JPH09235302A - Branched cyclodextrincarboxylic acid ester and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a branched cyclodextrincarboxylic acid ester capable of solubilizing a water-insoluble or slightly soluble substance and stabilizing unstable substances and useful for medicines, etc., by subjecting a branched cyclodextrin tricarboxylic acid or its salt to esterification reaction. SOLUTION: In this acid ester, the branched cyclodextrin carboxylic acid has an organic group containing at least one carboxyl group at 6-O position of at least one glucose unit of cyclodextrin ring and the carboxylic acid has 1 to 3 organic groups represented by the formula G-G-COOH (G is glucose unit). The carboxylic acid is specifically preferably 6-O- cyclomaltohexaosyl-(6→1)-α-D-glucosyl-(4→1)-O-α-D-glucuronic acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a branched cyclodextrin carboxylic acid ester and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Branched cyclodextrin carboxylic acids have greater solubility in water than conventional cyclodextrins or branched cyclodextrins as disclosed in JP-A-7-76594. Therefore, it exhibits an excellent effect of improving the solubility of a water-insoluble or sparingly soluble substance in water. If the branched cyclodextrin carboxylic acid having high water solubility can also be made to have lipophilicity, the solubility in water will be reduced and unstable substances can be stabilized.

[0003]

Means for Solving the Problems As a result of various investigations on this problem, the present inventors have found that cyclodextrin carboxylic acid ester is an amphipathic compound soluble in water and a solvent, and completed the present invention. Came to do. That is, the present invention provides a branched cyclodextrin carboxylic acid ester. The present invention also provides a method for producing a branched cyclodextrin carboxylic acid ester, which comprises subjecting a branched cyclodextrin carboxylic acid or a salt thereof to an esterification reaction. Furthermore, the present invention also provides a water solubility improver comprising the above ester. The present invention also provides a drug stability improver comprising the above ester. Furthermore, the present invention also provides a medicament comprising the above ester and a drug.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION The alcohol portion of the branched cyclodextrin carboxylic acid ester of the present invention contains a chain or cyclic primary, secondary or tertiary alcohol. Among them, aliphatic alcohols having 1 to 30 carbon atoms, preferably 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, and particularly preferably 1 to 8 carbon atoms are preferable. Examples of the chain alcohol include linear or branched alcohols having the above carbon number, and specific examples thereof include alkyl-alcohol, alkenyl-alcohol, alkynyl-alcohol and the like. Examples of the alkyl of the alkyl-alcohol include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n.
-Amyl, i-amyl, s-amyl, t-amyl, n-hexyl, 2-ethylbutyl, n-octyl, 2-ethylhexyl and the like can be mentioned. Examples of the alkenyl of the alkenyl-alcohol include allyl, vinyl, crotyl, 3-butenyl, 1-methyl-2-propenyl, 2-
Pentenyl, 3-pentenyl, 2-methyl-2-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 3-methyl-3-hexenyl and the like can be mentioned. Examples of the alkynyl of the alkynyl-alcohol include propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 3-methyl-2-pentynyl and the like. To be Examples of the cyclic alcohol include alicyclic alcohols having 4 to 6 carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, which may be substituted with 1 to 2 methyl groups or ethyl groups on the ring.

The branched cyclodextrin carboxylic acid of the branched cyclodextrin carboxylic acid ester of the present invention is a branched cyclodextrin carboxylic acid having an organic group containing at least one carboxyl group at the 6-O position of at least one glucose unit of the cyclodextrin ring. Dextrin carboxylic acid.

The cyclodextrin ring of the branched cyclodextrin carboxylic acid is, for example, α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin having 6, 7 or 8 glucose units. Preferably, the cyclodextrin ring is β-cyclodextrin having 7 glucose units. It is preferable that the organic group containing at least one carboxyl group has 1 to 6 glucose units, and at least one of the hydroxymethyl groups of glucose units in the organic group is oxidized to a carboxyl group. . The organic group is preferably represented by the formula (I):-(G) n-COOH (I) [wherein G represents a glucose unit and n represents an integer of 1 to 6]. The glucose unit represented by G is
Preferred are D-glucose units. The glucose unit is an α- or β-glycosidic bond, preferably α-
Glycosidically linked. In particular, it is preferable that the cyclodextrin ring is bound by an α- (1 → 6) bond. Further, when n is 2 or more, it is preferable that the glucose units are mutually α- (1 → 4) -bonded.

The branched cyclodextrin carboxylic acid is
Preferably, it has 1 to 3 organic groups represented by the formula (II): -GG-COOH (II) [wherein G has the same meaning as above].

