Liquid pharmaceutical composition

Abstract

The present invention provides a physically and chemically stable pharmaceutical liquid composition including sodium picosulfate, magnesium oxide, citric acid and malic acid and methods of making and using such a composition.

Claims

1. A method of treatment for cleaning the colon of a subject in need thereof, comprising orally administering to the subject an effective amount of a pharmaceutical composition comprising sodium picosulfate, magnesium oxide, citric acid, and malic acid, wherein the pharmaceutical composition is a solution with a pH in the range from 4.1 to 5.4.

2. The method of claim 1, wherein in the method is for pretreatment for colonoscopy.

3. The method of claim 1, wherein in the method is for pretreatment for surgery.

4. The method of claim 1, wherein in the method is for pretreatment for surgery colon X-ray.

5. The method of claim 1, wherein the sodium picosulfate, the magnesium oxide, the citric acid, and the malic acid are present in a weight ratio of 0.003 to 0.009:1 to 3:3.5 to 10.5:0.01 to 13 (sodium picosulfate:magnesium oxide:citric acid:malic acid).

6. The method of claim 1, wherein the composition further comprises one or more excipients chosen from pH adjusters, stabilizers, preservatives, sweeteners, and fragrance ingredients.

7. The method of claim 1, wherein the composition further comprises acesulfame potassium.

8. The method of claim 1, wherein the composition further comprises disodium edetate.

9. The method of claim 1, wherein the composition further comprises sodium benzoate.

10. The method of claim 1, wherein the composition further comprises sodium hydroxide.

11. The method of claim 1, wherein the composition further comprises sucralose.

12. A method of treatment for cleaning the colon of a subject in need thereof, comprising orally administering to the subject an effective amount of a pharmaceutical composition comprising sodium picosulfate, magnesium oxide, citric acid, and malic acid, wherein the pharmaceutical composition is a liquid with a pH ranging from 4.1 to 5.4, and further wherein the sodium picosulfate, the magnesium oxide, the citric acid, and the malic acid are present in a weight ratio of about 0.005:1.75:6:4.19 (sodium picosulfate:magnesium oxide:citric acid:malic acid).

13. The method of claim 12, wherein in the method is for pretreatment for colonoscopy.

14. The method of claim 12, wherein in the method is for pretreatment for surgery.

15. The method of claim 12, wherein in the method is for pretreatment for surgery colon X-ray.

16. The method of claim 12, wherein the composition further comprises one or more excipients chosen from pH adjusters, stabilizers, preservatives, sweeteners, and fragrance ingredients.

17. The method of claim 12, wherein the composition further comprises acesulfame potassium.

18. The method of claim 12, wherein the composition further comprises disodium edetate.

19. The method of claim 12, wherein the composition further comprises sodium benzoate.

20. The method of claim 12, wherein the composition further comprises sodium hydroxide.

21. The method of claim 12, wherein the composition further comprises sucralose.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a process flow diagram illustrating a method of manufacturing a pharmaceutical liquid composition according to an embodiment of the present invention.

OTHER EMBODIMENTS

(2) Although the present invention may be variously changed and include several embodiments, particular embodiments shown in the drawings will be described in detail in a detailed description. However, it is to be understood that the present invention is not limited to the particular embodiments, and various changes, equivalences and substitutions may be made without departing from the scope and spirit of the invention.

EXAMPLES

Example 1

(3) A pharmaceutical liquid composition was prepared by dissolving, in purified water in a weight ratio of 75, sodium picosulfate:magnesium oxide:citric acid:dl-malic acid in a weight ratio of 0.005:1.75:6:4.19, sodium benzoate in a weight ratio of 0.043 as a preservative, disodium edetate hydrate in a weight ratio of 0.035 as a stabilizer, sodium hydroxide in a weight ratio of 2.1 as a pH adjuster, acesulfame potassium in a weight ratio of 0.1, and sucralose in a weight ratio of 0.1 as a sweetener, and a fragrance ingredient in orange flavor in a weight ratio of 0.043.

Comparative Example 1

(4) A powder composition was prepared by including sodium picosulfate:magnesium oxide:citric acid in a weight ratio of 0.005:1.75:6, sodium hydrogen carbonate in a weight ratio of 0.21 as an excipient, acesulfame potassium qs (quantum satis) as a sweetener, and a fragrance ingredient having orange flavor qs (quantum satis).

Example 2

(5) The contents of sodium picosulfate, magnesium oxide and citric acid that are main components of a solution obtained by dissolving the liquid composition of Example 1 in water of 150 mL were compared with those of a solution obtained by dissolving the powder composition of Comparative Example 1 in water of 150 mL. The content comparison method is an experiment method pursuant to British Pharmacopoeia 2004 Compound Sodium Picosulfate Powder for Oral Solution and the measurement was made by high performance liquid chromatography. The results are shown in Table 1 below.

(6) TABLE-US-00001 TABLE 1 Ingredient Content Comparative Name Criteria Example 1 Example 1 Sodium picosulfate 90.0~110.0% 100.7% 100.1% Magnesium oxide 90.0~110.0% 101.0% 101.4% Citric acid 90.0~110.0% 100.1% 99.7%

(7) As a result of the experiment, it can be seen from Table 1 that there is no substantial difference between the contents of the main components of Example 1 and Comparative Example 1. Therefore, both the powder composition and the liquid composition are considered to have the same effect as a colon cleanser.

