WO2004046200A1 - 薬物徐放担体 - Google Patents
薬物徐放担体 Download PDFInfo
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- WO2004046200A1 WO2004046200A1 PCT/JP2003/014906 JP0314906W WO2004046200A1 WO 2004046200 A1 WO2004046200 A1 WO 2004046200A1 JP 0314906 W JP0314906 W JP 0314906W WO 2004046200 A1 WO2004046200 A1 WO 2004046200A1
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- hyaluronic acid
- acid derivative
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
Definitions
- the present invention relates to a sustained-release carrier for hyaluronic acid octaidogel, which sustainably releases a protein or peptide.
- sustained-release preparations of a protein or peptide having a medicinal effect a reduction in the recovery rate due to denaturation or aggregation of the protein or peptide during preparation or during sustained release is a major obstacle to practical use.
- sustained-release preparations using a hydrophilic hydrogel as a base material that reduce these problems have been reported, they have not yet been put to practical use.
- the material used as the sustained-release base material must be non-antigenic, non-mutagenic, non-toxic, and biodegradable, and the protein or peptide encapsulation rate, Sustained-release preparations, which have reached practical levels in terms of recovery rate and safety, have not yet been realized.
- Hyaluronic acid is a biomaterial (polysaccharide) isolated from the vitreous of bovine eyes by K. Meyer in 1934, and has long been known as a main component of a fine matrix.
- HA is D-glucuronic acid and N-acetyldarcosamine Is a kind of dalcosa dogglycan consisting of disaccharide units linked by ⁇ (1 ⁇ 3) glycosidic bonds (Formula (VI)).
- ⁇ is a biomedical material (Biomatera1a1), which has the same chemical and physical structure, has the same metabolic system as humans, and is the safest in terms of immunity and toxicity.
- Biomatera1a1 a biomedical material
- large-scale production of high molecular weight HA by microorganisms has become possible, and has been put to practical use in the fields of osteochondral remedies, cosmetics, and the like.
- hyaluronic acid derivative into which a hydrazide group (HZ) has been introduced is cross-linked with a cross-linking agent composed of N-hydroxysuccinimide (NHS).
- HA-HZ hyaluronic acid derivative
- NHS N-hydroxysuccinimide
- the inventors of the present invention have conducted intensive studies to solve such problems, and found that a hyaluronic acid derivative containing a group having an unsaturated bond with hyaluronic acid in a solution in the presence of a protein or a peptide contains a mercapto group.
- a compound or a hyaluronic acid derivative in which a mercapto group has been introduced into hyaluronic acid is chemically cross-linked with a compound having an unsaturated bond and formed into a gel with a hydrid.
- the present inventors have found that it can be a biodegradable and safe protein or peptide sustained release carrier that can be efficiently encapsulated and completed the present invention.
- a hyaluronic acid derivative in which an unsaturated bond is introduced into hyaluronic acid in a solution in the presence of protein or a peptide is used as a mercapto group.
- a sustained-release drug carrier characterized in that a compound containing the compound or a hyaluronic acid derivative in which a mercapto group is introduced into hyaluronic acid is chemically crosslinked and hydrogelated with a compound having an unsaturated bond.
- a method for producing a hyaluronic acid derivative having a mercapto group introduced therein is provided.
- the hyaluronic acid derivative produced in the step (a) is preferably a compound represented by the formula (I):
- Ri is a hydrogen atom, straight-chain or branched.
- Alkyl groups straight-chain or branched.
- R a2 , R a3 , R a4 , R a5 and R a6 each independently represent a hydrogen atom, a linear or branched alkyl group, a linear or branched — 6 alkenyl group, a linear or Straight chain or branched alkyl carbonyl group, straight chain Or a branched C 6 alkenylcarbonyl group, a straight-chain or branched C 6 alkynylcarbonyl group, or 1 S ⁇ 2 ⁇ H;
- Yi is a single bond, —N (—R 3 ) CO—, —N (—R 3 ) —, —CO—, or —CH 2 C ⁇ ,
- Y 2 is a single bond, one CON (—R 4 ) —, or —N (—R 4 ) —, and is a linear or branched Ci—i.
- R 2 , R 3 and R 4 are each independently a hydrogen atom, a linear or branched Ci-alkyl group, a linear or branched C ⁇ —i. It is a hydroxyalkyl group, polyalkylene oxide group, polypeptide group, or polyester group. )
- the polypeptide group is not particularly limited, but preferably comprises 1 to 20 amino acids.
