JP2001172202A - Injection composition including pyrogen-free branched cyclodextrin-carboxylic acid and method for removing pyrogen - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide pyrogen-free medicines of high safety to human bodies and animal drugs in which the solubility of water-insoluble or slightly water-soluble substances are improved in water. SOLUTION: The objective injection composition includes water-insoluble or slightly water-soluble substance and branched cyclodextrin-carboxylic acid in which the pyrogen content is adjusted to <= about 100 EU/g in these substances.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a water-insoluble or poorly water-soluble substance such as a drug or an animal drug, and a branched cyclodextrin-carboxylic acid, wherein the pyrogen is about 100%.
The present invention relates to an injectable composition adjusted to not more than EU / g and a method for removing pyrogen.

[0002]

2. Description of the Related Art Improving the solubility of water-insoluble or hardly-soluble substances in water is the most common and important problem in the field of medicine and the like. In order to solve such a problem, JP-A-7-215895 discloses a method for improving the water solubility of a compound in which a water-insoluble or hardly-soluble compound is combined with a branched cyclodextrin-carboxylic acid. Have been. On the other hand, pyrogens such as endotoxins are usually composed of water-soluble high-molecular-weight polysaccharides, and are extremely small, but are known to be severely impaired in kidney and liver functions by intravenous injection, etc. . However, pyrogens are colloidal particles and are difficult to remove.

[0003]

An object of the present invention is to provide an injectable composition containing a water-insoluble or hardly soluble substance from which pyrogen has been removed and a branched cyclodextrin-carboxylic acid, and a method for removing pyrogen. And

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have separated a composition containing a water-insoluble or hardly-soluble compound and a branched cyclodextrin-carboxylic acid. The molecular weight is about 1,000-8,
By filtering through a 000 hollow fiber ultrafiltration membrane, it was unexpectedly found that pyrogen could be efficiently removed. The present inventors have further studied based on this finding, and as a result, have completed the present invention. That is, according to the present invention, (1) a pyrogen of about 100 EU /
g. An injectable composition comprising a water-insoluble or poorly water-soluble substance adjusted to not more than 0.1 g and a branched cyclodextrin-carboxylic acid. (2) The item (1) wherein the pyrogen is adjusted to about 50 EU / g or less. (3) The injectable composition according to (1), which contains about 0.1 to 10 mol of branched cyclodextrin-carboxylic acid per 1 mol of water-insoluble or poorly water-soluble substance, The composition for injection according to (1), wherein the water-insoluble or poorly water-soluble substance is a medicine or an animal drug, (5) the water-insoluble or poorly water-soluble substance is
Antipyretic, anti-inflammatory, analgesic, tranquilizer, sedative, antitumor, antibacterial, antibiotic, antihyperlipidemic, antitussive / expectorant, muscle relaxant, antiepileptic, antiulcer , Antidepressants, antiallergic drugs, inotropic drugs, antiarrhythmic drugs, vasodilators, antihypertensive diuretics, antidiabetic drugs, antituberculous drugs, narcotic antagonists, hormonal drugs, fat-soluble vitamin drugs, ischemic disease drugs, Immune disease drug, Alzheimer's disease drug, osteoporosis drug,
Angiogenesis, retinopathy, retinal vein occlusion, senile discoid macular degeneration, cerebral vasospasm, cerebral thrombosis, cerebral infarction, cerebral obstruction, cerebral hemorrhage Drugs, drugs for subarachnoid hemorrhage, drugs for hypertensive encephalopathy, drugs for transient ischemic attack, drugs for multiple infarct dementia, drugs for arteriosclerosis, drugs for Huntington's disease, drugs for brain tissue disorders, Optic neuropathy, glaucoma, ocular hypertension,
The composition for injection according to (1), which is a therapeutic agent for retinal detachment, a therapeutic agent for arthritis, an antirheumatic drug, an antiasthmatic drug or a therapeutic agent for pollakiuria / urinary incontinence, and (6) a branched cyclodextrin-carboxylic acid, The injectable composition according to (1), which is a cyclodextrin having one organic group containing a carboxyl group at the 6-O position of at least one glucose unit of the cyclodextrin ring, (7) branched cyclodextrin- The 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-cyclomaltooctao) (Syl) -acetic acid, 3-O- (6-cyclomaltoheptaosyl)
-Propionic acid, 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, 6-O-cyclomaltoheptaosyl-O-α-D-
Injectable composition according to (1), which is maltosyl- (4 → 1) -O-α-D-glucuronic acid or a salt thereof, (8)
When the branched cyclodextrin-carboxylic acid is 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D-glucosyl-
(4 → 1) -Injectable composition according to (1), which is sodium-O-α-D-glucuronate, (9) containing a water-insoluble or poorly water-soluble substance and a branched cyclodextrin-carboxylic acid. Molecular weight of about 1,000 to
A method for removing pyrogen from the composition, wherein the composition is filtered through a hollow fiber ultrafiltration membrane of 8,000.
(10) The removal method according to (9), wherein the filtration is performed under an atmospheric pressure of about 0.05 to 1.0 kg / cm ^3. (11) The pore size of the hollow fiber ultrafiltration membrane is about 10 to 100 Å. (9) The removal method as described in (9), and (12) the two (9) to () hollow fiber ultrafiltration membranes having a cut-off molecular weight of about 1,000 to 8,000 which are directly connected and filtered. 11) A removal method according to any one of the above.

