KR810000695B1 - Process for preparing flurocarbon emulsions capable of carrying oxygen - Google Patents

Abstract

to 50:50 mixt. of 1>= of perfluorodecalin, perfluoromethyldecalin, a perfluoroalkane, or a perfluorinated C3-5 alkylcyclohexane, C5-7 alkyltetrahydrofuran or C4-6 alkyltetrahydropyran, and >=1 perfluorinated C9-11 tetraalkylamine, C4-6 N-alkylpiperidine or C5-7 N-alkylmorpholine and a nonionic wetting agent. Emulsions which are stable in the blood stream and are useful as blood substitutes and perfusion liqs. comprise 0.05-0.3 particles of C9-11 perfluorocarbon compds., phospholipid emulsifiers, and C8-22 fatty acids or their salts or monoglycerides in an aq. medium.

Description

Method for preparing oxygen transportable fluorocarbon emulsion

The present invention relates to a method for the preparation of an emulsion of an oxygen transportable fluorocarbon compound for injection and perfusion that is used in the orifice of a patient suffering from massive bleeding and for implantation of internal organs in implantation.

It has been reported by several researchers that emulsions of fluorocarbon compounds can already be used as artificial blood substitutes for mammals and preservative perfusates of internal organs to be transplanted, especially as injection substitutes that can carry oxygen It has been. [Mr. Laland. Leland C. Clark, Jr., F. Becattini and S. kaplan: The physiology of synthetic blood, Thoracic Cardiovascular Surgery of Thoracic Cardiovascular Surgery), 60, 757-773 (1970); RP Geyer, Fluorocarbon-polyol artificial blood substitutes., New England Journal of Medicine, 289, 1077-1082 (1973). ].

However, these emulsions are not practically satisfactory in terms of their pharmacological stability and in vivo safety. In order to practically use an emulsion of a fluorocarbon compound as an artificial blood substitute, it is necessary to develop a preparation that can be sufficiently stable for a long period of time without changing the particle size.

In emulsions of fluorocarbon compounds, particle size plays an important role in the toxicity and efficacy of the emulsion [Ke Yokoyama, K Yamanouchi, M. Wada-nabe, Armurashima, Tatsumodo, T. Hamano, H. Okaka Modo, Ti Suyama, Ar wadanabe and Ar Naito, Preparation of Perfluorodecalin Emulsion, Approach to the Red Cell Substitutes, Federation proceedings , 34, 1478-1483 (May 1975). Larger particle emulsions increase toxicity and shorten the retention time of particles in the bloodstream. Thus, when an emulsion of a fluorocarbon compound is intended to be used as an artificial blood substitute to save the life of a patient suffering from massive bleeding, its average particle size is 0.3 μ or less in diameter, preferably 0.2 μ or less It should be below (Japanese Patent Application Publication No. 22212/73).

In addition to the particle size, the emulsion of the fluorocarbon compound should be excreted from the body as quickly as possible after removal from the blood stream for use as an artificial blood substitute, after intravenous administration. Some of the present inventors have studied the excretion and toxicity of several kinds of fluorocarbon compound emulsions, and found that perfluorocarbon compounds having 9 to 11 carbon atoms are useful as artificial blood substitutes. Among them, perfluorodecalin was found to be particularly favorable [K. Yokoyama, K. Yamanouchi, and Armurashima: excretion of perfluorochemicals after intravenous administration of emulsion, pharmacologic paper, 23, 1368 1373 (June 1975).

In addition, some of the present inventors have treated the aforementioned fluorocarbon compounds with egg yolk phospholipids or soy phospholipids and small amounts of fatty acids or salts thereof having 8 to 22 carbon atoms or mixtures thereof with monoglycerides It has also been found that emulsions of fine and stable fluorocarbon compounds can be prepared from fluorocarbon compounds having 9 to 11 carbon atoms.

However, compared with the perfluorotributylamine emulsion after stabilization with a high molecular weight polyoxyethylene-polyoxypropylene copolymer emulsifier (Rp Geyer. Loc. Although excellent in excretion, poor stability in circulating blood flow after intravenous infusion, and half-life was about 2/3 of the former.