- the polyester group is not particularly limited, but is preferably a polyglycolic acid group or a polylactic acid group.
- X Is one N (-R,) one.
- 1 ⁇ is a hydrogen atom.
- Y 2 is preferably a single bond.
- it is preferably a straight-chain or branched- 4 alkylene group.
- formula (I) preferably R 2 and R. Is a hydrogen atom.
- the hyaluronic acid derivative produced in the step (b) is preferably a compound represented by the formula (II):
- R i a2 > R a3 , R a4 , K a5 , a6 , Y Y, Q i, R 2, and R 4 are as defined in the above formula (I),
- Y 3 is a single bond, one CO—, one C 6 H 4 —, one C ⁇ 2 —, one S ⁇ 2 _, -CH 2-
- Q 2 is linear or branched ⁇ —i. Alkylene group, straight or branched C ⁇ —i. It is a hydroxyalkylene group, polyalkylene oxide group, polypeptide group, or polyester group. )
- X 0 is 1 N (—R 1.
- 1 1 is a hydrogen atom.
- X 2 Is one of Qi—Ys—N (—R 2 ) —Y 3 —Q 2 —SH
- formula (II) preferably, is a single bond or one N (—R 3 ) —
- Y 2 is a single bond,
- formula (II) preferably a straight-chain or branched— 4 alkylene group.
- R 2 and R 3 are preferably a hydrogen atom.
- Y 3 is one CO—.
- Q 2 is a linear or branched alkylene group.
- the method comprises converting at least one or more hydroxyl group of hyaluronic acid into an N-substituted amide group having a substituent containing a mercapto group in an organic solvent.
- a method for producing a hyaluronic acid derivative into which a group has been introduced is provided.
- the resulting hyaluronic acid derivative into which the mercapto group has been introduced is preferably a compound represented by the formula (IIa):
- Ri is 7j ⁇ primary atom, straight chain or branched Ci—i.
- Alkyl groups straight or branched.
- R a2 , R a3 , R a4 , R a5, and R a6 each independently represent a hydrogen atom, a straight-chain or branched (: a 6- alkyl group, a straight-chain or branched_ 6 alkenyl group, a straight-chain or branched Branched C — 6 alkenyl group, straight or branched alkyl group, straight or branched C 6 alkenyl carbonyl group, straight or branched C 6 alkynyl carbonyl group, or 1 S ⁇ 2 OH ,
- X 2a is one Y — Qi — Y 2 — Q 3 — Y 3 — Q 2 — SH or one N (— R 2 ) — Y 3 — Q 2 — SH, Represents a single bond, one N (- R 3) CO-, -N (-R 3) -, -CO-, or - CH 2 C_ ⁇ is one,
- Upsilon 3 are each independently a single bond, One ⁇ -, One S-, one SO-, -S 0 2 - one N (- R 4) -, one C00-, One ⁇ _C_ ⁇ _, -CON (one R 4 ) —, one N (—R 4 ) CO—, or one N (—R 4 ) CON (one R 5 ) —
- Q 2 Q 3 and Q 2 are each independently linear or branched.
- Alkylene group straight-chain or branched.
- R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom, a linear or branched alkyl group, a linear or branched Ci-hydroxyalkyl group, a polyalkylene oxide group, a polypeptide group, or It is a polyester group.
- n -OH is a group represented by Preferably, they are a polyethylene oxide group and a polypropylene oxide group, and preferably, n is an integer of 1-20.
- the polypeptide group is not particularly limited, but preferably comprises 1 to 20 amino acids.
- the polyester group is not particularly limited, but is preferably a polyglycolic acid group or a polylactic acid group.
- X 0 is preferably 1 N (-R x ) 1.
- 1 ⁇ is a hydrogen atom.
- X 2a is one Y—Qi—Y 2 —Q 3 —Y 3 —Q 2 —SH.
- it is preferably a single bond or one N (—R 3 ) —.
- Y 2 is a single bond.
- Y 3 is a single bond.
- Q 2 and Q 3 are straight-chain or branched alkylene groups.
- R 2 and R 3 are a hydrogen atom.
- Y 3 is one CO—.
