Jelly-like medicinal composition of potassium iodide

Abstract

A jelly-like potassium iodide pharmaceutical composition exhibits excellent storage stability and excellent dissolution properties, and can be taken easily. The jelly-like potassium iodide pharmaceutical composition includes potassium iodide as an active ingredient, a gelling agent, and a dispersion medium.

Claims

1. A jellied oral pharmaceutical composition comprising potassium iodide as an active ingredient, a gelling agent, a dispersion medium, and a sweetener, wherein the gelling agent comprises 0.01 to 0.08% of .Math.-carrageenan and 0.1 to 0.3% of -carrageenan, the dispersion medium is a mixture of water and 7 to 15% glycerin, and the sweetener comprises 15 to 25% of D-sorbitol, wherein the jellied oral pharmaceutical composition is disposed in a stick package, the stick package containing the jellied oral pharmaceutical composition and air.

2. The jellied oral pharmaceutical composition as defined in claim 1, wherein the gelling agent is further combined with a carob bean gum at a -carrageenan:carob bean gum ratio of 6:4.

3. The jellied oral pharmaceutical composition as defined in claim 1, further comprising a stabilizer, wherein the stabilizer comprises any one selected from the group consisting of polyacrylic acid, partially neutralized polyacrylic acid, and a polyacrylic acid salt.

4. The jellied oral pharmaceutical composition as defined in claim 1, further comprising at least one selected from the group consisting of a buffer, a preservative, and a flavor.

5. The jellied oral pharmaceutical composition as defined in claim 1, wherein the gelling agent comprises 0.01 to 0.05% of .Math.-carrageenan and 0.2 to 0.3% of -carrageenan.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 illustrates quantitative test results (16.3 mg preparation).

(2) FIG. 2 illustrates dissolution test results (16.3 mg preparation).

(3) FIG. 3 illustrates purity test results (16.3 mg preparation).

(4) FIG. 4 illustrates quantitative test results (32.5 mg preparation).

(5) FIG. 5 illustrates dissolution test results (32.5 mg preparation).

(6) FIG. 6 illustrates purity test results (32.5 mg preparation).

(7) FIG. 7 illustrates dissolution behavior test results (32.5 mg preparation).

(8) FIG. 8 illustrates results of a questionnaire with regard to ease of intake.

DESCRIPTION OF EMBODIMENTS

(9) Examples of the formulation of the jelly-like potassium iodide pharmaceutical composition according to the invention are listed in Table 1.

(10) Note that the jelly-like potassium iodide pharmaceutical composition (jelly-like pharmaceutical composition) according to the invention is not limited thereto.

(11) TABLE-US-00001 TABLE 1 16.3 mg preparation 32.5 mg preparation Component Amount (mg) (%) Amount (mg) (%) Potassium iodide 16.3 1.63 32.5 1.625 .Math.-Carrageenan 5 0.5 10 0.5 -Carrageenan 1.1 0.11 2.2 0.11 Carob bean gum 1.9 0.19 3.8 0.19 Sodium polyacrylate 0.03 0.003 0.06 0.003 Glycerol 100 10 200 10 D-Sorbitol 200 20 400 20 Sodium saccharin 2 0.2 4 0.2 Sodium citrate 5 0.5 10 0.5 hydrate Citric acid hydrate 0.3 0.03 0.6 0.03 Propylparaben 0.15 0.015 0.3 0.015 Flavor 1 0.1 2 0.1 Purified water Proper quantity 66.722 Proper quantity 66.727 Total 1,000 100 2,000 100

Production Example

(12) The content (16.3 mg or 32.5 mg) of potassium iodide in the preparation (composition) was set in accordance with Preventive Administration of Stable Iodine Preparation in case of Nuclear Disaster. The 16.3 mg preparation listed in Table 1 was produced as described below.

(13) Note that the amount of each component mentioned below is based on 1 g of the preparation.

(14) 5 mg of sodium citrate hydrate, 0.3 mg of citric acid hydrate, 2 mg of sodium saccharin, and 100 mg of glycerol were added to a proper quantity of purified water, and the mixture was stirred and heated to obtain a solution. 5 mg of .Math.-carrageenan, 1.1 mg of -carrageenan, 1.9 mg of carob bean gum, 0.03 mg of sodium polyacrylate, and 0.15 mg of propylparaben were mixed with 200 mg of D-sorbitol, and the mixture was added to the solution, and the resulting mixture was stirred and heated to 80 C. to obtain a solution.

