JPH07267875A - Liquid preparation containing high concentration of aureobasidin - Google Patents

Abstract

PURPOSE:To obtain a liquid preparation having high concentration capable of clinically easily administering aureobasidin A (R106-I) useful as an antibacterial agent in the amount needed for treatment. CONSTITUTION:This liquid preparation having high concentration of R106-I contains R106-I, a polyoxiethylene castor oil-based activator and ethanol as essential components, preferably >=65 pts.wt. of the polyoxiethylene castor oil-based activator and >=30 pts.wt of ethanol based on 100 pts.wt. of R106-I, wherein the concentration of R106-I is 20-40w/w% base on the total of the preparation. This preparation is excellent in oral absorbability. Further, a capsule preparation obtained by filling this liquid preparation having high concentration in a gelatin hard capsule containing polyethylene glycol (PEG), is an excellent preparation free from breakage of the capsule and leakage of the contained liquid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a high-concentration solution preparation of aureobasidins which is useful as an antifungal agent for deep-seated mycosis. Deep-seated mycosis is caused by cancer, organ transplant,
It is a fatal disease for patients with immunosuppressive states such as acquired immune deficiency syndrome, and it is increasing in recent years. The preparation of the present invention is extremely useful as a preparation for treating such diseases.

[0002]

Aureobasidin A (antibiotic R106
Same as -I: hereinafter abbreviated as R106-I) is, for example, a strain belonging to the genus Aureobasidium (FERM-BP19).
38) is an antibiotic of a cyclic peptide with a molecular weight of 1101 and is expected to be useful as an antifungal agent, and many derivatives and related compounds thereof have been synthesized (JP-A-2-138296, JP-A-313896). 22995, JP-A-3-44398, and JP-A-4-305534). Hereinafter, in the present specification, aureobasidins including R106-I and its derivatives or related compounds are referred to as R106-
It is called Class I.

However, R106-I's are compounds which are extremely insoluble in water, and their oral absorbability when orally administered in a solid state is extremely low. Even when R106-Is are dissolved in oils and fats known to promote absorption of oily drugs (for example, medium-chain fatty acid triglyceride) and orally administered, the oral absorbability is not improved at all.

[0004]

In order to clinically use R106-Is, especially R106-I in patients with deep-seated mycosis, it depends on the fungus to be infected and the symptoms of the patient. A dosage of 25 mg to 2000 mg of R106-I can be easily administered, and an R106-I type preparation having good absorbability particularly when orally administered is desired.

In view of the above situation, the object of the present invention is to prepare a high-concentration solution formulation of R106-I, which can easily administer the dose of R106-I required for the treatment of deep-seated mycosis, and is particularly suitable for oral administration. To provide a formulation.

[0006]

[Means for Solving the Problems] As a result of intensive studies aimed at obtaining a high-concentration solution formulation which enables clinically easy oral administration of R106-Is, R106-Is and ethanol, polyoxyethylene castor oil The present invention has been completed by finding that oral administration of a high-concentration solution of R106-Is containing a system active agent as an essential component gives good oral absorption of R106-Is.

That is, the present invention contains R106-Is, polyoxyethylene castor oil-based activator and ethanol as essential components, and contains R106-Is at 10 w / w% with respect to the whole preparation. A certain R106-I type high concentration solution formulation.

The R106-I's in the present invention include
Strains belonging to the genus Aureobasidium (FERM-BP
The cyclic peptide antibiotic R106-1 produced by 1938) having a molecular weight of 1101 is preferable. Examples of the polyoxyethylene castor oil-based activator used in the present invention include polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. Examples of the polyoxyethylene castor oil include Cremophor EL (trade name; manufactured by BASF), NIKKOL CO-3, CO-10, CO-2.
0TX, CO-40TX, CO-50TX, CO-60
TX (trade name; manufactured by Nikko Chemicals Co., Ltd.) and the like.

Examples of the polyoxyethylene hydrogenated castor oil include NIKKOL HCO-5, HCO-10,
HCO-20, HCO-30, HCO-40, HCO-
50, HCO-60, HCO-80, HCO-100
(Product name: Nikko Chemicals), Cremo Hall RH4
0, RH60 (trade name; manufactured by BASF), Uniox HC-40, HC-50, HC-60 (trade name; manufactured by NOF Corporation) and the like. These polyoxyethylene castor oil type active agents have an average addition mole number of ethylene oxide of 20 to 10 from the viewpoint of oral absorbability of R106-I.
80, preferably in the range of 30 to 70, and HLB
The value is preferably in the range of 8 to 17.