- hyaluronic acid derivative into which the mercapto group has been introduced is preferably a compound represented by the formula
- R al is a hydroxyl group, a straight-chain or branched-amino group which may be mono- or di-substituted by a 6-alkyl group, a straight-chain or branched alkoxy group, or a sodium ion, potassium May form a carboxylate with a cation selected from the group consisting of an ion, a calcium ion, a magnesium ion, a lithium ion or an optionally substituted ammonium ion,
- R a2, R a3, R a4 , R a5 and R a6 are each independently a hydrogen atom, a linear or branched C - 6 alkyl group, straight or branched ( ⁇ _ 6 alkenyl group, a linear or Branched C ⁇ -e alkynyl group, straight or branched — 6 alkyl carbonyl group, straight or branched — 6 alkenyl carbonyl group, straight or branched alkynyl carbonyl group, or one S ⁇ 2 OH.)
- a repeating structure B represented by the above formula (II) or (IIa), wherein the proportion of the repeating structures A and B is preferably 95: 5 to: 10: 90, More preferably, it is 90:10 to 10:90, and still more preferably, it is 80:20 to 20:80.
- a method for producing a hyaluronic acid derivative into which the group having an unsaturated bond has been introduced comprising the step of:
- the hyaluronic acid derivative generated in the step (a) is preferably a hyaluronic acid derivative having at least one or more repeating structures represented by the above formula (I) in the molecule.
- the hyaluronic acid derivative produced in the step (b) is preferably a compound represented by the formula (IV):
- X 3 is one — one Y 2 — N (_R 2 ) — Y 3 — Q 4 , or one N (_R 2 ) — Y 3 -Q 4 ,
- R a2 R a3 R a4 R a5 and R a6 each independently represent a hydrogen atom, a straight-chain or branched alkyl group, a straight-chain or branched alkenyl group, a straight-chain or A branched alkynyl group, a straight-chain or branched alkylcarbonyl group, a straight-chain or branched C 6 alkenylcarbonyl group, a straight-chain or branched C alkynylcarbonyl group, or —S0 2 OH;
- Y 2 is a single bond, -CON (-R 4 )-, or 1 N (-R 4 )-,
- Y 3 is a single bond, one CO—, -N (—R 5 ) CO_, -N (one R 5 ) —, or one CH 2 C ⁇ ,
- Ci-alkylene group a linear or branched Ci-alkylene group, a linear or branched hydroxyalkylene group, a polyalkylene oxide group, a polypeptide group, or a polyester / group;
- R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom, a straight-chain or branched (: ⁇ . Alkyl group, a straight-chain or branched (.hydroxyalkyl group, a polyalkylene oxide group, a polyalkylene oxide group, A peptide group or a polyester group,
- Q 4 are a linear or branched C 2 _ 10 alkenyl group, or a linear or branched C
- n is an integer of 1 to 20.
- the polypeptide group is not particularly limited, but preferably comprises 1 to 20 amino acids.
- the polyester group is not particularly limited, but is preferably a polyglycolic acid group or a polylactic acid group.
- X 0 is preferably 1 N (-R x ) 1.
- X 3 is —Yi——Y 2 —N (—R 2 ) —Y 3 —Q 4 .
- it is preferably a single bond, -N (- R 3) CO- , or one N (—R 3 ) —, more preferably one N (—R 3 ) C ⁇ .
- Y 2 is a single bond, —CON (—R 3 ) —, more preferably one CON (—R 3 ) —.
- Y 3 is preferably a single bond, 1C-1 or 1N (-R 3 ) 1, and more preferably 1C-. In the formula (IV), preferably, it is a linear or branched alkylene group. In the formula (IV), preferably, R 2 and R 3 are a hydrogen atom. In Formula (IV), preferably Q 4 are a straight-chain or branched C 2 _ 10 alkenyl group.
- a hyaluronic acid derivative into which a group having an unsaturated bond has been introduced produced by the above method.
- the hyaluronic acid derivative into which the group having an unsaturated bond has been introduced preferably contains a repeating structure A represented by the above formula (III) and a repeating structure C represented by the above formula (IV),
- the ratio of the repeating structures A and C is 95: 5 to; L0: 90, preferably 90:10 to 10:90, and more preferably 80:20 to 20:80.
- a chemically cross-linked hyaluronic acid derivative obtained by chemically cross-linking the above-described hyaluronic acid derivative into which a group having an unsaturated bond has been introduced with an unsaturated bond-containing compound. Also provided is a chemically cross-linked hyaluronic acid derivative obtained by chemically cross-linking the above-mentioned hyaluronic acid derivative into which a mercapto group has been introduced with an unsaturated compound.