In addition, emulsions of fluorocarbon compounds prepared with high molecular weight nonionic surfactants, such as perfluorotributylamine emulsions, may be used in some proportion with commercial plasma extenders such as dextran, hydroxyethyl starch, or adjusted gelatin solutions. The perfluorodecalin emulsion described in Japanese Patent Application Laid-Open No. 69,219 / 75 cannot be used in admixture with an earlier plasma extender because it forms a precipitate upon mixing with the latter. . This precipitation is likely due to the breakdown of emulsified particles caused by the interaction between high concentrations of phospholipids in the emulsion and plasma extenders such as high molecular weight colloidal materials, dextran or hydroxyethyl starch.

In the case of massive bleeding, when an emulsion of a fluorocarbon compound is used as an injection or artificial blood substitute to save the patient's life, it is mixed with a plasma extender and isostatic, i.e., both colloidal solutions, ie It is important that the emulsion and the colloidal penetration pressure of the blood are the same so that the fluorocarbon compound emulsion provides oxygen, while the plasma extender maintains the circulating blood volume at an appropriate level. Therefore, in the preparation of the fluorocarbon emulsion emulsion to be used as artificial blood, it is preferable to use a plasma extender and an inert high molecular weight nonionic surfactant. Although these high molecular weight nonionic surfactants are effective for fluorocarbon compounds such as perfluorotributylamine and other amine type fluorocarbons as emulsifiers, they are 9 to 9, such as perfluorodecalin having high excretion rate. It is not suitable for the fluorocarbon compound having 11 carbon atoms.

In view of such circumstances, the present inventors have conducted extensive studies on the preparation of emulsions of these fluorocarbons having 9 to 11 carbon atoms represented by perfluorodecalin having high excretion rate. The present invention has been completed and found that it is stable in the air and can be mixed with a plasma extender without destroying emulsified particles.

According to the present invention there is provided a stable emulsion in a physiologically acceptable aqueous medium of an oxygen transportable perfluorocarbonate compound having a particle size of about 0.05 to 0.3 mu or a physiologically acceptable salt or monoglycelide thereof. This is (A) perfluorodecalin, perfluoromethyldecalin, perfluoroalcyclohexane in which the alkyl component has 3 to 5 carbon atoms, perfluoroalkyltetrahydrofuran in which the alkyl component has 5 to 7 carbon atoms, alkyl At least one perfluorocarbon compound having 9 to 11 carbon atoms selected from the group consisting of perfluoroalkane having 9 to 11 carbon atoms, wherein the component is perfluoroalkyltetrahydropyri having 4 to 6 carbon atoms; (B) Perfluoro tertiary-alkylamines having 9 to 11 carbon atoms, perfluoro having 4 to 6 carbon atoms in the alkyl component N- alkyl piperidin dinryu, and the alkyl component is from the group which is a N- alkyl morpholine flow perfluoroalkyl having from 5 to 7 carbon atoms, perfluoroalkyl of at least one having from 9 to 11 carbon atoms selected tertiary amine; High molecular weight nonionic surfactants having a molecular weight of about 2,000 to 20,000; Phospholipids; And at least one fatty acid compound having 8 to 22 carbon atoms; The ratio of the former perfluorocarbon compound and the perfluoro-tert-amine is 95 to 50 to 5 to 50 parts by weight.

High molecular weight nonionic surfactants to be mentioned later have a molecular weight of 2,000 to 20,000, and examples thereof include polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, and the like. I can lift it. The concentration of the electrical surfactant in the emulsion is about 2.0 to about 5.0, preferably 3.0 to 3.5 weight (W / V).

The symbol ＂% (W / V)＂ referred to in the present specification and claims means the amount of substance by weight (grams) based on 100 ml of the resulting emulsion.

Examples of perfluorocarbons (A) having 9 to 11 carbon atoms are perfluorocycloalkanes or perfluoroalkylcycloalkanes (eg, perfluoromethylpropylcyclohexane, perfluorobutylcyclohexane, perfluoro C _3-5 -alkylcyclohexanes such as trimethylcyclohexane, perfluoroethylpropylcyclohexane, perfluorodecalin and perfluoromethyldecalin; perfluoroC _4-6 -such as perfluorohexyltetrahydropyran- Alkyltetrahydropyrans; perfluoro C _5-7 -alkyltetrahydrofuran such as perfluoropentyltetrahydrofuran, perfluorohexyltetrahydrofuran and perfluoroheptyltetrahydrofuran; perfluorononane and perfluor Perfluoroalkanes having 9-11 carbon atoms such as rodecan).

