A preparation method of a composition containing sodium picosulfate and its product

Abstract

The invention provides a method for preparing a pharmaceutical composition, which comprises citric acid, magnesium oxide, potassium bicarbonate and sodium picosulfate and optionally a flavoring agent and / or a sweetener, and the method comprises the following steps: dissolving sodium picosulfate in an ethanol aqueous solution to obtain a sodium picosulfate solution; and wet granulating the sodium picosulfate solution with potassium bicarbonate. The composition prepared by the method has a high sodium picosulfate content, is evenly mixed, and has more stable properties.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of a composition containing sodium picosulfate and a product thereof. Background Art

[0002] The "China Cancer Statistics Report 2022" shows that the incidence of colorectal cancer in my country ranks second among all malignant tumors, and the mortality rate has risen from fifth to fourth. Colorectal cancer screening can effectively reduce the incidence and mortality of colorectal cancer. Among them, colonoscopy screening is an important means of early screening and diagnosis of colorectal cancer.

[0003] Compound sodium picosulfate granules (Prepopik) are an intestinal cleansing drug developed by Huiling Pharmaceuticals. The compound preparation consists of sodium picosulfate, magnesium oxide and citric acid. The mechanism of action is: sodium picosulfate is hydrolyzed by colonic bacteria to produce an active metabolite, which can directly act on the colon mucosa and exert its effect by stimulating colon peristalsis. The structural formula of sodium picosulfate is shown in formula (I). Magnesium oxide and citric acid can react with each other in solution to produce magnesium citrate, which is an osmotic laxative that can increase the moisture in the intestine. Compound sodium picosulfate granules are mainly used for colon cleansing before colonoscopy in adults.

[0004]

[0005] Compared with the intestinal cleansers currently used in clinical practice, compound sodium picosulfate granules have the following advantages:

[0006] 1) Adequate intestinal preparation, accurate bowel cleansing effect, and high polyp and adenoma detection rate;

[0007] 2) Oral medication requires a small amount of liquid, provides a better taste experience, and leads to high patient compliance;

[0008] 3) It has been on the market in China for nearly 6 years, has high clinical satisfaction, and has good prospects for clinical application.

[0009] Sodium picosulfate accounts for a very small proportion in the preparation, and the amount of sodium picosulfate in each bag (16.1g) of the prescription is only 0.01g, accounting for about 0.062%, and the preparation process has a greater impact on the quality of the product. Chinese patent CN101820859B discloses a method for preparing a drug product comprising citric acid, magnesium oxide, potassium bicarbonate and sodium picosulfate, including a pharmaceutical composition and an intermediate obtained by the method for obtaining fine particles, which uses an aqueous solution as a solvent to dissolve sodium picosulfate, and forms fine particles by spraying the sodium picosulfate aqueous solution on potassium bicarbonate using a rotary drum coater. Because potassium bicarbonate is easily soluble in water, the sodium picosulfate aqueous solution is sprayed into potassium bicarbonate to easily cause local wetting, resulting in local potassium bicarbonate dissolution, adhesion of sodium picosulfate, and then the local content of sodium picosulfate is too high, and the intermediate product and the final product are mixed unevenly. Therefore, it is necessary to improve the preparation process of the compound preparation. Summary of the invention

[0010] In order to overcome the problem of uneven mixing of sodium picosulfate intermediates and final products, the present invention studies a method for preparing a composition containing sodium picosulfate, and obtains a method for preparing a composition with high uniformity of sodium picosulfate content, which improves mixing uniformity and enhances drug stability.

[0011] The invention provides a method for preparing a composition containing sodium picosulfate and potassium bicarbonate, comprising the following steps: dissolving sodium picosulfate in an ethanol aqueous solution to obtain a sodium picosulfate solution; and wet granulating the sodium picosulfate solution and potassium bicarbonate.

[0012] The present invention also provides a method for preparing a pharmaceutical composition, which contains citric acid, magnesium oxide, potassium bicarbonate and sodium picosulfate and optional flavoring agents and / or sweeteners. The method of the present invention comprises the following steps: dissolving sodium picosulfate with an ethanol aqueous solution to obtain a sodium picosulfate solution; and wet granulating the sodium picosulfate solution with potassium bicarbonate.

[0013] uniform granules are prepared by a wet granulation process, and mixture 1 is obtained by drying and granulating;

[0014] Preferably, the method of the present invention further comprises the steps of: mixing anhydrous citric acid and magnesium oxide to obtain mixture 2; and adding mixture 1, flavoring agent and / or sweetener to the mixture 2 for total mixing to obtain a pharmaceutical composition of sodium picosulfate.