- the chemically crosslinked hyaluronic acid derivative preferably has the formula (V):
- X 0 is one O— or one N (— I one, and is a hydrogen atom, a straight-chain or branched alkyl group, a straight-chain or branched C ⁇ -hydroxyalkyl group, a polyalkylene oxide Group, polypeptide group, or polyester group,
- R a2 , R a3 , R a4 , R a5, and R a6 each independently represent a hydrogen atom, a linear or branched alkyl group, a linear or branched — 6 alkenyl group, a linear or branched alkynyl group, A straight-chain or branched alkyl carbonyl group, a straight-chain or branched C 6 alkenyl carbonyl group, a straight-chain or branched C 6 alkynyl carbonyl group, or one S ⁇ 2 ⁇ H;
- X 4 is _Y — C ⁇ —Ys— X 5 — Y 3 — Q 2 — S—L or N (—R 2 ) —Y 3 -Q 2 -S—L,
- X 5 is _Q 3 — or one N (— R 2 ) —
- Y 2 is a single bond, one ⁇ —, one S—, one SO—, one S0 2— , one N (—R 4 ) —, one COO—, one OC ⁇ 1, one CON (— R 4 ) — , -N (-R 4 ) CO— or one N (-R 4 ) CON (—R 5 ) —
- Q 1 , Q 2 and Q 3 are each independently a straight-chain or branched C—alkylene group, straight-chain or branched.
- R 2 and R 3 are each independently a hydrogen atom, a straight-chain or branched Ci-alkyl group, a straight-chain or branched.
- L is that form a L a connexion intramolecular or intermolecular crosslinking, such together the other repeating structures, and in some cases have Z at the end or in the middle of the main chain Z 2, Z 3, sigma 4 Oyobi 2 5 Including May be straight or branched C.
- Z There Z 2, Z 3, Z 4 and Z 5 are each independently one 0-, - S-, -S ⁇ one, - S_ ⁇ 2 - one N (- R 4) -, -CH (One R 6 )-, one C (-R 6 ) (one R 7 ) one, one CO—, one C ⁇ one, one C ⁇ one, -CON (one R 4 ) —, _N ( ⁇ R 4 ) CO—, or 1 N (— R 4 ) CON (1 R 5 ) —
- R 4 and R 5 are each independently a hydrogen atom, straight-chain or branched. Alkyl groups, straight or branched. A hydroxyalkylene group, a polyalkylene oxide group, a polypeptide group, or a polyester group,
- R 6 and R 7 are each independently a hydroxyl group
- one (CH (-R) CH 2 O ) n - (wherein, R represents a hydrogen atom or an alkyl group,) OH is a group represented by, preferably , A polyethylene oxide group or a polypropylene oxide group, and preferably n is an integer of 1 to 20.
- the polypeptide group is not particularly limited, but preferably comprises 1 to 20 amino acids.
- the polyester group is not particularly limited, but is preferably a polyglycolic acid group or a polylactic acid group.
- X 0 is 1 N (—R 1.
- 1 ⁇ is a hydrogen atom.
- X is 4 shows an Yi- Qi- Ya- X 5 - Y 3 - Q 2 - S- at which it had contact to the formula (V) L, preferably X 5 is, -. N (- R 2 ) - a.
- Y 2 is a single bond, -CON (-R 3 ) 1, more preferably 1 CON (—R 3 ) —.
- Y 3 is a single bond, one CO— or one N (—R 3 ) —, more preferably one CO—.
- R 2 and R 3 are a hydrogen atom.
- Q 2 and Q 3 are linear or branched alkylene groups.
- L is a straight-chain or branched-alkylene group which may be substituted by one or more hydroxyl groups, carboxy groups, straight-chain or branched alkyl groups, More preferably, there is a linear or branched ( ⁇ alkyleno group.
- the chemically crosslinked hyaluronic acid derivative preferably includes a repeating structure A represented by the above formula (III) and a repeating structure D represented by the above formula (V), and the abundance ratio of the repeating structures A and D is , Preferably 95: 5 to 10:90, more preferably 90:10 to 10:90, even more preferably 80:20 to 20:80.
- Figure 1 shows the results obtained by incubating the gel of Example 2 in 2 mL of PBS at 37 ° C, sampling 20 OLs over time, and quantifying EP ⁇ released into the buffer by RP-HPLC. It is a figure showing an example.
- FIG. 2 is a photograph showing a state in which a solution containing the hyaluronic acid derivative of the present invention is injected subcutaneously into a rat and an example of a recovered gel.