[0005] The branched cyclodextrin-carboxylic acid used in the injectable composition of the present invention includes not only its free carboxylic acid, but also its alkali metal (eg, lithium, sodium, potassium, etc.), alkaline earth metal (eg, , Calcium, magnesium, etc.). These branched cyclodextrin-carboxylic acids may be used alone or in combination of two or more, or may be used in a state where a free carboxylic acid and a salt thereof are mixed. The branched cyclodextrin-carboxylic acid is a cyclodextrin 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. The cyclodextrin ring of the branched cyclodextrin-carboxylic acid is, for example, 6,
It has 7 or 8 glucose units. Preferably,
The cyclodextrin ring has seven glucose units. Examples of the cyclodextrin include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and the like. At least one of the above
It is preferable that one organic group containing one carboxyl group has 1 to 3 glucose units, and at least one of the hydroxymethyl groups of the glucose units in the organic group is oxidized to a carboxyl group.

Specific examples of the above-mentioned 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-glucopyranoside uronic acid) (hereinafter α-CyDG-G ₂
-COOH; the following compounds are also abbreviated 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
_{-CyD-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-glucopyranoside uronic acid) (α-CyD-G ₁ -COOH), 6-O- Cyclomaltoheptaosyl- (6 → 1) -α-D-glucuronic acid
(Cyclomaltoheptaosyl- (6 → 1) -O-α-D-
Glucopyranosiduronic acid) (β-CyD-G ₁ -COO
H), 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 COOH), 2-O-} (6- cyclo maltooctaose O Sil) - acetic acid _{(γ-CyD-CH 2 COOH} ), 3-O-
(6-cyclomaltoheptaosyl) -propionic acid (β-
_{CyD-CH 2 CH 2 COOH)} , 2- hydroxy -3-O
-(6-cyclomaltoheptaosyl) -propionic acid (3
-O- (6- cyclo maltoheptaose O Sil) -2-hydroxy - propionic _{acid) (β-CyD-CH 2} CH (OH) -C
OOH), 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-Cy
DG ₃ -COOH) and the above salts [eg, β-
CyD-G ₂ -COOH sodium salt (cyclo maltoheptaose O sill of - (6 → 1) -O- α-D- glucopyranosyl - (4 → 1) -O- α-D- glucopyranoside guidance sodium Ron acid (Similarly β -CyD-G ₂ -COONa)))]. Above all, β-CyD-G ₂ -C
OONa is preferred.

