ETHANOL HARDENER AND USE THEREOF

Abstract

Disclosed are an ethanol hardener and the use thereof. The ethanol hardener contains ethanol, a water-soluble iodine preparation and water, wherein the volume percent of the ethanol is 76-98%, and the mass-volume ratio of the iodine element in the water-soluble iodine preparation to the iodine containing composition is 23-139 g/L. The iodine containing composition can be autoradiographed when injected into blood vessels, and has a better embolization effect and stability.

Claims

1. An iodine-containing composition, comprising: ethanol, a water-soluble iodine preparation and water, wherein the volume percentage of ethanol is 76%-98%; the mass-volume ratio of iodine in the water-soluble iodine preparation to the iodine-containing composition is 23-139 g/L.

2. The iodine-containing composition according to claim 1, wherein the iodine-containing composition is a pharmaceutical composition comprising ethanol, a water-soluble iodine preparation and water for injection, wherein the volume percentage of ethanol is 76%-98%; the mass-volume ratio of the water-soluble iodine preparation to the composition is 50-300 g/L; the mass-volume ratio of iodine in the water-soluble iodine preparation to the composition is 23-139 g/L; the balance is water for injection.

3. The iodine-containing composition according to claim 2, wherein the volume percentage of ethanol is 86%-90%; and/or, the mass-volume ratio of the water-soluble iodine preparation to the iodine-containing composition is 150-260 g/L; and/or, the water-soluble iodine preparation is iohexol; and/or, the iodine-containing composition consists of the following components: ethanol, the water-soluble iodine preparation and water for injection.

4. The iodine-containing composition according to claim 2, comprising amounts of ingredients per 1000 mL according to any of the following schemes: scheme A: the mass of iodine in 1000 mL of the iodine-containing composition is 23-139 g; TABLE-US-00043 ethanol 760-980 mL iohexol  50-300 g water for injection the balance scheme B: the mass of iodine in 1000 mL of the iodine-containing composition is 46-119 g; TABLE-US-00044 ethanol 800-900 mL iohexol 100-260 g water for injection the balance scheme C: the mass of iodine in 1000 mL of the iodine-containing composition is 23-139 g; TABLE-US-00045 ethanol 820-900 mL water-soluble iodine preparation  50-300 g water for injection the balance scheme D: the mass of iodine in 1000 mL of the iodine-containing composition is 46-71 g; TABLE-US-00046 ethanol 820-900 mL water-soluble iodine preparation 100-200 g water for injection the balance

5. The iodine-containing composition according to claim 1, wherein the iodine-containing composition is an iodine-containing composition for use as a medicament and/or an iodine-containing composition for use as an ethanol-based sclerosing agent; and/or, ethanol is ethanol for pharmaceutical injection; and/or, the volume percentage of ethanol is 78%-95%; and/or, the water-soluble iodine preparation is one or more of iohexol, ioversol and iodixanol; and/or, the mass-volume ratio of iodine in the water-soluble iodine preparation to the iodine-containing composition is 35-121 g/L; and/or, the mass-volume ratio of the water-soluble iodine preparation to the iodine-containing composition is 50-300 g/L; and/or, water is water for injection; and/or, the iodine-containing composition consists of ethanol, the water-soluble iodine preparation and water.

6. The iodine-containing composition according to claim 1, wherein when the iodine-containing composition is an iodine-containing composition for use as a medicament and/or an iodine-containing composition for use as an ethanol-based sclerosing agent, the iodine-containing composition for use as a medicament is an iodine-containing composition for treating vascular malformation; and/or, the volume percentage of ethanol is 80%, 82%, 83%, 86% or 90%; and/or, the water-soluble iodine preparation is iohexol; and/or, the mass-volume ratio of iodine in the water-soluble iodine preparation to the iodine-containing composition is 46 g/L, 49 g/L, 70 g/L, 71 g/L or 93 g/L; and/or, the mass-volume ratio of the water-soluble iodine preparation to the iodine-containing composition is 75 g/L, 100 g/L, 150 g/L, 200 g/L or 260 g/L.

