JPH07316065A - Pharmaceutical preparation of fr 901469 substance - Google Patents

Abstract

PURPOSE:To obtain the subject pharmaceutical preparation improved in hindrance to organisms such as hemolysis or local irritation by preparing a clathrate compound with cyclodextrins. CONSTITUTION:This pharmaceutical preparation for injection, drops, inhalant and/or nasal drops contains a clathrate compound of FR901469 substance of the formula with cyclodextrins (preferably 2-hydroxypropyl-beta-cyclodextrin). Furthermore, cyclodextrins are preferably included in an amount of 0.5-20 times based on the content of FR901469 substance.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cyclodextrin-containing preparation, more particularly to a preparation containing FR901469 substance and cyclodextrin, and is used in the medical field.

[0002]

Cyclodextrins are known to enhance the solubility of poorly water-soluble drugs by forming a so-called clathrate compound in which drug molecules are clathrated therein.

As an example, it has been reported that cinnarizine, which is a poorly water-soluble cerebral vasodilator, forms an inclusion compound with β-cyclodextrin to increase its solubility in water at 20 ° C. by about 5 times. (Chemical & Pharmaceutical Bulletin, Vol. 32, No. 10, 4179-4184 (1984)).

[0004]

The FR901469 substance has a chemical formula of C ₇₁ H ₁₁₆ N ₁₄ O ₂₃ .HCl (molecular weight 157
0.24), which is a cyclic peptide compound,
Its chemical structural formula is shown in Chemical Formula 1 below.

[0005]

[Chemical 1]

Since this FR901469 substance has a large molecular weight, it is difficult to be absorbed through the digestive tract by oral administration. Therefore, parenteral administration methods such as injections and drip can be considered, but the FR901469 substance aqueous solution has a problem that it cannot be injected intravenously because it shows biological damage such as hemolysis and local irritation.

[0007]

Means for Solving the Problems The present invention has been made to solve the above-mentioned drawbacks, and as a result of studies from various aspects, as a result of focusing on the chemical structure of FR901469 substance, inclusion with cyclodextrins It was from the viewpoint that this problem could be solved by making a compound.

Therefore, for various cyclodextrins, inclusion compounds with FR901469 substance were prepared,
As a result of a comparative examination of biotoxicity such as hemolysis and local irritation, it was confirmed that cyclodextrins have the expected effects, but 2-hydroxypropyl-
β-Cyclodextrin (2-Hydroxypropyl-β-cyclode
xtrin, hereinafter sometimes referred to as 2HP-β-CD) was found to have a remarkable effect.

The present invention has been completed as a result of further research based on the above new findings, and has as a basic technical idea a preparation of FR901469 substance containing FR901469 substance and cyclodextrins.

As the preparation of the present invention, parenteral preparations are preferable, and injections, infusions, insufflations (for example, aerosols, powdered inhalants, liquid inhalants, etc.), suppositories, external preparations ( Ointments, creams, liquids, etc.), eye drops, nasal drops and the like.

Examples of the cyclodextrins used in the present invention include α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, γ-cyclodextrin and dimethyl-β-cyclodextrin. As the cyclodextrin, all types other than those described above can be used, but 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD) and α-cyclodextrin are particularly preferable.

Next, a method for producing the preparation of the present invention, especially the preparation for parenteral administration, will be described.

To prepare an aqueous preparation such as an injection, an infusion, an insufflation (for example, an aerosol, a powdered inhaler, a liquid inhaler, etc.), an eye drop and a nasal drop, purified water or distilled water for injection is used. FR901469 substance is added to water, cyclodextrins are added thereto, and the mixture is stirred to dissolve FR901469 substance.

If desired, these preparations include isotonicity agents (eg sodium chloride), pH adjusters (eg hydrochloric acid, sodium hydroxide etc.), buffers (eg boric acid, etc.).
Conventional additives such as sodium monohydrogen phosphate, sodium dihydrogen phosphate and the like, preservatives (such as benzalkonium chloride) and thickeners (such as carboxyvinyl polymer) may be added.

For external preparations such as suppositories, ointments and creams, FR901469 substance and cyclodextrins are added to a heated and melted base (eg white petrolatum, liquid paraffin), and if desired, a preservative and an oxidizer are added. It is manufactured by adding commonly used additives such as an inhibitor, a stabilizer, a moisturizer, and a pH adjuster.

The content of cyclodextrins in the parenteral preparation of the present invention is not particularly limited, but if it is 0.5 to 20 times the content of the FR901469 substance contained in the preparation, a sufficient solubilizing effect is obtained. Is demonstrated.