More specifically, 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucosyl- (4 →
1) -O-α-D-glucuronic acid (α-CyD-G ₂ -C
OOH), 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-Cy
DG ₂ -COOH) is a branched cyclodextrin-carboxy containing α-cyclodextrin (6 glucose units), β-cyclodextrin (7 glucose units) and γ-cyclodextrin (8 glucose units), respectively. Maltose is α- (1 → 6) -linked to one glucose unit of the cyclodextrin ring, and the 6-hydroxymethyl group at the terminal glucose of the maltose is oxidized to a carboxyl group to form glucuronic acid. ing. Also, 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 -C
OOH), and 6-O-cyclomaltooctaosyl-
(6 → 1) -α-D-glucuronic acid (γ-CyD-G ₁ -C
In OOH), glucose is α- (1 → 6) -linked to one glucose unit of the cyclodextrin ring, and the hydroxymethyl group at the 6-position of the branched glucose is oxidized to a carboxyl group to form glucuronic acid. It is a branched cyclodextrin-carboxylic acid. And 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) is a branched cyclodextrin-carboxylic acid having a carboxymethyl group bonded to one glucose unit of the cyclodextrin ring. These branched cyclodextrin-carboxylic acids or salts thereof are
JP-A-7-76594 and JP-A-7-215895
Japanese Patent Laid-Open Publication No.
It can be produced by the method described in JP-A-210996, JP-A-10-210996 or the like or a method analogous thereto.

[0008] The water-insoluble or hardly soluble substance used in the composition for injection of the present invention is not particularly limited, and a substance useful as an active ingredient of a drug or an animal drug having such properties is appropriately selected. . Usually, as such a water-insoluble or poorly-soluble substance, a substance having a solubility of 10 mg / ml or less and whose improvement in water solubility is desired is used. Examples of water-soluble or poorly-soluble substances useful as active ingredients for pharmaceuticals and veterinary drugs include the following. (1) Antipyretic, analgesic, anti-inflammatory drugs salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, chlorpromazine, prochlorperazine, trifloperazine, atropine, scopolamine, morphine, pethidine, levorfinol, oxymorphone or salts thereof, etc. (2) tranquilizer diazepam, lorazepam, oxazepam, etc. (3) antibacterial agents griseofulvin, lancasidines [Journal of Antibiotics (J. Antibiotics), 38,
877-885 (1985)], an azole compound [2
-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -4-
[4- (2,2,3,3-tetrafluoropropoxy)
Phenyl-3- (2H, 4H) -1,2,4-triazolone, fluconazole, itraconazole, etc.) (4) Antibiotics gentamicin, dipecasin, canendomycin, lividomycin, topramycin, amikacin, fradiomycin, sisomicin, Tetracycline, oxytetracycline, lolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalotin, cephaloridin, cefotiam, cefotiamhexetil, cefsulodin, cefmenoxime, cefmetazol, cefazolin, cefotaximus, zefosamuximum, cefazomin, cefazoxin (5) Antitumor drug 6-O- (N-chloroacetylcarbamo) Il) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine aladinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, etc.

(6) Antihyperlipidemic agent Clofiplate, ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chemical and Pharmaceutical Co., Ltd.]
Bulletin (Chem. Pharm. Bull), 38, 2792
-2796 (1990)] etc. (7) Antitussive and expectorants Ephedrine, methylephedrine, noscapine, codeine, dihydrocodeine, allochloramide, chlorphedianol, picoperidamine, cloperastine, protokyrol, isoproterenol, salptamol, tereptalin or salts thereof (8) muscle relaxants pridinol, tubocurarine, pancuronium, etc. (9) antiepileptic drugs phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, etc. (10) antiulcer drugs, metoclopramide, etc. (11) antidepressants imipramine, clomipramine, noxiptilin, phenelzine, etc. ) Antiallergic drugs diphenhydramine, chlorpheniramine, tripelenamine, methdilamine, clemizole, diphenylpyralin, (13) cardiotonic drugs transbioxocamphor, terefilol, aminophylline, etilephrine, etc. (14) antiarrhythmic drugs propranolol, alprenolol, pfetrol, oxprenolol, etc. (15) vasodilators oxyfedrine, diltiazem, tolazoline , Hexobendine, bamethane, etc. (16) Antihypertensive diuretic hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, etc. (17) Antidiabetic drugs Glymidine, glipizide, phenformin, pformin, metformin, etc. (18) Antituberculosis drug isoniazid, (19) Narcotic antagonists Levallorphan, nalorphine, naloxone or salts thereof, etc. (20) Hormonal drugs Steroid hormones, e.g., dexamethasone, hexestrol, methimazole, Petamesazon, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, prednisolone, hydrocortisone, estriol, etc.