Specific examples of the branched cyclodextrin carboxylic acid include 6-O-cyclomaltohexaosyl-
(6 → 1) -α-D-glucosyl- (4 → 1) -O-α-D
-Glucuronic acid (Cyclomaltohexaosyl- (6 → 1)
-Α-D-glucopyranosyl- (4 → 1) -O-α-D-
Glucopyranosiduronic acid) (hereinafter, α-CyD-G ₂ -C
It may be abbreviated as OOH; the abbreviations of the following compounds are also shown in parentheses), 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D-glucosyl- (4 → 1)
-O-α-D-glucuronic acid (cyclomaltoheptaosyl- (6 → 1) -O-α-D-glucopyranosyl- (4 →
1) -O-α-D-glucopyranoside uronic acid) (β-Cy
_{D-G 2 -COOH), 6} -O- cycloalkyl maltooctaose O Sil - (6 → 1) -α- D- glucosyl - (4 → 1) -O- α
-D-glucuronic acid (cyclomaltooctaosyl- (6 →
1) -O-α-D-glucopyranosyl- (4 → 1) -O-
α-D-glucopyranoside uronic acid) (γ-CyD-G _2-
COOH), 6-O-cyclomaltohexaosyl- (6 →
1) -α-D-glucuronic acid (cyclomaltohexaosyl- (6 → 1) -O-α-D-glucopyranosideuronic acid)
(α-CyD-G ₁ -COOH), 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D-glucuronic acid (cyclomaltoheptaosyl- (6 → 1) -O-α- D-glucopyranoside uronic acid) (β-CyD-G ₁ -COOH), 6-
O-cyclomaltooctaosyl- (6 → 1) -α-D-glucuronic acid (cyclomaltooctaosyl- (6 → 1) -O
-Α-D-glucopyranoside uronic acid) (γ-CyD-G ₁
-COOH), 2-O- (6-cyclomaltohexaosyl) -acetic acid (α-CyD-CH ₂ COOH), 2-O- (6-
Cyclomaltoheptaosyl) -acetic acid (β-CyD-CH ₂ C
OOH), 2-O- (6-cyclomaltooctaosyl)-
Acetic acid (γ-CyD-CH ₂ COOH), 3-O- (6-cyclomaltoheptaosyl) -propionic acid (β-CyD-C
H ₂ CH ₂ COOH), 2-hydroxy-3-O- (6-cyclomaltoheptaosyl) -propionic acid (3-O- (6
-Cyclomaltoheptaosyl) -2-hydroxy-propionic acid) (β-CyD-CH ₂ CH (OH) -COOH),
7 ^A , 7 ^C -di-O- [α-D-glucuronyl- (1 → 4)-
O-α-D-glucosyl]-(1 → 6) -maltoheptaose (β-CyD- (G ₂ COOH) ₂ ), 6-O-cyclomaltoheptaosyl-O-α-D-maltosyl- ( 4 → 1)
-O-α-D-glucuronic acid (cyclomaltoheptaosyl- (6 → 1) -O-α-D-glucopyranosyl- (4 →
1) -O-α-D-glucopyranosyl- (4 → 1) -O-
α-D-glucopyranoside uronic acid) (β-CyD-G _3-
COOH) and the like.

More specifically, 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucosyl- (4 → 1)
-O-α-D-glucuronic acid (α-CyD-G ₂ -COO
H), 6-O-cyclomaltoheptaosyl- (6 → 1)-
α-D-glucosyl- (4 → 1) -O-α-D-glucuronic acid (β-CyD-G ₂ -COOH), and 6-O-cyclomaltooctaosyl-α-D-glucosyl- (4 → 1)
-O-α-D-glucuronic acid (γ-CyD-G ₂ -COO
H) is a branched cyclodextrin-carboxylic acid containing α-cyclodextrin (6 glucose units), β-cyclodextrin (7 glucose units) and γ-cyclodextrin (8 glucose units), respectively. Maltose is α- (1 → 6) -bonded to one glucose unit of the cyclodextrin ring, and the hydroxymethyl group at the 8-position of the terminal glucose of the maltose is oxidized to a carboxyl group to form glucuronic acid.

Further, 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucuronic acid (α-CyD-G _1-
COOH), 6-O-cyclomaltoheptaosyl- (6 →
1) -α-D-glucuronic acid (β-CyD-G ₁ -COO
H), and 6-O-cyclomaltooctaosyl- (6 →
1) -α-D-glucuronic acid (γ-CyD-G ₁ -COO
In (H), glucose is α- (1 → 6) -bonded to one glucose unit of the cyclodextrin ring, and the hydroxymethyl group at 6-position of the branched glucose is oxidized to a carboxyl group to form glucuronic acid. It is a branched cyclodextrin carboxylic acid.

Then, 2-O- (6-cyclomaltohexaosyl) -acetic acid (α-CyD-CH ₂ COOH), 2-O
-(6-Cyclomaltoheptaosyl) -acetic acid (β-CyD-
CH ₂ COOH), 2-O- (6-cyclomaltooctaosyl) -acetic acid (γ-CyD-CH ₂ COOH) was branched to one glucose unit of the cyclodextrin ring and a carboxymethyl group was bonded to it. It is a branched cyclodextrin carboxylic acid.

Such a branched cyclodextrin-carboxylic acid is described in JP-A-07-076594, and can be produced, for example, by the method described in the publication.

The esterification of this branched cyclodextrin carboxylic acid is carried out by a known method, for example, "PROTECTEB GROUPS IN ORGANIC SYNTHESIS" (Second Edition, 1991, Theodora W Green, etc.).
However, the following two methods are preferable. A method of reacting a branched cyclodextrin carboxylic acid or a salt thereof with an alcohol in the presence of an acid, and a method of reacting a branched cyclodextrin carboxylic acid or a salt thereof with an alkyl halide in the presence of a quaternary ammonium salt in a solvent.

