JPS59163315A - Carmofur-containing liposome - Google Patents

Abstract

PURPOSE:The titled preparation that is obtained by forming carmofur into liposome, thus being used as an anticancer agent with increased solubility and reduced side-effects. CONSTITUTION:The objective preparation is a liposome containing carmofur: 1- hexylcarbamoyl-5-fluorouracil. Carmofur has been widely used as an antitumor agent against pyrimidine metabolism-antagonizing malignant tumors and applied to gastric cancer, coli cancer and mammary cancer, however, it is very hardly soluble and relatively easily hydrolyzed under physiological conditions. The formation of liposome with carmofur increases the solubility of the compound in water more than 100 times, inhibits the hydrolysis even in 9.1pH, thus it can be prepared in an injection solution. The liposome is formed by the thin-film or solution-casting method and a phospholipid such as phosphatidylcholine is used as a medium.

Description

[Detailed description of the invention] Regarding the ribbon room.

Carmofur, ie 1-hexylcarba, is widely used in the treatment of colon cancer and breast cancer.

Carmofur is a fat-soluble substance that can be used in chloroform, acetone,
Easily soluble in glacial acetic acid, slightly soluble in benzene, methanol, and anhydrous ethanol. It hardly dissolves in water, and its solubility is less than 001. In addition, it is relatively stable in aqueous solutions with a pl of 44 or less, but is unstable in neutral to weak alkaline conditions and becomes susceptible to hydrolysis depending on the pH, and its half-life (t y2) is approximately 85 at pH 7. min, p11
At pH 8, it takes about 54 minutes, and at pH 12, it takes about 20 minutes.

As mentioned above, as a result of various studies on carmofur, which has the disadvantages of formulations such as extremely poor solubility in water and relatively easy hydrolysis under physiological conditions, we have found that by incorporating carmofur into liposomes, the above-mentioned properties can be improved. The present inventors have discovered that it is possible to improve this, and have completed the present invention.

Liposomal drugs are economical and safe because they exhibit efficacy even in much smaller amounts than drugs alone. This is particularly useful when applied to anti-malignant III tumor drugs that have strong side effects. It is not absorbed from the gastrointestinal tract, making it an excellent choice for intravenous, intramuscular, or intraperitoneal injections, and its blood concentration persists, making it suitable for fluorouracil drugs whose effects are time-dependent. ing.

Directivity to various organs can be adjusted by adjusting the amount used in liposome formation and the size of the liposomes, thereby allowing high concentration distribution to desired specific areas, such as the lungs, liver, tq% organs, kidneys, etc. becomes possible.

By making carmofur into liposomes like Jin, it is possible to compensate for its drawbacks and increase its usefulness.

The liposome formation can be carried out by the known thin film method, solution injection method, surfactant treatment method, etc.

Phospholipids such as phosphatidylcholine,
One type or a mixture of two or more of phosphatidylserine, phosphatidylethanolamine, lysolecithin, terhasphingomyelin, etc. can be used, and dicetylphosphaerine, cholesterol, etc. can also be added for extreme stabilization.

The weight ratio of phospholipids, such as egg yolk phosphatidylcholine and carmofur during production, is 1 part egg yolk phosphatidylcholine to 1 part carmofur, preferably 03 to 07, preferably 04 to 06.
is good.

The solubility of liposomes containing carmofur in water is improved by more than 100 times, and the hydrolysis angle is also pl+.
We succeeded in suppressing this at an alkaline level of 9.1.

As described above, the carmofur-containing liposome of the present invention is expected to be applied to injection preparations due to its improved water solubility and chemical stability.

The present invention will be explained in detail by examples.

Example: Making liposomes using the thin-film method using lumofur In an eggplant-shaped flask, the amounts of purified egg yolk phosphatylcholine, cholesterol phosphatylcholine, and yolkmofur shown in Table 1 were dissolved in 4 ml of chloroform, and then the solvent was removed using an evaporator. forming a thin film,
Furthermore, after adding 4 ml of physiological saline and peeling off the thin film, ultrasonic irradiation (25 watts) was performed for 1 hour to obtain a milky white liquid containing the target product. The entire amount of carmofur may be allowed to coexist from the beginning as in Example 2, or the same result can be obtained by gradually adding a portion of carmofur in the form of crystals during ultrasonic irradiation.

The resulting liquid containing the target product can be further concentrated by ultrafiltration, or alternatively, can be made into a powder by freeze-drying.

When the obtained liposomes were observed under an electron microscope, -
Multilamellar liposomes are seen, with a diameter of approximately 100
nm to 120 tlln.

The solubilization rate of liposomal carmofur is 033-0
72%, an improvement approximately 120 times that of carmofur alone.

Table 1 Composition of liposomes 127], 5], 4.32
60 3.0 28.83 2
4 3.4 13.3 The stability of this product will be further explained in detail using test examples.

Test Example: Stability of carmofur in aqueous solution by liposome formation. We developed a new measurement method of measuring the fluorescence intensity at 480 n+n for the reaction product of Flura+R, and investigated its stability in an aqueous solution. In other words, for carmofur monoworms,
Carmofur is saturated in a Phylnoton-Rohinson buffer solution of pH 1.7, and the solution 2. sme was diluted 2 times with the same buffer, and further diluted with 0.2 N NaOH3, 5 ml.
1! Add and set it as pl-49,'l. After that, 1 over time
Me samples were taken, and the fluorescence intensity was determined at 25°C.

For the liposome-forming power Lumofur, add 300 μl of Liboome solution (20 μg, 4×10 mol) and Flurum 20
μ stone (5XlO mol) f: Added L, then 1 over time
Me samples were taken and the fluorescence intensity was measured. however,
For liposomes, the region became 150
Triton X -100' (T
riton

The results are shown in Table 2.

Claims (1)

[Claims] Liposomes containing carmofur