Spirolactone oral suspension and preparation method thereof

Abstract

The invention discloses a spirolactone oral suspension and a preparation method thereof, and belongs to the technical field of preparation of spirolactone oral suspensions. The spirolactone oral suspension is prepared from the following components in parts by mass: 5 parts of spirolactone, 2.25 to 4.5 parts of a bacteriostatic agent, 4 to 7.5 parts of a pH (Potential of Hydrogen) regulator, 1 to 3 parts of a de-foaming agent, 0.5 to 6 parts of a suspending aid, 3 to 8 parts of a sweetening agent, 18 to 25 parts of a wetting agent, 2 to 4 parts of a flavoring agent and 970 to 1020 parts of water, the defoaming agent is simethicone emulsion, and the suspending aid is sodium carboxymethyl cellulose. The xanthan gum is replaced by the sodium carboxymethyl cellulose, the sodium carboxymethyl cellulose can be completely dissolved and dispersed without long-time stirring in the production process, and the dispersed solution is uniform and does not form micelles; the ratio of spirolactone to sodium carboxymethyl cellulose is limited, and simethicone emulsion is added, so that the redispersibility of the obtained suspension is good, and the compliance of patients and the accuracy of administration dosage are improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of spironolactone oral suspension, and particularly relates to a spironolactone oral suspension and a preparation method thereof. Background Art

[0002] Disclosing the information of this background art section is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Spironolactone is an artificially synthesized steroid compound with the chemical name of 17β-hydroxy-3-oxo-7α-(acetylthio)-17α-pregn-4-ene-21-carboxylic acid-γ-lactone and the chemical formula of C 24 H 32 O 4 S. Its structure is similar to that of aldosterone and it is a competitive inhibitor of aldosterone, which can be used as a low-potency diuretic. Spironolactone is mainly used clinically for refractory edema accompanied by increased aldosterone, such as the treatment of congestive heart failure, additional therapy for hypertension, and edema in patients with cirrhosis. In addition, since spironolactone can reduce male hormones in the body, it is also suitable for the treatment of various skin diseases, such as acne, hirsutism, androgenetic alopecia, and rosacea and other metabolic diseases. At present, the spironolactone used clinically is mainly tablets and capsules. Based on the current clinical application situation, for patients with heart failure or pediatric patients, there are problems such as inconvenient swallowing when using tablets. Developing a spironolactone oral liquid preparation with accurate dosage is urgently needed clinically.

[0004] At present, the main types of spironolactone oral suspensions on the market are the spironolactone oral suspension studied by CMP Pharma and the spironolactone oral suspension studied by Nova. Among them, the composition of the spironolactone oral suspension studied by CMP Pharma includes sorbic acid, potassium sorbate, anhydrous citric acid, sodium citrate, dimethicone emulsion, sodium saccharin, xanthan gum, ammonium glycyrrhizinate (Magnasweet) 110, glycerol, banana essence, and purified water. The composition of the spironolactone oral suspension studied by Nova includes sodium benzoate, sucrose, citric acid, sodium citrate, strawberry essence, Tween 80, simethicone emulsion, xanthan gum, and purified water. Xanthan gum is used as a suspending agent in both of the above two spironolactone oral suspensions. However, xanthan gum is prone to form lumps when swelling in water and requires long-term stirring to be evenly dispersed, resulting in a long preparation time for the spironolactone oral suspension. Moreover, during production and storage, the xanthan gum solution will spontaneously form micelles, which will form a tail when using a laser particle size analyzer to detect the particle size of the preparation, affecting the detection of the particle size distribution of the product and being unfavorable for the control and monitoring of the drug quality. Therefore, preparing a spironolactone oral suspension without xanthan gum is of great significance for improving the quality of the preparation.

[0005] Sodium Carboxymethyl Cellulose (CMC-Na for short) is a multifunctional material widely used in many industries. CMC-Na forms a viscous solution after being dissolved in water, and has good thickening, film-forming, bonding, lubrication and stability properties. CMC-Na can be used as an excellent suspending agent, which can effectively increase the viscosity of the suspension and slow down the sedimentation rate of solid particles, thereby improving the stability of the suspension. Patent US4837211A discloses adding an appropriate amount of water to a solid mixture containing about 5-95% spironolactone and about 10-95% sodium carboxymethyl cellulose. In the resulting liquid composition, spironolactone at a concentration of about 0.1-1.0% can effectively suspend and defoam. However, patent US20170119796A1 discloses that although the above method can overcome the problem of uniformity, the resulting suspension does not have long-term stability. After storage at 25±2°C and 40±5% relative humidity, it will cause increased sedimentation, and can only be mixed by shaking violently for 60-120s. This greatly reduces patient compliance, especially for elderly patients, if spironolactone is not evenly dispersed throughout the suspension, the possibility of dosing errors is greatly increased. Therefore, it is of great significance to prepare a spironolactone oral suspension with a simple preparation process, suitable for mass production, stable product quality and good re-suspensibility. Summary of the invention

[0006] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a spironolactone oral suspension and a preparation method thereof. Compared with the existing composition and preparation method, the spironolactone oral suspension provided by the present invention has a simple production process, is suitable for mass production, has a high degree of control over product quality, has good re-suspensibility of the obtained product, and improves the convenience of taking medicine for patients and the accuracy of dosage.