The salt of branched cyclodextrincarboxylic acid which can be used in these reactions is, for example, an inorganic salt such as an alkali metal salt (eg, lithium salt, sodium salt, potassium salt, etc.) or an alkaline earth metal salt (eg, salt). , Calcium salts, magnesium salts, etc.), such as quaternary ammonium salts (eg, tetramethylammonium salt, tetraethylammonium salt, tetrabutylammonium salt, trimethylbenzylammonium salt, etc.), tertiary amine salts (eg, triethylamine) , N, N-
Dimethylaniline salt, pyridine salt, etc.) and the like. Of these, organic salts, particularly quaternary ammonium salts, are preferred.

The method (1) is effective when esterification is carried out with a relatively lower alcohol such as methyl or ethyl, and the desired product can be easily obtained. In this method, a solvent is not particularly necessary and the alcohol is used in excess as a solvent. Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as benzenesulfonic acid and p-toluenesulfonic acid, and various cation exchange resins. The amount of the acid used is 0.05 to 10 times the mol of the carboxylic acid as the raw material. The reaction temperature can be widely carried out from cooling to heating, but room temperature to 50 ° C. is suitable in consideration of decomposition of raw materials.

By the method of (1), any ester form can be produced. Usually, this reaction is carried out in a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction. Examples of preferable solvents include amides such as dimethylformamide and dimethylacetamide, sulfur-containing compounds such as dimethylsulfoxide and sulfolane, and nitriles such as acetonitrile. Examples of the quaternary ammonium salt include tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, trimethylbenzylammonium hydroxide and the like. The amount of the quaternary ammonium salt used is 0.9 to 2 times mol, preferably 0.9 to 1.2 times mol, of the carboxylic acid as the raw material. As the alkyl halide, the alkyl halide corresponding to the ester is used. The halogen may be chlorine, bromine or iodine, but is preferably iodide. The amount of the alkyl halide used is 1.0 to 10 times mol, preferably 1 to 4 times mol, of the starting carboxylic acid. Reaction temperature is cooling ~
Although it can be widely performed up to heating, room temperature to 50 ° C is suitable in consideration of decomposition of the raw materials.

In order to isolate and purify the desired ester form from the reaction mixture obtained by the method, chromatographic separation usually used, for example, purification with adsorption resin HP-20, ion exchange resin, etc., solvent extraction, liquid purification Perform sex exchange, crystallization, etc.

Like the branched cyclodextrin carboxylic acid, this ester is soluble in water and also soluble in a solvent. Therefore, it solubilizes the water-insoluble or sparingly soluble substance and at the same time stabilizes the unstable substance. Also,
When it is applied to a drug due to its increased lipophilicity, it has good characteristics such as good transfer to tissues and therefore improvement in bioavailability.