(15) After the addition of a solution prepared by dissolving 16.3 mg of potassium iodide in purified water, the mixture was stirred.

(16) After the addition of 1 mg of a strawberry flavor (flavor), the mixture was stirred.

(17) After sterilizing the mixture at 80 C. for 1 hour, 1 g of the mixture was put in a stick-like container, and cooled to room temperature.

(18) An accelerated stability test (40 C., 75% RH) was performed using the 16.3 mg preparation (contained in a stick-like container) produced as described above, and a 32.5 mg preparation (contained in a stick-like container) produced in the same manner as described above. The results are shown in FIGS. 1 to 6.

(19) (1) A quantitative Test was Performed as Described Below.

(20) Preparation of Sample Solution

(21) The preparation was accurately weighed in an amount equivalent to about 65 mg of potassium iodide. After the addition of 60 mL of water, the preparation was dispersed by heating in a water bath at about 80 C., and then cooled, followed by the addition of water to accurately adjust the amount of the mixture to 100 mL. 10 mL of the mixture was accurately pipetted. 10 mL of an internal standard solution (i.e., a solution of ethyl p-hydroxybenzoate in acetonitrile (3.fwdarw.1000)) was added, followed by the addition of water to adjust the amount of the mixture to 100 mL to obtain a sample solution.

(22) Preparation of Standard Solution

(23) Quantitative potassium iodide was dried at 105 C. for 4 hours, and about 65 mg of the potassium iodide was weighed, followed by the addition of water to accurately adjust the amount of the mixture to 100 mL. 10 mL of the mixture was accurately pipetted. 10 mL of an internal standard solution was added, followed by the addition of water to adjust the amount of the mixture to 100 mL to obtain a standard solution.

(24) Measurement Method

(25) 5 L of the sample solution and 5 L of the standard solution were subjected to high-performance liquid chromatography under the following conditions, and the ratio of the peak area of iodide ions to the peak area of the internal standard was calculated to calculate the content (amount) of potassium iodide.

(26) Measurement Conditions

(27) Detector: UV absorptiometer (measurement wavelength: 225 nm) Column: A column packed with octadecylsilylated silica gel for liquid chromatography was used. Mobile phase: The mobile phase was prepared by adding 0.5 mL of a 0.5 mol/L tetrabutylammonium hydrogen phosphate solution and 300 mL of acetonitrile to 700 mL of water, and adjusting the pH of the mixture to 3.0 using phosphoric acid.
(2) A Dissolution Test was Performed as Described Below.
Test Conditions

(28) 900 mL of water was used as a test liquid, and the test was performed at 50 rpm in accordance with Dissolution Test (Method 2) specified by the Japanese Pharmacopoeia (see General Tests).

(29) Test Method

(30) The preparation removed from the stick-like container was subjected to the dissolution test. When 30 minutes had elapsed, 20 mL or more of the eluate was removed, and filtered through a membrane filter having a pore size of 0.45 m or less. After removing 10 mL of the filtrate, the subsequent filtrate was diluted with water so as to include about 18 g/mL of potassium iodide to obtain a sample solution.

(31) Preparation of Standard Solution

(32) Quantitative potassium iodide was dried at 105 C. for 4 hours, and about 36 mg of the potassium iodide was weighed, followed by the addition of water to accurately adjust the amount of the mixture to 100 mL. 5 mL of the mixture was accurately weighed, and water was added to the mixture to adjust the amount of the mixture to 100 mL to obtain a standard solution.

(33) Measurement Method

(34) 5 L of the sample solution and 5 L of the standard solution were subjected to high-performance liquid chromatography under the following conditions, and the peak area of iodide ions was calculated to calculate the content (amount) of potassium iodide.

(35) Measurement Conditions

(36) The same conditions as those employed for the quantitative test were used.

(37) (3) A Purity Test was Performed as Described Below.

(38) Preparation of Sample Solution

(39) 6 g of the jelly was weighed. After the addition of 8 mL of water, the jelly was dispersed by heating in a water bath at about 80 C. After cooling the dispersion, 11 mL of acetonitrile was added to the dispersion, and the mixture was centrifuged. 5 mL of the supernatant liquid was collected, followed by the addition of water to adjust the amount of the mixture to 25 mL to obtain a sample solution.