- the sustained-release drug carrier of the present invention is a mercapto group-containing conjugate containing a hyaluronic acid derivative in which an unsaturated bond is introduced into hyaluronic acid in a solution in the presence of a protein or a peptide, or a hyaluronic acid. It is characterized in that a hyaluronic acid derivative having a mercapto group introduced therein is chemically cross-linked with an unsaturated conjugated product and hydrogelated.
- the sustained-release drug carrier of the present invention has the following excellent features.
- Chemical cross-linking includes inter-molecular or intra-molecular cross-linking by covalent bonds, and may also have inter- and intra-molecular cross-linking at the same time.
- the pH at the time of cross-linking is not particularly limited, but is preferably pH that gives priority to the selective reaction of the unsaturated bond and the mercapto group without denaturing the protein or peptide and prevents the reaction with the protein or the amino group containing a peptide.
- a pH can be selected by a person skilled in the art, for example, pH 3.0-9.0, preferably pH 6.0-8.5.
- the group having an unsaturated bond is not particularly limited, but includes, for example, a methacryl group, an acryl group, a maleimide group, a vinylsulfone group, an acetylenecarponyl group and the like.
- a cross-linking agent used when a group having an unsaturated bond is introduced into hyaluronic acid a compound containing two or more mercapto groups that react with an unsaturated bond and a nucleophilic addition reaction in the same molecule is used.
- DTT dithiothreitol
- butanedithiol butanedithiol
- polyethylene glycol dithiol polyethylene glycol dithiol
- peptides containing two or more cysteines and the like can be mentioned.
- a cross-linking agent used when a mercapto group is introduced into hyaluronic acid a compound containing two or more groups having an unsaturated bond that reacts with a mercapto group in a nucleophilic addition reaction in the same molecule is used.
- ethylene glycol dimethacrylate, ethylenebisacrylamide, tris-2-maleimidoethylamine, 1,8-bismaleimidotriethylene glycol, 1,4-bismaleimidyl-1,2,3-dihydroxybutane and the like can be mentioned.
- the basic compound used is not particularly limited. Examples thereof include carbonates such as sodium carbonate and sodium hydrogen carbonate, hydroxides such as sodium hydroxide and sodium hydroxide, aqueous ammonia, pyridine, triethylamine, and ethylenediamine. And amines such as ethanolamine, ethanolamine and triethanolamine, preferably amines, and more preferably triethanolamine. In this case, a preferable concentration is 10 to 2 OzLZmL.
- the method for preparing the hyaluronic acid derivative into which the group having an unsaturated bond is introduced is not particularly limited.For example, a method in which glycidyl ether methacrylate or methacrylic anhydride is directly reacted with the hydroxyl group of HA (J. Biome) d. Mat. Res. 54, 115-121, 2001), it is difficult to obtain a high introduction rate. This is probably because hyaluronic acid forms a higher-order structure in aqueous solution by hydrogen bonding and hydrophobic interaction, and the reactivity of functional groups such as hydroxyl group and carboxylic acid group is low. A high crosslink density is desirable to extend the sustained release of proteins and peptides.
- a substituent into the hydroxyl group of the glucuronic acid moiety For this purpose, it is desirable to introduce a substituent into the hydroxyl group of the glucuronic acid moiety.
- hyaluronic acid is converted into a tertiary ammonium salt, dissolved in a polar organic solvent such as dimethylsulfoxide (DMSO), and a cup of 1-ethyl-3- (3-dimethylaminopropyl) lipodiimide (EDC) is dissolved.
- DMSO dimethylsulfoxide
- EDC 1-ethyl-3- (3-dimethylaminopropyl) lipodiimide
- It can be prepared by a method of reacting with an amide or hydrazide having an unsaturated bond in the presence of a ring agent.
- the amine having an unsaturated bond is not particularly limited, and examples thereof include arylamine, diarylamine, 4-amino-11-butene, acrylic hydrazi
- a hydrazide group-modified hyaluronic acid is obtained by condensing a carboxylic acid of hyaluronic acid with a dihydrazide or an amino group-containing compound such as adipic dihydrazide (ADH) or ethylenediamine with a condensing agent such as EDC.
- ADH adipic dihydrazide
- EDC condensing agent
- Derivatives (HAZ) or amino group-modified hyaluronic acid derivatives (HA-amino groups) are synthesized and reacted with methacrylic anhydride.
- the method for preparing the mercapto group-introduced hyaluronic acid derivative is not particularly limited.