Thus, the branched cyclodextrin carboxylic acid ester of the present invention is incorporated with a water-insoluble or sparingly soluble compound as an active ingredient to improve its water solubility. The water-insoluble or sparingly soluble substance to be used is not particularly limited, including drugs useful as active ingredients of pharmaceuticals having such properties, cosmetics, foods and drinks, agricultural chemicals, veterinary drugs for which water solubility is desired to be improved. A substance useful as an active ingredient such as is appropriately selected. Usually, as such a water-insoluble or sparingly soluble substance, a substance having a solubility of 10 mg / ml or less and which is desired to have improved water solubility is used. Examples of insoluble or sparingly soluble drugs useful as active ingredients of pharmaceuticals and veterinary drugs include antipyretic, analgesic and anti-inflammatory agents,
For example, salicylic acid, sulpirine, flufenamic acid, diclofenac, indomethacin, chlorpromazine,
Prochlorperazine, trifluoperazine, atropine,
Examples thereof include scopolamine, morphine, pethidine, levorfinol, oxymorphone and salts thereof. As tranquilizers, diazepam, lorazepam, oxazepam, and the like, as antibacterial agents, for example, griseofulvin, lancasidins [J. Antibiotics, 38, 877-885 (19
85)], azole compounds [2-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1-
Iyl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl-3- (2H, 4H) -1,
2,4-triazolone, fluconazole, itraconazole, etc.] are antibiotics, for example, gentamicin, dibekacin, canendomycin, ribidomycin,
Tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, lolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin,
Cephalolysin, cefotiam, cefotiam hexetil, cefsulodin, cefmenoxime, cefmetazole,
Cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, azthreonam or salts thereof and the like are antitumor agents such as 6-O- (N-chloroacetylcarbamoyl) fumagillol (TNP-470), bleomycin, methotrexate, actino. Mycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole, bestatin,
Azimexone, glycyrrhizin, etc. are used as antihyperlipidemic agents, for example, clofibrate, 2-chloro-3- [4
-(2-Methyl-2-phenylpropoxy) phenyl] ethyl propionate [Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 3
8,2792-2796 (1990)], and the like as an antitussive antitussive agent, for example, ephedrine, methylephedrine,
Noscapine, codeine, dihydrocodeine, alochlamide, chlorfedianol, picoperidamine, cloperastine, protoxylol, isoproterenol, salbutamol, terebutaline or salts thereof, etc., as muscle relaxants such as pridinol, tubocurarine, pancuronium, etc. As an agent, for example, phenytoin, ethosuximide, acetazolamide, chlordiazeboxoxide and the like, as an anti-ulcer agent, for example, metoclopramide and the like, as antidepressant, for example, imipramine, clomipramine, noxiptiline, phenelzine and the like, as an antiallergic agent. , For example, diphenhydramine, chlorpheniramine, triperenamine, metdilamine, clemizole, diphenylpyraline, methoxyphenamine, etc. , For example, transpioxocamphor, terephylol, aminophylline, etilefrine, etc., as antiarrhythmic agents, for example, propranolol, alprenolol, bufetrol, oxprenolol, etc., as vasodilators, for example, oxyfedrine, Diltiazem, tolazoline, hexobendine, bamethane, etc., as hypotensive diuretics, for example, hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, etc. as antidiabetic agents, for example,
Glymidine, glipzide, phenformin, buformin, metformin, etc. are antituberculous agents, for example,
Isoniazid, ethambutol, para-aminosalicylic acid, etc., as narcotic antagonists, for example, levallorphan, nalorphine, naloxone or salts thereof, etc., as hormonal agents, mainly steroid hormones such as dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone. , Triamcinolone acetonide, fluocinolone acetonide, prednisolone, hydrocortisone, estriol, etc., as fat-soluble vitamin agents, vitamins A, vitamins D, vitamins E,
Vitamin Ks, folic acid (vitamin M), etc., such as vitamin A ₁ , vitamin A ₂ and retinol palmitate as vitamins A, vitamin D ₁ as vitamins D,
D ₂ , D ₃ , D ₄ and D ₅ are α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and dl-α-tocopherol nicotinate as vitamin Es, and vitamin K ₁ as vitamin Ks. K ₂ ,
Examples include K ₃ and K ₄ . As a vitamin derivative,
Examples include various derivatives of the above vitamins. For example, 5,
Examples thereof include vitamin D ₃ derivatives such as 6-trans-cholecalciferol, 25-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, and vitamin D ₂ derivatives such as 5,6-trans-ergocalciferol. Other examples of poorly soluble drugs include piroxicam, diacerine, diltiazem, megestrol acetate, nifedipine, nicerogolin, ketoprofen,
Examples include naproxen, ibuprofen, prostaglandins and the like.

Examples of the water-insoluble or sparingly soluble compound useful as an active ingredient of cosmetics include, for example, methyl cinnamate,
Ethyl cinnamate, dl-α-tocopherol acetate, α-tocopherol (vitamin E), trichlorocarbanilide, eugenol, isoeugenol, ethyl methylphenylglycidate, geranyl acetate, piperonal, hexyl laurate, yonone, cinnamyl acetate. , Decyl oleate, terpenyl acetate and the like.

Examples of water-insoluble or sparingly soluble compounds useful as active ingredients of agricultural chemicals include benomyl, carbendazim, fuveridazole, thiophanate, thiophanate methyl, trialimol, prochloraz, oxadixyl, dazomet, captan, captahol, quinomechi. Owner, Bancoal (registered trademark), probenazole, diethofencarp, ferrimzone, etc. may be mentioned.

Examples of the water-insoluble or sparingly-soluble compound useful as an active ingredient of foods and drinks include L-ascorbic acid stearic acid ester, benzoic acid, ionone (yonone), isoeugenol, ergocalciferol (vitamin D ₂ ), Eugenol, butyl paraoxybenzoate, isopropyl paraoxybenzoate, β-carotene,
Citronellyl formate, cholecalciferol (vitamin D
₃ ), cinnamyl acetate, phenethyl acetate, ethyl cinnamate, dibutyl hydroxytoluene, vitamin A oil, allyl hexanoate, propyl gallate, methyl β-methyl ketone, folic acid, riboflavin butyrate, lecithin, dl
-Α-tocopherol and the like can be mentioned.

In the present invention, the mixing ratio of the branched cyclodextrin carboxylic acid ester and the water-insoluble or sparingly soluble compound is not particularly limited and can be selected from a wide range, but considering the water solubility of these substances, The branched cyclodextrin carboxylic acid ester is used in an amount of 0.1 to 500 mol, preferably 0.5 to 50, more preferably 1 to 5 mol, and particularly preferably 1 to 3 mol per 1 mol of the water-insoluble or sparingly soluble compound. Mix in the range.

The water solubility improver and stability improver of the present invention can be produced by a known method by mixing a branched cyclodextrin carboxylic acid ester with a target water-insoluble or sparingly soluble compound. The inclusion compound of the substance with a branched cyclodextrin carboxylic acid ester can be prepared, for example, by the following four methods. (1) Coprecipitation method (Crassons et al., 5th Conference of Pharmaceutical Technology (5th lnt. Conf. Pharmaceutical Tech
, Paris, May 30-June 1, 1989, (2) Freeze-drying or spray-drying method [Kurumi (Kur
Ozumi) et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 23,3062.
(1975); Kata et al., Pharmaz (Pharm
azie) 39,856 (1984)], (3) Phase-solution diagram crystallization method (Uekama et al., International Journal of Pharmaceuticals (Int.
Pharmac. ) 10, 1 (1982)), (4) Kneading method [J. Szejtli et al., "Cyclodextrins and the inclusion complex thereof (Cyclodextrins and the inclusion complex).
ir inclusion complexes), Akadeimial Kiado, Budapest (1)
982), p. 109-114; Kyowa Jap. Prov.
Pat. Pubin. No. 106 698 (1982)].

