JPS5859911A - Azaphospholine composition for rectal infusion - Google Patents

Abstract

PURPOSE:To prepare the titled composition which can be administered by rectal infusion, by adding a specific amount of an azaphospholine compound useful as an anti-malignant tumor agent, to a specific substrate composed of a saturated fatty acid glyceride and polyoxyethylene sorbitan monostearate. CONSTITUTION:The titled composition is prepared by compounding (A) 85-125 pts.wt.,especially 106.9pts.wt. of an azaphospholine compound, e.g. cyclophosphamide, etc., (B) 1280-1340 pts. wt., especially 1318.1pts.wt of a saturated fatty acid glyceride, preferable a mixture of mono-triglyceride of satruated fatty acid, and (C) 50-100pts.wt., especially 75.0pts.wt. of a polyoxyethylene sorbitan monostearate. The composition can be administered by rectal infusion without causing irritation and damage, and exhibits comparable absorptivity to intravenous injection.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to azaphosphorin compositions for rectal administration.

Azophosphorins, such as cyclophos-7amide, are known as excellent antineoplastic agents; they do not themselves exhibit antineoplastic effects, but their nine metabolites (true mustard-like substances) have the ability to alkylate in vivo. It is thought that the effect is shown by changing to .

Traditionally, azophosphorines have been administered orally or by intravenous injection, but not rectally. In general, rectal administration has the advantage that it has less influence on metabolic reactions in the liver than oral administration, and is easier to apply than intravenous administration, so rectal administration has been desired for azophosphorines as well. However, azophosphorin compositions for intrarectal administration using conventional bases are irritating and cause damage to the intestinal viscosity when administered intrarectally, and/or do not have sufficient absorption rates. Until now, there has been no known case of successful intrarectal administration of azophosphorines due to the unavailability of these drugs.

It is therefore an object of the present invention to provide azophosphorin compositions suitable for rectal administration.

As a result of intensive research, the present inventor, Hirohiro, found that a preparation containing adephosphorin in a specific base composition does not cause any irritation or damage to the application site when administered intravenously, and surprisingly, it can be administered intravenously. The present invention was completed based on the knowledge that the absorption rate is approximately the same as that of injection.

The present invention contains 85 to 125 parts (by weight, the same applies hereinafter) of azophospho') 7'lA, 1280 parts of saturated fatty acid glyceride
This is an Azophos hepta-olin composition for rectal administration consisting of ~1340 parts and 50-100 parts of I dioxyethylene sorbitan monostearate.

Although many compositions are generally known as preparations for rectal administration, compositions other than those of the present invention have disadvantages such as poor absorption of azophos-7-olins or damage to the mucous membrane at the absorption site.

Examples of azophosphorins used in the present invention include Cyclophosphamide*
), ifosf7 i 1' (rfosfimld*
), totiphosfamide (Trofosfamides)
) and sufosfamide (Sufo-sfamld.)
can be mentioned.

As a saturated fatty acid glyceride, the number of carbon atoms is 11 to 1
Mono-, di- and triglyceride mixtures of 7 saturated fatty acids, especially Uite, fsol H-15 (Dynamite
Norpel Chemical Company products) are preferred.

As an example of polyoxyethylene sorbitan monostearate, Tween 60 and 61 (Atlas Co., Ltd., product), especially Tween 61, are suitable.

In the composition of the present invention, the blending ratio of each component is also critical, and the intended purpose cannot be achieved unless the blending ratio is within the above-mentioned range. The most desirable blending ratio is 106.9 parts of azaphosphorin to 131 parts of saturated aliphatic glyceride.
8.1 parts and 75.0 parts of polyoxyethylene sorbitan monostearate.

The composition of the present invention is a white solid preparation, and when administered to the human body, it is formulated into a suppository by a conventional method.For example, a predetermined amount of saturated fatty acid glyceride and Weigh it and place it on a water bath at about 60℃.
Dissolve and mix to make a uniform suspension, add azophosphorin to this, dissolve while stirring, and place in a suppository molding machine.
Use as a suppository.

