JPH09241168A - Amphotericin b carrier - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an amphotericin B carrier capable of reducing the toxicity of amphotericin B as an antifungal agent, adjusting the amount of loading thereof, high in property for staying in the blood, having a target directing property, and useful as a carrier for a medicine. SOLUTION: This amphotericin B carrier is obtained by using a publicly known method for forming a liposome by mixing a membrane forming component containing a compound of the formula [X is a divalent residue; (p) is 0, 1; OA is a 2-4C oxyalkylene; (n) is 1 1000, R<1> , R<2> are each an 8-30C fatty acid residue; R<3> is OH, a methoxy or an ethoxy] with amphotericin B. The compound of the formula contains >=20wt.% oxyalkylene part content based on the total liposome membrane forming component. The compound of the formula is obtained e.g. by performing an ester interchanging reaction of phosphatidylcholine with a (poly)oxyalkylene derivative having OH at one terminal and R<3> group at another terminal in the presence of phospholipase D.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an amphotericin B carrier composed of liposomes, and more specifically to an amphotericin B carrier used as a drug carrier for efficiently administering amphotericin B which is an antifungal agent.

[0002]

BACKGROUND OF THE INVENTION Amphotericin B is an excellent antifungal agent for patients with pulmonary diseases whose immunocompetence has been impaired.
Side effects such as fever, vomiting, convulsions, hypersensitivity, and anemia are strong and clinical use is limited (Drugs, 44 , 9).
-35 (1994)). Therefore, for the purpose of reducing toxicity, many methods for producing a liposome preparation in which amphotericin B is supported in a bilayer membrane of a liposome and the like have been disclosed (JP-A-59-173133, US4766046, US4).
663167).

However, amphotericin B is a water-insoluble drug, and when it is encapsulated in liposomes, it is carried in a lipid bilayer. However, it has been pointed out that simply encapsulating it in a liposome has a small amount to be carried, and the toxicity is low, but the blood retention is low, and a sufficient effect cannot be obtained.

On the other hand, it has been reported that by supporting amphotericin B on a polyethylene glycol-modified liposome, good retention in blood and reduction of toxicity can be achieved. (ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 3
9 , 1954 (1995)). However, even with such a polyethylene glycol-modified liposome, the amount of amphotericin B carried is still small, and a sufficient effect has not been obtained yet.

[0005]

The object of the present invention is to reduce the toxicity of amphotericin B, to control the amount (content) of amphotericin B carried in a wide range, and to maintain the retention in blood. To provide a high amphotericin B carrier. Another object of the present invention is to reduce the toxicity of amphotericin B, to widely control the amount of amphotericin B carried, and to have amphotericin B having high blood retention and targeting property. It is to provide a carrier.

[0006]

The present invention is the following amphotericin B carrier. (1) An amphotericin B carrier in which amphotericin B is supported in a liposome, wherein a compound represented by the following general formula (1) is used as a liposome membrane-forming component, and the content of oxyalkylene moiety is changed to all liposome membrane-forming components. An amphotericin B carrier (first amphotericin B carrier), characterized in that the content thereof is 20% by weight or more.

Embedded image [In the formula, X represents a divalent residue, and p represents 0 or 1. OA
Represents an oxyalkylene group having 2 to 4 carbon atoms, and n represents a positive number of 1 to 1000 in terms of the average number of moles of the added oxyalkylene group. R ¹ and R ² each represent a fatty acid residue having 8 to 30 carbon atoms. R ³ represents a hydroxyl group, a methoxy group or an ethoxy group. (2) An amphotericin B carrier in which amphotericin B is carried in a liposome, which comprises a compound represented by the following general formula (2) as a liposome membrane-forming component (second Amphotericin B carrier).