[0015] Preferably, the concentration of the ethanol aqueous solution in the method of the present invention is 40% to 90%.

[0016] More preferably, the concentration of the ethanol aqueous solution in the method of the present invention is 60% to 70%;

[0017] Preferably, the mass ratio of sodium picosulfate to ethanol aqueous solution in the method of the present invention is 1:1 to 1:6.

[0018] More preferably, the mass ratio of sodium picosulfate to ethanol aqueous solution in the method of the present invention is 1:4.

[0019] Preferably, the flavoring agent in the method of the present invention is selected from one or more of sucrose, cranberry flavor, raspberry flavor, and orange powder flavor.

[0020] More preferably, the flavoring agent in the method of the present invention is orange powder flavor.

[0021] Preferably, the sweetener in the method of the present invention is selected from one or more of sucralose, saccharin sodium, and aspartame.

[0022] More preferably, the flavoring agent in the method of the present invention is sodium saccharin.

[0023] The present invention also provides a composition or a pharmaceutical composition containing sodium picosulfate and potassium bicarbonate, which is prepared by the method of the present invention.

[0024] In the present invention, the inventor creatively selected an ethanol aqueous solution with higher volatility as the solvent of sodium picosulfate. The sodium picosulfate content of the pharmaceutical composition produced by the method is more uniform and has good stability.

[0025] The present invention will be further described with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of the present invention. DETAILED DESCRIPTION

[0026] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0027] In the following specific implementations, the instruments and raw materials used are as follows:

[0028] Instruments: Mini-GG experimental wet mixing granulator, WBG-5F multifunctional fluidized bed, HLS-50 laboratory hopper mixer, BT-1001 intelligent powder tester;

[0029] Raw materials: sodium picosulfate, purchased from Jiangsu Haici Biopharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group, properties: white powder; purity: 99%;

[0030] Magnesium oxide, anhydrous citric acid, potassium bicarbonate, sodium saccharin, and flavors were all commercially available products, and anhydrous ethanol (analytical grade) was purchased from Nanjing Chemical Reagent Co., Ltd.

[0031] [Example 1] Preparation of sodium picosulfate solution and study of its stability

[0032] 1.1 Preparation of Sodium Picosulfate Solution

[0033] According to the components and contents in Table 1, sodium picosulfate solutions 1 to 7 were prepared respectively, and the preparation steps were as follows:

[0034] Add sodium picosulfate to purified water or ethanol aqueous solution, and heat and stir in a constant temperature water bath for 20 minutes.

[0035] Observe the dissolution of the sodium picosulfate solution.

[0036] Table 1. Sodium Picosulfate Solution

[0037]

[0038]

[0039] 1.2 Stability of Sodium Picosulfate Solution

[0040] The dissolution results of sodium picosulfate solutions 1 to 7 are shown in Table 1. When the solvent is purified water and 40%-70% ethanol aqueous solution, sodium picosulfate is completely dissolved and has good stability.

[0041] [Example 2] Preparation of a pharmaceutical composition of sodium picosulfate

[0042] 2.1 Preparation of pharmaceutical compositions of sodium picosulfate

[0043] According to the components and their contents in Table 2, pharmaceutical compositions 1 to 6 of sodium picosulfate were prepared respectively, and the preparation steps were as follows:

[0044] Sodium picosulfate is added to purified water or ethanol aqueous solution, heated and stirred in a constant temperature water bath until visually dissolved, potassium bicarbonate is placed in a wet granulator or a multifunctional fluidized bed, and then wet granulated or fluidized bed granulated using the sodium picosulfate ethanol aqueous solution as a binder, dried, and sieved to obtain a mixture 1 of sodium picosulfate and potassium bicarbonate;

[0045] Anhydrous citric acid and magnesium oxide are placed in a hopper mixer and mixed, so that the magnesium oxide is wrapped and adhered to the anhydrous citric acid to obtain mixture 2. Then, saccharin sodium, flavor and mixture 1 are added and mixed to obtain a pharmaceutical composition of sodium picosulfate.

[0046] Table 2. Pharmaceutical compositions 1 to 7 (unit dose packaging, per bag)

[0047]

[0048] Note: The ethanol aqueous solution is removed during the drying process.

[0049] [Example 3] Powder property detection

[0050] In this example, the powder properties of the pharmaceutical compositions 1 to 7 prepared in Example 2 and the mixture 1 in the preparation process were measured.

