WO1995021624A1

WO1995021624A1 - High-concentration aureobasidin preparation in solution form

Info

Publication number: WO1995021624A1
Application number: PCT/JP1995/000145
Authority: WO
Inventors: Hironobu Hiraga; Hisae Igarashi; Takaaki Ohkuma
Original assignee: Nippon Kayaku Kabushiki Kaisha
Priority date: 1994-02-08
Filing date: 1995-02-03
Publication date: 1995-08-17

Abstract

A high-concentration aureobasidin A (R106-I) preparation in solution form excellent in peroral absorbability of R106-I. The preparation contains as the essential ingredients R106-I useful as an antimycotic, polyoxyethylene-castor oil surfactant and ethanol preferably in amounts of, respectively, 100, at least 65 and at least 30 parts by weight. The concentration of R106-I in the preparation ranges from 20 to 40 w/w %. A capsular preparation made by filling the above preparation into a hard gelatin capsule containing polyethylene glycol (PEG) is an excellent preparation free from capsule breakage and leakage of the contents.

Description

Description High-concentration solution formulation of aureobasidins

The present invention relates to a high concentration solution preparation of aureobasidin useful as an antifungal agent for deep mycosis. Deep mycosis is a fatal disease for patients with suppressed immunity, such as cancer, organ transplantation, and acquired immunodeficiency syndrome, and has been increasing in recent years. The preparation of the present invention is extremely useful as a preparation for treating such diseases.

Background art

Aureobasidin A (same as antibiotic R106-I; hereinafter abbreviated as R106-1) is, for example, a strain belonging to the genus Aureobasidium (FERM-BP1938). EP 3 is an antibiotic of cyclic peptides, and is expected to be useful as an antifungal agent.A large number of their derivatives and analogous compounds are also synthesized.

52092, JP-A-3-44398, EP 507484. Hereinafter, in the present specification, aureobasidins including R106-I and its derivatives or analogs are referred to as R106-1.

However, R106-Is are very poorly soluble compounds in water, and have extremely low oral absorbability when administered orally in solid form. Oral administration of R106-Is dissolved in fats and oils (eg, medium-chain fatty acid triglycerides) known to promote the absorption of oily drugs does not show any improvement in oral absorbability .

For patients with deep mycosis, the clinical use of R106-Is, especially R106-I, depends on the infected fungus and the symptoms of the patient, but daily doses of 25 mg There is a need for a formulation of R106-1 which can easily administer 20001118 at a dose of 1¾106-1 and has good absorbability, especially when administered orally.

An object of the present invention is to provide a dosage of R 10 which is necessary for treating

(6) Highly concentrated solution of R106-1 that can easily administer Class I, especially for oral administration It is to provide a suitable formulation.

Disclosure of the invention

As a result of intensive studies aimed at obtaining a high-concentration solution of R106-1 that can easily orally take R106-I clinically, R106-1 and ethanol and polio Completed the present invention by finding that the oral absorption of R106-I is good when a high concentration solution of R106-I containing oral kissetylene castor oil-based activator as an essential component is good. did.

That is, the present invention contains R106-I, a polyoxyethylene castor oil-based activator and ethanol as essential components, and contains R106-I in an amount of at least 10 w% based on the whole preparation. 06-1 related to high concentration solution preparations.

BEST MODE FOR CARRYING OUT THE INVENTION

As R106-1 in the present invention, a cyclic peptide substance R106-I having a molecular weight of 1101, which is produced by a strain belonging to the genus Aureobasidium (FERM-BP1938), is preferable.

Examples of the polyoxyethylene castor oil-based activator used in the present invention include polyoxyethylene castor oil ゃ polyoxetylene hard castor oil and the like. Polyoxyethylene castor oil includes, for example, Cremophor EL (trade name, manufactured by BASF), NI KKOL CO-3. CO-10, CO-20 TX, CO-40 TX, CO-50TX, CO-60TX (trade name) ; Nikko Chemicals Co., Ltd.).

Examples of polyoxyethylene hydrogenated castor oil include NI KKOL HCO-5, HCO-10, HCO-20, HCO-30, HCO-40, HCO-50, ΗCO-60, HCO-80, and HCO-100. (Trade name; Nikko Chemicals), Cremophor RH40, RH60 (trade name; BASF), UNIOX HC-40, HC-50, HC-60 (trade name; manufactured by NOF Corporation) .