Examples of the perfluoro tertiary-amine (B) having 9-11 carbon atoms include perfluoro tertiary-alkylamine having 9-11 carbon atoms, for example, perfluoro N, N-dibutyl mono Perfluorotrialkyl such as methylamine, perfluoro N, N-diethylpentylamine, perfluoro N, N-diethylhexylamine, perfluoro N, N-dipropylbutylamine and perfluorotripropylamine Amines; Perfluoro N, N-dialkylcyclohexylamine having 0-11 carbon atoms such as perfluoro N, N-diethylcyclohexylamine; Perfluoro NC _4-6 -alkylpiperidine such as perfluoro N-pentylpiperidine, perfluoro N-hexylpiperidine and perfluoro N-butylpiperidine; Perfluoro NC _5-7 -alkylmorpholines such as perperfluoro N-pentylmorpholine, perfluoro N-hexylmorpholine and perfluoro N-heptylmorpholine.

The weight ratio of perfluorocarbon compound (A) to perfluoro tert-amine (B) to be used is 50-95 to 50-5, and the total amount of (A) and (B) contained in the emulsion is About 10 to 50% (W / V).

Phospholipids used as emulsifier adjuvant in the present invention are those that are commonly used in this technical system, and those containing egg yolk phospholipid or soybean phospholipid are preferable. The content in the emulsion is 0.1 to about 1.0% (W / V), preferably about 0.4 to about 0.6% (W / V).

Fatty acid compounds used as tanning aids include physiologically acceptable salts such as fatty acids having 8-22 carbon atoms, sodium or potassium salts or monoglycerides thereof, for example caprylic acid, capric acid, Lactic acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, arachidonic acid and its sodium or potassium salts and monoglycerides. These fatty acid compounds may be used alone or in mixtures of two or more in very small amounts of 0.004-0.1% (W / V), preferably about 0.02-0.04% (W / V). Suitable among these fatty acid compounds are compounds having 14-20 carbon atoms and their physiologically acceptable salts, most preferred are potassium palmitate and potassium oleate in view of their good solubility and ease of preparing emulsions.

The emulsion of the fluorocarbon compound of the present invention is a physiologically acceptable aqueous medium such as distilled water, or uniformly mixed with the foregoing amounts of the aforementioned components in an isotonic solution to make a coarse emulsion, which is then about 100 to 500 kg. It is injected at a temperature of up to 55 ° C. through a slit under a pressure of / cm 2 to emulsify the coarse emulsion to impart shear force and mixing action on the basis of strong velocity gradient until the desired particle size is obtained.

Uniform mixing of the materials to be used is carried out using conventional mixers such as homo blenders or propeller stirrers.

The coarse emulsion is obtained by a high pressure hmogenizer, which has a high pressure pump, which is injected through the slit under high pressure at a very high speed to give shear and miscibility to the liquid. By homogenizing a mixture of two immiscible liquids. Typical homogenizers on the market include Manton-Gaulin type homogenizers. [The homogenizers of this brand are the United States-Manton-Slanted Matthew Pack Co., Ltd. Co., Inc.), which has a multistage valve in combination with two or more valves each having a single spring therein, whereby a slit is formed.

This mixture is circulated several times in this type of homogenizer under a total pressure of about 500 kg / cm 2 to produce a stable emulsion of the present invention. The operating temperature is maintained up to 55 ° C., preferably between 25-40 ° C.

The emulsion of the present invention has a dispersed phase of ultrafine pulverized particles whose diameter is 0.2 μm or less or at most 0.3 μm or less. In addition, since it does not exhibit growth in particle size, it is stable even if heated or stored for a long time. Therefore, the emulsion of the present invention is highly safe for animals administered against the deleterious effects due to aggregation of emulsion particles.

In addition, the emulsion of the present invention is retained for a long time in the circulating blood stream so that the oxygen-carrying capacity is maintained for a long time.

For example, compared with the emulsion of a fluorocarbon compound prepared using phospholipid as an emulsifier by the method described in Japanese Patent Application Laid-Open No. 69219/75, the emulsion of the present invention is an emulsion of an animal. Retained longer in the bloodstream. The excretion of the emulsions according to the invention from the body is much faster than with the perfluorotributylamine emulsifiers.