7. The iodine-containing composition according to claim 1, comprising amounts of ingredients per 1000 mL according to any of the following schemes: scheme a: TABLE-US-00047 ethanol 760-980 mL mass of iodine  23-139 g water for injection the balance scheme b: TABLE-US-00048 ethanol 760-980 mL iohexol  50-300 g water for injection the balance scheme c: TABLE-US-00049 ethanol 800-900 mL iohexol 100-260 g water for injection the balance scheme d: TABLE-US-00050 ethanol 820-900 mL ioversol or iodixanol  49-71 g water for injection the balance

8. The iodine-containing composition according to claim 1, comprising amounts of ingredients per 1000 mL according to any of the following schemes: scheme 1: TABLE-US-00051 ethanol 830 ml iohexol 200 g water for injection the balance scheme 2: TABLE-US-00052 ethanol 820 ml ioversol 150 g water for injection the balance scheme 3: TABLE-US-00053 ethanol 900 ml iodixanol 100 g water for injection the balance scheme 4: TABLE-US-00054 ethanol 980 ml iohexol  50 g water for injection the balance scheme 5: TABLE-US-00055 ethanol 760 ml iohexol 300 g water for injection the balance scheme 6: TABLE-US-00056 ethanol 800 ml iohexol 260 g water for injection the balance scheme 7: TABLE-US-00057 ethanol 860 ml iohexol 150 g water for injection the balance scheme 8: TABLE-US-00058 ethanol 950 ml iohexol  50 g water for injection the balance scheme 9: TABLE-US-00059 ethanol 900 ml iohexol 100 g water for injection the balance scheme 10: TABLE-US-00060 ethanol 860 ml iohexol  75 g water for injection the balance scheme 11: TABLE-US-00061 ethanol 780 ml iohexol 150 g water for injection the balance

9. A method of preparing the iodine-containing composition according to claim 1, comprising: mixing the water-soluble iodine preparation, ethanol and water; wherein the mixing can be implemented by stirring; the iodine-containing composition can be a transparent and clear solution; the iodine-containing composition can be sterilized at high temperature; the iodine-containing composition can be contained in an ampoule.

10. (canceled)

11. A method of treating vascular malformation, comprising: administering to a patient a therapeutically effective amount of the iodine-containing composition according to claim 1; wherein the patient can be a mammal, such as a mouse or a human; the iodine-containing composition can be administered by injection.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0087] FIG. 1 is a radiograph showing the in-vitro enhancing effect of the sclerosing agents prepared in Examples 1, 5 and 7 and Comparative Examples 2 and 3.

[0088] FIG. 2 is a radiograph showing the in-vitro enhancing effect of the sclerosing agents prepared in Examples 1, 5 and 7 and Comparative Examples 2 and 3 after being left standing for 3 min.

[0089] FIG. 3 is a radiograph showing the in-vivo enhancing effect in a rat of the sclerosing agent prepared in Example 1.

[0090] FIG. 4 is a radiograph showing the in-vivo enhancing effect in a rat of the sclerosing agent prepared in Example 5.

[0091] FIG. 5 is a radiograph showing the in-vivo enhancing effect in a rat of the sclerosing agent prepared in Example 7.

[0092] FIG. 6 is a radiograph showing the in-vivo enhancing effect in a rat of the sclerosing agent prepared in Comparative Example 2.

[0093] FIG. 7 is a radiograph showing the in-vivo enhancing effect in a rat of the sclerosing agent prepared in Comparative Example 3.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0094] The present invention is further illustrated by the following examples, which are not intended to limit the present invention. Experimental procedures without specified conditions in the following examples were performed in accordance with conventional procedures and conditions, or in accordance with instructions.