[0007] In order to achieve the above object, the technical solution of the present invention is:

[0008] The first aspect of the present invention provides a spironolactone oral suspension, which comprises, by weight:

[0009] 5 parts of spironolactone, 2.25-4.5 parts of antibacterial agent, 4-7.5 parts of pH regulator, 1-3 parts of defoaming agent, 0.5-6 parts of suspending agent, 3-8 parts of sweetener, 18-25 parts of wetting agent, 2-4 parts of flavoring agent, 970-1020 parts of water;

[0010] The defoaming agent is simethicone emulsion, and the suspending agent is sodium carboxymethyl cellulose.

[0011] In the present invention, xanthan gum is replaced with sodium carboxymethyl cellulose which is more easily dispersed and less likely to form agglomerates. During the production process, sodium carboxymethyl cellulose can be completely dissolved and dispersed without the need for long-term stirring, simplifying the production process, shortening the production time, effectively saving costs, and the dispersed solution is uniform without forming micelles, avoiding the interference of xanthan gum on the detection of product particle size distribution, and being beneficial to product quality control and monitoring. The present invention also limits the ratio of spironolactone to sodium carboxymethyl cellulose and adds dimethicone emulsion as an antifoaming agent. The redispersibility of the suspension in the obtained product is good, and the uniform dispersion of spironolactone can be achieved by shaking for 5 - 10 s, which is beneficial to improving patient compliance and the accuracy of the administered dose.

[0012] In some embodiments of the present invention, the concentration of spironolactone in the spironolactone oral suspension is 5 mg / mL.

[0013] In some embodiments of the present invention, the bacteriostatic agent is selected from at least one of sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, butylated hydroxytoluene, and butylated hydroxyanisole; preferably, the bacteriostatic agent is sorbic acid and potassium sorbate.

[0014] In some embodiments of the present invention, the pH regulator is selected from at least one of anhydrous citric acid, sodium citrate, acetate, aconitate, glutarate, malate, succinate, and tartrate; preferably, the pH regulator is anhydrous citric acid and sodium citrate.

[0015] In some embodiments of the present invention, the sweetening agent is selected from at least one of aspartame, sodium saccharin, sucralose, ammonium glycyrrhizinate, and sodium cyclamate; preferably, the sweetening agent is aspartame.

[0016] In some embodiments of the present invention, the wetting agent is selected from at least one of glycerol, propylene glycol, and a mixture of glycerol and propylene glycol; preferably, the wetting agent is glycerol.

[0017] In some embodiments of the present invention, the flavoring agent is essence, preferably, the essence is selected from at least one of banana essence, cherry essence, orange essence, and strawberry essence.

[0018] In some embodiments of the present invention, the spironolactone oral suspension, by mass fraction, comprises:

[0019] 5 parts of spironolactone, 0.25 - 0.5 part of sorbic acid, 2 - 4 parts of potassium sorbate, 1 - 2.5 parts of anhydrous citric acid, 3 - 5 parts of sodium citrate, dimethicone emulsion, 0.5 - 6 parts of sodium carboxymethyl cellulose, 3 - 8 parts of aspartame, 18 - 25 parts of glycerol, 2 - 4 parts of essence, and 970 - 1020 parts of water.

[0020] In the present invention, simethicone emulsion is used as a defoaming agent and carboxymethyl cellulose is used as a suspending agent, and the synergistic effects of defoaming and thickening are good. This prescription is one of the better prescriptions in the embodiments of the present invention.

[0021] In some embodiments of the present invention, the spironolactone oral suspension comprises, by weight:

[0022] 5 parts of spironolactone, 0.5 parts of sorbic acid, 2 parts of potassium sorbate, 1.8 parts of anhydrous citric acid, 4.6 parts of sodium citrate, 2 parts of simethicone emulsion, 4 parts of sodium carboxymethyl cellulose, 5 parts of aspartame, 20 parts of glycerin, 3 parts of flavor, water;

[0023] The amount of water used is such that the concentration of spironolactone in the spironolactone oral suspension reaches 5 mg / mL.

[0024] This prescription is one of the best prescriptions in the embodiments of the present invention.

[0025] In some embodiments of the present invention, the spironolactone oral suspension comprises, by weight:

[0026] 5 parts of spironolactone, 0.5 parts of sorbic acid, 2 parts of potassium sorbate, 1.8 parts of anhydrous citric acid, 4.6 parts of sodium citrate, 2 parts of simethicone emulsion, 6 parts of sodium carboxymethyl cellulose, 4 parts of aspartame, 20 parts of glycerin, 3 parts of flavor, water;

[0027] The amount of water used is such that the concentration of spironolactone in the spironolactone oral suspension reaches 5 mg / mL.

[0028] This prescription is one of the better prescriptions in the embodiments of the present invention.