The amount of the polyoxyethylene castor oil-based activator used is usually 65 parts by weight or more, preferably 80 parts by weight or more, relative to 100 parts by weight of R106-Is.
The upper limit is not particularly limited and can be determined according to the volume of the preparation. The amount of ethanol used is
It is 30 parts by weight or more, preferably 35 parts by weight or more, relative to 100 parts by weight of R106-Is. The upper limit is not particularly limited, but can be determined according to the volume of the preparation and the amount of the polyoxyethylene castor oil-based active agent. Usually less than 500 parts by weight

The amount based on the whole formulation is usually R106-
Type I is 10 w / w% or more, preferably 20-40 w / w
%, And the polyoxyethylene castor oil-based activator is 10%.
w / w% or more, preferably 20 to 50 w / w%, ethanol 7 to 40 w / w%, preferably 8 to 30 w / w%
It is preferably in the range of.

Depending on the dosage form of the present invention, if the amount of ethanol added is too large, the volatility of ethanol may lead to instability of the quality of the preparation, and due to its dehydrating property, for example, in the case of gelatin capsules. However, it causes inconvenience such as loss of flexibility of the gelatin capsule and cracking. In such a case, if an unsaturated higher fatty acid having a high solubility of R106-Is is added to the formulation, the required amount of ethanol can be reduced, and the oral absorbability can be reduced without increasing the volume of the formulation. A good formulation can be obtained.

The unsaturated higher fatty acid is not particularly limited as long as it can be used for medicinal purposes, but preferred examples include unsaturated fatty acids having 18 to 20 carbon atoms. Examples of these fatty acids include oleic acid, linoleic acid, linolenic acid, and arachidonic acid. The amount of these fatty acids added is usually in the range of 0 to 200 parts by weight per 100 parts by weight of R106-Is, and in the range of 10 to 60 w / w% relative to the whole preparation.

Further, in consideration of clinical usability (ease of drinking, portability), an ordinary hard gelatin capsule can be filled with the highly concentrated solution preparation of the present invention to prepare a hard gelatin capsule preparation. However, problems such as cracking of the capsule and leakage of the content liquid may occur. Therefore, if necessary, fill a hard gelatin capsule containing polyethylene glycol (PEG) with the drug solution to prevent leakage of the liquid from the capsule or the capsule. It is possible to prevent cracks and the like. PEG
As a hard gelatin capsule containing, for example, those manufactured by Nippon Elanco Co., Ltd. described in JP-A-3-80930 can be used. According to the above publication, the content of PEG differs slightly depending on the molecular weight of PEG used. That is, when the molecular weight is 200 to 1540 relative to gelatin in the gelatin capsule composition: 1 to 50 w / w
% When the molecular weight is 4000: 0.5 to 15w
/ W% When the molecular weight is 6000: 0.5 to 10w
/ W% When the molecular weight is 20,000: 0.1-5 w /
A range of w% is preferred. Further, the high-concentration solution preparation of the present invention can be used as a syrup or the like, if necessary.

In addition to the above components, the high-concentration solution preparation of the present invention may contain pharmaceutical additives such as R106-I type solubilizing agents, antioxidants, preservatives and the like.

In a gelatin hard capsule containing PEG,
When the high-concentration solution preparation of the present invention is filled, rarely, there arises a problem that the dissolution property is lowered due to insolubilization of gelatin hard capsules and poor dispersibility of the internal liquid. In this case, it is effective to add an antioxidant to the drug solution if necessary, and in the high-concentration solution preparation of the present invention, vitamin E is particularly effective.
It is effective to add a derivative such as a salt, a tocopherol or its ester, and an antioxidant such as ascorbic acid, acetaminophen, and riboflavin, and a fat-soluble antioxidant is preferable. The content of the antioxidant is preferably 0.01 to 10 w / w%, more preferably 0.1 to 5 w / w%, based on the whole preparation.

When a fat or oil containing an unsaturated bond is added to the formulation as a solubilizing agent for R106-Is, vitamin Es, butylhydroxytoluene, butylhydroxyanisole, etc. are used for the purpose of preventing the fat and oil from being oxidized. Antioxidants can be used. The blending amount of these antioxidants is 0.0001 parts by weight to 0.
It is in the range of 01 parts by weight. Further, in order to prevent changes due to oxidation of lipids, it is also usual to replace the atmosphere in the container or the package containing the preparation with an inert gas such as nitrogen gas or to use an oxygen scavenger.

