Pharmaceutical composition containing spironolactone, preparation method and application thereof

Abstract

The present application belongs to the field of pharmacy, and discloses a pharmaceutical composition containing spironolactone, a preparation method thereof, and an application thereof, wherein the composition comprises spironolactone, a matrix selected from at least one of stearic acid, cellulose acetate, octadecyl alcohol, beeswax, and cellulose acetate phthalate, and an auxiliary material. The microtablets of the spironolactone pharmaceutical composition of the present application are small in size, and are easy for children to take in divided doses; the dissolution rate and the bioavailability of improving in vivo absorption are high.

Description

Field of the Invention

[0001] The present application belongs to the field of pharmacy. Specifically, the present application provides a pharmaceutical composition containing spironolactone and a preparation method and application thereof. Background Art

[0002] Spironolactone is chemically named 17β-hydroxy-3-oxo-7α-(acetylthio)-17α-pregnane-4-ene-21-carboxylic acid γ-lactone. Its chemical structure is very similar to aldosterone. Therefore, it acts as a competitive inhibitor of aldosterone, acting on the distal convoluted tubule and the cortical segment of the collecting duct, antagonizing the potassium excretion and sodium retention effect of aldosterone on the above-mentioned parts, and promoting Na + and water discharge, reducing K + The secretion of potassium is stimulated, thus producing a diuretic effect, and it is called a "potassium-sparing diuretic". Spironolactone has a slow, mild and long-lasting diuretic effect, so it is often used in combination with the potent diuretic furosemide in clinical practice. It is mainly used for refractory edema accompanied by elevated aldosterone, such as nephrotic syndrome, ascites due to cirrhosis and congestive heart failure. Spironolactone is insoluble in water and belongs to BCS class II, with low solubility and high permeability. Its low solubility leads to low in vitro dissolution and poor in vivo bioavailability, which limits its clinical application. Increasing solubility has become the key to improving its in vitro dissolution and enhancing its efficacy.

[0003] At present, most domestic hospitals adopt the method of grinding spironolactone tablets into powder and packaging them or cutting one tablet into multiple small tablets. Although this solves the problem of clinical dosage, due to the small dosage of spironolactone for children, pharmacists need to divide one spironolactone tablet into 10 or more portions, which may lead to inaccurate dosage packaging. In addition, spironolactone is insoluble in water, and the traditional powder grinding method is highly hydrophobic and water-dispersible, which makes it difficult to ensure uniform drug dispersion and may lead to inaccurate dosage. In addition, spironolactone tablets have an unpleasant odor and a bitter taste after grinding, which affects children's medication compliance. In addition, the operation is cumbersome, and pharmacists need to perform individualized dosage division for children of different age groups, weights, and diseases, which is inconvenient for clinical medication.

[0004] Microtablets refer to miniature tablets with a diameter of less than 3 mm that are pressed by a special tablet press. Microtablets are dose-dispersible preparations. After oral administration, microtablets are evenly dispersed in the gastrointestinal tract, reducing irritation to the gastrointestinal tract. The gastrointestinal transport and absorption of drugs are less affected by the gastric emptying rate, so the individual differences are small; the drug release behavior of microtablets is the sum of the drug release behaviors of multiple small units that make up a dose. After oral administration, defects in the preparation process of individual small units will not have a serious impact on the drug release behavior of the overall preparation. For people with large individual differences in drug metabolism, such as the elderly and young children, or for drugs whose dosage needs to be adjusted at any time, microtablets are an ideal dosage form. Patients can count and take microtablets according to individual medication plans, and the measurement is more accurate. Compared with other multi-unit dosage forms, microtablets have more regular shapes and more uniform sizes. Since microtablets are pressed by fixed molds, they have the characteristics of ordinary tablets. Their tablet weight and size are precisely controllable, and the production reproducibility is good. Each microtablet unit has equal size, weight, and drug content. However, due to its smaller size, it needs to be pressed by a special tablet press with multiple punches, which places higher requirements on the fluidity, compressibility and uniformity of the powder. Summary of the invention

[0005] On the one hand, the present application provides a spironolactone-containing pharmaceutical composition, which includes spironolactone, a matrix and excipients; wherein the matrix is ​​selected from at least one of stearic acid, cellulose acetate, octadecyl alcohol, beeswax and cellulose acetate phthalate; preferably cellulose acetate.

[0006] Furthermore, the weight ratio of spironolactone to the matrix is ​​1:0.5-4, and can be 1:0.5, 1:0.8, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4 or a range formed by any two of the above values ​​and a value within the range, preferably 1:0.8-2.

[0007] In the present invention, the weight ratio of spironolactone to excipients is 1:1-5, and can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5 or a range formed by any two of the above values ​​and a value within the range, preferably 1:2-4.