[0029] A second aspect of the present invention is a method for preparing the above-mentioned spironolactone oral suspension, comprising:

[0030] Dissolving sodium carboxymethylcellulose in part of water, adding simethicone emulsion and stirring, then adding antibacterial agent and sweetener and stirring, then adding pH adjuster and stirring to obtain a first solution;

[0031] dissolving spironolactone in a wetting agent to obtain a first suspension;

[0032] The first suspension is added to the first solution, a flavoring agent is added and stirred, water is added to a set amount, and the mixture is stirred to obtain a spironolactone oral suspension.

[0033] In some embodiments of the present invention, the preparation method includes adding sodium carboxymethyl cellulose to a part of water, stirring, and mixing evenly. It should be noted that the present invention does not limit the stirring speed and stirring time in this step, as long as the goal of sufficient mixing can be achieved. For example, a certain stirring speed can be adopted to make sodium carboxymethyl cellulose fully swell and mix evenly. It can be stirred at a stirring speed of 500 - 1500 rpm for 10 - 20 min, or other stirring speeds and stirring times can also be selected.

[0034] In some embodiments of the present invention, after adding simethicone emulsion, or after adding bacteriostatic agent and sweetening agent, or after adding pH regulator, it is stirred at a stirring speed of 500 - 1500 rpm for 5 - 15 min.

[0035] In some embodiments of the present invention, the preparation method includes adding spironolactone to a wetting agent and dispersing spironolactone evenly at a stirring speed of 1500 - 2500 rpm.

[0036] In some embodiments of the present invention, the preparation method includes adding the first suspension to the first solution under stirring, and the stirring speed is 800 - 1200 rpm.

[0037] In some embodiments of the present invention, after adding flavoring agent, it is stirred at a stirring speed of 500 - 1500 rpm for 3 - 10 min.

[0038] The beneficial effects of the present invention are as follows:

[0039] The present invention provides an oral suspension of spironolactone. Xanthan gum is replaced with sodium carboxymethyl cellulose which is more easily dispersed and not easy to form clusters. During the production process, sodium carboxymethyl cellulose can be completely dissolved and dispersed without long - time stirring, which simplifies the production process, shortens the production time, effectively saves costs, and the dispersed solution is uniform and will not form micelles, avoiding the interference of xanthan gum on the detection of product particle size distribution, which is beneficial to product quality control and monitoring. The present invention also limits the ratio of spironolactone to sodium carboxymethyl cellulose and adds simethicone emulsion as an antifoaming agent. The redispersion property of the suspension in the obtained product is good, and the spironolactone can be evenly dispersed by shaking for 5 - 10 s, which is beneficial to improving patient compliance and the accuracy of the administered dose. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The specification drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0041] Figure 1 It is the particle size distribution diagram of the oral suspension of spironolactone prepared in Example 1 of the present invention;

[0042] Figure 2 It is the particle size distribution diagram of the spironolactone oral suspension prepared in Example 3 of the present invention;

[0043] Figure 3 It is the particle size distribution diagram of the spironolactone oral suspension prepared in Comparative Example 1 of the present invention;

[0044] Figure 4 It is the particle size distribution diagram of the spironolactone oral suspension prepared in Comparative Example 2 of the present invention;

[0045] Figure 5 It is the particle size distribution diagram of the spironolactone oral suspension prepared in Comparative Example 3 of the present invention;

[0046] Figure 6 It is the particle size distribution diagram of the spironolactone oral suspension prepared in Comparative Example 4 of the present invention; Figure 7 It is the particle size distribution diagram of the spironolactone oral suspension prepared in Comparative Example 5 of the present invention. Detailed implementation manners

[0047] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0048] In the following examples, the drugs and reagents used are all conventional commercially available products and can be obtained by purchase.

[0049] Example 1

[0050] The composition of a batch of 2 L spironolactone oral suspension is shown in Table 1.

[0051] Table 1 Prescription composition of Example 1

[0052] Material Name Dosage (g) Usage Spironolactone 10 Active Ingredient Sorbic Acid 1 Bacteriostatic Agent Potassium Sorbate 4 Bacteriostatic Agent Anhydrous Citric Acid 3.6 pH Regulator Sodium Citrate 9.2 pH Regulator Simethicone Emulsion 4 Defoaming Agent Sodium Carboxymethylcellulose 8 Suspending Agent Aspartame 10 Sweetening Agent Glycerol 40 Wetting Agent Essence 6 Flavoring Agent Purified Water Up to 2L Dispersion Medium

[0053] The preparation method of the above spironolactone oral suspension is as follows:

[0054] (1) Add sodium carboxymethylcellulose to 1.6 L of purified water, stir at 1000 rpm for 15 min to disperse, add silicone oil emulsion and continue to stir for 10 min, add sorbic acid, potassium sorbate, aspartame and stir at 1000 rpm for 10 min, add anhydrous citric acid and sodium citrate and stir at 1000 rpm for 10 min to obtain the first solution;

[0055] (2) Take another container, add spironolactone to glycerol, stir at 2000 rpm to disperse spironolactone evenly to obtain the first suspension;

[0056] (3) Under the condition of stirring at 1000 rpm, add the first suspension into the first solution, add essence and stir for 5 min, supplement purified water to 2 L, and continue stirring for 10 min to make the mixture uniform, thus obtaining the spironolactone oral suspension.