[0095] In the following examples, iohexol and ioversol were purchased from Zhejiang Starry Pharmaceutical Co., Ltd.; iodixanol was purchased from Lianyungang Runzhong Pharmaceutical Co., Ltd.; ethanol was purchased from Hunan Jiudian Pharmaceutical Co., Ltd.; water for injection was purchased from Thermofisher; iodized oil injection was purchased from Yantai Luyin Pharmaceutical Co., Ltd., with a specification of 10 mL, an iodine content of 37%-41% (w/w; taking the median 39%) and a density of about 1.355 g/mL.

EXAMPLE 1

[0096] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 93 g:

TABLE-US-00024 ethanol 830 ml iohexol 200 g water for injection the balance

[0097] Preparation: 200 g of iohexol was added into ethanol, and the mixture was continuously stirred to mix well. The balance of water for injection was slowly added to obtain a transparent and clear solution. Glass ampoules were filled with the solution, sealed, and sterilized at a high temperature of 121° C. for 15 minutes to obtain the agent.

EXAMPLE 2

[0098] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 71 g:

TABLE-US-00025 ethanol 820 ml ioversol 150 g water for injection the balance

[0099] The preparation method referred to that in Example 1.

EXAMPLE 3

[0100] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 49 g:

TABLE-US-00026 ethanol 900 ml iodixanol 100 g water for injection the balance

[0101] The preparation method referred to that in Example 1.

EXAMPLE 4

[0102] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 23 g:

TABLE-US-00027 ethanol 980 ml iohexol 50 g water for injection the balance

[0103] The preparation method referred to that in Example 1.

EXAMPLE 5

[0104] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 139 g:

TABLE-US-00028 ethanol 760 ml iohexol 300 g water for injection the balance

[0105] The preparation method referred to that in Example 1.

EXAMPLE 6

[0106] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 121 g:

TABLE-US-00029 ethanol 800 ml iohexol 260 g water for injection the balance

[0107] The preparation method referred to that in Example 1.

EXAMPLE 7

[0108] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 70 g:

TABLE-US-00030 ethanol 860 ml iohexol 150 g water for injection the balance

[0109] The preparation method referred to that in Example 1.

EXAMPLE 8

[0110] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 23 g:

TABLE-US-00031 ethanol 950 ml iohexol  50 g water for injection the balance

[0111] The preparation method referred to that in Example 1.

EXAMPLE 9

[0112] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 46 g:

TABLE-US-00032 ethanol 900 ml iohexol 100 g water for injection the balance

[0113] The preparation method referred to that in Example 1.

EXAMPLE 10

[0114] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 35 g:

TABLE-US-00033 ethanol 860ml iohexol  75 g water for injection the balance

[0115] The preparation method referred to that in Example 1.

EXAMPLE 11

[0116] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 70 g:

TABLE-US-00034 ethanol 780 ml iohexol 150 g water for injection the balance

[0117] The preparation method referred to that in Example 1.

Comparative Example 1

[0118] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 162 g:

TABLE-US-00035 ethanol 700 ml iohexol 350 g water for injection the balance

[0119] The preparation method referred to that in Example 1.

Comparative Example 2

[0120] The sclerosing agent comprised the following amounts of ingredients per 6 mL, without water for injection, wherein the mass of iodine in 6 mL of the sclerosing agent was 1.355 g:

TABLE-US-00036 ethanol 5 ml iodized oil injection 1 ml

[0121] Preparation: Absolute ethanol and iodized oil were mixed at a ratio of 5:1. and the mixture was shaken to mix well; alternatively, anhydrous ethanol and iodized oil were mixed into an emulsion using two syringes connected to a three-way connector. The agent was prepared right before use.

Comparative Example 3

[0122] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 14 g:

TABLE-US-00037 ethanol 950 ml iohexol  30 g water for injection the balance

[0123] The preparation method referred to that in Example 1.

Comparative Example 4

[0124] The sclerosing agent comprised the following amounts of ingredients per 1000 mL, wherein the mass of iodine in 1000 mL of the sclerosing agent was 162 g:

TABLE-US-00038 ethanol 760 ml iohexol 350 g water for injection the balance

[0125] The preparation method referred to that in Example 1.