Embedded image [In the formula, X represents a divalent residue, and p represents 0 or 1. OA
Represents an oxyalkylene group having 2 to 4 carbon atoms, and n represents a positive number of 1 to 1000 in terms of the average number of moles of the added oxyalkylene group. R ¹ and R ² each represent a fatty acid residue having 8 to 30 carbon atoms. -N (H) q-Im is an antibody or antibody fragment containing a lysine residue, q is 0 or 1, Y ¹ is an organic residue capable of binding to a lysine residue in the antibody or antibody fragment, Y ^{1 to} N are , Q = 1 indicates Y ¹ -N, and q = 0 indicates Y ¹ = N. ]

In the general formulas (1) and (2), R ¹
As the C 8-30 fatty acid residue represented by R ² and R ² , a C 8-20 fatty acid residue is preferable. Specific examples of such fatty acid residues include caprylic acid, pelargonic acid, capric acid, undecanoic acid,
Fatty acid residues of saturated fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, solotic acid, montanic acid, melissic acid and 2-ethylhexanoic acid; oleic acid, linoleic acid,
Fatty acid residues of unsaturated fatty acids such as linolenic acid, erucic acid and 2,4-octadecadienoic acid; fatty acid residues of branched fatty acids such as isostearic acid; hydroxyl groups in alkyl groups such as ricinoleic acid and 12-hydroxystearic acid And fatty acid residues of fatty acids having Among these, myristic acid, palmitic acid, stearic acid, oleic acid, 2, because of the ability to form stable liposomes,
Fatty acid residues of 4-octadecadienoic acid are preferable, and fatty acid residues of myristic acid, palmitic acid, stearic acid, and oleic acid are particularly preferable. The two fatty acid residues R ¹ and R ² may be different residues.

In the general formulas (1) and (2), OA
The oxyalkylene group represented by is an oxyalkylene group having 2 to 4 carbon atoms, and is an oxyethylene group, an oxypropylene group, an oxytrimethylene group, an oxy-1-ethylethylene group, an oxy-1,2-dimethylethylene group. Group, oxytetramethylene group and the like. These oxyalkylene groups are groups obtained by addition-polymerizing alkylene oxides such as ethylene oxide, propylene oxide, oxetane, 1-butene oxide, 2-butene oxide and tetrahydrofuran.

In the general formulas (1) and (2), n is 1
It is a positive number of ˜1000, preferably 10 to 300, and more preferably 20 to 120. When n is 2 or more, the types of the oxyalkylene groups may be the same or different. In the latter case, they may be added randomly or in blocks. In the case of imparting hydrophilicity, it is most preferable that ethylene oxide alone is added as OA, and in this case, n is preferably 10 or more. When different types of alkylene oxides are added, it is desirable that ethylene oxide is added in an amount of 20 mol% or more, preferably 50 mol% or more.

In the general formulas (1) and (2), the divalent residue represented by X is not particularly limited, and examples thereof include the following groups.

Embedded image

In the general formula (2), -Y ^{1 to} N (H) q
Examples of the group represented by -Im include the following groups.

[Chemical 6]

Here, the antibody or antibody fragment represented by Im is an antibody or antibody fragment that specifically binds to a site where amphotericin B is to be administered intensively, and imparts targeting property to the amphotericin B carrier. It is for. Examples of such antibodies or antibody fragments include antibodies such as IgG, IgM, IgA, and IgE, and antibody fragments obtained by digesting these with an enzyme such as pepsin. These antibodies may be derived from any animal species such as human, mouse, rabbit, rat, pig, cow, sheep and bird,
In the case of a monoclonal antibody, it may be obtained from any hybridoma cell.

In the first and second amphotericin B carriers of the present invention, the liposome membrane-forming components other than those of the general formula (1) or (2) are those conventionally used as the liposome membrane-forming components. Can be used without restrictions. Specifically, phospholipids such as diphosphatidylglycerol, cardiolipin, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, soybean lecithin, egg yolk lecithin, and phosphatidylcholine, and polymerizable phospholipids having an unsaturated group in the fatty acid moiety; sulfoxyribosyl diglyceride. , Glycolipids such as digalactosyl diglyceride and lactosyl diglyceride;
Non-polar lipids such as cholesterol; nonionic surfactants, phosphatidyl polyethylene glycol, "Bioche
m. Biophys. Acta, 1066, 29-36 (1991) ”, a reaction product of phosphatidylethanolamine and polyethylene glycol, and a mixture thereof.