- hyaluronic acid is converted into a tertiary ammonium salt, dissolved in a polar organic solvent such as dimethylsulfoxide (DMSO), and 1-ethyl-3- ( 3-dimethylaminopropyl) can be prepared by, for example, reacting with a mercapto group-containing amine or hydrazide in the presence of a coupling agent such as carbodiimide (EDO).
- a coupling agent such as carbodiimide (EDO).
- the amine having a mercapto group is not particularly limited, and examples thereof include 2-aminoethane-1-thiol, 3-aminopropane-11-thiol, and thioglycolic acid hydrazide.
- a carboxylic acid of hyaluronic acid and a divalent hydrazide such as adipic acid dihydrazide (ADH) or a compound containing an amino group such as ethylenediamine or an amino group-containing compound are combined with 1-ethyl-3- (3-dimethylaminopropyl) carpoimide (EDC).
- ADH adipic acid dihydrazide
- EDC 1-ethyl-3- (3-dimethylaminopropyl) carpoimide
- a hydrazide group-modified hyaluronic acid derivative (HAZ) or an amino group-modified hyaluronic acid derivative (HA-amino group)
- HZ hydrazide group-modified hyaluronic acid derivative
- HA-amino group for example, N-succinimidyl One 3— [2-pyridyldithio] pull
- SPDP pionate
- DTT reducing agent
- the rate of introduction of the hydrazide group into the hyaluronic acid derivative is not particularly limited, but is usually preferably 5 mol% or more, more preferably 10 mol% or more per glucuronic acid of the hyaluronic acid derivative in order to obtain a gel having no fluidity.
- the rate of introduction of the amino group into the hyaluronic acid derivative is at least 5 mol%, preferably at least 10 mol%, per HA glucuronic acid in order to obtain a gel having no fluidity.
- the rate of introduction of the group having an unsaturated bond into the hyaluronic acid derivative is not particularly limited, but is preferably 5 mol% or more, more preferably 10 mol% or more per glucuronic acid of the hyaluronic acid derivative to obtain a gel having no fluidity. Particularly preferred.
- the rate of introduction of the mercapto group into the hyaluronic acid derivative is not particularly limited, but is at least 5 mol%, preferably at least 10 mol /%, per dalucic acid of hyaluronic acid in order to obtain a gel having no fluidity.
- the ratio of the mercapto group to the group having an unsaturated bond is not particularly limited, and can be selected by those skilled in the art.
- a mercapto group: unsaturated bond 3: 1 to 1 : 1 is preferred. More preferably, it is 2: 1-1.5: 1.
- a method for preparing a hydrogel composed of an HA derivative and a protein or peptide having a pharmacological action includes, for example, dissolving the HA derivative and the protein or peptide in phosphate-buffered saline, and then adding a crosslinking agent thereto to homogenize the solution. Disperse and react at room temperature or 4 ° C.
- This cross-linking method has a relatively slow reaction rate, so it is more uniform It has the advantage of cross-linking HA and preparing a uniform gel. This is effective for stabilizing and prolonging the sustained release performance.
- the hyaluronic acid used in the present invention may be hyaluronic acid obtained by any method, such as hyaluronic acid extracted from animal fiber, hyaluronic acid obtained by fermentation, or obtained by chemical synthesis.
- the origin is not limited, such as hyaluronic acid.
- the hyaluronic acid may be subjected to a further treatment such as a hydrolysis treatment.
- the HA of the present invention also includes modified HA modified by various methods, and alkali metal salts such as sodium, potassium and lithium.
- HA is often modified with a hydroxyl group and a hydroxyl group, but in the present invention, any part of the modified HA may be modified.
- the modified HA is not particularly limited, and may be modified in any manner. Examples thereof include sulfated HA (WO 95Z25751 pamphlet) and N-sulfated HA (WO 98Z45335). Pamphlet), esterified HA (EP 0216453, WO 98/08876 pamphlet, EP 0341745), periodate oxidized HA, Amide-modified HA and the like can be mentioned.
- the molecular weight of the hyaluronic acid used in the present invention is not particularly limited, and any molecular weight of hyaluronic acid can be used, but usually 50 to 3.5 million daltons, preferably 10,000 to 2 million daltons of hyaluronic acid. Acids can be used.