According to the composition of the present invention, an azophosphorin preparation for rectal administration of excellent quality can be obtained, and the absorption of azophos-7-olins is also extremely good. That is, when the cyclofusufamide sea bream formulation according to the present invention and the intrarectal administration formulation other than the present invention are respectively administered to animals, the formulation according to the present invention has about 1.6 times more cyclofusphamide than other suppository formulations. The blood production area of metabolites of phosphamide is also approximately 6
．． 1 times more blood # than administration by injection, 1.3 times more
Therefore, when a preparation consisting of the composition of the present invention is administered to a patient, it is expected to exhibit approximately the same medicinal effect as an injection.

Next, the tube of the present invention will be explained in more detail with reference to Examples and Test Examples.

Example Wite, Desol H-15 (1318, 1 part) and Tween 61 (75,0 parts) were accurately weighed and heated at about 60°C on a water bath.
The mixture was heated to , and dissolved and mixed to form a uniform suspension.

Cyclophosphamide (106,99) was added to this suspension and dissolved with stirring, and the mixture was put into a suppository molder to form a suppository.

Test Example 1 A cyclophos-7amide preparation was administered rectally and orally to rabbits, and the amount of cyclophosphamide in whole blood was determined. ! The time course of the blood concentration of the product was measured, and the difference in cyclophosphate absorption depending on the route of administration was investigated. It was administered rectally to rabbits so that Five male rabbits (average weight of about 2 yu), Japanese and American, were used. Blood was collected from the ear vein before administration of the suppository and after a predetermined period of time had elapsed after administration, and the concentration of cyclophosphamide 11 degrees in the whole blood was measured. The determination was carried out by quantifying the true mustard-like substance in total nll according to the method described in Shionoi Research Institute Annual Report, Vol. 17, pp. 114-121, 1967.

As a control, commercially available endoxan tablets for oral administration (registered trademark, Illi, manufactured by Shionogi & Co., Ltd., containing 50 Da of cyclophosphaty per tablet, hereinafter referred to as control product) were used. ] Two tablets were orally administered to rabbits (average body weight of 2 kg), and the concentration of cyclophosphamide metabolites in whole blood was measured in the same manner as above. The results are shown graphically in FIG.

In 1a>r, the vertical axis represents cyclophostuamide metabolite I11 degrees in whole blood, and the unit is μ haze. The horizontal axis represents the elapsed time after administration of cyclophosphamide; the solid line in the graph is for the case when the suppository of the present invention was administered rectally, and the broken line is for the case when the control product was administered; each is the average value of 5 birds. It shows. Based on this graph, the value of the lower surface of the whole blood concentration time curve AUG''' is calculated using the trapezoidal formula:
When administering the product of the present invention, it was 86.96 μf/vd・br.
So, in the case of the control product, it is 14.30μ? /-・hr.

The product of the present invention exhibited approximately 6.1 times the area under the blood concentration of cyclophosphamide *heavy substance compared to the commercially available control product. father,
As a feature of the product of the present invention, the time to reach the maximum blood concentration is approximately 1.5 hours earlier than that of the control product, indicating that clinical effects can be expected to occur earlier.

Test Example 2 Cyclophosphamide was administered rectally and intravenously to rabbits, and the time course of the blood concentration of cyclophosphamide metabolites in whole blood was measured to determine the effect of cyclophosphamide absorption depending on the administration route. I looked into the differences.

(Test method) The present invention suppository obtained in Example 1 in the same manner as Test Example 1 was tested as cyclophosphant (in terms of anhydride) at 50III.
Cyclophosphamide was administered rectally to rabbits at a concentration of 9 y/y, and the concentration of cyclophosphamide metabolites in whole blood was measured before and after administration.