In the first amphotericin B carrier of the present invention, the content of the compound represented by the general formula (1) is such that the compound represented by the general formula (1) is based on the total membrane-forming components of the liposome. The content of the oxyalkylene part in the composition is 20% by weight or more. If it is less than this content, the amount of amphotericin B carried becomes low, and a sufficient effect cannot be obtained, which is not preferable.

In the first amphotericin B carrier of the present invention, amphotericin B is mixed with a membrane-forming component containing a compound represented by the general formula (1), and a liposome is formed from such a mixture by a known method. However, the following method is preferable. First, the compound represented by the general formula (1), the other film forming component and amphotericin B are dissolved in an organic solvent such as chloroform, and then the organic solvent is removed to form a dry lipid.

Next, 1 to 30% by weight of the dried lipid is added.
Hydration is performed preferably by adding a 5 to 15 wt% sucrose aqueous solution. This gives amphotericin B-supporting liposomes. The method for hydration is not particularly limited, and a method conventionally used for producing liposomes can be used. Specific methods include an extrusion method, a vortex mixer method, an ultrasonic method, a surfactant removal method, a reverse phase evaporation method, an ethanol injection method, a prevesicle method, a French press method, a W / O / W emulsion method, Examples include an annealing method and a freeze-thaw method. By selecting these methods, liposomes having various sizes and morphologies such as multilamellar liposomes, small unilamellar vesicles, and large unilamellar vesicles can be produced, and the first amphotericin B delivery of the present invention can be carried out. The body is obtained. In the present invention, there is no particular limitation on the size or shape of the liposome.

In order to produce the compound represented by the general formula (1), for example, the following method may be mentioned. 1) A method of performing a transesterification reaction of phosphatidylcholine and a (poly) oxyalkylene derivative having a hydroxyl group at one end and an R ³ group at the other end in the presence of phospholipase D. 2) having phosphatidylethanolamine, a carboxyl group at one end and an R ³ group at the other end (poly)
An oxyalkylene derivative, N-cyclohexyl-
N ′-(2-morpholinoethyl) carbodiimide = meso-p-toluenesulfonate, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole, etc. dehydration condensation A method of dehydration condensation in the presence of an agent. The details of the method for producing the compound represented by the general formula (1) are described in JP-A-7-157493 and JP-A-7-291853.

In the second amphotericin B carrier of the present invention, the content of the compound represented by the general formula (2) in the total membrane-forming components of the liposome is 0.1 to 30 mol%, preferably 1 to 20 mol. % Is appropriate. In this case, the content of the oxyalkylene part is preferably 20% by weight or more based on the total membrane-forming components of the liposome, but may be less than 20% by weight. That is, when the oxyalkylene group content is 20% by weight or more, amphotericin B
However, since the second amphotericin B carrier of the present invention has targeting property, it is not always necessary to increase the loading amount, and the content of the oxyalkylene moiety is 20% by weight. Even if it is less than, a sufficient medicinal effect is obtained. In the general formula (2), since the formula weight of the antibody or antibody fragment represented by Im greatly varies depending on the type, the antibody or antibody fragment represented by Im is used for calculating the content of the oxyalkylene moiety. The formula weight of the general formula (2) excluding the formula weight of is adopted. When the content of the compound represented by the general formula (2) is less than 0.1 mol%, a sufficient targeting effect cannot be obtained, and it becomes difficult to increase the amount of amphotericin B supported. On the other hand, when it exceeds 30 mol%, the stability of the liposome is lowered.