[0051] The BT-1001 intelligent powder tester was used to measure the angle of repose and bulk density of each sample, and the measurement was repeated three times. The angle of repose was calculated by the boundary fitting method, and the bulk density was determined by the fixed volume method. The results are shown in Table 3.

[0052] Table 3. Powder properties test results

[0053]

[0054] It can be seen from Table 3 that the fluidity of the sodium picosulfate pharmaceutical composition prepared by wet granulation using ethanol aqueous solution as solvent is better than that using purified water as solvent and fluidized bed granulation, and can better meet the fluidity requirements in the production process.

[0055] [Example 4] Content and content uniformity detection

[0056] In this example, the uniformity of the sodium picosulfate content of the pharmaceutical compositions 1 to 7 prepared in Example 2 was measured.

[0057] Detection method: Take one portion of the composition, place it in a 200 ml volumetric flask, add 100 ml of solvent, shake and ultrasonicate to dissolve, cool, dilute to scale with solvent, shake well, filter, take the filtrate, prepare 10 portions in parallel, and detect by HPLC. The results are shown in Table 4.

[0058] Table 4. Results of determination of sodium picosulfate content and content uniformity

[0059]

[0060]

[0061] As shown in Table 4, when the concentration of ethanol aqueous solution is 60%-70%, the sodium picosulfate content and content uniformity of the sodium picosulfate pharmaceutical composition prepared by wet granulation meet the requirements within 3 months; the sodium picosulfate content of the sodium picosulfate pharmaceutical composition prepared by fluidized bed granulation is already below the limit at 0 month, which does not meet the requirements.

[0062] [Example 5] Stability test

[0063] In this example, the influencing factors (60° C.) and acceleration (40±2° C., RH 75±5%) were studied on the commercially available reference preparation and the pharmaceutical compositions 1, 4, and 5 prepared in Example 2, respectively.

[0064] Detection method: Take a portion of the sample, place it in a 200 ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve and dilute to the scale, shake well, filter, take the filtrate, and perform HPLC detection. The results are shown in Table 5.

[0065] Table 5. Research results of influencing factors (60℃) and accelerated (40±2℃, RH 75±5%)

[0066]

[0067]

[0068] The results showed that the following effects could be achieved by using 60%-70% ethanol aqueous solution as a solvent to dissolve sodium picosulfate and coating the sodium picosulfate ethanol aqueous solution on the surface of potassium bicarbonate by wet granulation: 1) improving the powder properties of mixture 1, with better fluidity and more uniform mixing; 2) increasing the content and content uniformity of sodium picosulfate, with a more stable content of sodium picosulfate within 3 months; 3) improving product stability, with a slower growth of related substances.

Claims

1. A method for preparing a composition containing sodium picosulfate and potassium bicarbonate, characterized in that: The preparation method comprises the following steps: dissolving sodium picosulfate with an ethanol aqueous solution to obtain a sodium picosulfate solution; and wet granulating the sodium picosulfate solution with potassium bicarbonate to obtain a mixture.

2. A method for preparing a pharmaceutical composition comprising citric acid, magnesium oxide, potassium bicarbonate and sodium picosulfate and optionally a flavoring agent and / or a sweetener, the method comprising the following steps: dissolving sodium picosulfate in an ethanol aqueous solution to obtain a sodium picosulfate solution; The sodium picosulfate solution and potassium bicarbonate are used for wet granulation to obtain a mixture 1.

3. The method according to claim 2, characterized in that The preparation method further comprises the following steps: mixing anhydrous citric acid and magnesium oxide to obtain mixture 2; and adding mixture 1 obtained by wet granulation, flavoring agent and / or sweetener to mixture 2 for total mixing to obtain the pharmaceutical composition.

4. The method according to claim 1 or 2, characterized in that: The concentration of the ethanol aqueous solution is 40% to 90%.

5. The method according to claim 1 or 2, characterized in that: The concentration of the ethanol aqueous solution is 60% to 70%.

6. The method according to claim 1 or 2, characterized in that: The mass ratio of the sodium picosulfate to the ethanol aqueous solution is 1:1 to 1:

6.

7. The method according to claim 6, characterized in that The mass ratio of the sodium picosulfate to the ethanol aqueous solution is 1:

4.

8. The method according to claim 2, characterized in that: The flavoring agent is selected from one or more of sucrose, cranberry flavor, raspberry flavor, and orange powder flavor, and the sweetener is selected from one or more of sucralose, saccharin sodium, and aspartame.

9. A composition containing sodium picosulfate and potassium bicarbonate, characterized in that: Prepared according to the method of claim 1.

10. A pharmaceutical composition, characterized in that Prepared according to the method of claim 2.

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