[0057] Sodium carboxymethylcellulose is added to purified water and dispersed for 15 min to obtain a clear and transparent solution. Finally, the prepared spironolactone oral suspension is observed to have no obvious lumps and the spironolactone is evenly dispersed.

[0058] Example 2

[0059] A batch of 20 L of spironolactone oral suspension is composed as shown in Table 2.

[0060] Table 2 Prescription composition of Example 2

[0061] Material Name Dosage (g) Usage Spironolactone 100 Active Ingredient Sorbic Acid 10 Bacteriostatic Agent Potassium Sorbate 40 Bacteriostatic Agent Anhydrous Citric Acid 36 pH Regulator Sodium Citrate 92 pH Regulator Simethicone Emulsion 40 Defoaming Agent Sodium Carboxymethylcellulose 120 Suspending Agent Aspartame 80 Sweetening Agent Glycerol 400 Wetting Agent Essence 60 Flavoring Agent Purified Water Up to 20L Dispersion Medium

[0062] The preparation method of the above spironolactone oral suspension is as follows:

[0063] (1) Add sodium carboxymethylcellulose to 16 L of purified water, disperse it by stirring at 1000 rpm for 15 min, add silicone oil emulsion and continue stirring for 10 min, add sorbic acid, potassium sorbate, aspartame and stir at 1000 rpm for 10 min, add anhydrous citric acid and sodium citrate and stir at 1000 rpm for 10 min to obtain the first solution.

[0064] (2) Take another container, add spironolactone to glycerol, and stir at 2000 rpm to make the spironolactone evenly dispersed to obtain the first suspension.

[0065] (3) Under the condition of stirring at 1000 rpm, add the first suspension into the first solution, add essence and stir for 5 min, supplement purified water to 20 L, and continue stirring for 10 min to make the mixture uniform, thus obtaining the spironolactone oral suspension.

[0066] Sodium carboxymethylcellulose is added to purified water and dispersed for 15 min to obtain a clear and transparent solution. Finally, the prepared spironolactone oral suspension is observed to have no obvious lumps and the spironolactone is evenly dispersed.

[0067] Comparative Example 1

[0068] Prepare the composition by replacing sodium carboxymethylcellulose with xanthan gum. A batch of 2 L of spironolactone oral suspension is composed as shown in Table 3.

[0069] Table 3 Prescription composition of Comparative Example 1

[0070]

[0071]

[0072] The preparation method of the above spironolactone oral suspension is as follows:

[0073] (1) Add xanthan gum to 1.6 L of purified water, stir at 1000 rpm for 30 min for dispersion, add silicone oil emulsion and continue stirring for 10 min, add sorbic acid, potassium sorbate, aspartame and stir at 1000 rpm for 10 min, add anhydrous citric acid and sodium citrate and stir at 1000 rpm for 10 min to obtain the first solution;

[0074] (2) Take another container, add spironolactone to glycerol, stir at 2000 rpm to disperse spironolactone evenly to obtain the first suspension;

[0075] (3) Under stirring at 1000 rpm, add the first suspension to the first solution, add essence and stir for 5 min, make up purified water to 2 L, and continue stirring for 10 min to make it evenly mixed, then the spironolactone oral suspension is obtained.

[0076] Compared with sodium carboxymethylcellulose, when xanthan gum is used as a suspending agent and added to purified water for dispersion, there are a large number of lumps, the dispersion time is longer, and obvious lumps exist in the finally prepared spironolactone oral suspension, and the aggregation of the active pharmaceutical ingredient is obvious.

[0077] Comparative Example 2

[0078] The composition was prepared by replacing sodium carboxymethylcellulose with xanthan gum, and a batch of 2 L spironolactone oral suspension is shown in Table 4.

[0079] Table 4 Prescription composition of Comparative Example 2

[0080] Material Name Dosage (g) Usage Spironolactone 10 Active Ingredient Sorbic Acid 1 Bacteriostatic Agent Potassium Sorbate 4 Bacteriostatic Agent Anhydrous Citric Acid 3.6 pH Regulator Sodium Citrate 9.2 pH Regulator Simethicone Emulsion 4 Defoaming Agent Xanthan Gum 8 Suspending Agent Aspartame 10 Sweetening Agent Glycerol 40 Wetting Agent Essence 6 Flavoring Agent Purified Water Up to 2L Dispersion Medium

[0081] The preparation method of the above spironolactone oral suspension was optimized for the xanthan gum lump phenomenon, and the steps are as follows:

[0082] Add xanthan gum to 1.6 L of purified water, stir at 1000 rpm for 30 min for dispersion, and filter through a 20 μm HPP filter membrane;

[0083] Add silicone oil emulsion and continue stirring for 10 min, add sorbic acid, potassium sorbate, aspartame and stir at 1000 rpm for 10 min, add anhydrous citric acid and sodium citrate and stir at 1000 rpm for 10 min to obtain the first solution;

[0084] (3) Take another container, add spironolactone to glycerol, stir at 2000 rpm to disperse spironolactone evenly to obtain the first suspension;

[0085] (4) While stirring at 1000 rpm, add the first suspension into the first solution, add essence and stir for 5 min, supplement purified water to 2 L, and continue stirring for 10 min to make it evenly mixed, thus obtaining spironolactone oral suspension.