(40) Preparation of Standard Solution

(41) 1 mL of the sample solution was accurately weighed, and water was added to the sample solution to accurately adjust the amount of the mixture to 200 mL to obtain a standard solution.

(42) Measurement Method

(43) 5 L of the sample solution and 5 L of the standard solution were subjected to high-performance liquid chromatography under the following conditions, and the peak area of iodide ions in the standard solution and the peak area of impurities in the sample solution were calculated to calculate the content (amount) of impurities.

(44) Measurement Conditions

(45) Detector: UV absorptiometer (measurement wavelength: 210 nm) Column: A column packed with octadecylsilylated silica gel for liquid chromatography was used. Mobile phase A: A mobile phase A was prepared by adding 0.5 mL of a 0.5 mol/L tetrabutylammonium hydrogen phosphate solution and 300 mL of methanol to 700 mL of water, and adjusting the pH of the mixture to 2.8 using phosphoric acid. Mobile phase B: A mobile phase B was prepared by adding 5 mL of a 0.5 mol/L tetrabutylammonium hydrogen phosphate solution and 500 mL of methanol to 500 mL of water, and adjusting the pH of the mixture to 2.8 using phosphoric acid. Flowing of mobile phases: The mixing ratio of the mobile phase A to the mobile phase B was changed to control the concentration gradient.

(46) It was confirmed from the test results that the jelly-like pharmaceutical composition according to the invention exhibits excellent storage stability.

(47) FIG. 7 illustrates the dissolution behavior test results obtained using the 32.5 mg preparation.

(48) (1) The Dissolution Behavior Test was Performed as Described Below.

(49) Test Conditions

(50) The dissolution behavior test was performed under the same conditions as those employed for the dissolution test.

(51) Test Method

(52) The preparation removed from the stick-like container was subjected to the dissolution behavior test. 10 mL of the eluate was collected at an appropriate timing, and water heated to 370.5 C. was added immediately. The collected eluate was filtered through a membrane filter having a pore size of 0.45 m or less. After removing 3 mL of the filtrate, the subsequent filtrate was diluted with water so as to include about 18 g/mL of potassium iodide to obtain a sample solution.

(53) Preparation of Standard Solution

(54) A standard solution was prepared in the same manner as described above in connection with the dissolution test.

(55) Measurement Method

(56) 5 L of the sample solution and 5 L of the standard solution were subjected to high-performance liquid chromatography under the following conditions, and the peak area of iodide ions was calculated to calculate the content (amount) of potassium iodide.

(57) Measurement Conditions

(58) The same conditions as those employed for the quantitative test were used.

(59) It was confirmed from the test results that the jelly-like pharmaceutical composition according to the invention exhibits excellent dissolution properties.

(60) The effect of the mixing ratio of the gelling agent to D-sorbitol was also determined.

(61) A preparation was produced in the same manner as described above using the formulation listed in Table 2, and the state of the resulting preparation was evaluated.

(62) The total amount of each of Samples No. 1 to No. 7 was 1 g (16.3 mg preparation), and the total amount of each of Samples No. 8 to No. 10 was 2 g (32.5 mg preparation).

(63) TABLE-US-00002 TABLE 2 Sample Component (%) 1 2 3 4 5 6 7 8 9 10 Potassium iodide 1.63 1.63 1.63 1.63 1.63 1.63 1.63 1.625 1.625 1.625 .Math.-Carrageenan 0.47 0.47 0.5 0.5 0.5 0.39 0.5 0.61 0 0 -Carrageenan 0.11 0.11 0.12 0.12 0.11 0.09 0.12 0 0.61 0.3 Carob bean gum 0.19 0.19 0.2 0.2 0.19 0.15 0.2 0.19 0.19 0.19 Sodium polyacrylate 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 Glycerol 10 10 10 10 10 10 10 10 10 10 D-Sorbitol 20 25 20 25 20 30 30 20 20 20 Sodium citrate hydrate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Citric acid hydrate 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 Propylparaben 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 Purified water Proper Proper Proper Proper Proper Proper Proper Proper Proper Proper quantity quantity quantity quantity quantity quantity quantity quantity quantity quantity Total 100 100 100 100 100 100 100 100 100 100

(64) Samples No. 1 to No. 10 listed in Table 2 were in the form of a jelly-like composition.