More specifically, (1) the target inclusion compound is added to the aqueous solution of the ester of the present invention, and if necessary, heated and stirred (shaking). The inclusion compound is obtained by removing the remaining unreacted inclusion compound by filtration, centrifugation, or the like. (2) The ester of the present invention is dissolved in water, the target inclusion compound is added thereto and mixed for 10 minutes to several hours,
Then freeze-drying [M. Kurozum
i) et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 23, 142 (197).
5)] to obtain powder. When this is dissolved in water and the unreacted inclusion product is removed, an aqueous solution of the inclusion compound is obtained. (3) The inclusion complex is previously dissolved in an appropriate water-compatible organic solvent, and this is brought into contact with the ester of the present invention in an aqueous solution, and then the organic solvent and water are distilled off under vacuum.
Or freeze-dried [EP-A-5194428, JP-A
5-178765 (Japanese Patent Application No. 03-150507, Japanese Patent Application No. 03-230489)], water is added to the residue to dissolve it, and the unreacted inclusion product is removed to obtain an aqueous solution of the inclusion compound. . (4) The acidic inclusion compound is dissolved in ammonia water, the ester of the present invention is added thereto, and freeze-dried.
Excess ammonia is removed during the freeze-drying process,
An inclusion compound of an ammonium salt of an inclusion product is obtained. (5) The inclusion compound is dissolved in a lipophilic organic solvent (for example, ethyl ether), mixed with a saturated aqueous solution of the ester of the present invention, shaken vigorously for 10 minutes to several hours, and then allowed to stand in a cool place overnight. Place it to precipitate the inclusion reaction product, and then centrifuge,
Separate by filtration. The obtained powder is dissolved in water to obtain an aqueous solution of the clathrate compound. (6) Mixing both the inclusion compound and the powder of the ester of the present invention,
Add a small amount of water to this and knead [Wai Nakai
(Y. Nakai et al., Chemical and Pharmaceutical Bulletin, Chem. Pharm. Bull.), 26, 2.
419 (1978), or thereafter freeze-dried. (7) Regarding the inclusion complex, an aqueous solution of the inclusion compound is obtained by mixing the aqueous solution of the ester of the present invention with the aqueous solution of the inclusion complex.

The aqueous solution or powder thus obtained according to the known inclusion method is in most cases an inclusion body or forms a complex by electrostatic or hydrophobic interaction or hydrogen bond. doing. Therefore, the term “inclusion body” in the present specification means not only an inclusion body and a complex itself,
It means a mixture of an inclusion complex, a complex, a free inclusion compound and / or a free ester of the present invention. That is, the obtained powder and aqueous solution may contain a water-insoluble or sparingly soluble compound which is an uninclusion body or an uncomplex, and / or a free ester of the present invention, in addition to the inclusion complex and the complex. Such powders and aqueous solutions, including the contact body itself,
It is extremely water-soluble and has the property of being instantly soluble in water.

The composition of the present invention may be an aqueous solution or powder itself obtained in this way, and if desired, known additives such as excipients, binders, lubricants and the like may be used as appropriate to obtain a suitable composition. It can be in the form of pharmaceuticals, cosmetics, foods and drinks, agricultural chemicals, veterinary drugs and the like. For example, in order to improve the powder properties of the powder obtained above (storage bottles, filling properties into vial containers, etc., specific volume, antistatic, etc.), sugars, preservatives, stabilizers, antistatic agents, etc. May be added. When manufactured as an injection, the powder obtained by this operation is easily dissolved in distilled water or an isotonic aqueous solution prepared with sodium chloride and sugars (glucose, mannitol, inositol, etc.). After dissolution, the active ingredient can be administered as an injection at an effective in-vivo drug concentration for the target disease as an injection intravenously, intramuscularly, subcutaneously, in an organ, or directly to a lesion such as a tumor site or tumor excision site. . Also,
When it is manufactured as an oral preparation, that is, tablets, capsules, granules, fine granules, wraps or drops, liquids and the like can be manufactured. Usually, known excipients, lubricants, binders, dispersants, stabilizers, coloring agents, absorption improving (accelerating) agents and the like are used in these formulations. In addition, the above powder may be used for injection administration, administration agents other than oral administration, for example, mucosal administration agents such as nose, buccal cavity, sublingual, rectal, vaginal, uterine or transdermal administration agents, and implants according to a conventional method. It is possible. In addition, each of the above-mentioned preparations for administration can be molded into various controlled-release preparations and targeted preparations for administration, and is also used as a raw material for producing such preparations.