[0086] Compared with sodium carboxymethylcellulose, when xanthan gum is used as a suspending agent and added to purified water for dispersion, the dispersion time is longer. After filtering through a 20-μm filter membrane, there are no obvious lumps in the xanthan gum solution. Finally, the spironolactone oral suspension prepared has no obvious lumps and the aggregation of the active pharmaceutical ingredient is not obvious, but this process is relatively complex.

[0087] Comparative Example 3

[0088] Replace sodium carboxymethylcellulose with carbomer to prepare the composition. The composition of a batch of 2-L spironolactone oral suspension is shown in Table 5.

[0089] Table 5 Composition of the Prescription in Comparative Example 3

[0090]

[0091]

[0092] The preparation method of the above spironolactone oral suspension is as follows:

[0093] (1) Add carbomer into 1.6 L of purified water, stir at 1000 rpm for 30 min for dispersion, add silicone oil emulsion and continue stirring for 10 min, add sorbic acid, potassium sorbate, and aspartame, stir at 1000 rpm for 10 min, add anhydrous citric acid and sodium citrate, and stir at 1000 rpm for 10 min to obtain the first solution;

[0094] (2) Take another container, add spironolactone into glycerol, and stir at 2000 rpm to make the spironolactone evenly dispersed to obtain the first suspension;

[0095] (3) While stirring at 1000 rpm, add the first suspension into the first solution, add essence and stir for 5 min, supplement purified water to 2 L, and continue stirring for 10 min to make it evenly mixed, thus obtaining spironolactone oral suspension.

[0096] Compared with sodium carboxymethylcellulose, when carbomer is used as a suspending agent and added to purified water for dispersion, the dispersion time is longer. Finally, the spironolactone oral suspension prepared has lumps and obvious aggregation of the active pharmaceutical ingredient.

[0097] Comparative Example 4

[0098] Replace sodium carboxymethylcellulose with gum arabic to prepare the composition. The composition of a batch of 2-L spironolactone oral suspension is shown in Table 6.

[0099] Table 6 Composition of the Composition in Comparative Example 4

[0100]

[0101]

[0102] The preparation method of the above spironolactone oral suspension is as follows:

[0103] (1) Add gum arabic to 1.6 L of purified water, stir at 1000 rpm for 30 min for dispersion, add silicone oil emulsion and continue to stir for 10 min, add sorbic acid, potassium sorbate, aspartame and stir at 1000 rpm for 10 min, add anhydrous citric acid and sodium citrate and stir at 1000 rpm for 10 min to obtain the first solution;

[0104] (2) Take another container, add spironolactone to glycerol, stir at 2000 rpm to disperse spironolactone evenly to obtain the first suspension;

[0105] (3) Under the condition of stirring at 1000 rpm, add the first suspension to the first solution, add essence and stir for 5 min, make up purified water to 2 L, and continue to stir for 10 min to make it evenly mixed, then the spironolactone oral suspension is obtained.

[0106] Compared with sodium carboxymethylcellulose, when using gum arabic as a suspending agent and adding it to purified water for dispersion, the dispersion time is longer, and there are still lumps in the finally prepared spironolactone oral suspension.

[0107] Comparative Example 5

[0108] Modify the mass ratio of spironolactone to sodium carboxymethylcellulose to 1:1.5, add silicone oil emulsion as an antifoaming agent to prepare the composition, and the composition of a batch of 2 L spironolactone oral suspension is shown in Table 7.

[0109] Table 7 Composition of the composition in Comparative Example 5

[0110] Material Name Dosage (g) Usage Spironolactone 10 Active Ingredient Sorbic Acid 1 Bacteriostatic Agent Potassium Sorbate 4 Bacteriostatic Agent Anhydrous Citric Acid 3.6 pH Regulator Sodium Citrate 9.2 pH Regulator Simethicone Emulsion 4 Defoaming Agent Sodium Carboxymethylcellulose 15 Suspending Agent Aspartame 10 Sweetening Agent Glycerol 40 Wetting Agent Essence 6 Flavoring Agent Purified Water Up to 2L Dispersion Medium

[0111] The preparation method of the above spironolactone oral suspension is as follows:

[0112] (1) Add sodium carboxymethylcellulose to 1.6 L of purified water, stir at 1000 rpm for 30 min for dispersion, add silicone oil emulsion and continue to stir for 10 min, add sorbic acid, potassium sorbate, aspartame and stir at 1000 rpm for 10 min, add anhydrous citric acid and sodium citrate and stir at 1000 rpm for 10 min to obtain the first solution;

[0113] (2) Take another container, add spironolactone to glycerol, stir at 2000 rpm to disperse spironolactone evenly to obtain the first suspension;

[0114] (3) While stirring at 1000 rpm, add the first suspension into the first solution, add essence and stir for 5 min, supplement purified water to 2 L, and continue stirring for 10 min to make it evenly mixed, thus obtaining spironolactone oral suspension.