Since the second amphotericin B carrier of the present invention has a targeting property due to an antigen or an antigen fragment, it has a higher accumulation property in a target tissue or cell as compared with conventional liposomes. Therefore, even if the dose of amphotericin B is reduced, a sufficient drug effect can be obtained. When the same amount of amphotericin B as in the conventional case is administered, the amount of amphotericin B carried may be small.

The second amphotericin B carrier of the present invention can be easily produced, for example, by the following method. : A method of preparing a liposome containing a compound having a group capable of reacting with an antibody at the terminal of an oxyalkylene group represented by the following general formula (3) as a film-forming component, and then reacting the liposome with the antibody. : A compound having a group capable of reacting with an antibody at the terminal of an oxyalkylene group represented by the following general formula (3) is reacted with an antibody to produce a compound represented by the general formula (2), A method for preparing a liposome by using it as a membrane-forming component. In either method, the liposome can be produced in the same manner as in the case of the first amphotericin B carrier.

[0021]

Embedded image And so on. X, p, OA, n, R ¹ and R ² have the same meanings as described above. ]

In the above manufacturing method, Y ² of the general formula (3) is used.
When the group capable of reacting with the antibody or antibody fragment represented by is an oxycarbonylimidazole group, the liposome containing the compound as a membrane-forming component and the antibody or antibody fragment are mixed and reacted in an appropriate buffer. Can be manufactured by. In this case, the oxycarbonylimidazole group (Y ² ) reacts with the lysine residue in the antibody or antibody fragment to form a carbamic acid bond, and the antibody or antibody fragment is bound to the liposome.

In the above production method, when the group capable of reacting with the antibody or antibody fragment represented by Y ² in the general formula (3) is a carboxyl group, a liposome containing such a compound as a membrane-forming component and an antibody or antibody fragment. With a water-soluble dehydrating condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in a suitable buffer such as phosphate buffer, acetate buffer, carbonate buffer, etc. , Preferably pH = 4-12, temperature 0
It can be produced by reacting at -60 ° C. In this case, the carboxyl group (Y ² ) reacts with the lysine residue in the antibody or antibody fragment, and the antibody or antibody fragment is bound to the liposome via the amide bond.

In the above production method, when the group capable of reacting with the antibody or antibody fragment represented by Y ² in the general formula (3) is an aldehyde group, a liposome containing such a compound as a membrane-forming component and an antibody or antibody fragment. Can be produced by mixing and reacting with and in an appropriate buffer. In this case, the antibody or antibody fragment is bound to the liposome by forming a Schiff base. Further, the above reaction can be carried out by using a reducing agent such as sodium borohydride to form an N-alkyl bond for bonding.

In the above manufacturing method, Y ² of the general formula (3) is used.
When the group capable of reacting with the antibody or antibody fragment represented by is an oxycarbonylimidazole group, such a compound and the antibody or antibody fragment are mixed in a suitable buffer and reacted to form a carbamic acid bond. By binding, the compound represented by the general formula (2) can be produced. Next, a liposome is prepared using the obtained compound as a film-forming component.

In the above-mentioned production method, when the group capable of reacting with the antibody or antibody fragment represented by Y ² in the general formula (3) is a carboxyl group, such compound and the antibody or antibody fragment are placed in an appropriate buffer. By using a water-soluble dehydrating condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, preferably at pH = 4 to 12 and at a temperature of 0 to 60 ° C. The compound represented by (2) can be produced. In this case, the carboxyl group (Y ² ) reacts with the lysine residue in the antibody or antibody fragment to form an amide bond and bond to each other to obtain the compound represented by the general formula (2). As another method, the compound represented by the general formula (3) is used in an organic solvent such as chloroform, methanol or ethanol.
And a compound represented by N-hydroxysuccinimide, 4
-Hydroxyphenyl dimethyl sulfonium methyl sulfate and the like BOP reagent, 1,1'-carbonyldiimidazole, N-cyclohexyl-N '-(2-morpholinoethyl) carbodiimide meso-p-toluene =
Sulfonate, dicyclohexylcarbodiimide, diethyl phosphorocyanidate, N-ethoxycarbonyl-
It can also be produced by reacting with a dehydrating condensing agent such as 2-ethoxy-1,2-dihydroquinoline and then reacting this with an antibody or antibody fragment in an appropriate buffer. Next, a liposome is prepared using the obtained compound as a film-forming component.