A preferred formulation in the present invention is a hard gelatin capsule containing a PEG-containing hard gelatin capsule filled with a solution having the following composition. Note that w / w%
Is the ratio to the whole solution. R106-I 15-40 w / w% More preferably 20-40 w / w% Polyoxyethylene 15-60 w / w% More preferably 20-50 w / w% Castor oil-based activator (average number of moles of ethylene oxide added 30- 70) ethanol 5 to 50 w / w%, more preferably 7 to 40 w / w% oleic acid 10 to 60 w / w%, more preferably 15 to 50 w / w% fat-soluble antioxidant 0 to 10 w / w%, more preferably 0. .1 to 5 w / w%

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

[0020]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Example 1 R106-I 1.0 g (29.4 w / w%) HCO-60 (trade name) 1.4 g (41.2 w / w%) (polyoxyethylene hydrogenated castor oil) ethanol 1.0 g (29.4w / w%) ─────────────────────────────── Total 3.4g Ethanol 1.0g HCO- 60 (average added mole number 6
0, HLB value 14), 1.4 g was added, and if necessary, heated to completely dissolve, and 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 filled into a Japanese Pharmacopoeia No. 2 normal hard capsule (manufactured by Elanco Japan Co., Ltd.) to obtain a hard capsule.

Example 2 R106-I 1.0 g (32.3 w / w%) Cremophor EL (trade name) 0.85 g (27.4 w / w%) (polyoxyethylene castor oil: number of moles of ethylene oxide added) 35-40, HLB value 12-14) Ethanol 0.4 g (12.9 w / w%) Extra olein (trade name) 0.85 g (27.4 w / w%) (oleic acid) ────── ───────────────────────── Total 3.1 g Cremophor EL (average added mole number 35, HLB value 12
-14), 0.85 g, and oleic acid (extra olein: trade name, manufactured by NOF CORPORATION), 0.85 g, and ethanol 0.4 g were added and mixed, and R106-I 1.
0 g was added and, if necessary, heated to completely dissolve. 0.31 g of this drug solution (0.1 g as the amount of R106-I) was filled into a Japanese Pharmacopoeia No. 2 PEG-containing hard capsule (manufactured by Elanco Japan Ltd.) to give a hard capsule.

Example 3 R106-I 1.0 g (32.1 w / w%) Cremophor EL (trade name) 0.85 g (27.2 w / w%) (polyoxyethylene castor oil) ethanol 0.4 g (12.8 w / w%) Extra olein (trade name) 0.85 g (27.2 w / w%) (oleic acid) Tocopherol acetate 0.022 g (0.7 w / w%) ──────── ─────────────────────── Total 3.122g Cremophor EL, 0.85g and oleic acid (extra olein: trade name, NOF Corporation), 0 To 0.85 g, 0.4 g of ethanol was added, 0.022 g of tocopherol acetate was further added and mixed, and 1.0 g of R106-I was added to this, and if necessary, heated to completely dissolve.
0.31 g of this chemical (0.1% as the amount of R106-I)
g) was filled into a Japanese Pharmacopoeia No. 2 PEG-containing hard capsule (manufactured by Japan Elanco Co., Ltd.) to give a hard capsule. still,
The hard capsules used in Examples 1, 2 and 3 are manufactured by Nippon Elanco Co., Ltd., and the PEG-containing hard capsules have a molecular weight of 400.
It is a gelatin hard capsule containing 5.3 w / w% of PEG of 0 with respect to the whole coating, and a normal hard capsule is P
Figure 3 shows a conventional hard gelatin capsule containing no EG. Similar hard capsules were used also in Comparative Examples 1 and 4 shown below.

Comparative Example 1 0.1 g of amorphous powder of R106-I was filled into Japanese Pharmacopoeia No. 2 normal hard capsules (manufactured by Elanco Japan Co., Ltd.) to obtain hard capsules.

Control Example 2 R106-I 1.0 g (2.0 w / w%) Medium-chain fatty acid triglyceride 49.0 g (98.0 w / w%) (Panasate 800, trade name, manufactured by NOF CORPORATION) ─── ──────────────────────────── Total 50.0g Panacet 800,49.0g R106-I, 1.0
g was added, and if necessary, heated to completely dissolve it to obtain a test solution.

Control Example 3 R106-I 1.0 g (10.0 w / w%) Hydroxypropylcellulose 5.0 g (50.0 w / w%) (HPC) Ethanol 4.0 g (40.0 w / w%) ────────────────────────────── Total 10.0g Ethanol, 4.0g R106-I, 1.0g and H
5.0 g of PC was added and, if necessary, heated to completely dissolve. At the time of oral administration, distilled water was added to this drug solution to uniformly disperse the drug solution, and the volume was raised to 100 ml (0.1 g / 10 ml as the amount of R106-I) to obtain a test solution.