The emulsion of the present invention can be used as an injection solution after being physiologically made into an isotonic solution. It may be used in admixture with commercial plasma extenders such as mosttran, hydroxy ethyl starch and adjusted gelatin. It can also be used as a blood substitute for mammals and perfusion for internal organ preservation.

The invention is described in more detail by the examples described below, but the invention is not limited by these examples.

In Examples, the particle size was measured by the centrifugal sedimentation method (Pharmaceutical Paper 22 (12), 2966-2971 (1974)) proposed by Kei Yokohama, Aizu Suzuki, Ai Utsumi and Ar Naito.

Example 1

300 g of polyoxyethylene-polyoxypropylene copolymer (molecular weight: 10,800) was dissolved in 8 L of distilled water. To this solution was added a mixture containing 40 g soybean phospholipid, 2 g potassium oleate and 3 kg perfluorodecalin and 300 g perfluorotripropylamine. The resulting mixture was stirred in a mixer to form a crude emulsion. The resulting coarse emulsion is placed in a liquid tank of a jet emulsifier (manton-gaulin company), which is emulsified 12 times through a valve at a high pressure of 200-500 kg / cm 2, while the liquid temperature is 35 ±. The emulsion was maintained at 5 ° C. The resulting emulsion contained perfluorodecalin 30.5 (W / V) and 2.9% (W / V) of perfluorotripropylamine. The average particle diameter was 0.09-0.1 μ when measured by centrifugal precipitation. This emulsion did not actually exhibit particle size growth when placed in an injection bottle and heat sterilized at 115 ° C. for 12 minutes in a specific rotary sterilizer. Table 1 shows the particle size distribution of the emulsion and the particle size distribution of the emulsion of perfluorodecalin prepared alone without using perfluoro tripropylamine.

As can be seen from Table 1, when stored at 4 ° C. for 6 months, the emulsion of the present invention showed no agglomeration, and the average particle diameter did not change substantially.

Except for using perfluoropentyltetrahydrofuran in place of perfluorodecalin, the same procedure as described above was carried out to obtain results similar to those described above.

Example 2

To 8 liters of distilled water, 330 g of polyoxyethylene octyl ether (average molecular weight: 3,500) was added. 40 g of soy phospholipid and 2 g of potassium oleate were added to this solution, and the resulting mixture was stirred in a mixer to prepare a dispersion. To this dispersion was added a mixture containing 3 kg of perfluoromethyldecalin and 600 g of perfluoro-N-pentylpiperidine, and the resulting mixture was stirred in a mixer to produce a crude emulsion. The emulsion produced by thoroughly emulsifying the crude emulsion in the same manner as in Example 1 was filled in a small bottle. The emulsion containing bottles were heat sterilized at 115 ° C. for 12 minutes in a rotary sterilizer. This emulsion contained 29.7% (W / V) of perfluoromethyl decalin and 5.8% (W / V) of perfluoro-N-pentylpiperidine. Table 1 shows the particle size distribution after sterilization, the average particle diameter after 6 months storage at 4 ° C., and those of the reference emulsion of perfluorodecalin alone.

Example 3

In 2 liters of distilled water, 100 g of polyoxyethylene-polyoxypropylene having an average molecular weight of 8,350 was dissolved. To the resulting solution, 20 g of egg yolk phospholipid and 0.5 g of oleic acid were added, and the mixture was stirred in a mixer to prepare a dispersion. To this dispersion was added a mixture containing 340 g of perfluorodecalin and 250 g of perfluorodibutylmonomethylamine, and the resulting mixture was stirred in a mixer to produce a crude emulsion. This crude emulsion was emulsified in the same manner as in Example 1, and sterilized by heating at 115 ° C. for 12 minutes in a rotary sterilizer. This emulsifier contained 25.3% (W / V) of perfluorodecalin and 9.8% (W / V) of perfluoro dibutyl monomethylamine. Table 1 shows the average particle diameters and particle size distributions of this emulsion and those of a reference sample of the emulsion prepared by using perfluorodecalin alone. Table 1 also shows the average particle diameter of this emulsion after 6 months of storage at 4 ° C.