- the protein and peptide having a medicinal effect are not particularly limited, but include, for example, erythropoietin (EPO), knowinglyulocytocoloni stimulating factor (G-CSF), interferon- ⁇ , ⁇ , ⁇ , (INF-, ⁇ , r), Trompopoetin
- TPO serial neurotrophic factor
- CNTF serial neurotrophic factor
- TNFbp tumour-necrosis factor binding protein
- IL-10 interleukin-10
- FMS-like tyrosine-like rice Flt-3
- growth hormone MON GH
- insulin insulin-like growth factor-1
- IGF-1 insulin-like growth factor-1
- PDFG platelet-derived growth factor
- IL-1ra interleukin-1 1 receptor
- BDN F brain-derived neurotrophic Factor
- KGF Keratinocyte Growth Factor
- SCF Stem Cell Factor
- MDF Megakaryo Site growth differentiation factor
- OPG osteoprotegerin
- lebutin parathyroid hormone
- PTH basic fibroblast growth factor
- BMP bone morphogenetic protein
- GLP-1 bone morphogenetic protein
- GLP-1 dalgongon-like peptide I-1
- antibody diapody, and the like.
- the hyaluronic acid derivative gel of the present invention is not particularly limited, but may be, for example, a hydrid sol or an organosol, and is preferably a hydrosol.
- the sustained-release carrier of the present invention is a pharmaceutical preparation comprising one or more pharmaceutically acceptable diluents, wetting agents, emulsifiers, dispersants, auxiliaries, preservatives, buffers, binders, stabilizers and the like.
- the composition can be administered in any suitable form depending on the intended route of administration.
- the route of administration may be parenteral or oral.
- Injectable fine particles can be formed by, for example, a method of drying after gelation, freeze-crushing, a method of preparing a fine gel by emulsion method, followed by drying, a spray drying method, a supercritical solution method, etc. Dry fine particles:
- Known methods can be employed, such as a method for preparing particles, a method of administering the composition in a solution state before the completion of the crosslinking reaction, and a method of crosslinking in the body.
- the NMR measurement was performed using a nuclear magnetic resonance apparatus JNM-ECA500 (manufactured by JEOL Ltd.) using heavy water as a solvent.
- the introduction ratio of the substituent was determined from the integral ratio of the peak specific to the introduced substituent and the peak derived from hyaluronic acid.
- High-performance liquid chromatography (RP-HPLC) analysis using a reversed-phase column was carried out using a Waters 600 S controller, a 717 p1 us autosampler, and a 486 UV absorption spectrometer (Waters) under the following measurement conditions. went.
- EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
- ADH adipic acid dihydrazide
- Example 1-1 Batches 1 to 3 HA-HZ, 90 mg each, were dissolved in 0.45 mL of 10 OmM phosphate buffer pH 8 (HA-HZ2% w / v), and 0.54 mL of methacrylic anhydride was added and reacted at room temperature for 1 day with stirring. The precipitate was washed with ethanol, washed, and dried. Also, the MA introduction rate in the obtained HA-MA Table 1 shows the results quantified by the NMR method. (Compare HA and HA—MA N-acetyl group, 2.1 ppm (3H), HA—MA methacryl group vinyl proton, 5.5-6.0 ppm (2H)).
- HA-MAI 1 mg of HA-MAI with 29% MA introduction rate from batch 3 of Example 1-2 and £ 1008 dissolved in 0.25 mL of phosphate buffer pH 7.4 (PBS) (Room temperature, stirred for 1 hour).
- PBS phosphate buffer pH 7.4
- TAA triethanolamine
- DTT dithiothreitol
- Example 13 Same as Example 13 except that the gel prepared in Example 1 to 3 was not dialyzed and a 10 2 L solution of acetic acid (223.2 mg / niL PBS, 2 times the molar amount of DTT) was added. EPO-encapsulated HA hydrogel was prepared in the same manner.
- Example 3 In situ cross-linked EPO-encapsulated HA hydrogel
- Example 1 In batch 2 of HA-2, 22 mg of HA-MA with a MA introduction rate of 29% and £ 0400 were dissolved in 0.48 mL of a phosphate buffer, pH 7.4 (PBS) (at room temperature). , Stirring for 1 hour). To this was added 3.5 L of triethanolamine (TEA) and 20 iL of dithiothreitol (DTT) (92.55 mg / mL). After stirring at room temperature for 10 minutes, the mixture was filled in an lmL syringe, and after 120 minutes of DTT-added calo, 100 L was subcutaneously administered to the rat (using a 22-gauge needle). Four hours later, the gel was recovered from the subcutaneous tissue. Figure 2 shows photographs of the gel injected into the subcutaneous rat and the recovered gel. It can be seen that the solution of this composition crosslinks and gels under the skin. Comparative Example 1
- Example 1 The procedure of Example 1 was repeated except that 5 L of dithiothreitol (DTT) (92.55 mg / mL) was added, and the reaction was performed in PBS at pH 8.0 without adding TEA.