As a control, commercially available endoxan for injection (registered trademark, manufactured by Shiono Yoshiyaku Co., Ltd., dicyclophosphide per 1 vial) was used as a control.
anhydrous equivalent) looM9 and sodium chloride 45mg
contained, hereinafter referred to as the control product. 1 vial was administered intravenously to rabbits (average body weight: 2 kg), and the concentration of cyclophosphamide metabolites in whole blood was measured. The results are shown graphically in Figure 2.

In FIG. 2, the vertical and horizontal axes have the same meanings as in FIG. 1, and the solid line represents the case in which the suppository of the present invention was administered rectally.]
The broken lines indicate the case where a commercially available injection endoxan, which is a control product, was administered intravenously, and each is shown as the average value of 5 birds. Based on this graph, the area under the whole blood concentration time curve A
When the value of ucO = 4 is calculated using the trapezoidal formula, when the product of the present invention is administered, t11B is 6.96 μC-hr, and when the control product is administered, it is 68.35 μC-hr. The amount of metabolites of cyclophosphamide in blood was approximately 1.3 times that of the commercially available product.

Test Example 3゜The suppositories of the present invention obtained in Example in the same manner as Test Example 1 were used as cyclophosphamide (in terms of anhydride) at 5011v/
cyclophos-7amide metabolite #Ift in whole blood before and after administration.
It was measured.

As a control, a suppository having the following composition (hereinafter referred to as the control product) was administered rectally to rabbits in the same manner as above, and the concentration of cyclophosphamide metabolites in whole blood was measured. We investigated the differences in the absorption of

Control product composition: Cyclophosphamide 106.9
~Medium chain fatty acid triglycerides 100.
0■1500.0111p The results are shown graphically in FIG.

In Fig. 3, the vertical and horizontal axes have the same meanings as in Fig. 1, and the solid line represents the cyclophosphamide metabolite when the suppository of the present invention is administered rectally, and the dashed line represents the control product when administered rectally. The absorption curve (average value of 5 birds) is shown. Based on this graph, when the value of the area under the whole blood concentration time curve AUCO = 6 is calculated using the trapezoidal formula, it is 86.96 fit/ld when the product of the present invention is administered.
・hr, and in the case of the control product it is 55.65μ -・h
The product of the present invention exhibited a blood concentration of cyclophosphite metabolites approximately 1.6 times lower than that of the control product.

Test Example 4 In order to determine the irritation of the composition of the present invention to local mucous membranes, the composition 0.1) obtained in Example was administered to the eyelids of normal rabbits, and the cornea, conjunctiva, and iris were examined over time. The tissue was observed and the degree of irritation was measured.

For comparison, an aqueous suspension of cyclophosphane Z containing cyclophosphane p in an amount corresponding to the above composition was prepared and used as a control.

The rabbits used were 3 male Japanese white male rabbits per group, and the Drais* method [Pharmacy @ Vol. 20, No. 2] was used.

329-342Tm, 1969] was used. The results show only the irritation to the conjunctiva, as there is no effect on the cornea or iris.Table 1
Shown below.

Table 1 From Table 1 it is clear that the compositions of the invention, like the aqueous suspensions, have very low irritation to the local mucous membranes.

[Brief explanation of the drawing]

Figure 1, #! Figures 2 and 3 show absorption curves of cyclophosphant metabolites, respectively.

Claims (1)

[Scope of Claims] 1. Azophos 7 oligomer for rectal administration, consisting of 85 to 125 parts (by weight, the same applies hereinafter) of azophosphorins, 1280 to 1340 parts of saturated fatty acid glyceride, and 50 to 100 parts of polyoxyethylene sorbitan monostearate. y
type composition. The azophosphorin composition for rectal administration according to claim 1, which comprises 106.9 parts of λ azophosphorin, 1318.1 parts of saturated fatty acid glyceride, and 75.0i1 of I-lyoxyethylene sorbitan monostearate.