These polyoxyethylene castor oil-based activators have an average addition monoethylene number of ethylene oxide in the range of 20 to 80, preferably 30 to 70 in view of the oral absorbability of R106-1, force preferred _n and those having an HLB value in the range of 8 to 1 7 The amount of the polyoxyethylene castor oil-based activator used is usually at least 65 parts by weight, preferably at least 80 parts by weight, per 100 parts by weight of R106-1. The upper limit is not particularly limited, and can be determined according to the volume of the preparation. The amount of ethanol used is at least 30 parts by weight, preferably at least 35 parts by weight, based on 100 parts by weight of R106-I. The upper limit is not particularly limited, and can be determined according to the volume of the preparation and the amount of the polyoxetylene castor oil-based active agent. Usually, it is 500 parts by weight or less.

The amount relative to the whole preparation is usually 10 wZw% or more for R106-Is, preferably 20 to 40 ww%, and 1% for the polyoxetylene castor oil-based active agent. 0 w / w% or more, preferably 20 to 50 wZw%, preferably ethanol? To 40 wZw%, more preferably 8 to 30 wZw%.

Depending on the dosage form of the present invention, if the amount of ethanol is too large, the quality of the dosage form becomes unstable due to its volatility. Inconveniences such as cracking due to losing the flexibility of the capsule occur. In such a case, adding a highly soluble unsaturated higher fatty acid of the R106-I class to the preparation can reduce the required amount of ethanol to be added, without increasing the capacity of the preparation. A highly absorbable preparation can be obtained. The unsaturated higher fatty acid is not particularly limited as long as it can be used for medicine, but preferred are unsaturated fatty acids having 18 to 20 carbon atoms. Examples of these fatty acids include oleic acid, linoleic acid, linolenic acid, arachidonic acid and the like. The amount of these fatty acids to be added is usually in the range of 0 to 200 parts by weight based on 100 parts by weight of R106-I, and 10 to 60 parts by weight for the whole preparation. It is in the range of wZw%.

Furthermore, in consideration of clinical usability (ease of drinking and portability), a hard gelatin capsule preparation obtained by filling a high-concentration solution formulation of the present invention into a normal hard gelatin capsule can be obtained. If necessary, filling the hard gelatin capsule containing polyethylene glycol (PEG) with a drug solution can cause problems such as cracking of the capsule and cracking of the capsule and leakage of the liquid content. It can prevent liquid leakage and capsule cracking. As a hard gelatin capsule containing PEG, for example, For example, those manufactured by Elanco Japan Co., Ltd. described in JP-A-3-80930 can be used. According to the above-mentioned publication, the content of the PEG slightly varies depending on the molecular weight of the PEG used. That is, for the gelatin in the gelatin capsule composition,

If the molecular weight is between 200 and 150, then 50 w / w%

0.5 to 15 w / w% when the molecular weight is 400000

0.5 to 10 wZw% when the molecular weight is 600

If the molecular weight is 2 0 0 0 0 .1 ~ 5 w / w%

Is preferable.

The high-concentration solution preparation of the present invention can also be used as a syrup or the like, if necessary.

The high-concentration solution preparation of the present invention may contain, in addition to the above-mentioned components, pharmaceutical additives such as an auxiliary agent for dissolving R106-I, an antioxidant and a preservative.

When hard gelatin capsules containing PEG are filled with the high-concentration solution preparation of the present invention, there is a rare problem that the dissolution of the hard gelatin capsules is reduced due to insolubilization or poor dispersibility of the internal solution. Sometimes. In this case, it is effective to add an antioxidant to the drug solution if necessary. In the high-concentration solution preparation of the present invention, in particular, derivatives such as vitamin Es, tocoflorones or esters thereof, ascorbic acid, and a It is effective to add an antioxidant such as cetaminophen and riboflavin, and a fat-soluble antioxidant is preferable.

The compounding amount of the antioxidant is preferably from 0.01 to 10 wZw%, more preferably from 0.1 to 5 wZw%, based on the whole preparation.

In addition, when fats and oils containing unsaturated bonds are incorporated into the preparations as solubilizers of R106-1 class, vitamin Es, butylhydroxytoluene, butylhydroxydisole are used to prevent oxidation of fats and oils. And the like. The compounding amount of these antioxidants is in the range of 0.001 to 0.01 parts by weight based on 1 part by weight of fats and oils. In addition, in order to prevent changes due to oxidation of lipids, it is common practice to replace the atmosphere in the container or packaging containing the drug product with an inert gas such as nitrogen gas, or to use an oxygen scavenger.

Preferably, in the present invention, a solution having the following composition is PEG-containing O 95/21624

It is a hard gelatin capsule filled in a hard gelatin capsule. Note that w / w% is a ratio to the whole solution.