Effect Example 1 Tests of Imaging Effect

[0126] 1.1 Test of In-Vitro Imaging Effect

[0127] The agents of Example 1 (containing 200 g of iohexol and 93 g of iodine per 1000 mL), Example 5 (containing 300 g of iohexol and 139 g of iodine per 1000 mL), Example 7 (containing 150 g of iohexol and 70 g of iodine per 1000 mL), Comparative Example 2 (containing 167 mL of iodized oil injection and 225.8 g of iodine per 1000 mL) and Comparative Example 3 (containing 30 g of iohexol and 14 g of iodine per 1000 mL) were loaded into syringes and tested under X-ray (C-shaped arm) for the in-vitro imaging effect; the agent of Comparative Example 2 was prepared right before use. The in-vitro imaging effect is shown in FIG. 1. After the sclerosing agents were left standing for 3 minutes, the in-vitro enhancing effect was observed under X-ray (C-shaped arm), as shown in FIG. 2.

[0128] In FIG. 1, the agents of Example 7, Example 5 and Example 1 showed significantly stronger effect than Comparative Example 2, while for Comparative Example 2, a non-uniform effect was observed immediately after preparation. More severe condition was observed after only 3 minutes of standing, as shown in FIG. 2. More oil droplets of large particle size were observed to be separated from ethanol. This indicates that the agent of Comparative Example 2 may have compromised in-vivo enhancing effect and safety. The agent of Comparative Example 3 showed weak enhancing effect and was incapable of providing sufficient enhancing effect for tracing in-vivo.

[0129] 1.2 Test of In-Vivo Enhancing Effect

[0130] Male SD rats were selected for the test. After anesthesia by sodium pentobarbital, the rats were administered with the agents of Example 1 (containing 200 g of iohexol and 93 g of iodine per 1000 mL), Example 5 (containing 300 g of iohexol and 139 g of iodine per 1000 mL), Example 7 (containing 150 g of iohexol and 70 g of iodine per 1000 mL), Comparative Example 2 (containing 167 mL of iodized oil injection and 225.8 g of iodine per 1000 mL) and Comparative Example 3 (containing 30 g of iohexol and 14 g of iodine per 1000 mL) by injection via inferior vena cava to test the in-vivo enhancing effect of the agents, as shown in FIGS. 3-7. The enhancing effect of Example 1 is shown in FIG. 3. The enhancing effect of Example 5 is shown in FIG. 4. The enhancing effect of Example 6 is shown in FIG. 5. The enhancing effect of Comparative Example 2 is shown in FIG. 6. The enhancing effect of Comparative Example 3 is shown in FIG. 7. The results showed that Example 7 had similar enhancing effect to Comparative Example 2, Examples 5 and 1 had significantly stronger effect than Comparative Example 2, and no significant enhancing effect was observed for Comparative Example 3.

[0131] It can be seen from the test results of in-vivo and in-vitro enhancing effect that the sclerosing agent of Comparative Example 3 has no significant enhancing effect in vivo and cannot function to trace ethanol; the enhancing effects of Examples 5 and 1 are significantly stronger than that of Comparative Example 2, and Example 7 is similar to Comparative Example 2 in enhancing effect. However, the sclerosing agent prepared in Comparative Example 2 is extremely unstable in system. It separates in a short term into iodized oil and ethanol, and should be prepared right before administration, which is inconvenient for clinical use. In addition, the unstable system also brings great risks in safety, including compromised tracing effect of the preparation and formation of embolism due to iodized oil droplets in circulation.

Effect Example 2 Viscosity Test

[0132] The viscosity of Examples 1, 5 and 7 and ethanol was measured by a capillary viscometer at an ambient temperature of 20° C. The capillary diameter was 0.5-0.6 mm and the viscometer constant was 0.005085 mm.sup.2/s.sup.2. The time difference of liquid passing through the capillary was recorded. See Table 1 for details.