[0115] By changing the ratio of spironolactone to sodium carboxymethylcellulose and adding dimethicone emulsion as an antifoaming agent, the finally prepared spironolactone oral suspension was observed to have no obvious lumps, and spironolactone was evenly dispersed, but the solution viscosity was on the high side, not easy to pour, and not conducive to accurate dosage distribution during the use by patients.

[0116] Detection of key attributes of the compositions in each example and comparative example:

[0117] Detect the properties, pH value, particle size, viscosity, sedimentation volume ratio, redispersibility and total impurities of the compositions in each example and comparative example. The particle size is detected by the laser particle size analyzer method. The detection results are shown in Tables 11, 12 and 13. The specific detection methods are as follows:

[0118] 1. Properties: Take an appropriate amount of this product and visually observe it in a well-lit place.

[0119] 2. pH value:

[0120] (1) Calibration of pH meter: Select the standard buffer solution according to the sample detection value, and calibrate the pH meter according to the instrument operation procedure.

[0121] (2) Take this product and determine it according to law (General Chapter 0631, Volume IV, Chinese Pharmacopoeia 2020 Edition), repeat the determination 2 times, and take the average value.

[0122] 3. Particle size:

[0123] (1) Solution preparation:

[0124] Saturated spironolactone solution: Weigh 1 g of spironolactone raw material medicine, add 10 L of water, ultrasonicate for 3 h, and filter by suction through a 0.22 μm filter membrane (PES) to obtain it.

[0125] (2) The detection method parameters are shown in Table 8.

[0126] Table 8 Detection parameters

[0127] Sample Name Spironolactone Oral Suspension Refractive Index 1.54 Absorptivity 0.100 Density <![CDATA[1.00g / cm 3 > Dispersant Name Saturated Spironolactone Solution Refractive Index 1.330 Dispersion Model General Sensitivity Conventional Particle Type Non-spherical Ultrasonic Intensity before Measuring in Sample Cell 50％ Ultrasonic Time before Measuring in Sample Cell 120s Background Measuring Time 10s Sample Measuring Time 12s Number of Cycles 3 Interval Time 0s Rotational Speed 1800 rpm / min Light Shielding Rate 8% - 20% (Actually 10% - 12%)

[0128] (3) Determination method

[0129] Turn on the computer, run the software to set each test parameter with "detection method parameters". Measure 500 mL of saturated spironolactone solution as the detection dispersion medium. Initialize the instrument. After deducting the background, use a dropper to add the self-developed sample (about 8 mL). Wait until the light obscuration is within the range of 8% - 20% (actual: 10% - 12%). Stop adding the sample, click to start the detection. The sample detection time is 12 s. Collect data, measure three times continuously. After saving the spectrum, clean the instrument and prepare for the next measurement.

[0130] 4. Viscosity:

[0131] Take 10 mL of the test sample and inject it into the outer cylinder of the coaxial cylinder rotational viscometer. Immerse the inner cylinder into the sample in the outer cylinder to the specified height. Use a No. 21 rotor, adjust the rotation speed to 40 rpm. Drive the inner cylinder or the outer cylinder to rotate through the motor, measure the rotational angular velocity (ω) and the torque (M) received by the surface of the rotating cylinder. Substitute the parameters of the measurement system into the following formula to calculate the dynamic viscosity of the sample:

[0132]

[0133] In the formula, η is the dynamic viscosity, Pa·s;

[0134] M is the torque on the surface of the rotating cylinder, N·m;

[0135] h is the depth of the inner cylinder immersed in the sample, m;

[0136] ω is the angular velocity of the inner cylinder's self-rotation, rad / s;

[0137] Ri and Ro are the radii of the inner cylinder and the outer cylinder respectively, m.

[0138] 5. Sedimentation volume ratio:

[0139] Use a 100 mL stoppered graduated cylinder to measure 50 mL of the test sample, stopper it tightly, shake it vigorously for 1 minute, and record the initial height H of the suspension 0 , let it stand for 3 hours, record the final height H of the suspension, and calculate according to the following formula:

[0140] Sedimentation volume ratio = H / H 0

[0141] 6. Redispersibility:

[0142] Take the test sample solution after standing for 3 hours in the sedimentation volume ratio test item. After sedimentation, gently shake it again to observe the redispersion of the sample. The solution of the sample can be quickly redispersed after being shaken again.

[0143] 7. Related substances (total impurities):

[0144] (1) Preparation of the solution

[0145] Blank solution (diluent): Measure 80 mL of acetonitrile, 180 mL of tetrahydrofuran, and 740 mL of water. Shake well to obtain.