Example 3

(8) A liquid composition was prepared by dissolving, in purified water in a weight ratio of 75, sodium picosulfate:magnesium oxide:citric acid in a weight ratio of 0.005:1.75:6, and adding, as a solubilizing agent, each of polyoxyethylene hydrogenated castor oil, polyethylene sorbitan monooleate, polyoxyethylene octyl dodecyl ether, polysorbate 20, polysorbate 60 and polysorbate 80 at 5.0 wt. % with respect to the total liquid weight. The liquid composition was left under the room temperature conditions (25° C., 60%) to check whether precipitation occurs, and a time point (day) when precipitation occurs at 5.0 vol. % on the bottom of a sample container was measured. The results are shown in Table 2 below.

(9) TABLE-US-00002 TABLE 2 Room Temperature Conditions (when Raw Material Name precipitation occurs: day) Polyoxyethylene hydrogenated castor oil 20 Polyethylene sorbitan monooleate 17 Polyoxyethylene octyl dodecyl ether 17 Polysorbate 20 23 Polysorbate 60 22 Polysorbate 80 20

(10) As can be seen in Table 2, it can be confirmed that precipitates are formed at 5.0 vol. % or more as a result of applying a solubilizing agent, and the solubilizing agent does not contribute to prevention of precipitation.

Example 4

(11) A liquid composition was prepared by dissolving, in purified water in a weight ratio of 75, sodium picosulfate:magnesium oxide:citric acid in a weight ratio of 0.005:1.75:6, using, as organic acid in a weight ratio of 4.19, each of citric acid, dl-malic acid, maleic acid, tartrate, fumaric acid, lactic acid, sodium citrate, aspartic acid, succinic acid, glutamic acid, hydrochloric acid, phosphoric acid, sulfuric acid and acetic acid, and adding, as a pH adjuster, sodium hydroxide in a weight ratio of 2.1 for each pH. The liquid composition was left for 24 months under the room temperature conditions (25° C., 60%) to check whether precipitation occurs. A time point (day) when precipitation occurs at 5.0 vol. % on the bottom of a sample container was measured and shown in Table 3 below. The content of the substance related to sodium picosulfate produced after 24 months was measured and shown in Table 4 below.

(12) TABLE-US-00003 TABLE 3 Room Temperature Conditions (when Raw Material Name pH precipitation occurs: day) Sodium hydroxide + 5.4 2 Citric acid 4.7 18 4.1 280 Sodium hydroxide + 5.4 — dl-malic acid 4.7 — 4.1 — Sodium hydroxide + 5.4 2 Maleic acid 4.7 10 4.1 350 Sodium hydroxide + 5.4 2 Tartrate 4.7 2 4.1 77 Sodium hydroxide + 5.4 2 Fumaric acid 4.7 18 4.1 98 Sodium hydroxide + 5.4 2 Lactic acid 4.7 14 4.1 105 Sodium hydroxide + 5.4 2 Sodium citrate 4.7 10 4.1 91 Sodium hydroxide + 5.4 2 Aspartic acid 4.7 18 4.1 77 Sodium hydroxide + 5.4 2 Succinic acid 4.7 18 4.1 98 Sodium hydroxide + 5.4 2 Glutamic acid 4.7 14 4.1 98

(13) As can be seen in Table 3, it can be confirmed that precipitation occurs within 24 months in all cases of organic acids other than malic acid.

(14) TABLE-US-00004 TABLE 4 Room Temperature Raw Material Name pH Conditions (wt. %) Sodium hydroxide + 5.4 0.19 Citric acid 4.7 0.32 4.1 2.61 Sodium hydroxide + 5.4 0.25 dl-malic acid 4.7 0.39 4.1 1.98 Sodium hydroxide + 5.4 0.31 Maleic acid 4.7 0.49 4.1 2.91 Sodium hydroxide + 5.4 0.26 Tartrate 4.7 0.46 4.1 2.97 Sodium hydroxide + 5.4 0.18 Fumaric acid 4.7 0.60 4.1 2.75 Sodium hydroxide + 5.4 0.26 Lactic acid 4.7 0.74 4.1 2.74 Sodium hydroxide + 5.4 0.18 Sodium citrate 4.7 0.46 4.1 2.25 Sodium hydroxide + 5.4 0.21 Aspartic acid 4.7 0.58 4.1 2.95 Sodium hydroxide + 5.4 0.24 Succinic acid 4.7 0.66 4.1 2.18 Sodium hydroxide + 5.4 0.15 Glutamic acid 4.7 0.49 4.1 2.27

(15) As can be seen in Table 4, it was confirmed that in the case of including malic acid, Substance A related to sodium picosulfate (4-[(pyridine-2-yl)(4-hydroxyphenyl)methyl]phenyl sodium sulfate) is generated at 2.0 wt. % or less in the above-mentioned pH range.

(16) Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings.

(17) FIG. 1 is a process flow diagram illustrating a method of preparing a pharmaceutical liquid composition according to an embodiment of the present invention.

(18) The method of preparing a pharmaceutical liquid composition may include the steps of weighing citric acid and magnesium oxide to prepare a mixture (S110), mixing malic acid and sodium hydroxide with the mixture prepared in step S110 (S120), mixing sodium picosulfate with the mixture prepared in step S120 (S130), and adding purified water to the mixture in step S130 (S140).

(19) In step S110, a pH adjuster, a stabilizer, a sweetener and the like may be added to the mixture.

(20) In some cases, step S110 and step S120 may be performed at the same time, and steps S110, S120 and S130 may be performed at the same time. Further, although steps S110, S120 and S130 have been illustrated in the order mentioned, the order is not limited thereto.

(21) Although the embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.