific examples of the substituent include a linear or branched alkyl group, an alkoxy group, an alkenyl group, an aryl group, an alkylene oxide group, a cycloalkyl group, and a heterocyclic group.
  • one or more selected from functional substituents such as a hydroxyl group, an amino group, a hydrazide group, a mercapto group, a hydroxyl group, and an aldehyde group. May have a substituent. Further, the functional substituent may have a protecting group in some cases.
  • the alkyl group has 1 to 12 carbon atoms, and preferably has 1 to 12 carbon atoms. ⁇ 6.
  • the alkoxy group has 1 to 12 carbon atoms, and preferably has 1 to 6 carbon atoms.
  • the alkenyl group has 2 to 12 carbon atoms, and preferably has 2 to 6 carbon atoms.
  • the aryl group has 6 to 18 carbon atoms, and preferably has 6 to 12 carbon atoms.
  • the alkylene oxide group is a group represented by — (CH (—R) CH (—R ′) ⁇ ) n- H ( where R and R ′ are a hydrogen atom or —5 alkyl group).
  • n is an integer of 1 to 20.
  • the cycloalkyl group has 3 to 8 carbon atoms, and preferably has 3 to 6 carbon atoms.
  • the heterocyclic group is, for example, a 5- to 6-membered heterocyclic group having one or more hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and is unsaturated, saturated, or partially unsaturated. It may be saturated.
  • the polyaddition product or polycondensate of the substituent having a functional group is not particularly limited, and examples thereof include poly (oligo) C 6 alkylene glycol, poly (oligo) amino acid, and a combination of diamine and dicarponic acid. .
  • the modification charge is preferably nonionic or anionic.
  • the HA derivative disappearance rate is a rate at which HA is eliminated at invivo or invitro. Since the adjustment method of the present invention is particularly effective in invivo, it is preferable to measure the disappearance rate at invivo, in particular, blood retention (blood disappearance rate) as an index.
  • the measurement of the disappearance rate is not particularly limited, and can be measured by a method known to those skilled in the art.
  • the disappearance rate when measuring the disappearance rate of HA using the retention of HA in the blood as an index, the change over time in the blood concentration is measured, and the kinetic analysis is performed to quantify the clearance from the blood. This is defined as the disappearance rate.
  • the elimination rate is measured in vitro, for example, hyaluronidase is added, and the hyaluronan derivative is applied over time by gel permeation chromatography (ge 1 permeation on chroma to og raphy, GPC). May be measured.
  • HA used in the present invention is not particularly limited as long as it has an HA skeleton.
  • modified HA in which a part of HA is modified or a salt of HA and modified HA (sodium salt, potassium salt, magnesium salt, calcium salt) Salt, aluminum salt, etc.).
  • the HA used in the present invention may be HA obtained by any method, such as HA extracted from animal fiber, HA obtained by fermentation, or HA obtained by chemical synthesis. Not limited.
  • the substance having a pharmacological action is not particularly limited, and low molecular compounds, proteins, peptides, and the like can be used.
  • low molecular compounds include, for example, anti-cancer agents (eg, alkylating agents, chemotherapy drugs, alkaloids, etc.), immunosuppressants, anti-inflammatory drugs (steroid drugs, non-steroidal anti-inflammatory drugs, etc.), anti-rheumatic drugs Agents, anti-J (J-lactam antibiotics, aminoglycoside antibiotics, macrolide antibiotics, tetracycline antibiotics, new quinolone antibiotics, sulfa drugs, etc.).
  • anti-cancer agents eg, alkylating agents, chemotherapy drugs, alkaloids, etc.
  • immunosuppressants e.g., anti-inflammatory drugs (steroid drugs, non-steroidal anti-inflammatory drugs, etc.), anti-rheumatic drugs Agents, anti-J (J-lactam antibiotics, aminoglycoside antibiotics, macrolide antibiotics, tetracycline antibiotics, new quinolone antibiotics, sulfa drugs, etc.).