[0146] Mobile phase preparation: Mobile phase A [acetonitrile - tetrahydrofuran - water (8:18:74)]: Measure 80 mL of acetonitrile, 180 mL of tetrahydrofuran, and 740 mL of water. Shake well and ultrasonicate to obtain.

[0147] Mobile phase B: Acetonitrile.

[0148] Blank excipient solution: Precisely measure 1 mL of blank excipient, place it in a 50 mL volumetric flask, dilute to the mark with diluent, and shake well to obtain.

[0149] Reference stock solution

[0150] Spironolactone stock solution (5 μg / mL): Precisely weigh 5 mg of spironolactone, place it in a 20 mL volumetric flask, dissolve and dilute to the mark with diluent, shake well. Precisely measure 1 mL and place it in a 50 mL volumetric flask, dilute to the mark with diluent, and shake well to obtain.

[0151] Impurity F stock solution (50 μg / mL): Precisely weigh 5 mg of impurity F (canrenone), place it in a 100 mL volumetric flask, dissolve and dilute to the mark with diluent, and shake well to obtain.

[0152] Note: An appropriate amount of ethanol (3 - 5 mL) can be added to dissolve it, and then dilute to the mark with diluent.

[0153] Reference solution (spironolactone: 0.2 μg / mL, impurity F: 2.0 μg / mL): Precisely measure 2 mL of impurity F (canrenone) stock solution and 2 mL of spironolactone stock solution, place them in a 50 mL volumetric flask, dilute to the mark with diluent, and shake well to obtain.

[0154] System suitability solution (spironolactone: 100 μg / mL, impurity F: 2.0 μg / mL): Weigh 5 mg of spironolactone reference substance, place it in a 50 mL volumetric flask, add 2 mL of impurity F (canrenone) stock solution, dissolve and dilute to the mark with diluent, and shake well to obtain.

[0155] Note: An appropriate amount of ethanol (3 - 5 mL) can be added to dissolve it, and then dilute to the mark with diluent.

[0156] Test solution (100 μg / mL): Precisely measure 1 mL of spironolactone oral suspension (equivalent to 5 mg of the main component), place it in a 50 mL volumetric flask, dilute to the mark with diluent, and shake well to obtain.

[0157] Note: When preparing the test solution, first add 10 - 20 mL of diluent to the volumetric flask, then measure this product into the volumetric flask. When diluting with diluent, add it while shaking the volumetric flask, and make the volume constant after fully dissolving.

[0158] (2) Chromatographic conditions

[0159] Chromatographic column: Agilent ZORBAX SB-C8, 150×4.6 mm, 3.5 μm;

[0160] Mobile phase A: Acetonitrile - tetrahydrofuran - water (8∶18∶74);

[0161] Mobile phase B: Acetonitrile;

[0162] Flow rate: 1.8 mL / min;

[0163] Detection wavelength: 254 nm;

[0164] Column temperature: 50 °C;

[0165] Sample injection volume: 50 μL;

[0166] The elution program is shown in Table 9 below.

[0167] Table 9 Elution program

[0168] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 100 0 35 100 0 35.1 0 100 50 0 100 50.1 100 0 60 100 0

[0169] (3) Operating method

[0170] Precisely measure the blank solution, blank excipient solution, system suitability solution, reference solution and test solution, and inject them into the liquid chromatograph respectively, and record the chromatogram. Among them, the number of sample injections and requirements are shown in Table 10.

[0171] Table 10 Number of sample injections and requirements for related substance determination

[0172]

[0173] (4) Calculation formula

[0174]

[0175]

[0176] In the formula: B: Content of the reference substance; M 对 : Weighing amount of the reference substance (mg); A 对 : Peak area of the reference solution; V 对 : Dilution volume of the reference solution (mL); A 供 : Peak area of the test substance; V 供 : Dilution volume of the test substance mL; V transfer: Volume of the test substance taken (mL).

[0177] Table 11 Detection results of the properties, pH value and particle size of the composition

[0178]

[0179]

[0180] Table 12 Detection Results of Viscosity, Sedimentation Volume Ratio and Redispersibility of the Composition

[0181] Sample Viscosity Sedimentation Volume Ratio Redispersibility Example 1 43 mPa·s 1.0 5s Example 2 180 mPa·s 1.0 10s Control Example 1 112 mPa·s 1.0 15s Control Example 2 110 mPa·s 1.0 15s Control Example 3 156 mPa·s 1.0 40s Control Example 4 79 mPa·s 1.0 60s Control Example 5 218 mPa·s 1.0 40s

[0182] Table 13 Total Impurity Detection Results of Related Substances of the Composition

[0183]

[0184]

[0185] It can be seen from the preparation processes of the compositions of each example and comparative example that using sodium carboxymethylcellulose as a suspending agent has the simplest process and a shorter dispersion time, which can effectively save costs.

[0186] It can be seen from the detection results of the compositions of each example and comparative example that when using sodium carboxymethylcellulose as a suspending agent, qualified products can be obtained in both small and large batches. When using xanthan gum, carbomer and gum arabic as suspending agents, the particle size of the composition is affected by the suspending agent, and qualified samples cannot be prepared.