R 1 06-I 15 5-40 wZw% more preferably 20-40 w / w% Polyoxyethylene 15 5-60 w / w% more preferably 20-50 ww% Castor oil-based activator

(Average number of moles of ethylenoxide 30-70)

Ethanol 5-50 wZw%, more preferably 7-40 wZw%

Oleic acid 10 to 60 w / w%, more preferably 15 to 50 wZw% Fat-soluble antioxidant 0 to 10 w / w%, more preferably 0.1 to 5 wZw%

The preparation of the present invention can be prepared by a usual method without employing a special method. That is, for example, a polyoxyethylene castor oil-based activator and ethanol are mixed with an unsaturated higher fatty acid, an antioxidant, etc., if necessary, and then R106-I is added, followed by heating if necessary. The solution can be prepared by dissolving R106-Is while mixing, and filling the resulting solution, for example, into a hard gelatin capsule, if necessary.

Hereinafter, the present invention will be described in detail with reference to examples. The present invention is not limited to only these.

Example 1

R 1 06-I 1.0 g (29.4 w / w%) HCO-60 (brand name) 1.4 g (4 1.2 w / w%)

(Polyoxetylene hard castor oil:

Average number of moles of ethylenoxide added

60, HLB value 1 4)

Ethanol 1.0 g (29.4 w / w%) Total 3.4 g

To 1.0 g of ethanol, 1.4 g of HC-60 was added, and if necessary, heated to dissolve completely. Then, 1.0 g of R106-I was added and dissolved. 0.34 g of this drug solution (0.1 g as the amount of R106-I) was added to the Japanese Pharmacopoeia No. 2 normal hard capsule. O 95/21624

(Made by Elanco Japan Co., Ltd.) to obtain hard capsules.

Example 2

R 1 06-I 1, 0 g (32.3 w / w%)

Cremophor EL (brand name) 0, 8 5 g (27.4 wZw%)

(Polyoxyethylene castor oil:

Average number of moles of ethylenoxide added

35-40, HLB value 1 2-14)

Ethanol 0.4 g (12.9 w / w%)

Extra olein (brand name) 0.85 g (27.4 w / w%)

(Oleic acid) 3.1 g in total

To 0.85 g of Cremophor EL and 0.85 g of oleic acid (trade name, manufactured by NOF CORPORATION), add 0.4 g of ethanol and mix, and add R106-I to this. Add 0 g and heat if necessary to completely dissolve. 0.31 g of this solution (0.1 g in terms of the amount of R106-I) was filled into a hard capsule containing PEG containing Japanese Pharmacopoeia No. 2 (manufactured by Nippon Elanco Co., Ltd.) to obtain hard capsules .

Example 3

R 1 06-I 10 g (32.1 vi / vf%) Cremophor EL (brand name) 0 85 g (27 2 w / w%)

(Polyoxetylene castor oil)

Ethanol 0 4 g (1 2, 8 w / w% extra olein (brand name) 0 85 g (27.2 w / w%) (oleic acid)

Tocoproyl drunk acid 0.022 g (0.7 total 3.1 2 g

Cremophor EL, 0.85 g and oleic acid (extra olein: trade name, Nippon Oil & Fat Co., Ltd.) O 95/21624

Was added and mixed, and 1.0 g of R106-I was added thereto, and if necessary, heated to dissolve completely. 0.31 g (0.1 in terms of the amount of R106-1) of this drug solution was filled into a hard capsule containing PEG containing Japanese Pharmacopoeia No. 2 (manufactured by Nippon Elanco Co., Ltd.) to obtain a hard capsule.

The hard capsules used in Examples 1, 2 and 3 and Control Examples 1 and 4 were manufactured by Nippon Elanco Co., Ltd., and PEG-containing hard capsule was PEG having a molecular weight of 4,000 with respect to the whole skin. A hard gelatin capsule containing 3 wZw%, and a normal hard capsule refers to a normal hard gelatin capsule containing no PEG.

Control Example 1

0.1 g of an amorphous-powder of R106-I was filled into a Japanese Pharmacopoeia No. 2 normal hard capsule (manufactured by Elanco Japan Co., Ltd.) to obtain a hard capsule.

Control 2

R 1 06-I 1.0 g (20 w / w%) Medium chain fatty acid triglyceride 49.0 g (98 0

(Panaset 800, trade name, manufactured by NOF Corporation) Total 50.0 g

Panassate 800, 49.02, 11106-1, 1.1 g was added, and if necessary, heated to dissolve completely to prepare a test solution.