As described above, the branched cyclodextrin-carboxylic acid ester of the present invention improves the solubility of a water-insoluble or sparingly soluble compound in water and is highly safe to the human body. , Oral, oral, sublingual, eye drops, syrup,
It has extremely high utility value as an external preparation for skin, nasal agent, pulmonary agent, rectal suppository, and agent for mucosal application, and is useful as a drug for humans and non-human mammals (monkey, cow, dog, etc.). is there. Also, like pharmaceuticals and veterinary drugs, cosmetics, pesticides,
Beverages and the like can also be produced by using a desired additive according to a conventional method.

[0029]

The present invention will be described in more detail below with reference to Examples, Experimental Examples and Reference Examples, but these do not limit the present invention. Example 1 Methyl ester 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D
-Glucosyl- (4 → 1) -O-α-D-glucuronic acid sodium salt (hereinafter abbreviated as GUG-β-CyD sodium) 1.
0 g (0.669 mmol) was suspended in 80 ml methanol. Dry cation exchange resin Dowex 50W x 8
(H type) (manufactured by Dow Chemical Co.) 4 g was added, and the mixture was stirred at room temperature for 18 hours. The resin was filtered with a glass filter, and the resin was washed with methanol. The filtrate and the washing solution were combined, and methanol was distilled off under reduced pressure. The residue was dissolved in 20 ml of water and adjusted to pH 7.05 with 0.5N caustic soda. This solution was applied to a column of about 180 ml of anion exchange resin IRA-958 (C1 type) (manufactured by Rohm and Haas) SV =
Conducted at 0.5-1. The column was washed with 1 liter of water. The eluent was checked under the following TLC conditions to fractionate the desired product. The fractions were combined and freeze-dried. (Profit 41
6 mg) 300 mg of this dried product was dissolved in 20 ml of water, and further passed through a column of about 180 ml of anion exchange resin IRA-958 (C1 type), and washed with water. Fractions of interest were collected and concentrated under reduced pressure to about half volume. Concentrated liquid is cation exchange resin IR
-120B (H type) (made by Rohm and Haas) about 50
It was passed through a column of ml and washed with 150 ml of water. The eluates were combined and freeze-dried to obtain 95.9 mg of GUG-β-CyD methyl ester. ¹³ C-NMR (270 MHz,
The D ₂ O) chart is shown in FIG. A carbon signal based on the methyl ester was observed at 54.44 ppm. The TLC conditions for fractionating this product are as follows. TLC; silica gel Merck Kiesel Gel 60 (F
₂₅₄ No5715) Developing solvent; 1-propanol / ethyl acetate / water / acetic acid (6: 4: 2: 4) detection reagent; naphthresorcin / sulfuric acid (heating)

Example 2 Ethyl ester 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D
-Glucosyl- (4 → 1) -O-α-D-glucuronic acid
7.5 g (5.09 mmol) (hereinafter abbreviated as GUG-β-CyD) was suspended in about 100 ml of dimethylformamide. Tetrabutylammonium hydroxide (13.5 g, 10% methanol solution, 5.20 mmol) was added, and the mixture was thoroughly stirred and then concentrated to dryness under reduced pressure. Dimethylformamide 75
The dry solid was dissolved by adding ml. 2.4 g of ethyl iodide (1
(5.38 mmol) was added and the mixture was stirred at room temperature for about 20 hours.
After completion of the reaction, the solvent was concentrated under reduced pressure. Water 10 for residue
After dissolving by adding 0 ml, the mixture was washed 3 times with 70 ml of chloroform. The washed aqueous layer was concentrated under reduced pressure to remove the solvent. This solution is polystyrene resin Diaion HP-2
The column was connected to a 0 (Mitsubishi Chemical) 500 ml column. Water 500
After washing with ml, the mixture was eluted with 5% methanol water and 10% methanol water. The eluent was fractionated under the TLC conditions of Example 1 and the target fractions were collected and concentrated to dryness under reduced pressure. Methanol / acetone was added to the dried solid to be pulverized. After cooling, the powder was collected by filtration and dried under reduced pressure at 50 ° C. The profit is 5.
At 5 g, the yield was 71.1% from GUG-β-CyD. Elemental analysis of this _{product: C 56 H 92 O 46 ·} 1H 2 O = 151
Calculated as 9.33 C: 44.27% H: 6.24% Measured value C: 44.38% H: 6.48% ¹³ C-NMR (270 MHz, d ₆ -DMSO) of this product showed 13 Carbon signals based on ethyl ester were observed at .65 ppm and 60.597 ppm. In addition, ¹ H-NMR (2
At 70 MHz, d ₆ -DMSO), a triplet based on the methyl group proton of ethyl ester was observed at around 1.2 ppm.