(21) Fat-soluble vitamins Vitamin A: Vitamin A ₁ , Vitamin A ₂ and retinol palmitate Vitamin D: Vitamin D ₁ , D ₂ , D ₃ , D ₄ and D
₅ Vitamin Es: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate Vitamin Ks: Vitamin K ₁ , K ₂ , K ₃ and K ₄ folic acid (vitamin M) (22) various derivatives of vitamin derivatives vitamins, for example, 5,6-trans - cholecalciferol, 25-hydroxycholecalciferol, vitamin D ₃ derivatives such as 1-alpha-hydroxycholecalciferol, 5,6 trans - Vitamin D ₂ derivatives such as ergocalciferol, etc. (23) Others hydroxycam, diaserine, diltiazem, megestrol acetate, nifedipine, nicerogolin, ketoprofen, naproxen, ibuprofen, prostaglandins, etc. Disease cure Drug, Alzheimer's disease drug, osteoporosis drug, angiogenesis drug, retinopathy drug, retinal vein occlusion drug, senile discoid macular degeneration, cerebral vasospasm drug, cerebral thrombotic drug, cerebral infarction drug Drugs, drugs for cerebral obstruction, drugs for intracerebral hemorrhage, drugs for subarachnoid hemorrhage, drugs for hypertensive encephalopathy, drugs for transient ischemic attack,
Multiple infarct dementia drug, arteriosclerosis drug, Huntington's disease drug, brain tissue disorder drug, optic neuropathy drug, glaucoma drug, ocular hypertension drug, retinal detachment drug arthritis drug, antirheumatic drug Drugs, antiasthmatics, pollakiuria / urinary incontinence,
Drugs for treating atopic dermatitis, drugs for treating allergic rhinitis and the like are also used.

The composition for injection of the present invention can be produced by a known method by mixing a branched cyclodextrin-carboxylic acid with a desired water-insoluble or hardly-soluble substance. The preparation of the inclusion compound of the substance with the branched cyclodextrin-carboxylic acid can be carried out, for example, generally by the following four methods. (1) Coprecipitation method [Crassons et al., 5th Conference of Pharmaceutical Technology (5th lnt. Conf. Pharmaceutical Technol.)
ogy), Paris, 30 May-1 June 1989
Days], (2) freeze-drying or spray-drying method [Kurozumi (Kuroz
umi) et al., Chemical and Pharmaceutical
Bulletin (Chem. Pharm. Bull.), 23, 3062 (19
75); Kata et al., Pharmazie.
39,856 (1984)], (3) Phase-melt crystallization method [Uekama et al., International Journal of Pharmaceuticals (Int. J. Pharm).
c. ) 10, 1 (1982)], (4) Kneading method [J.
J. Szejtli et al., "Cyclodextrins and their inclusion complexes (Cyclodextrins and their inclus).
ion complexes ””, Akadeimi
al Kiado), Budapest (1982), p. 1
09-114; Kyowa Jap. Prov. Pat. Pubin. No. 1
06 698 (1982)].