[0187] It can be seen from the examples and comparative examples that the compositions of Example 1 and Example 2 are the best compositions for preparing spironolactone oral suspension.

[0188] It can be seen from the detection results of the compositions of Example 1, Example 2 and Comparative Example 5 that spironolactone and sodium carboxymethylcellulose should be in a certain proportion. Exceeding this proportion will result in too high solution viscosity, affecting the accuracy of dosing, and the redispersibility will become poor during clinical use, affecting the safety and effectiveness of clinical use.

[0189] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A spironolactone oral suspension, characterized in that In parts by mass, including: 5 parts of spironolactone, 2.25-4.5 parts of antibacterial agent, 4-7.5 parts of pH regulator, 1-3 parts of defoaming agent, 0.5-6 parts of suspending agent, 3-8 parts of sweetener, 18-25 parts of wetting agent, 2-4 parts of flavoring agent, 970-1020 parts of water; The defoaming agent is simethicone emulsion, and the suspending agent is sodium carboxymethyl cellulose.

2. The spironolactone oral suspension according to claim 1, wherein The concentration of spironolactone in the spironolactone oral suspension is 5 mg / mL; The antibacterial agent is selected from at least one of sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, butylated hydroxytoluene and butylated hydroxyanisole; preferably, the antibacterial agent is sorbic acid and potassium sorbate; The pH regulator is selected from at least one of anhydrous citric acid, sodium citrate, acetate, aconitate, glutarate, malate, succinate and tartrate; preferably, the pH regulator is anhydrous citric acid and sodium citrate; The sweetener is selected from at least one of aspartame, saccharin sodium, sucralose, ammonium glycyrrhizinate and sodium cyclamate; preferably, the sweetener is aspartame; The wetting agent is selected from at least one of glycerol, propylene glycol, and a mixture of glycerol and propylene glycol; preferably, the wetting agent is glycerol; The flavoring agent is an essence. Preferably, the essence is selected from at least one of banana essence, cherry essence, orange essence and strawberry essence.

3. The spironolactone oral suspension according to claim 2, wherein The spironolactone oral suspension comprises, by weight: 5 parts of spironolactone, 0.25-0.5 parts of sorbic acid, 2-4 parts of potassium sorbate, 1-2.5 parts of anhydrous citric acid, 3-5 parts of sodium citrate, simethicone emulsion, 0.5-6 parts of sodium carboxymethyl cellulose, 3-8 parts of aspartame, 18-25 parts of glycerin, 2-4 parts of flavor, and 970-1020 parts of water.

4. The spironolactone oral suspension according to claim 2, wherein The spironolactone oral suspension comprises, by weight: 5 parts of spironolactone, 0.5 parts of sorbic acid, 2 parts of potassium sorbate, 1.8 parts of anhydrous citric acid, 4.6 parts of sodium citrate, 2 parts of simethicone emulsion, 4 parts of sodium carboxymethyl cellulose, 5 parts of aspartame, 20 parts of glycerin, 3 parts of flavor, water; The amount of water used is such that the concentration of spironolactone in the spironolactone oral suspension reaches 5 mg / mL.

5. The spironolactone oral suspension according to claim 2, characterized in that The spironolactone oral suspension comprises, by weight: 5 parts of spironolactone, 0.5 parts of sorbic acid, 2 parts of potassium sorbate, 1.8 parts of anhydrous citric acid, 4.6 parts of sodium citrate, 2 parts of simethicone emulsion, 6 parts of sodium carboxymethyl cellulose, 4 parts of aspartame, 20 parts of glycerin, 3 parts of flavor, water; The amount of water used is such that the concentration of spironolactone in the spironolactone oral suspension reaches 5 mg / mL.

6. A method for preparing the spironolactone oral suspension according to claim 1, characterized in that: include: Dissolving sodium carboxymethylcellulose in part of water, adding simethicone emulsion and stirring, then adding antibacterial agent and sweetener and stirring, then adding pH adjuster and stirring to obtain a first solution; dissolving spironolactone in a wetting agent to obtain a first suspension; The first suspension is added to the first solution, a flavoring agent is added and stirred, water is added to a set amount, and the mixture is stirred to obtain a spironolactone oral suspension.

7. The preparation method according to claim 6, characterized in that: The preparation method comprises adding sodium carboxymethyl cellulose into a portion of water, stirring and mixing uniformly.

8. The preparation method according to claim 6, characterized in that: After adding the simethicone emulsion, or after adding the antibacterial agent and the sweetener, or after adding the pH adjuster, stirring is performed at a stirring speed of 500-1500 rpm for 5-15 minutes.

9. The preparation method according to claim 6, characterized in that: The preparation method comprises adding spironolactone into a wetting agent and uniformly dispersing the spironolactone at a stirring speed of 1500-2500 rpm.

10. The preparation method according to claim 6, characterized in that: The preparation method comprises adding the first suspension to the first solution under stirring at a stirring speed of 800-1200 rpm; Preferably, after adding the flavoring agent, stirring is performed at a stirring speed of 500-1500 rpm for 3-10 min.

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