- DTT dithiothreitol
- An EPO-encapsulated HA hydrogel was prepared in the same manner as in Example 1.
- Example 2 The procedure of Example 1 was repeated except that 10 L of dithiothreitol (DTT) (92.55 mg / mL) was added to the EPO-encapsulated HA hydrate gel prepared in Example 1 and reacted in PBS at pH 8.0 without adding TEA.
- DTT dithiothreitol
- Test Example 1 Measurement of EPO recovery of EPO encapsulated HA hydrated mouth gel
- Table 2 shows the time required for gelling and the recovery rate of EP ⁇ recovered from the gel relative to the charged EP ⁇ . Table 2 Sample Reaction time EPO recovery
- Test Example 2 Sustained release of EP ⁇ from preparation of HA hydrogel encapsulating BP O
- Example 2 The gel of Example 2 was incubated in 2 mL of PBS with 37, and 200 L was sampled over time. EPO released into the buffer was quantified by RP-HPLC.
- Figure 1 shows the release of EPO from the gel when the EPO recovered and degraded with hyaluronidase immediately after gel preparation is 100%. After 12 days, hyaluronidase was added. It can be seen that the EPO in the gel is not denatured and 90% or more is released slowly.
- the protein or peptide is cross-linked in situ while maintaining the biological activity of the protein or peptide, and a sustained-release preparation of protein or peptide encapsulated in hydrogel is obtained. It can be prepared.
- Test Example 3 In situ crosslinked EPO-encapsulated EPO-encapsulated sustained-release performance from HA hydrated gel After adding DTT to the solution prepared in Example 3 and allowing it to stand at room temperature for 150 minutes, 120 L was subcutaneously administered to rats. The EPO concentration in the serum was measured with an ELISA kit (Roche Diagnistics GmbH, Mannheim, Germany). Table 3 shows the average residence time (MRT) analyzed by a non-comparison model using WinNonlin ver. 2.1 (Pharsight). MRT of EPO solution, EPO + HA ( ⁇ ? 2 million dalton, 1% concentration) solution is shown.
- the sustained-release drug carrier of the present invention retains the biological activity of the protein or peptide and can encapsulate them in an insitu chemical cross-linking or HA hydrogel, thereby enabling sustained release of the protein or peptide with excellent recovery.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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JP2004553228A JP4636883B2 (ja) | 2002-11-21 | 2003-11-21 | 薬物徐放担体 |
AU2003284634A AU2003284634A1 (en) | 2002-11-21 | 2003-11-21 | Sustained release drug carrier |
US10/536,031 US7816316B2 (en) | 2002-11-21 | 2003-11-21 | Sustained release drug carrier |
EP03774146A EP1564220A4 (en) | 2002-11-21 | 2003-11-21 | EXCIPIENT FOR DELAYED RELEASE MEDICINE |
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JP2002-338167 | 2002-11-21 | ||
JP2002338167 | 2002-11-21 |
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WO2004046200A1 true WO2004046200A1 (ja) | 2004-06-03 |
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PCT/JP2003/014906 WO2004046200A1 (ja) | 2002-11-21 | 2003-11-21 | 薬物徐放担体 |
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US (1) | US7816316B2 (ja) |
EP (1) | EP1564220A4 (ja) |
JP (1) | JP4636883B2 (ja) |
AU (1) | AU2003284634A1 (ja) |
WO (1) | WO2004046200A1 (ja) |
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WO2008136536A1 (ja) | 2007-05-01 | 2008-11-13 | National University Corporation Tokyo Medical And Dental University | 化学架橋ヒアルロン酸誘導体を含むハイブリッドゲルおよびそれを用いた医薬組成物 |
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Also Published As
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US20060110458A1 (en) | 2006-05-25 |
AU2003284634A1 (en) | 2004-06-15 |
EP1564220A1 (en) | 2005-08-17 |
JPWO2004046200A1 (ja) | 2006-03-16 |
US7816316B2 (en) | 2010-10-19 |
EP1564220A4 (en) | 2010-03-17 |
JP4636883B2 (ja) | 2011-02-23 |
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