More specifically, (1) a target inclusion compound is added to an aqueous solution of a branched cyclodextrin-carboxylic acid (hereinafter sometimes simply referred to as cyclodextrin), and if necessary, heated. And stir (shake). When the remaining unreacted clathrate is removed by filtration, centrifugation, or the like, an clathrate is obtained. (2) A method of dissolving cyclodextrin in water, adding the target inclusion compound thereto, mixing for 10 minutes to several hours, and then freeze-drying (M. Kurozumi (M. Kuro)
zumi) et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 23, 142 (1).
975)) to obtain a powder. This is dissolved in water, and an unreacted clathrate is removed to obtain an aqueous solution of the clathrate. (3) The inclusion compound is dissolved in a suitable water-soluble organic solvent in advance, and this is brought into contact with cyclodextrin in an aqueous solution, and then the organic solvent and water are distilled off in vacuo or freeze-dried. (EP-A-519428, JP-A-5-178765), water is added to the residue to dissolve it, and the unreacted clathrate is removed to obtain an aqueous solution of the clathrate. (4) The acidic inclusion compound is dissolved in aqueous ammonia, to which cyclodextrin is added and freeze-dried. During the freeze-drying process, excess ammonia is removed, and an inclusion compound of the ammonium salt of the inclusion compound is obtained. (5) The inclusion compound is dissolved in a lipophilic organic solvent (for example, ethyl ether, etc.), mixed with a saturated aqueous solution of cyclodextrin, shaken vigorously for 10 minutes to several hours, and then allowed to stand overnight in a cool place. Then, the inclusion reaction product is precipitated, and then separated by centrifugation and filtration. The obtained powder is dissolved in water to obtain an aqueous solution of the clathrate compound. (6) Both powders of the inclusion compound and the cyclodextrin are mixed, and a small amount of water is added thereto and kneaded [Y. Nakai et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 26, 241
9 (1978), or thereafter freeze-dried. (7) For the inclusion compound, an aqueous solution of the inclusion compound is obtained by mixing the aqueous solution of cyclodextrin and the aqueous solution of the inclusion compound.

The aqueous solution or powder thus obtained according to the known clathration method is often an inclusion complex or forms a complex by electrostatic, hydrophobic interaction or hydrogen bonding. are doing. Therefore, in the present specification, the clathrate compound includes not only the clathrate, the complex itself,
Also meant is a mixture of inclusion complex, complex, free inclusion compound and / or free cyclodextrin. That is, the obtained powder and aqueous solution may contain, in addition to the clathrate and the complex, an unclathrate or an uncomplexed water-insoluble or sparingly soluble compound and / or free cyclodextrin. Such powders and aqueous solutions, including themselves, have extremely high water solubility and also have the property of being instantaneously soluble in water.

The injectable composition of the present invention may be an aqueous solution obtained as described above, or a solution obtained by dissolving the obtained powder in a suitable solvent. Injectable carriers to be used may be appropriately added. As the carrier for injections, for example, solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents and the like are used. Examples of the solvent include water for injection, physiological saline, Ringer's solution and the like. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride,
Glycerin, D-mannitol and the like can be mentioned. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like.

The composition for injection of the present invention is obtained by mixing a composition obtained by mixing the above-mentioned various components with a molecular weight cut off of about 1,000 to 1,000.
8,0000, preferably about 2,000 to 7,000,
By filtering through a hollow fiber ultrafiltration membrane more preferably of 3,000 to 7,000, particularly preferably of about 6,000, pyrogen (eg, endotoxin) can be efficiently removed. As such a hollow fiber ultrafiltration membrane, a commercially available one can be appropriately used,
For example, a hollow fiber membrane ultrafiltration membrane SIP-0013 manufactured by Asahi Kasei Corporation having a molecular weight cutoff of 6,000; a pencil type module (20φ × 130 mm) or the like is used. The pore size of the hollow fiber ultrafiltration membrane is usually about 10 to 100 angstroms, preferably about 20 to 60 angstroms. Although only one hollow fiber ultrafiltration membrane may be used, if necessary, two or more (for example, two to three, preferably two) may be directly used. In particular, a hollow fiber ultrafiltration membrane having a molecular weight cutoff of 6,000 and a molecular weight cutoff of 3,000
A combination of 0 hollow fiber ultrafiltration membrane is preferred. Before use, the hollow fiber ultrafiltration membrane is immersed in, for example, a sodium hypochlorite solution for about 1 to 30 hours, and then a pyrogen-free aqueous solution for injection having a pH of about 7 to about 7 is used. Wash to 0.0. Pressure during ultrafiltration is generally about 0.05~1.0kg / cm ^3, preferably set to about 0.1~0.5kg / cm ^3. Filtration can be performed at room temperature, and is preferably performed under aseptic conditions.