  • proteins and peptides include, for example, erythropoietin (EP ⁇ ⁇ ), granule oral site colony stimulating factor (G-CSF), interferon-one, ⁇ ⁇ r, (INF-hi, ⁇ , r), thrombopoietin (TPO), Serial Neutrokinetic Factor (CNTF), Tumeric Necrosis Factor-1 (TNF), Tumeric Necrosis Factor-1 Binding Protein (TNFbp), Interleukin-10 (IL-10), Similar to FMS Tyrosine kinase (F1t-3), Growth hormone (GH), Insulin, Insulin-like growth factor_1 (IGF-1), Platelet-derived growth factor (PDGF), Interleukin-11 receptor antagonist (IL — 1 ra), Brain-derived neurotrophic factor (BDNF), keratinocyte growth factor (KGF), stem cell factor (SCF), megakaryocyte Growth differentiation factor (MGDF), osteoprotegerin (OPG), lebutin,
  • the carboxylic acid of HA is condensed with ethylenediamine (EDA) or adipic dihydrazide (ADH) with 1-ethyl-3- (3-dimethylaminopropyl) carposimide (EDC) to have an amino group or hydrazide group.
  • EDA ethylenediamine
  • ADH adipic dihydrazide
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carposimide
  • HA-AM, HA-HZ the size HA
  • AM and HZ are preferably treated with, for example, succinic anhydride, etc., and converted to carboxylic acid to make the total charge anion.
  • the order of conjugate of the substance having a pharmacological action with regulation of the rate of HA elimination is not limited.
  • a substance having a pharmacological action may be conjugated to the HA derivative whose disappearance rate has been adjusted, or the rate of HA disappearance may be adjusted after conjugating the pharmacological substance.
  • the method for preparing the conjugate comprising the HA derivative with a controlled blood elimination rate obtained in this way and a protein having a medicinal effect is based on the method used for conjugates of known polymers and proteins.
  • the above-mentioned amino- or hydrazide-modified HA (HA-AM, HA-AZ) is synthesized, and a part of this is synthesized with N-succinimidyl 3- [2-pyridyldithio] propionate (N-Succinimidyl 3- [ 2-pyr i dy 1 dithio] roionate, SPDP) to introduce a mercapto group and prepare HA-SA.
  • surplus AM and HZ are treated with, for example, anhydrous succinic acid, etc., and — converted into a group having a carboxyl group such as NHCOCH 2 CH 2 C ⁇ OH or NHNHCOC H 2 CH 2 COOH, and the total charge It is more preferable to use anion.
  • maleimide group, pinyl sulfo Introduce a functional group that specifically reacts with thiols such as thiol groups
  • a conjugate may be prepared by introducing a maleimide group into an amino group of a protein with maleimidobutylyloxysulfosuccin ether, and reacting this with HA-SH.
  • the length of the spacer between the protein and the backbone of the HA derivative may be adjusted or a site-specific conjugate may be used. it can.
  • a specific method for adjusting the disappearance rate of HA there is a method of measuring the disappearance time of a plurality of HAs having different substituent introduction rates, and selecting an HA having a desired disappearance time from the measured values. The disappearance times of multiple HAs with different ratios were measured, and the results were used to derive a correlation between the substituent introduction rate and the disappearance time of the HA, and based on the correlation, the substituents that resulted in the desired disappearance time And a method of calculating the introduction rate of the compound.
  • the correlation between the rate of introduction of the substituent and the rate of disappearance can be determined using a known method such as the least square method.
  • the least squares method is a method of determining a parameter of a model such that a sum of squares of a difference between a measurement result and a value obtained from a model function is minimized.
  • the least squares solution can be obtained by solving a system of linear equations where the model function is linear with respect to the parameters. If the model function is nonlinear linear with respect to the parameters, it is necessary to determine the parameters by iterative improvement, and it is possible to obtain a least squares solution by the steepest descent method, Marquardt method, Gauss-Newton method, etc. Become.
  • the production of the HA derivative in which the substituent is introduced at a desired ratio can be carried out by a method known to those skilled in the art.
  • EDA ethylenediamine
  • ADH adipic acid dihydrazide
  • the amount of EDC added to HA and the amount of substituent introduced based on the concentration of hyaluronic acid in the reaction solution can be adjusted.
  • the rate of disappearance may be adjusted by changing the introduction ratio of the substituent and the molecular weight of HA.