In the above production method, when the group capable of reacting with the antibody or antibody fragment represented by Y ² of the general formula (3) is an aldehyde group, such compound and the antibody or antibody fragment are placed in an appropriate buffer. The compound represented by the general formula (2) can be produced by mixing with the above compound to form a Schiff base and binding them. Furthermore, by performing this reaction using a reducing agent such as sodium borohydride, an N-alkyl bond can be formed and bonded. Next, a liposome is prepared using the obtained compound as a film-forming component.

In order to produce the compound represented by the general formula (3), for example, the following method can be mentioned. 1) Phosphatidylethanolamine is reacted with a (poly) oxyalkylene derivative having a carboxylic acid halide group at both ends in the presence of a tertiary amine, and then the active ester group remaining in the obtained compound is hydrolyzed. How to disassemble and obtain. 2) Phosphatidylethanolamine and carbonyl-N-oxysuccinimide group at both ends, or carbonyl-1-oxybenzotriazole group, carbonyl-
N-oxy-5-norbornene-2,3-dicarboximide and other (poly) oxyalkylene derivative having an activated ester group is reacted, and then the active ester group remaining in the obtained compound is hydrolyzed. How to get it. 3) Transesterification of phosphatidylcholine and (poly) oxyalkylene having hydroxyl groups at both ends in the presence of phospholipase D, and the obtained compound is further subjected to succinic anhydride, monochloroacetic acid, or N, N'-carbonyldiene. The method of obtaining by acting imidazole. Details of the method for producing the compound represented by the general formula (3) are described in JP-A-7-157493 and JP-A-7-242680.
It is described in JP-A-7-242681 and JP-A-7-291853.

[0029]

The amphotericin B carrier according to claim 1 of the present invention contains a specific amount of the compound represented by the general formula (1) as a liposome membrane-forming component, and therefore reduces the toxicity of amphotericin B. In addition, the amount of amphotericin B carried (content) can be widely adjusted,
Moreover, it has high retention in blood. Since the amphotericin B carrier of claim 2 of the present invention contains the compound represented by the general formula (2) as a liposome membrane-forming component, the toxicity of amphotericin B can be reduced and the amphotericin B The carried amount (content) can be widely adjusted, the blood retention is high, and the targeting property is provided.

[0030]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will now be described in more detail with reference to specific examples, but the present invention is not limited thereto. Example 1-1 Dipalmitoylphosphatidylcholine 3.96 mg
(5.4 μmol) and cholesterol 1.04 mg
(2.7 μmol) was dissolved in 300 μl of chloroform. Amphotericin B 0.75 mg (0.
8 μmol) and 1.95 mg of a compound represented by the following formula (4) (molecular weight of polyethylene glycol part: about 3000) corresponding to 6 mol% thereof (content of polyethylene glycol part: 26% by weight) were heated and dissolved. Chloroform (300 μl) was added and mixed well, and the solvent was evaporated under a nitrogen gas atmosphere, and then dried under reduced pressure.

Embedded image

Here, 30% of a 9% by weight sucrose aqueous solution is used.
Liposomes were prepared by adding 0 μl and repeating freeze-thawing four times. Next, pore size 0.4, 0.2, 0.1
The particle size of the liposome was adjusted by sequentially passing through a μm membrane. Then centrifuge (100000r
pm, 10 minutes) to obtain the desired amphotericin B-containing liposome. Next, the liposomes obtained above were added to methanol to prepare 2 ml, and 405 nm
The amount of amphotericin B in the liposome was quantified from the absorbance of. The results are shown in Table 1.