The content of the pyrogen in the composition for injection of the present invention is usually about 100 EU / g or less, preferably about 50 EU / g or less, particularly preferably about 30 EU / g or less. The content of pyrogen in the composition for injection of the present invention can be determined according to a method known per se. More specifically, as described in the test examples described below, Toxicolor System Et-2 set (standard endotoxin) manufactured by Seikagaku Corporation, Toxicolor System LS
The endotoxin concentration (EU) can be determined from the absorbance at 405 nm using an endotoxin measuring reagent such as -20 sets. The composition for injection of the present invention thus obtained can be freeze-dried with a sterilized freeze dryer and stored in a powdered state, or it can be sealed and stored in an injection container (eg, ampoule) as it is. You can also.

The content of the water-insoluble or poorly soluble substance in the injectable composition of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1% by weight, based on the whole preparation. It is about 1 to 50% by weight, more preferably about 0.5 to 20% by weight. The content of the branched cyclodextrin-carboxylic acid in the injectable composition of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight based on the whole preparation. It is about. The mixing ratio of the branched cyclodextrin-carboxylic acid and the water-insoluble or poorly soluble substance in the injectable composition of the present invention is not particularly limited and can be selected from a wide range, but in consideration of the water solubility of these substances, The branched cyclodextrin-carboxylic acid is used in an amount of about 0.1 to 20 mol, preferably about 0.1 to 10, more preferably about 0.2 to 5 mol, and particularly preferably about 0.1 mol to 1 mol of the water-insoluble or poorly soluble substance. About 1-2
Mix in molar range. The content of other additives in the injectable composition of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. is there. As described above, the injectable composition of the present invention has improved water solubility of a water-insoluble or hardly soluble substance, and is free of pyrogen, so that it is highly safe for the human body, and has excellent pharmaceutical properties (for example, various diseases). It is used in humans and non-human mammals (eg, rats, mice, guinea pigs, monkeys, cows, dogs, pigs, etc.) as prophylactic / therapeutic agents and veterinary drugs. The composition for injection according to the present invention can be administered intravenously, intramuscularly, subcutaneously or intraorganically, or directly to a lesion. The dose of the composition for injection of the present invention varies depending on the administration subject, administration route, disease and the like. For example, when the composition is used as a therapeutic agent for ulcer, the active ingredient (water It is about 0.1 to 500 mg, preferably about 1 to 100 mg, more preferably 5 to 100 mg as an insoluble or poorly soluble substance, and can be administered intravenously once or several times a day.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples and Test Examples, but these do not limit the present invention.

【Example】

Test Example 1 De-Endotoxinated β-CyD-G ₂ -C
Production of OONa A hollow fiber ultrafiltration membrane manufactured by Asahi Kasei Corporation: SIP-001
3, molecular weight cut off 6,000 (code No. 25952FL)
T, IL-22; module size; 20φ × 130L
(Mm); capacity: 1000 ml; pore size: 0.22 um) and 3.5 L of sodium hypochlorite solution (NaClO 500).
(4% NaOH solution containing 0 ppm) for 20 hours. Next, prepare washing with 1.5 L of an endotoxin-free aqueous solution for injection until the pH of the passing solution is 7.0.
On the other hand, 5 g of β-CyD-G ₂ -COONa powder
The aqueous solution dissolved in the injection water of Corning Csta
Cellulose / acetate membrane filter manufactured by R Company: Aseptic filtration using IL-22, and then hollow fiber membrane ultrafiltration membrane previously pretreated with sodium hypochlorite solution:
The mixture was passed through SIP-0013, fractionated by 10 ml each, a total of 70 ml was collected, and then freeze-dried for one day and night in a freeze-dryer previously sterilized to obtain β-CyD-G ₂ -COON.
4.6 g of a colorless powder of a were obtained. The endotoxin concentration of this product was measured. The measurement of the endotoxin concentration is performed using the Toxicolor System Et-2 set (standard endotoxin) manufactured by Seikagaku Corporation and the Toxicolor System LS.
The endotoxin concentration (EU) was determined from the absorbance at 405 nm using -20 sets of endotoxin measuring reagents. Table 1 shows the results. [Table 1] Sample 405 nm absorbance EU value (EU / g) 0.1538 14.2 β-CyD-G ₂ -COONa for endotoxin detreatment 0.5045 537.7 β-CyD-G _{2 for} endotoxin untreated -COONa Water for injection 0.0265 0.0 Blank 0.0274 0.0