Control Example 4 R106-I 1.0 g (15.4 w / w%) PEG400 5.0 g (76.9 w / w%) Cremophor EL (trade name) 0.5 g (7.7 w / w%) ─────────────────────────────── Total 6.5g PEG400, 5.0g with Cremophor EL (trade name), 0. 5 g and 1.0 g of R106-I were added, and if necessary, heated to completely dissolve. 0.65g of this solution
(0.1 g as the amount of R106-I) was filled in Japanese Pharmacopoeia No. 0 normal hard capsule (manufactured by Elanco Japan Co., Ltd.) to obtain a hard capsule.

Control Example 5 R106-I 1.0 g (19.5 w / w%) Mannitol 2.0 g (39.0 w / w%) Microcrystalline cellulose 2.0 g (39.0 w / w%) SDS 0.1 g (2.0 w / w%) Magnesium stearate 0.025 g (0.5 w / w%) ───────────────────────── ─────── Total 5.125 g R106-I, 1.0 g, mannitol, 2.0 g, microcrystalline cellulose, 2.0 g, SDS (sodium dodecyl sulfate), 0.1 g and magnesium stearate, 0 0.025 g was mixed well in an agate mortar, and 0.5125 g thereof was compressed into tablets (the amount of R106-I was 0.1
g) to give tablets.

Test Example 1 The capsules prepared in Examples 1 and 2 were orally administered to a group of 3 beagle dogs (body weight: about 10 kg). As a control, Cremophor EL (trade name), 20g R106-
Add 1g of I to dissolve and add water for injection to 100ml
The injection prepared as (R106-I amount of 0.1 g / 10 ml) was intravenously injected through the forelimbs of a beagle dog.
In addition, the capsules, solutions and tablets prepared in Control Examples 1 to 5 were orally administered. The dose was R1 in both the examples and reference examples.
06-I was 100 mg / head. 0.5 after administration,
Blood was collected 1, 2, 4, and 6 hours later to obtain R106 in plasma.
-I amount was measured by liquid chromatography-ultraviolet absorptiometry. The maximum blood concentration (Cmax) and the area under the blood concentration time curve (AUC) from 0 to 6 hours were determined from the obtained blood concentration values at each time point. Also, AUC at the time of oral administration
Was divided by AUC at the time of intravenous administration and multiplied by 100 to obtain a bioavailability (BA)%. The results are shown in Table 1.

[0030]

[Table 1] Table 1 ──────────────────────────────────── Cmax AUC B A Dispersion in water Condition (μg / ml) (μg hr / ml) (%) ──────────────────────────────────── —Intravenous injection—22.3 ——Clear and colorless aqueous solution Example 1 1.19 3.06 13.7 No white emulsion or precipitate was observed. Example 2 1.17 3.53 15.8 No white emulsion or precipitate was observed. Control Example 1 0.12 0.44 2.0 R106-I Wetting of particles was poor and the particles floated on the water surface. Control Example 2 0.10 0.28 1.3 Separated into two phases. After standing, oily matter floats. Control Example 3 0.28 0.87 3.9 Good dispersibility. White suspension, precipitate after standing. Control Example 4 0.33 1.01 4.5 Dispersibility is good. White suspension, precipitate after standing. Control Example 5 0.11 0.38 1.7 Disintegration and dispersibility were good. There is a precipitate after standing. ────────────────────────────────────

As is clear from the results in Table 1, the formulations of Examples 1 and 2 showed higher Cmax and AUC values than any of the formulations of Control Examples 1 to 5, and had a bioavailability (BA). Is extremely excellent.

Test Example 2 A normal hard capsule and a PEG-containing hard capsule were filled with the drug solution obtained by the formulation of Example 2, put in a vial with a screw cap, and air-tightly stored at 25 ° C.
The normal hard capsule and the PEG-containing hard capsule are as described above. One and three months after the start of storage, the number of broken capsules when a load pressure of 5 kg was applied in the lateral direction of this capsule was measured. The number of cracked pieces was divided by the number of tested pieces to multiply by 100 to obtain a value (%). The results are shown in Table 2.

[0033]

[Table 2] Table 2 ──────────────────────────────────── Storage period Start date 1 month 3 months ──────────────────────────────────── Normal hard capsule 0 50 80 111G-containing hard capsule 0 0 0 ─ ─────────────────────────────────── (Unit:%)

As is clear from the results shown in Table 2, the formulation in which the R106-I high-concentration solution formulation of the present invention is filled in a PEG-containing hard capsule is excellent in safety even after long-term storage.