Example 4

35 g of polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 15,800 was dissolved in 800 ml of distilled water. To this solution, 4 g of egg yolk phospholipid and 0.1 g of monoglyceride of lauric acid were added, and the resulting mixture was stirred in a mixer to prepare a dispersion. To the dispersion was added a mixture containing 350 g of perfluorohexyltetrahydropyran and 40 g of perfluoro N, N-diethylcyclohexylamine, and the resulting mixture was stirred in a mixer to produce a crude emulsion. The coarse emulsion was emulsified in the same manner as in Example 1, and the emulsion produced was embodied in small portions. The bottles containing this emulsion were heat sterilized at 115 ° C. for 12 minutes in a rotary sterilizer. This emulsion contained 35.7% (W / V) of perfluorohexyl tetrahydropyran and 4.1% (W / V) of perfluoro-N, N-diethylcyclohexylamine.

The average particle diameter of this emulsion and the thing of the reference sample of the emulsion prepared using perfluorohexyl tetrahydropyran alone after sterilization are shown in Table 1. The emulsion showed no change in particle size even after 6 months storage at 4 ° C.

TABLE 1a

Note: ^* A: polyoxyethylene-polyoxypropylene copolymer average molecular weight: A ₁ 10,800; A ₂ 8,350; A ₃ 15,800 B: Polyoxyethylene octyl ether Average molecular weight: 3,500

TABLE 1b

Example 1

[Mixed Test of Plasma Weight Agent]

For clinical use for injection, the emulsion of the present invention is preferably used in combination with a plasma weighting agent to compensate for the lack of colloidal osmotic pressure. When mixing this emulsion with a plasma extender, a reversible precipitation phenomenon likely caused by the interaction between both colloidal solutions is not detected, indicating that the difficulties that may be encountered when using this emulsion as an injection solution are eliminated. Do it.

The emulsion used in this experiment was prepared in the same manner as in Example 3, at various concentrations of perfluorodecalin-perfluoro-N, N-dibutylmethylamine (5: 2) emulsion [polyoxyethylene-polyoxy Propylene copolymer, 2.4% (W / V); Egg yolk phospholipid, 0.6% (W / V); Potassium oleate, 0.04% (W / V) and perfluorodecalin emulsions of various concentrations prepared by the method described in Japanese Patent Application Laid-open No. 69.219 / 75 [yolk phospholipid, 4% (W / V) ; It was 0.02% (W / V) of potassium oleate. Each emulsion was made into an isotonic solution with lactic acidized Ringer's solution or caffex-ringer's bicarbonate solution, and then mixed with a plasma extender to obtain a final concentration of 1-6% (W / V), followed by mixing at room temperature. The formation of the precipitate was then visually observed for 6 hours. Plasma extenders used were hydroxyethyl starch (HES) (average molecular weight: 200,000, 20% (W / V) saline, manufactured by Ajinomodo Co., Ltd.), and dextran 40 (dextran (average molecular weight: 40,000) 10% (W / V). Saline: The Green Cross Company].

The results are shown in Table 2 and 3.

TABLE 2

TABLE 3

Note:-: non-precipitated

+: Deposit formation

From the results obtained above, it is clear that the emulsion of the present invention is much less affected by the presence of a plasma weighting agent compared to the emulsion prepared by the method described in Japanese Patent Application Publication No. 69219/75. This was obtained by mixing the emulsion of the present invention in any proportion with Dextran 40 and HES formulations by adding Dextran 40 and HES with final concentrations of 2% (W / A) and 3% (W / V), respectively. It is possible to make physiological colloidal isotonicity.

Similar results to those described above can also be found in the emulsions prepared in Examples 1, 2 and 4.

Experimental Example 2

In order to evaluate the efficacy of the emulsion according to the present invention, a study on exchange-transfusion was conducted in rats.

In this experiment, emulsions of two types of emulsions of the present invention and fluorocarbon compounds, perfluorodecalin and perfluorodibutylmonomethylamine prepared in Example 3 and Japanese Patent Application Laid-Open No. 69,219 / 75 The perfluorodecalin emulsion which stabilized with egg yolk phospholipid by the method of description was used.

The components of the sheep emulsion are shown in Table 4.