[0019]

[Test Example 2] Selection of hollow fiber membrane ultrafiltration membrane treated with endotoxin Using the same method as in Test Example 1, the molecular weight cut-off was 3,000.
The 0, 6,000, and 10,000 hollow fiber ultrafiltration membranes are treated with a sodium hypochlorite solution, and β-Cy is treated in the same manner.
Endotoxin treatment was performed using ₅ g of DG ₂ -COONa aqueous solution, and the endotoxin concentration (EU) was determined from the absorbance at 405 nm using the same reagent for measuring endotoxin, and the molecular weight cutoff was 3,000, 6,000, 1
The endotoxin treatment effect of a hollow fiber ultrafiltration membrane directly connected to 000 and the molecular weight cut off of 6,000 and 3,000 was determined. Table 2 shows the results. [Table 2] Sample 405 nm absorbance EU value (EU / g) Molecular weight cut-off 3,000 0.255 24 Molecular weight cut-off 6,000 0.152 14 Molecular weight cut-off 10,000 0.556 548 Molecular weight cut-off 6,000 When 0.248 23 3,000 direct methods endotoxin untreated 0.524 534 β-CyD-G2- COONa injection water 0.026 0 blank 0.028 0

[0020]

Example 1 Production of β-CyD-G ₂ -COONa / lansoprazole deendotoxinized preparation In the same manner as in Test Example 1, hollow fiber ultrafiltration membrane manufactured by Asahi Kasei Corporation: SIP-0013, molecular weight cutoff 6,000 (code No. 25952 FLT, IL-22; module size; 20φ × 130 L (mm); capacity: 1000 ml; pore size: 0.22 μm) was treated with 3.5 L of sodium hypochlorite solution
(4% NaOH containing 5000 ppm NaClO)
Solution) for 20 hours. Then, the endotoxin-free aqueous solution for injection (1.5 L) was used to adjust the pH of the passing solution to 7.
Prepare to wash to 0. On the other hand, lansoprazole 19mg
Is dissolved in 5 ml of methanol, and β-C
The yD-G ₂ -COONa powder 384mg was dissolved in water 5 ml. Stir the aqueous solution with the methanol solution and mix.
Stir for 30 seconds. The solvent was distilled off from the obtained solution under reduced pressure,
The residue was dissolved in 10 ml of water to obtain an aqueous solution. This aqueous solution was made up to 50 ml with water for injection.
Star cellulose / acetate membrane filter: sterile-filtered using IL-22, then passed through a hollow fiber ultrafiltration membrane: SIP-0013 previously pretreated with sodium hypochlorite solution, totaling 100 ml And then freeze-dried for 24 hours in a freeze-dryer that has been sterilized beforehand, and then lansoprazole and β-CyD-G ₂ -CO
0.34 g of a colorless powder of a preparation containing ONa was obtained.

[0021]

Test Example 3 β-CyD-G ₂ -C obtained in Example 3
The endotoxin concentration of the OONa / lansoprazole deendoxinated preparation was measured. The endotoxin concentration was measured by measuring the endotoxin concentration (EU) by absorbance at 405 nm using an endotoxin measuring reagent of Toxicolor System Et-2 set (standard endotoxin) manufactured by Seikagaku Corporation and Toxicolor System LS-20 set. . Table 3 shows the results. [Table 3] Sample 405 nm absorbance EU value (EU / g) Preparation of Example 3 0.289 27.8 Water for injection 0.027 0.0

[0022]

EFFECT OF THE INVENTION The composition for injection according to the present invention has improved water solubility of water-insoluble or hardly soluble substances and is free of pyrogen, so that it has high safety to the human body.
Can be used as animal medicine.