Test Example 3 The drug solutions obtained by the formulations of Examples 2 and 3 were filled in a PEG-containing hard capsule, placed in a screw cap vial, and air-tightly 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 is Japanese Pharmacopoeia Dissolution Test No. 2
The method was performed according to the method (paddle method). The specific test method is as follows.

Operation of Paddle Method The tester was immersed in purified water in a container whose temperature was previously adjusted to 37 ° C. Take one capsule, put the capsule in a sinker and submerge it in the center of the container, and immediately start rotation. During operation, the thermometer was removed, a lid was used to prevent evaporation of the test solution, and the tester was rotated smoothly at 50 rpm, taking care not to cause shaking and vibration. After 30 minutes, a fixed amount of the eluate was collected from a position 10 mm away from the container wall, between the liquid surface of the eluate and the upper end of the stirring blade. Immediately filter the collected eluate by an appropriate method, quantify the filtrate, and obtain the elution rate. However, for filtration, R10 in the eluate
A material that does not affect the quantitative determination due to the adsorption of 6-I or the eluate from the material used for filtration was used. Further, the same operation was performed for two capsules, and the average value of the dissolution rate after 30 minutes was obtained. The results are shown in Table 3.

[0037]

[Table 3] Table 3 ──────────────────────────────────── Storage period 1 month 2 months 3 months ───────────────── ──────── 25 ℃ 40 ℃ 25 ℃ 40 ℃ 25 ℃ 40 ℃ ────────────── ────────────────────── Example 2 95 69 105 57 57 110 40 Example 3 103 102 102 103 88 88 106 93 ────────── ────────────────────────── (Unit:%)

As is clear from the results in Table 3, the formulation prepared by filling the PEG-containing hard capsules with the drug solution of Example 3 containing the antioxidant had a very good R106-I dissolution even after long-term storage. Is.

[0039]

EFFECTS OF THE INVENTION As shown in the above examples and test examples, the high-concentration solution formulation of R106-I of the present invention is a formulation of a size that can be clinically easily administered and has high oral absorbability. The blood concentration was sufficient to exhibit pharmacological actions such as antifungal activity even at low doses. Further, by filling the high-concentration solution preparation of the present invention into a PEG-containing hard capsule, cracking of the capsule does not occur even during long-term storage,
Further, by adding an antioxidant, the drug can be dissolved well and can be made into a physically stable formulation, which is useful for the treatment of fungal diseases and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area A61K 47/12 G 47/34 G 47/42 A

Claims (10)

[Claims] 1. Aureobasidins, polyoxyethylene castor oil-based activator and ethanol are contained as essential components, and aureobasidins are contained in an amount of 10 w / w based on the whole preparation.
% High-concentration solution formulation of aureobasidins. 2. Aureobasidins are contained in an amount of 65 parts by weight or more of polyoxyethylene castor oil-based active agent and 30 parts by weight or more of ethanol with respect to 100 parts by weight of aureobasidins, and aureobasidin A is contained in an amount of 20 to 20 parts by weight based on the whole preparation. The high-concentration solution preparation according to claim 1, containing 40 w / w%. 3. An unsaturated higher fatty acid is further contained.
Or the formulation of 2. 4. The average addition mole number of ethylene oxide in the polyoxyethylene castor oil-based activator is 30 to 70.
And the HLB value is in the range of 8-17. 5. Aureobasidins of 20 to 40 w / w%, polyoxyethylene castor oil-based activator of 20 to 50 w / w%, and ethanol of 7 to 40 w / w based on the whole preparation.
w% and unsaturated higher fatty acid having 18 to 20 carbon atoms to 10
The high-concentration solution preparation according to claim 2 or 3, which has a concentration of about 60 w / w%. 6. The high-concentration solution preparation according to claim 3, wherein the unsaturated higher fatty acid is oleic acid. 7. A gelatin hard capsule preparation filled with the preparation according to 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 shell. 9. A hard gelatin capsule preparation according to claim 8, further comprising an antioxidant added to the high-concentration solution preparation according to any one of claims 1 to 6. 10. A solution containing aureobasidins, 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 as essential components. , Their proportion to the total solution is 20-40 w / w% aureobasidin Polyoxyethylene castor oil-based activator (average addition mole number of ethylene oxide 30-70) 20-50 w / w% ethanol 7-40 w / w% Oleic acid 15 to 50 w / w% Fat-soluble antioxidant 0.1 to 5 w / w% Solution filled with polyethylene glycol-containing gelatin hard capsules