Example 3 Isopropyl ester 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D
-Glucosyl- (4 → 1) -O-α-D-glucuronic acid
5.0 g (3.39 mmol) (hereinafter abbreviated as GUG-β-CyD) was suspended in about 100 ml of dimethylformamide. After adding 8.8 g of tetrabutylammonium hydroxide (10% methanol solution, 3.39 mmol) and stirring well,
Concentrated to dryness under reduced pressure. 50 ml of dimethylformamide was added to dissolve the dried substance. Isopropyl iodide 1.73 g
(10.2 mmol) was added and the mixture was stirred at room temperature for 25 hours.
After distilling off the solvent, the residue was dissolved in 50 ml of water to give 0.5N.
The pH was adjusted to 8.5 with caustic soda. Chloroform 30
Wash 3 times with ml. The washing solution was adjusted to pH 5 with 0.3N hydrochloric acid, and the solvent was evaporated under reduced pressure. A column of 500 ml of polystyrene resin Diaion HP-20 (manufactured by Mitsubishi Chemical) was connected. After washing with 500 ml of water, elution was carried out with 10% aqueous methanol and 15% aqueous methanol. The eluent was fractionated under the TLC conditions of Example 1 and the target fractions were collected and concentrated to dryness under reduced pressure. 30 ml of acetone was added to the dried solid, and the mixture was thoroughly stirred and cooled to 5 ° C. The precipitate is collected by filtration and under reduced pressure 5
After drying at 0 ° C. for about 6 hours, 2.3 g of the desired GUG-β-CyD isopropyl ester was obtained. ¹ H-NMR (3
In 00 MHz, d ₆ -DMSO), a doublet based on the methyl group proton of isopropyl ester was observed at around 1.2 ppm.

Example 4 The following ester body was produced according to the method of Example 2. n- propyl ester ^{* 1 H-NMR (270MHz,} d 6 -DMSO) 0.9ppm ( triplet, C H ₃₎ 1.60~1.75ppm _{(multiplet, OCH 2 C H 2 CH 3} ) n- butyl ester ^{* 1 H-NMR (300MHz,} d 6 -DMSO) 0.9ppm ( triplet, C H ₃₎ 1.30~1.50ppm _{(multiplet, CH 2 C H 2 CH 3} ) 1.60~1. 70 ppm _{(multiplet, OCH 2 C H 2 CH 2} ) * 13 C-NMR (270MHz, d 6 -DMSO) 13.315ppm, 18.188ppm, 29.792ppm, 6
3.938Ppm, or four carbon signals were identified to be based on butyl ester n- hexyl ester * Elemental _{analysis; C 60 H 100 O 46 ·} 4.5H 2 O = 1638.
49 Theoretical value; C 43.98% H 6.70% Measured value; C 43.88% H 6.85% * ¹ H-NMR (270 MHz, d ₆ -DMSO) 0.9 ppm (triplet line, C H ₃ ) 1.2~1.3ppm _{(multiplet, CH 2 (C H 2)} 3 CH 3) 1.5~1.6ppm ( _{multiplet, OCH 2 C H 2 CH 2} ) n- octyl ester * ¹ H- NMR (270 MHz, d ₆ -DMSO) 0.9 ppm (triplet line, C H ₃ ) 1.2 to 1.35 ppm (multiple line, CH ₂ (CH ₂ ) ₅ CH ₃ ) 1.5 to 1.7 ppm ( _{multiplet, OCH 2 C H 2 CH 2} )

Example 5 Ethyl ester 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D
-Glucosyl- (4 → 1) -O-α-D-glucuronic acid
5.0 g (3.39 mmol) (hereinafter abbreviated as GUG-β-CyD) was suspended in about 100 ml of dimethylformamide. Tetramethylammonium hydroxide pentahydrate 0.675 g (3.
A solution of 73 mmol) dissolved in 30 ml of methanol was added, and the mixture was stirred well and then concentrated to dryness under reduced pressure. Add 200 ml of dimethylformamide and add 1.59 g of ethyl iodide.
(10.2 mmol) was added and the mixture was stirred for 30 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in 100 ml of water. This was washed 3 times with 50 ml of chloroform. A strong basic resin DIAION PA406 (C
(Type 1) 100 ml was added and stirred for 1 hour. The resin is filtered off,
The resin was washed with 200 ml of water. The filtrate and the washing solution were combined, to which 50 ml of strongly acidic resin IR-120B (H ⁺ type) was added and stirred for 1 hour. Remove the resin by filtration, and add 100 ml of water.
The resin was washed with. The filtrate and washings were combined and concentrated to dryness under reduced pressure. Methanol / acetone was added to the dried solid to be pulverized. After cooling, the precipitate was collected by filtration and dried at 50 ° C. Yield 2.4 g This product was found to be identical to the GUG-β-CyD ethyl ester obtained in Example 2.

Example 6 747.6 mg of GUG-β-CyD ethyl ester was added to H ₂ O.
To a solution dissolved in 5 ml, 6-O- (N-chloroacetylcarbamoyl) fumagillol (hereinafter, referred to as TNP-470
Abbreviated) 100 mg is added. This suspension was shaken on a reciprocal shaker for 2 hours, filtered through a 0.2 μm filter, and the filtrate was freeze-dried to give GUG-β-ethyl ester / T.
639 mg of lyophilized powder of NP470 complex was obtained. When the content of TNP-470 in this product was measured by HPLC, it was 10.1% (w / w). HPLC conditions; column; CAPCELL PAK C ₁₈ AG (φ4.6 m
m × 25 cm) eluent; H ₂ O / CH ₃ CN = 1: 1 elution rate; 10 ml / min detection; 210 nm injection amount; 10 μl solubility of TNP-470: solubility of the above powder in water was measured at room temperature , TNP-470 solubility was determined by HPLC method. TNP-470 25 mg / ml, H ₂ O at room temperature.