Claims (12)

[Claims] 1. An injectable composition comprising a water-insoluble or poorly water-soluble substance whose pyrogen is adjusted to about 100 EU / g or less, and a branched cyclodextrin-carboxylic acid. 2. The injectable composition according to claim 1, wherein the pyrogen is adjusted to about 50 EU / g or less. 3. A branched cyclodextrin-carboxylic acid is used in an amount of about 0.1 to 1 per mol of a water-insoluble or poorly water-soluble substance.
The composition for injection according to claim 1, which contains 0 mol. 4. The composition for injection according to claim 1, wherein the water-insoluble or poorly water-soluble substance is a drug or an animal drug. 5. The method of claim 1, wherein the water-insoluble or poorly water-soluble substance is an antipyretic,
Anti-inflammatory, analgesic, tranquilizer, sedative, anti-neoplastic, antibacterial, antibiotic, antihyperlipidemic, antitussive / expectorant, muscle relaxant, antiepileptic, antiulcer, anti-depressant Drugs, antiallergic drugs, inotropic drugs, antiarrhythmic drugs, vasodilators, antihypertensive diuretics,
Antidiabetic drugs, antituberculosis drugs, narcotic antagonists, hormonal drugs, fat-soluble vitamin drugs, drugs for ischemic diseases, drugs for immune diseases,
Alzheimer's disease drug, osteoporosis drug, angiogenesis drug, retinopathy drug, retinal vein occlusion drug, senile discoid macular degeneration, cerebral vasospasm drug, cerebral thrombotic drug, cerebral infarction drug, Drug for cerebral obstruction, drug for intracerebral hemorrhage, drug for subarachnoid hemorrhage, drug for hypertensive encephalopathy, drug for transient ischemic attack, drug for multiple infarct dementia, drug for arteriosclerosis,
Huntington's disease drug, brain tissue disorder drug, optic neuropathy drug, glaucoma drug, ocular hypertension drug, retinal detachment drug, arthritis drug, antirheumatic drug, antiasthmatic drug or pollakiuria or urinary incontinence drug The composition for injection according to claim 1, which is: 6. A branched cyclodextrin-carboxylic acid,
The composition for injection according to claim 1, which is a cyclodextrin 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. 7. The method according to claim 1, wherein 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 (3-O- (6-cyclomaltoheptaosyl) -2-hydroxy-propionic acid) (β-CyD-C
_{H 2 CH (OH) -COOH)} , 7 A, 7 C - di -O- [α-D
-Glucuronyl- (1 → 4) -O-α-D-glucosyl]
-(1 → 6) -maltoheptaose, 6-O-cyclomaltoheptaosyl-O-α-D-maltosyl- (4 → 1)-
O-α-D-glucuronic acid or a salt thereof.
The composition for injection according to the above. 8. The method according to claim 8, wherein the branched cyclodextrin-carboxylic acid is 6
-O-cyclomaltoheptaosyl- (6 → 1) -α-D-
The composition for injection according to claim 1, which is sodium glucosyl- (4 → 1) -O-α-D-glucuronate. 9. A composition comprising a water-insoluble or poorly water-soluble substance and a branched cyclodextrin-carboxylic acid, which is filtered through a hollow fiber ultrafiltration membrane having a molecular weight cut-off of about 1,000 to 8,000. Removing pyrogen from the composition. 10. The method according to claim 9, wherein the filtration is performed under an atmospheric pressure of about 0.05 to 1.0 kg / cm ³ . 11. The hollow fiber ultrafiltration membrane having a pore size of about 1
The removal method according to claim 9, wherein the pressure is 0 to 100 Å. 12. A molecular weight cut off of about 1,000 to 8,000.
10. The two ultrafiltration hollow fiber membranes are directly connected to each other for filtration.
12. The removal method according to any one of claims 11 to 11.