  • the NMR measurement was performed using a nuclear magnetic resonance apparatus JNM-ECA500 (manufactured by JEOL Ltd.) using heavy water as a solvent.
  • the rate of introduction of the substituent was determined from the integral ratio of the peak specific to the introduced substituent and the peak derived from hyaluronic acid.
  • Detection wavelength fluorescence (excitation 490 nm, fluorescence 5, 18 nm)
  • unit means a repetitive structure containing a disaccharide of D-dalcuronic acid and N-acetyldarcosamine as a skeleton contained in a hyaluronic acid (HA) derivative.
  • HA-HZ hyaluronic acid derivatives
  • HZ hydrazide groups
  • HA Dissolve hyaluronic acid having a molecular weight of 2.5 ⁇ 10 4 daltons (manufactured by Denki Kagaku Kogyo Co., Ltd.) at a concentration of 1.0% in distilled water, and adjust the pH to 4.7 to 4.8 with 5N: ⁇ . Was.
  • MWCO 12k-14k tareton
  • HZ hyaluronic acid
  • HA-HZ An HA derivative into which the title HZ was introduced (HA-HZ) was obtained in the same manner as in Example 1-1-1 above, and the introduction rate of HZ in the obtained HA-HZ was determined by proton NMR. As a result, 6% (b0), 49% (b2), and 71% (b3) of the carboxylic acid of HA were converted to HZ.
  • Example 1-1-1-3 Synthesis of hyaluronic acid mono-HZ (MW58 OKDa) In addition to dissolving HA (manufactured by Denki Kagaku Kogyo Co., Ltd.) with a molecular weight of 5.8 ⁇ 10 5 reton at a concentration of 0.25% in distilled water
  • HA-HZ HA derivative into which the title HZ was introduced
  • the HZ incorporation rate of the obtained HA-HZ was determined by proton NMR, and 8% (c 0), 56% (c 2), and 73% (c 3) of the carboxylic acid in HA were converted to HZ. It had been.
  • Fluorescein-1-isothiocyanate Fluorescein-1-isothiocyanate (Fluo rescein-4-isothiocyanate, FITC) dissolved in 1/10 volume of dimethyl sulfoxide (
  • SA / HZ (TNBS) 250 (a 0, b 0, c 0), 80 (a 2, b 2.c 2), 40 (a 3, b 3, c 3) (mo 1 / At a charging ratio of mo 1), succinic anhydride (SA) dissolved in 3.5 mL of DMSO was added and reacted similarly.
  • the reaction mixture was purified by dialysis against a large excess of distilled water, and the resulting aqueous solution was freeze-dried.
  • Each of the obtained samples was dissolved to a predetermined concentration, and the FITC concentration was quantified from the absorbance at 494 nm of the sample solution diluted to 0.25 mg ZmL, and the concentration of each unit was calculated according to the following formula.
  • conversion to molar fraction and calculation of the weight fraction derived from HA in the derivative were performed.
  • TNBS trinitrobenzenesulfonic acid
  • HZ group (%) HZ group (%) Unit Unit Unit HA
  • HA-HZ NMR TNBS (mol%) (mol%) (mol%) (weight%) a0 3-1.06 1.94 97.00 99.75 b0 6-1.35 4.65 94.00 98.24 c0 8-1.48 6.52 92.00 97.15 a2 42-1.36 40.64 58.00 79.30 b2 49 1 1.50 47.50 51.00 76.57 c2 56-1.77 54.23 44.00 74.14 a3 59-1.22 57.78 41.00 72.56 b3 71-1.25 69.75 29.00 68.55 c3 73-1.09 71.91 27.00 67.80
  • the nine HA derivatives of Example 1 were administered once intravenously at a dose of 10 mg / kg to rats intravenously, before administration, and after administration at 0.25, 1, 2, 4, 6, 8, 10, 12 and After 24 hours, the mixture was centrifuged at 0 L (heparin treatment) to obtain plasma. This plasma sample was stored at 120 ° C until measurement.
  • the standard sample for calibration curve and the sample for measurement were analyzed by GPC.
  • WinNonlin Ver 2.1 Belgium Science
  • MULTI RUNGE
  • the target parameters were calculated overnight.