Example 7 761 mg of GUG-β-CyD butyl ester was dissolved in 20 ml of ethanol containing 20% water, and TNP-47 was added to this solution.
0 100 mg was added, and the mixture was shaken and stirred on a reciprocal shaker at room temperature for 2 hours, then, the solvent was distilled off under reduced pressure on a rotary evaporator, and then dried. The obtained powder was vacuum dried in the presence of phosphorus pentoxide to obtain 870 mg of GUG-β-.
A powder of CyD butyl ester / TNP-470 complex was obtained. When the content of TNP-470 in this product was measured by HPLC, it was 10.7%.

Experimental Example 8 GUG-β-CyD ethyl ester / T obtained in Example 6
50 mg of NP-470 complex in water for injection, physiological saline, 5
T when dissolved in 1 ml of each glucose solution and left at room temperature
The stability of NP-470 was investigated by HPLC. as a result,
Stability of 95% or more was observed up to 8 hours. As a target, 5 mg of TNP-470 was suspended in 1 ml of water for injection and allowed to stand at room temperature, and 1 hour later, TNP-470 was 12%,
The disassembly was remarkable.

[0037]

INDUSTRIAL APPLICABILITY The branched cyclodextrin carboxylic acid ester of the present invention solubilizes a water-insoluble or sparingly soluble substance and at the same time stabilizes an unstable substance. In addition, when it is applied to a drug due to its increased lipophilicity, it has good characteristics such as good transfer to tissues and therefore improvement in bioavailability. Therefore, the branched cyclodextrin carboxylic acid ester of the present invention is useful as a water solubility-improving agent and stability improving agent for water-insoluble or sparingly-soluble substances useful as active ingredients for pharmaceuticals, cosmetics, foods and drinks, agricultural chemicals, veterinary drugs, etc. Is.

[0038]

[Brief description of drawings]

FIG. 1 is an NMR chart of the target product of Example 1.

Claims (13)

[Claims] 1. A branched cyclodextrin carboxylic acid ester. 2. The branched cyclodextrin carboxylic acid is
The ester according to claim 1, which is a branched cyclodextrin carboxylic acid having an organic group containing at least one carboxyl group at the 6-O position of at least one glucose unit of the cyclodextrin ring. 3. The ester according to claim 2, wherein the cyclodextrin ring of the branched cyclodextrin carboxylic acid has 7 glucose units. 4. The ester according to claim 2, wherein the organic group has 1 to 6 glucose units, and at least one hydroxymethyl group of the glucose unit in the organic group is oxidized to a carboxyl group. 5. The organic group is represented by the formula (I): — (G) n—COOH (I) [wherein G represents a glucose unit and n represents an integer of 1 to 6]. The listed ester. 6. The branched cyclodextrin-carboxylic acid is 6-O-cyclomaltohexaosyl- (6 → 1) -α-D.
-Glucosyl- (4 → 1) -O-α-D-glucuronic acid,
6-O-cyclomaltoheptaosyl- (6 → 1) -α-D
-Glucosyl- (4 → 1) -O-α-D-glucuronic acid,
6-O-cyclomaltooctaosyl- (6 → 1) -α-D
-Glucosyl- (4 → 1) -O-α-D-glucuronic acid,
6-O-Cyclomaltohexaosyl- (6 → 1) -α-D
-Glucuronic acid, 6-O-cyclomaltoheptaosyl-
(6 → 1) -α-D-glucuronic acid, 6-O-cyclomaltooctaosyl- (6 → 1) -α-D-glucuronic acid, 2
-O- (6-cyclomaltohexaosyl) -acetic acid, 2-O
-(6-Cyclomaltoheptaosyl) -acetic acid, 2-O-
(6-Cyclomaltooctaosyl) -acetic acid, 3-O- (6
-Cyclomaltoheptaosyl) -propionic acid, 2-hydroxy-3-O- (6-cyclomaltoheptaosyl)-
Propionic acid, 7 ^A , 7 ^C -di-O- [α-D-glucuronyl- (1 → 4) -O-α-D-glucosyl]-(1 → 6)-
Maltoheptaose or 6-O-cyclomaltoheptaosyl-O-α-D-maltosyl- (4 → 1) -O-α-
The ester according to claim 1, which is D-glucuronic acid. 7. A branched cyclodextrin carboxylic acid,
The ester according to claim 2, which has 1 to 3 organic groups represented by the formula (II): -GG-COOH (II) [wherein G represents a glucose unit]. 8. The ester according to claim 1, which is an ester with an aliphatic alcohol having 1 to 30 carbon atoms. 9. A method for producing a branched cyclodextrin carboxylic acid ester, which comprises subjecting a branched cyclodextrin carboxylic acid or a salt thereof to an esterification reaction. 10. A water solubility improver comprising the ester according to claim 1. 11. A drug stability improver comprising the ester according to claim 1. 12. A medicine comprising the ester according to claim 1 and a drug. 13. The medicine according to claim 12, which is for injection.