Viscosity=time difference×viscometer constant

TABLE-US-00039 TABLE 1 Group Time difference (s) Viscosity (mm.sup.2/s) Example 1 (20% iohexol) 582 2.96 Example 5 (30% iohexol) 863 4.39 Example 7 (15% iohexol) 496 2.52 Ethanol 245 1.25

[0133] The test results show that the preparations of the present invention significantly improve the viscosity of the ethanol-based sclerosing agent and can be beneficial to improving the enhancing effect.

Effect Example 3 Embolic Effect in Rabbit Ear Vein

[0134] Sixty healthy male rabbits with body weight of 2.5±0.2 kg were selected and divided into 6 groups of 10. The rabbits were anesthetized with a 3% sodium pentobarbital solution by intraperitoneal injection at 0.8 mL/kg. An anticoagulated and disinfected PE-8 catheter (0.20 mm×0.36 mm) was inserted into the distal end of the ear vein, until the end of the catheter reached the midpoint of the ear vein. The in-vitro end of the catheter was connected with a 1-mL syringe through a cannula.

[0135] 0.1 mL of each of the sclerosing agents of various embodiments with different components was injected at a constant speed through the PE-8 catheter. After 30 seconds, the catheter was slowly and gently withdrawn, and a cotton pad was used for hemostasis. Both left and right ears of the animals were treated with the same procedures. The animals after sclerosing treatment were accommodate in individual cages. After a one-month recovery period, after visual inspection, a normal saline containing India ink was slowly injected at the distal end of the ear vein, so as to observe and record whether the blood vessels were completely embolized. The embolization ratio in each group was recorded (Table 2).

TABLE-US-00040 TABLE 2 Embolic effect of sclerosing agents with different components in rabbit ear vein Volume of ethanol Mass of Ratio of completely per 1000 mL iohexol embolized Group (mL) per 1000 mL (g) vessels Example 1  830 200 100% (20/20)** Example 2  820 150  90% (18120)* Example 3  900 100  85% (17120)* Example 4  980  50  85% (17120)* Example 5  760 300  85% (17120)* Example 6  800 260  85% (17/20)* Example 7  860 150  95% (19120)** Example 8  950  50  65% (13/20) Example 9  900 100  90% (18/20)* Example 10  860  75  85% (17/20)* Example 11  780 150  80% (16/20) Comparative  700 350  25% (5/20)* Example 1 Comparative  833 167 mL of  45% (9/20) Example 2 iodized oil Comparative  950  30  60% (12/20) Example 3 Control group 1000   0  60% (12/20) (absolute ethanol) Notes: in Table 2, “*” denotes p < 0.05; “*” indicates p < 0.01 vs. absolute ethanol, Chi-square fisher's exact test.

[0136] The results showed that the vascular embolization ratios of Examples 1, 5, 7, 4, 6, 9 and 10 were all greater than 85% and were significantly higher than that of the absolute ethanol group (p<0.05), and the vascular embolization ratios of Examples 8 and 11 were greater than 65% and were higher than that of the absolute ethanol group. The vascular embolization ratios of Comparative Examples 1 and 2 were only 25% and 45%, respectively, significantly lower than those of the compositions of the present invention; the vascular embolic effect of Comparative Example 3 was similar to that of absolute ethanol, and was also significantly lower than those of the compositions of the present invention.

[0137] Ethanol works as an angiosclerosis agent by destroying blood vessels through its strong dehydration and denudation effects, and it is generally believed that a higher concentration gives a better sclerosing effect. However, ethanol has high mobility in blood vessels and a short time for actually acting on lesions, such that more ethanol is required to ensure the therapeutic effect for treating vascular malformation, thus inevitably increasing the safety risk.

[0138] The compositions of the present invention, when injected into blood vessels, not only facilitate autoradiography in blood vessels to avoid irreversible damage caused by unfavorable entry into normal tissues, but also have a surprising sclerosing and embolic effect stronger than that of absolute ethanol on the blood vessels. In addition, at present, no document has reported that water-soluble iodine preparations have a therapeutic effect on vascular malformations. In the test process, the inventor did not find any therapeutic effect on vascular malformations of any individual water-soluble iodine preparation.