Control 3

R 1 06—I 1.0 g (10.0 w / w%) hydroxypropyl cellulose 5.0 g (50.0 w / w% (HPC)

Etano-mono 4.0 g (40.0 w / w%) Total 1 0.0 g

RIO 6-1 and 1.Og and 5.0 g of HPC were added to 4.Og of ethanol and heated if necessary to dissolve completely. At the time of oral administration, add 100 ml of distilled water to this solution and disperse it uniformly (0.1 l gZl O as R106-I). O 95/21624

ml) to give a test solution.

Control Example 4

R 1 06-I 1.0 g (15.4 w / w%)

PEG 4 0 0 5.0 g (76.9 w / w%) Cremophor EL (brand name) 0.5 g (7.7 total 6.5 g

To 5.0 g of PEG 400, 0.5 g of Cremophor EL (trade name) and 1.0 g of R106-I were added and, if necessary, completely dissolved by heating. 0.65 g (0.1 g in terms of the amount of R106-I) of this drug solution was filled in a Japanese Pharmacopoeia No. 0 normal hard capsule (manufactured by Nippon Elanco Co., Ltd.) to obtain a hard capsule.

Control 5

R 1 06-I 1.0 g (19.5

Mannitol 2.0 g (39.0

Microcrystalline cellulose 2.0 g (39.0 w /%)

SDS 0.1 (2.0 w / w%) Magnesium stearate 0.025 g (0.5 w / w%) Total 5.1 2 5 g

RIO 6-1, 1.O g, mannitol, 2.0 g, microcrystalline cellulose, 2.0 g, SDS (sodium dodecyl sulfite), 0.1 lg and magnesium stearate, 0.025 g of agate mortar Then, 0.5125 g of the mixture was tableted (0.1 lg as the amount of R106-I) to give tablets.

Test example 1

Three beagle dogs (body weight: about 10 kg) in a group were orally administered the capsules prepared in Examples 1 and 2. As a control, 1 g of R106-I was added to 20 g of Cremophor EL (trade name) to dissolve it, and water for injection was added to 100 ml (0.1 g as the amount of R106-I). / \ 0 ml) was injected intravenously from the forelimbs of beagle dogs. Oral capsules, liquids and tablets prepared in Controls 1 to 5 Was administered. The dose was 100 mgZ for R106-I in both the examples and the control. Blood was collected 0.5, 1, 2, 4 and 6 hours after administration, and the amount of R 106-I in plasma was measured by liquid chromatography ultraviolet absorption spectrophotometry. From the blood concentration values obtained at each time point, the maximum blood concentration (Cmax) and the area under the blood concentration time curve (AUC) from 0 to 6 hours were determined. The bioavailability (BA)% was determined by dividing the AUC at the time of oral administration by the AUC at the time of intravenous administration and multiplying by 100. Table 1 shows the results.

table 1

Cmax AUC B A Dispersion state in water

(Og / ml) ig hr / ml) (%) Intravenous injection 1 2.2.3 Clear colorless aqueous solution Example 1 1.19.3.0 6 13.7 No white emulsion or sediment was observed Was.

Example 2 1. 1 7 3.5 5 3 15.8 No white emulsion, sediment, etc. were observed.

Control Italy 11 0.12 0.44 2.0 R 106-1 Particles are poorly wet, and particles float on the water surface. Control Italy J 2 0.1 0 0. 28 1. 3 Separated into two phases. An oily substance floats after standing still.

Control Italy J 30. 28 0. 87 3.9 Dispersibility is good. White suspension, sediment after standing. Control Italy J 4 0.3 3 1. 0 1 4.5 Dispersibility is good. White suspension, precipitate after standing. Control Italy J 50. 1 1 0. 3 8 1.7 Disintegration and dispersibility are good.

There is sediment after standing. O 95/21624

10 As is evident from the results in Table 1, the formulations of Examples 1 and 2 show higher Cmax and AUC values than any of the formulations of Controls 1 to 5, and the bioavailability (BA) Is extremely excellent.

Test example 2

The drug solution obtained by the formulation of Example 2 was filled in a normal hardened capsule and a hard capsule containing PEG, placed in a vial with a screw cap, and airtightly stored at 25 ° C. The normal hard capsule and the hard capsule containing PEG are as described above. One and three months after the start of storage, the number of cracking force capsules when a load pressure of 5 kg was applied to the capsule in the horizontal direction was measured. The number of broken pieces was divided by the number of tested pieces to obtain a value (%) multiplied by 100. Table 2 shows the results.

Table 2 Storage period 1 month at start 3 months Normal gelatin capsule 0% 50% 80%

Hard gelatin capsules containing PEG 0% 0% 0% As is evident from the results in Table 2, the high-concentration solution formulation of R106-1 of the present invention filled with PEG-containing hard gelatin capsules has been used for a long time. Its stability is excellent even after storage.