  • WinNonlin performs a model-independent analysis using the data of the last three measurement points of each individual, and calculates the half-life (t 1/2), mean blood residence time (MRT), and total clearance (C 1) did.
  • Table 2 shows the results of model-independent kinetic analysis. Looking at the total clearance (C 1) value, a 0 is 2.4 times a 3, b 0 «b 3 3.7 times, and so on. 0 is. It was 5.8 times that of 3, indicating that the higher the introduction rate of HZ, the slower the HA derivative disappears from the blood. Comparing HA derivatives with similar HZ introduction rates, the HA derivative with a higher molecular weight has a smaller C1 value, and the higher the molecular weight of HA, the greater the degree of improvement in blood retention. Indicated. The same tendency was observed for MRT and t12 shown in Table 2.
  • Table 3 shows the results of the kinetic analysis of the HA derivative taking into account the nonlinear region.
  • MULTI RUNGE
  • Vds s and Vmax are equal for HA derivatives with the same molecular weight and that the affinity for the receptor involved in HA clearance changes with the HZ introduction rate.
  • the Vds s value, Vmax, and Km were calculated by fitting analysis (Table 3).
  • the Vmax of a0-a3 was 2.8 times the Vmax of c0_c3, indicating that the HA derivative having a smaller molecular weight disappeared from the blood earlier.
  • the introduction rate of HZ is high, such as the Km value of a3 is 3.6 times the Km value of a0 and the Km value of c3 is 18.9 times the Km value of c0. It was shown that Km became larger. That is, it was suggested by the fitting analysis that the higher the introduction rate of HZ, the lower the affinity with the receptor and the slower the disappearance of the HA derivative from the blood. As shown above, the results of both model-independent analysis and kinetic analysis taking into account nonlinearity indicate that the half-life in blood is prolonged as the carboxylic acid modification rate of the HA derivative and the molecular weight of the HA derivative increase. Rukoto has been shown.
  • the hyaluronic acid derivative of the present invention can control the rate of metabolism of the HA derivative in the body, and can control and prolong the blood retention property. To provide a biodegradable and safe pharmacokinetic control technology that enables adjustment of the blood exposure pattern that is optimal for the subject.

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Abstract

La présente invention se rapporte à un procédé de régulation de la vitesse d'extinction d'un dérivé d'acide hyaluronique (HA), consistant à modifier le pourcentage de substituants introduits dans l'acide carboxylique de l'acide glucuronique du dérivé HA, ou consistant à changer le poids moléculaire du dérivé HA. En outre, l'invention se rapporte à un conjugué de médicament dans lequel un dérivé d'acide hyaluronique dont la vitesse d'extinction est régulée est utilisé en tant que vecteur afin de prolonger ou de réguler la durée de demi-vie du médicament dans le sang.
PCT/JP2004/000004 2002-12-27 2004-01-05 Vecteur de medicament WO2004060404A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006028110A1 (fr) * 2004-09-07 2006-03-16 Chugai Seiyaku Kabushiki Kaisha Processus de production de la modification de l'acide hyaluronique hydrosoluble
WO2006082184A3 (fr) * 2005-02-01 2007-06-07 Organon Nv Conjugues d'un polypeptide et d'un oligosaccharide
US8524885B2 (en) * 2006-03-07 2013-09-03 Prochon Biotech Ltd. Hydrazido derivatives of hyaluronic acid
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
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WO2006028110A1 (fr) * 2004-09-07 2006-03-16 Chugai Seiyaku Kabushiki Kaisha Processus de production de la modification de l'acide hyaluronique hydrosoluble
WO2006082184A3 (fr) * 2005-02-01 2007-06-07 Organon Nv Conjugues d'un polypeptide et d'un oligosaccharide
US8106007B2 (en) 2005-02-01 2012-01-31 N.V. Organon Conjugates of a polypeptide and a pentasaccharide
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
US8524885B2 (en) * 2006-03-07 2013-09-03 Prochon Biotech Ltd. Hydrazido derivatives of hyaluronic acid
US8940888B2 (en) 2006-03-07 2015-01-27 Prochon Biotech Ltd. Hydrazido derivatives of hyaluronic acid
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
US11555172B2 (en) 2014-12-02 2023-01-17 Ocugen, Inc. Cell and tissue culture container

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