[0139] Therefore, the water-soluble iodine preparation of a specific content and ethanol of a specific content in the composition work together to provide the synergistic effect.

[0140] For the synergistic effect, the inventor supposed that the composition achieves a proper viscosity due to the water-soluble iodine with a specific content in the formulation, such that the composition can stay at the lesions for a certain time to produce a sufficient sclerosing and damaging effect on the lesions, thus generating a significantly improved embolic effect and no other side effect.

[0141] The poor embolic effect of Comparative Example 1 may be attributed to the low ethanol concentration, which impairs its sclerosing effect.

[0142] For the weak embolic effect of Comparative Example 2, it is presumed that the following two reasons may be possible: the iodine oil dilutes the concentration of ethanol; the iodized oil and ethanol are mutually incompatible and are separated after administration into blood vessels, and the iodized oil is easy to deposit and attach on vascular endothelium because the density and the viscosity of the iodized oil are higher than those of the ethanol, and as such, the iodized oil blocks the sclerosing effect of ethanol on the lesions by direct contact, rather than prolongs the retention time of ethanol.

[0143] The weak embolic effect of Comparative Example 3 is attributed to the low concentration of the water-soluble iodine preparation, which reduces the retention time and impairs the sclerosing effect.

[0144] Therefore, the sclerosing agent of the present invention not only realizes the effect of accurately tracing ethanol, but also significantly improves the angiosclerosis effect.

Effect Example 4 Stability Test

[0145] The sclerosing agents prepared in some examples of the present invention and Comparative Example 4 were selected for accelerated stability test. The sclerosing agents were preserved for 6 months under the conditions of 40±2° C. and 75±5% humidity, and samples were taken for content assay before and after sterilization and at 1, 2, 3 and 6 months. The results of the sclerosing agents prepared in some examples of the present invention are detailed in Tables 3 and 4. For the sclerosing agent of Comparative Example 4, a small amount of iohexol precipitate was found in the solution after several hours of standing. The “labeled amounts” in Tables 3 and 4 refer to the specified amount of the active ingredient in a unit dose form.

[0146] The methods for content assay of iohexol and ethanol can be found in the Chinese Pharmacopoeia, 2015 edition.

TABLE-US-00041 TABLE 3 Iohexol content in percent of labeled amount Before After Group sterilization sterilization 1 month 2 months 3 months 6 months Example 1 98.9% 98.7% 98.2% 98.1% 97.8% 97.1% Example 4 99.8% 99.8% 99.5% 99.4% 98.7% 98.8% Example 5 100.3% 99.8% 99.9% 99.7% 99.1% 98.7% Example 6 101.2% 101.2% 100.7% 100.4% 99.8% 100.0% Example 7 99.4% 99.5% 99.3% 98.9% 98.7% 98.0% Example 8 100.9% 100.4% 100.5% 100.1% 99.8% 99.2%

TABLE-US-00042 TABLE 4 Ethanol content in percent of labeled amount Before After Group sterilization sterilization 1 month 2 months 3 months 6 months Example 1 100.2% 100.0% 99.7% 99.4% 99.1% 98.7% Example 4 99.5% 99.1% 99.0% 98.5% 98.2% 98.0% Example 5 98.6% 98.2% 98.0% 97.2% 97.1% 96.8% Example 6 99.2% 99.2% 99.0% 98.7% 98.5% 98.0% Example 7 100.2% 99.7% 99.5% 99.4% 99.1% 98.6% Example 8 100.1% 99.9% 99.4% 99.2%% 99.1% 98.5%

[0147] As can be seen from the above Tables 3 and 4, the stability data of the components suggest that the sclerosing agents of the present invention had a content within a predetermined range in the accelerated stability test and have good stability. In contrast, the composition prepared in Comparative Example 4 (the content of the water-soluble iodine preparation exceeds the range of the present application) cannot be preserved for a long period of time because a small amount of the water-soluble iodine preparation precipitate was found after several hours of standing.