TABLE 4

* Polyoxyethylene-polyoxypropylene copolymer (molecular weight 8,350)

To make the emulsion an electrolyte and a colloidal isotonic solution, one volume of the exaggerated electrolyte solution shown in Table 4 was added to nine volumes of the emulsion, and then one volume of the resulting emulsion containing the electrolyte was referred to as Ringer lactic acid solution or reference. As a mixture, it was mixed with 3 volumes of 6% hydroxyethyl starch (molecular weight 40,000-50,000) solution before use in rat plasma.

Mice (Wistas, body weight 200-250 g) continue bleeding from the carotid artery and alternate transfusion through the tail vein alternately to 1%, 4% and 7% hematocrit under 100% oxygen atmosphere to replace electrolyte and hydr Exchange-transfusion was with an emulsion containing oxyethyl starch or plasma.

Then, the survival time of the exchange transfused mice was measured.

The results are shown in Table 5. As is evident in Table 5, the emulsions of the present invention are much more effective in saving the lives of massively bleeding animals compared to perfluorodecalin emulsions stabilized with phospholipids.

TABLE 5

Note: This value was obtained from 5 rats in each group.

Experimental Example 3

The emulsion of the fluorocarbon compound of the present invention obtained in Example 3 and the emulsion obtained by Japanese Patent Application Laid-Open No. 69,219 / 75 were used for the acute toxicity test. To make these emulsions an isotonic solution, one volume of electrolyte was added to nine volumes of emulsion before use. The components of these emulsions are shown in Table 4. As test animals, male rats of a Wister race of 100-120 g body weight were used. Emulsions were injected intravenously into these mice, and survival was observed for 1 week after the injection. The results obtained are shown in Table 6. As can be seen from Table 6, the LD ₅₀ of both emulsions was 130 ml / kg body weight, which was extremely low toxicity.

TABLE 6

Experimental Example 4

In vitro experiments were performed using rabbit red blood cells to test the hemolytic effect of the fluorocarbon derivatives in the extracorporeal circulatory system.

The preparation of the emulsion used in Experimental Example 2 as shown in Table 4 was mixed with the ringer solution treated with lactic acid to give a substantially physiologically isotonic solution. The resulting isotonic emulsion formulations were mixed with heparin treated earthenware blood in ratios of 3: 1, 1: 1 and 1: 3 to prepare test sample solutions. The hemolytic effect was assessed by measuring the free hemoglobin content in 8 ml of blood after preservation at 37 ° C. for 6 hours. Measurement of hemoglobin treated with hemolysis was directed to the cyanometemoglobin method (Kampen, E. J. and Ziilstram, W. J. Clin, Chim. Acta. 6,538, 1961).

The results obtained are shown in Table 7.

TABLE 7

As can be seen from Table 7, the hemolytic effect of the emulsions according to the invention was much less than that of the prior art, and there was no significant difference from that of the lactic acidized ringer solution used as reference.

Claims (1)

Perfluorodecalin, perfluoromethyldecalin, perfluoroalkylcyclohexane having 3 to 5 carbon atoms in the alkyl component and perfluoroalkyltetrahydrofuran having 5 to 7 carbon atoms in the alkyl component, 4 in the alkyl component -At least one perfluorocarbon compound having 9-11 carbon atoms selected from the group consisting of perfluoroalkyltetrahydropyrans and perfluoroalkanes having 6 carbon atoms; Perfluoro tert-alkylamines, perfluoro N-alkylpiperidine alkyl group having 4-6 carbon atoms and perfluoro N-alkylmorpholine having 5-7 carbon atoms alkyl Perfluoro tertiary-amine compounds having 9-11 carbon atoms selected from; 2.0-5.0% (W / V) nonionic surfactant having a molecular weight of 2,000-20,000; 0.1-1.0% (W / V) phospholipids; And 0.004-0.1% (W / V) of at least one fatty acid having 8-22 carbon atoms [The total amount of the perfluorocarbon compound and the perfluoro tert-amine in emulsion is 10-50% (W / V), and the weight ratio of the perfluoro carbon compound to the perfluoro tertiary amine is 95-50: 5-50], and oxygen transportable perfluorocara having an average particle size of 0.05-0.3μ. A process for preparing a stable emulsion or physiologically acceptable salt or monoglyceride thereof in a physiologically acceptable aqueous medium of the present compound.