Example 1-2 As in Example 1-1, but instead of the compound of formula (4), a compound of the following formula (5) (molecular weight of polyethylene glycol part about 2200, content of polyethylene glycol part: (20% by weight) was used to prepare amphotericin B-containing liposomes, and the amount of amphotericin B supported in the liposomes was measured. The results are shown in Table 1.

Embedded image

Comparative Example 1 In the same manner as in Example 1-1, except that the compound of the formula (4) was replaced by a compound of the following formula (6) (molecular weight of polyethylene glycol part: about 1000): 6 mol% (content of polyethylene glycol part) The amount of amphotericin B contained in the liposome was measured, and the amount of amphotericin B carried in the liposome was measured. The results are shown in Table 1.

Embedded image

Example 1-3 An amphotericin B-containing liposome was prepared in the same manner as in Example 1-1, except that the compound of the formula (4) was used in an amount of 8 mol% (content of polyethylene glycol portion: 35% by weight). The amount of amphotericin B loaded therein was measured. The results are shown in Table 1.

Example 1-4 In the same manner as in Example 1-1, except that the compound of the formula (4) was added at 10 mol% (content of polyethylene glycol part: 43
(Wt%) was used to prepare amphotericin B-containing liposomes, and the amount of amphotericin B supported in the liposomes was measured. The results are shown in Table 1.

Example 1-5 In the same manner as in Example 1-1, except that the compound of the formula (4) was added in an amount of 12 mol% (content of polyethylene glycol part: 52
(Wt%) was used to prepare amphotericin B-containing liposomes, and the amount of amphotericin B supported in the liposomes was measured. The results are shown in Table 1.

Example 1-6 In the same manner as in Example 1-1, except that the compound of the formula (4) was added in an amount of 15 mol% (polyethylene glycol part content: 65).
(Wt%) was used to prepare amphotericin B-containing liposomes, and the amount of amphotericin B supported in the liposomes was measured. The results are shown in Table 1.

Comparative Example 2 An amphotericin B-containing liposome was prepared in the same manner as in Example 1-1, except that the compound of the formula (4) was used in an amount of 3 mol% (polyethylene glycol portion content: 13% by weight). The amount of amphotericin B carried was measured. The results are shown in Table 1.

[0039]

[Table 1]

Example 2-1 3.96 mg of dipalmitoylphosphatidylcholine
(5.4 μmol) and cholesterol 1.04 mg
(2.7 μmol) was dissolved in 300 μl of chloroform. Amphotericin B 0.75 mg (0.
8 μmol) and 6 mol% of the compound of the following formula (7) (molecular weight of polyethylene glycol part: about 3000) 1.95 mg (content of polyethylene glycol part: 26% by weight) under heating and dissolved in chloroform 30
0 μl was added and mixed well, the solvent was evaporated under a nitrogen gas atmosphere, and further dried under reduced pressure.

Embedded image

Here, 30% 9% by weight aqueous sucrose solution
Liposomes were prepared by adding 0 μl and repeating freeze-thawing four times. Next, pore size 0.4, 0.2, 0.1
The particle size of the liposomes was adjusted by sequentially passing through a membrane of μm, followed by centrifugation (100,000 rp).
m, 10 minutes).

Next, the liposome was added to the above with 5 mM MES.
Buffer solution-Dispersed in 1 ml of physiological saline, 20 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 20 mg of N-hydroxysulfosuccinimide were added, and after stirring at room temperature for 10 minutes, 200
μl of HEPES buffer (pH = 7.5) was added, and the pH was adjusted to 7.5 with 1N aqueous sodium hydroxide solution. Here, GP present on the surface of mouse lung endothelial cells
Monoclonal antibody 34A that specifically binds to 120 and ¹²⁵ I-3 radiolabeled with this antibody
4A was added, and the mixture was stirred at room temperature for 2 hours. Then, the product was purified by centrifugation (4 ° C., 100,000 rpm, 10 minutes) to obtain amphotericin B-containing liposomes having targeting property.