(65) Whether or not the jelly-like composition (jelly) could be easily discharged using an air push-type stick-like package was also evaluated from the viewpoint of ease of intake.

(66) In Sample No. 6 and Sample No. 7, the ratio (content) of D-sorbitol (sugar (sweetener)) was 30%. Sample No. 7 in which the ratio (content) of .Math.-carrageenan was 0.5%, and the ratio (content) of -carrageenan was 0.12% was in the form of jam-like jelly, and part of the preparation remained without being discharged when the preparation was discharged using an air push-type stick-like package.

(67) Sample No. 6 in which the ratio (content) of D-sorbitol was 30% was in the form of a loose, but elastic jelly

(68) Therefore, the content of the sweetener (D-sorbitol) is preferably set to 30% or less, and more preferably 15 to 25%.

(69) Sample No. 8 in which the ratio (content) of .Math.-carrageenan was 0.61% and the ratio (content) of -carrageenan was 0%, and Samples No. 9 and No. 10 in which the ratio (content) of .Math.-carrageenan was 0% and the ratio (content) of -carrageenan was 0.61% or 0.3%, were in the form of jelly. Note that Sample No. 8 had very high viscosity. Samples No. 9 and No. 10 could be discharged using an air push-type stick-like package, were very soft, and immediately broke due to physical stimulation.

(70) Therefore, it suffices that the jelly-like composition include either .Math.-carrageenan or -carrageenan, but it is preferable that the jelly-like composition include both .Math.-carrageenan and -carrageenan.

(71) The content of -carrageenan is preferably set to 0.05 to 0.6%.

(72) The content of .Math.-carrageenan is preferably set to 0.01 to 0.6%.

(73) The effect of the content of glycerol was determined.

(74) A 32.5 mg preparation was produced in the same manner as described above according to the formulation listed in Table 3.

(75) TABLE-US-00003 TABLE 3 Sample Component (%) 11 12 13 14 15 16 17 18 Potassium iodide 1.625 1.625 1.625 1.625 1.625 1.625 1.625 1.625 .Math.-Carrageenan 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 -Carrageenan 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 Carob bean gum 0.19 0.19 0.19 0.19 0.19 0.19 0.19 0.19 Sodium polyacrylate 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 Glycerol 10 5 20 15 13 17 0 7 D-Sorbitol 20 20 20 20 20 20 20 20 Sodium saccharin 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Sodium citrate hydrate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Citric acid hydrate 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 Propylparaben 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 Flavor 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Purified water Proper Proper Proper Proper Proper Proper Proper Proper quantity quantity quantity quantity quantity quantity quantity quantity Total 100 100 100 100 100 100 100 100

(76) When glycerol was not added (Sample No. 17), the resulting preparation was in the form of jelly, but was very soft, and was not suitable for an air push-type application.

(77) Sample No. 13, which had a glycerol content of 20%, was solidified in the form of jelly in a state in which bubbles remained.

(78) Therefore, the content of glycerol is preferably set to 3 to 20%, more preferably 5 to 17%, and still more preferably 7 to 15%.

(79) FIG. 8 illustrates the results of a questionnaire with regard to ease of intake depending on the presence or absence of the sweetener and the flavor (strawberry flavor).

(80) FIG. 8 illustrates the results of a comparison between a plain preparation that did not include sodium saccharin and a flavor and the 16.3 mg preparation according to the invention.

(81) It was confirmed from the results illustrated in FIG. 8 that the jelly-like pharmaceutical composition according to the invention can be taken easily.

(82) A formulation that can produce a jelly that can be easily discharged using an air push-type stick-like package, and is as soft as (or softer than) baby food was determined in view of the intended use (target age group) of the preparation.

(83) Sample No. 10 in which the ratio (content) of -carrageenan was 0.3% and the ratio (content) of .Math.-carrageenan was 0% immediately broke due to physical stimulation. Therefore, a small amount of .Math.-carrageenan was added while setting the ratio of -carrageenan to 0.3% or less.

(84) The formulation is listed in Table 4.