[0017]

The effects of the present invention will be described with reference to the following test examples.

[0018]

[Test Example 1: Hemolytic test] The hemolytic test was performed according to the Akaishi method. That is, test liquid (FR901469 substance 1 m
g / ml aqueous solution (pH 5.2, osmotic pressure ratio 1.0), 2H
P-β-CD (5-fold molar addition) was placed in a 10 ml Spitz tube and preheated at 37 ° C for 2 minutes to prepare rabbit blood (New
(New Zealand White rabbit blood) added and mixed,
Warm at 37 ° C. for 30 minutes. Then 1 at 3000 rpm
Centrifugation was carried out for 0 minutes, and the presence or absence of hemolysis in the supernatant and the degree thereof were visually observed.

The obtained results are shown in Table 1 below together with the results of the local irritation test described below. As a control, the test was conducted using a physiological saline solution of FR901469 substance as a test solution. As is clear from these results, hemolysis occurred in the control, but hemolysis was not observed in the case of the formulation using cyclodextrin.

[0020]

[Table 1]

[0021]

[Test Example 2: Local irritation test] Test liquid (FR901469
Substance 1 mg / ml aqueous solution (pH 5.2, osmotic pressure ratio 1.
0), 2HP-β-CD 5 times molar addition) to rabbit (New
It was administered to the vastus lateralis muscle of a New Zealand White male rabbit) (1 ml of the test solution was administered for about 10 seconds), the degree of muscle damage was observed, and the local damage of the test substance was investigated. Observation was performed 2 days after the administration to determine the grade.

The judgment was made according to the following grades I to IV. Grade I: Local injury is equivalent to or weaker than that of physiological saline in the judgment 2 days after administration. Grade II: 0.425 as judged 2 days after administration
Its local toxicity is weaker than that of% acetic acid, but its local toxicity is stronger than that of physiological saline. Grade III: 1.7% as judged 2 days after administration
Its local damage is weaker than that of acetic acid, but its local damage is equal to or stronger than that of 0.425% acetic acid. Grade IV: The local toxicity is equivalent to or stronger than that of 1.7% acetic acid as judged 2 days after administration.

The results obtained are as shown in the above table. As a control, FR901469 as a test solution
The test was carried out using a saline solution of the substance. As is evident from these results, in the control, grade II
It was judged to be I (injection is not possible for grades III and above), and it cannot be used as an injection, but when using cyclodextrins, it was confirmed that it was grade I and could be used as an injection.

[0024]

EXAMPLES The present invention will be described below with reference to examples.

[0025]

Example 1 FR901469 substance (MW: 1570.
24) 1.5 g, 2HP-β-CD (MW: 1406.
6 (calculated value), degree of substitution: 4.7) 22.3 g, and Na
4.5 g of Cl was weighed and mixed and dissolved in water for injection. To the resulting solution was added 1N-HCl and p
After adjusting H (pH 4.0), use water for injection to 500
The total amount was adjusted to mL. These are subjected to aseptic filtration, filled in a sealed container and sealed, and an injection (2HP-β having the following formulation is prepared.
-2H of FR901469 substance to which CD was added 5 times by mole
P-β-CD formulation) was obtained.

FR901469 substance 10 mg 2HP-β-CD 45 mg NaCl 9 mg 1N-HCl q. s. (PH 4) Water for injection to 1 ml

[0027]

[Example 2] FR901469 substance as an aqueous phase component,
2HP-β-CD, propylene glycol and methyl paraoxybenzoate are added to purified water and heated to 70 ° C to dissolve. On the other hand, as an oil phase component, stearyl alcohol, polyoxyethylene hydrogenated castor oil, glyceryl monostearate and propyl paraoxybenzoate are added to white petrolatum and dissolved by heating at 70 ° C.

The above water phase component and oil phase component are heated (7
At 0 ° C.), mix and stir to obtain 100 g of cream with the following formulation.

FR901469 substance 0.2 g 2HP-β-CD 3 g white petrolatum 25 g stearyl alcohol 20 g propylene glycol 12 g polyoxyethylene hydrogenated castor oil 4 g glyceryl monostearate 1 g methyl paraoxybenzoate 0.1 g propyl paraoxybenzoate 0.1 g purification Water

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Claims (3)

[Claims] 1. A FR901469 substance preparation containing a FR901469 substance and cyclodextrins. 2. The preparation according to claim 1, wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. 3. The preparation according to claim 1 or 2, wherein the preparation is an injection, drip, inhalation, eye drop and / or nasal drop.