Test example 3

The drugs obtained by the formulations of Examples 2 and 3 were filled into hard gelatin capsules containing PEG, placed in vials with screw caps, and airtightly stored at 25 ° C and 40 ° C. One, two and three months after the start of storage, a dissolution test was performed on each of these capsules. The test method was based on the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). The specific test method is as follows.

The paddle was immersed in purified water in a vessel whose temperature had been previously adjusted to 37 ° C. One capsule was taken, the capsenole was placed in a sinker, submerged in the center of the container, and rotation started immediately. During operation, remove the thermometer and cover to prevent evaporation of the test solution. O 95/21624

The unit was rotated smoothly at 50 rpm, and care was taken to avoid shaking and vibration.

After 30 minutes, a certain amount of eluate was collected from a position 1 Omm away from the vessel wall, between the liquid level of the eluate and the upper end of the stirring blade. The collected eluate was immediately filtered, and the filtrate was quantified to determine the elution rate. However, either the filtered R 1 0 6- 1 in the eluate is adsorbed, or eluate as well with the two _c further capsules was used that does not affect the quantification by from material used for the filtration Then, the average value of the elution rate after 30 minutes was determined. Table 3 shows the results.

Table 3 Storage period 1 month 2 months 3 months

25 ° C 40 ° C 25 ° C 40 ° C 25 ° C 40 ° C Example 2 9 5% 6 9% 1 05% 5 7% 1 1 0% 40% Example 3 1 0 3% 102% 103% 8 8% 1 06% 93% As is evident from the results in Table 3, the formulation in which the drug solution of Example 3 containing an antioxidant was filled in a PEG-containing hard capsule can be stored for a long period of time. The dissolution of R106-1 is extremely good.

Industrial applicability

As shown in the above Examples and Test Examples, the high-concentration solution preparation of R106-Is of the present invention is a preparation having a size that can be easily administered clinically, and has high L and oral absorption. Even at a low dose, the blood concentration was sufficient to exhibit pharmacological effects such as antifungal activity. In addition, by filling the high-concentration solution formulation of the present invention into PEG-containing hard capsules, the capsules do not crack even during long-term storage, and the addition of an antioxidant provides good dissolution, It can be a physically stable preparation, and is useful for treatment of mycosis and the like.

Claims

The scope of the claims

1. A high-concentration solution preparation of oleobasidin, which contains aureobasidin, a polyoxyethylene castor oil-based activator and ethanol as essential components, and contains at least 1 Ow / w% of aureobasidin relative to the whole preparation.

2. More than 65 parts by weight of polyoxyethylene castor oil-based activator and more than 30 parts by weight of ethanol based on 100 parts by weight of aureobasidin. Formulation c of claim 1 containing 0 ww%

3. The preparation according to claim 1, further comprising an unsaturated higher fatty acid.

4. The claim 1 wherein the average added mole number of ethylene oxide in the polyoxyethylene castor oil-based activator is in the range of 30 to 70 and the HLB value is in the range of 8 to 17. To any one of paragraphs 3 to 3.

5. 20 to 40 w / w% of aureobasidin, 20 to 50 wZw% of polyethylene castor oil-based surfactant, 7 to 40 w / w% of ethanol, and The preparation according to claim 3 or 4, comprising 10 to 60 wZw% of an unsaturated higher fatty acid having 18 to 20 carbon atoms.

6. The preparation according to any one of claims 3 to 5, wherein the unsaturated higher fatty acid is oleic acid.

7. A hard gelatin capsule formulation filled with the formulation of any one of claims 1 to 6.

8. The hard gelatin capsule preparation according to claim 7, which is a hard gelatin capsule containing polyethylene glycol in the capsule skin.

9. The hard gelatin capsule preparation according to claim 8, further comprising an antioxidant added to the preparation according to any one of claims 1 to 6.

10. A solution containing, as essential components, an aureobasidin, a polyoxyethylene castor oil-based activator having an average addition mole number of ethylene oxide of 30 to 70, ethanol, oleic acid, and a fat-soluble antioxidant. The ratio of aureobasidins to the total solution is 20 to 40 wZw%

Polyoxyethylene Castor oil-based activator

(Average number of moles of ethylenoxide 30 to 70) 20 to 50 w / w% Ethanol 7 to 4 Ow w%

Oleic acid 15 to 50 w / w%

Fat-soluble antioxidant 0.1 to 5 wZw%

Formulation _{c in} which a solution of