(85) TABLE-US-00004 TABLE 4 Sample Component (%) 19 20 21 22 Potassium iodide 1.625 1.625 1.625 1.625 .Math.-Carrageenan 0.03 0.01 0.02 0.05 -Carrageenan 0.2 0.2 0.2 0.3 Carob bean gum 0.13 0.13 0.13 0.19 Sodium polyacrylate 0.003 0.003 0.003 0.003 Glycerol 10 10 10 10 D-Sorbitol 20 20 20 20 Sodium saccharin 0.2 0.2 0.2 0.2 Sodium citrate hydrate 0.5 0.5 0.5 0.5 Citric acid hydrate 0.03 0.03 0.03 0.03 Propylparaben 0.015 0.015 0.015 0.015 Purified water Proper Proper Proper Proper quantity quantity quantity quantity Total 100 100 100 100

(86) In Table 4, the unit for the ratio (content) of each component is mass %.

(87) In Samples No. 19 to No. 22, the ratio (content) of carob bean gum was adjusted corresponding to the ratio (content) of -carrageenan (i.e., -carrageenan:carob bean gum=6:4).

(88) The softness of Samples No. 19 to No. 22 listed in Table 4 was compared with that of commercially-available baby food.

(89) Measurement of Softness

(90) The softness (N/m.sup.2) was measured using a rheometer (CR-500DX manufactured by Sun Scientific Co., Ltd.).

(91) Specifically, the sample was put in a container having a diameter of 40 mm up to a height of 15 mm, and the softness was measured using a plunger having a diameter of 20 mm at a compression rate of 10 mm/sec and a clearance of 5 mm.

(92) The softness of commercially-available baby food Uragoshi Ringo was 465.0 N/m.sup.2, the softness of commercially-available baby food Tomato & Fruits Dessert was 659.2 N/m.sup.2, the softness of Sample No. 19 was 353.5 N/m.sup.2, the softness of Sample No. 20 was 331.2 N/m.sup.2, the softness of Sample No. 21 was 340.8 N/m.sup.2, and the softness of Sample No. 22 was 455.4 N/m.sup.2.

(93) Specifically, Samples No. 19 to No. 22 were softer than the commercially-available baby food.

(94) Note that it is considered that softness of 500 N/m.sup.2 or less is required to swallow food.

(95) Measurement of Spread Due to Fall

(96) 2 g of each of Samples No. 19 to No. 22 and commercially-available baby food Tomato & Fruits Dessert was put in an air push-type stick-like package, and discharged vertically at a height of 25 cm (allowed to fall) to measure the spread area.

(97) The spread area of the commercially-available baby food was 406 mm.sup.2, the spread area of Sample No. 19 was 351 mm.sup.2, the spread area of Sample No. 20 was 372 mm.sup.2, the spread area of Sample No. 21 was 359 mm.sup.2, and the spread area of Sample No. 22 was 349 mm.sup.2. Specifically, the spread area of Samples No. 19 to No. 22 was close to that of the commercially-available baby food.

(98) It was thus confirmed that Samples No. 19 to No. 22 had softness almost equal to that of the commercially-available baby food.

(99) Production Scale and Stirring Conditions

(100) Samples No. 19 to No. 22 were produced on a laboratory scale, and the stirring operation was performed using a stirring bar.

(101) Since a large-scale commercial production process utilizes equipment provided with a high-speed stirrer, it is considered that the state of the resulting product is affected by the production scale and the stirring mechanism.

(102) Therefore, a product having the same formulation as that of Sample No. 19 and a product having the same formulation as that of Sample No. 22 were produced on a large scale using equipment provided with a high-speed stirrer, and the softness of each product was measured.

(103) The softness of the product having the same formulation as that of Sample No. 19 was 261 N/m.sup.2, and the softness of the product having the same formulation as that of Sample No. 22 was 274 N/m.sup.2 (i.e., an improvement in softness was observed with respect to Samples No. 19 and No. 22).

CONCLUSION

(104) It was confirmed from the evaluation results that a jelly-like preparation having softness close to that of baby food can be obtained by setting the ratio (content) of -carrageenan to 0.1 to 0.5%, and setting the ratio (content) of .Math.-carrageenan to 0.01 to 0.08%.

INDUSTRIAL APPLICABILITY

(105) The iodine preparation according to the invention is in the form of jelly, and can be adjusted in softness corresponding the target age group (e.g., newborn baby or infant).