Comparative Example 3 An amphotericin B-containing liposome having no polyethylene glycol moiety was obtained in the same manner as in Example 1-1, except that the compound represented by the formula (4) was not used. It was The amount of amphotericin B carried in the obtained liposome was 14.58 μg per 1 mg of lipid.

Example 3-1 The liposomes (amphotericin B carrier) obtained in Examples 1-1, 2-1 and Comparative Example 3 were intravenously injected into a mouse, and 1
Amphotericin B in the tissues after the lapse of time and after 6 hours was evaluated by quantifying by high performance liquid chromatography and shown in Tables 2 and 3.

[0045]

[Table 2]

[0046]

[Table 3]

Example 4-1 BALB / c was intranasally infected with A. fumigatus: MF-13 at 2.0 × 10 ⁶ conidia / mouse BALB / c
A treatment experiment was carried out using a mouse lung aspergillosis model. The amphotericin B carriers obtained in Examples 1-1 and 2-1 and Comparative Example 3 were repeatedly administered for 5 days, and then for 1 week for 4 weeks.
The dosage for survival at 00% is Comparative Example 3 10.0 mg / kg Example 1-1 3.0 mg / kg Example 2-1 2.0 mg / kg, which carries the example, particularly 34A. An excellent pharmacological effect was obtained with the liposomes.

In the same administration method, a dose of 2.0 mg
The survival rate after 4 weeks at 4 kg / kg was Comparative Example 3 20%, Example 1-1 80%, Example 2-1 100%, and excellent survival rates were obtained with the Examples.

From the results of Examples 1-1 to 1-6 (Table 1), the amphotericin B carrier of the present invention was determined according to the molecular weight and content of the oxyalkylene moiety of the compound represented by the general formula (1). It is clear that the amount (content) of amphotericin B carried in the liposome can be adjusted. Furthermore, from the results of Example 2-2 (Table 2), it is clear that the amphotericin B carrier of the present invention having an antibody has excellent blood retention and targeting property. Regarding the toxicity, from the results of Example 4-1, the amphotericin B-supporting liposome containing 20% by weight or more of the polyethylene glycol portion according to the present invention has reduced toxicity as compared with the liposome having no polyethylene glycol portion, and the antibody It is clear that the one carrying the thiophene has a markedly reduced toxicity.

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Claims (2)

[Claims] 1. An amphotericin B carrier in which amphotericin B is supported in a liposome, wherein a compound represented by the following general formula (1) is used as a liposome membrane-forming component, and the total content of oxyalkylene moieties forms a liposome membrane. An amphotericin B carrier, which is contained in an amount of 20% by weight or more based on the components. Embedded image [In the formula, X represents a divalent residue, and p represents 0 or 1. OA is an oxyalkylene group having 2 to 4 carbon atoms, and n is an average addition mole number of the oxyalkylene group of 1 to 100.
Indicates a positive number of 0. R ¹ and R ² each have 8 to 3 carbon atoms
The fatty acid residue of 0 is shown. R ³ represents a hydroxyl group, a methoxy group or an ethoxy group. ] 2. An amphotericin B carrier in which amphotericin B is carried in a liposome, which comprises a compound represented by the following general formula (2) as a liposome membrane forming component. Embedded image [In the formula, X represents a divalent residue, and p represents 0 or 1. OA is an oxyalkylene group having 2 to 4 carbon atoms, and n is an average addition mole number of the oxyalkylene group of 1 to 100.
Indicates a positive number of 0. R ¹ and R ² each have 8 to 3 carbon atoms
The fatty acid residue of 0 is shown. -N (H) q-Im is an antibody or antibody fragment containing a lysine residue, q is 0 or 1, Y ¹ is an organic residue capable of binding to a lysine residue in the antibody or antibody fragment, and Y ^{1 to} N are , Q = 1, Y ¹ -N, and q = 0, Y ¹ =
N. ]