[0008] In the present invention, the excipients are not limited, and can be any pharmaceutically acceptable excipients in the art. Preferably, the excipients include a binder, a disintegrant, a filler and a lubricant.

[0009] In the present invention, the term "pharmaceutically acceptable" refers to substances that can be effectively used for the intended use within the scope of pharmaceutical-medical decision-making without causing excessive toxicity, irritation, allergic response and the like.

[0010] In the present invention, the weight ratio of the binder to the disintegrant is 1:0.5-1.5, and can be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or a range formed by any two of the above values ​​and a value within the range.

[0011] In the present invention, the weight ratio of the binder to the filler is 1:3-9, and can be 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or a range formed by any two of the above values ​​and a value within the range.

[0012] In the present invention, the weight ratio of the adhesive to the lubricant is 1:0.25-0.5, and can be 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5 or a range formed by any two of the above values ​​and a value within the range.

[0013] In the present invention, the binder is not limited and is a common binder in the art, preferably at least one selected from hydroxypropyl methylcellulose, povidone K30, low-substituted hydroxypropyl cellulose and sodium carboxymethyl cellulose.

[0014] In the present invention, the disintegrant is not limited and is a common disintegrant in the art, preferably at least one selected from cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone.

[0015] In the present invention, the filler is not limited and is a common filler in the art, preferably at least one selected from microcrystalline cellulose, corn starch and lactose.

[0016] In the present invention, the lubricant is not limited and is a common lubricant in the art, preferably selected from magnesium stearate and / or stearic acid.

[0017] In the present invention, the composition is a tablet. In order to make it convenient for children to use, the tablet is a micro tablet. The diameter of the tablet is 1-3 mm, which can be 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm or a range formed by any two of the above values ​​and a value within the range. The thickness of the tablet is 1-3 mm, which can be 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm or a range formed by any two of the above values ​​and a value within the range.

[0018] In the present invention, the weight of the tablet is 10-15 mg / tablet, and can be 10 mg / tablet, 11 mg / tablet, 12 mg / tablet, 13 mg / tablet, 14 mg / tablet, 15 mg / tablet or a range formed by any two of the above values ​​and a value within the range.

[0019] In the present invention, the impurity content in the tablet is less than 0.3 weight%, and can be 0.3 weight%, 0.28 weight%, 0.25 weight%, 0.2 weight%, 0.18 weight%, 0.15 weight%, 0.1 weight%, 0.07 weight%, 0.05 weight%, 0.01 weight% or a range formed by any two of the above values ​​and a value within the range.

[0020] In the present invention, the impurities are the remaining substances except the spironolactone, matrix and auxiliary materials.

[0021] In the present invention, the dissolution amount of the tablet in vitro dissolution for 30 minutes is higher than 80%. The in vitro dissolution conditions are: 1000 ml of pH 6.8 phosphate buffer (containing 0.1% sodium dodecyl sulfate) as the dissolution medium, and the rotation speed is 75 revolutions per minute.

[0022] On the other hand, the present application provides a method for preparing a spironolactone-containing composition, the method comprising: (1) mixing spironolactone and a matrix in the presence of an organic solvent; (2) removing the organic solvent from the mixed product obtained in step (1) and then crushing it; (3) mixing the crushed product obtained in step (2) with an auxiliary material to granulate; wherein the matrix has been described above and will not be repeated here.

[0023] In the present invention, the removal method is not limited, and any method that can easily remove the solvent is sufficient, and air-blast drying is preferred.

[0024] In the present invention, the weight ratio of spironolactone to the substrate in the method is as described above and will not be repeated here.

[0025] In the present invention, the weight ratio of spironolactone and the auxiliary materials in the method is described above and will not be repeated here.

[0026] In the present invention, the weight ratio of spironolactone, matrix and excipients in the method is similar to the weight ratio in the composition, and the weight ratio of spironolactone, matrix and excipients in the composition is used as the weight ratio of the method. The weight ratio of spironolactone, matrix and excipients in the composition has been described above and will not be repeated here.

[0027] In the present invention, the types, components and dosages of the auxiliary materials in the method have been described above and will not be repeated here.

[0028] In the present invention, the organic solvent is not limited as long as it can dissolve spironolactone and the matrix and can be easily removed. It is preferably at least one of ethyl acetate, methyl acetate, methanol, ethanol, dichloromethane, n-hexane and acetone.

[0029] In the present invention, in order to make spironolactone and the matrix soluble and easy to remove, the content of spironolactone in the mixed system of step (1) is 10-40% by weight, and can be 10% by weight, 15% by weight, 20% by weight, 30% by weight, 35% by weight, 40% by weight or a range formed by any two of the above values ​​and a value within the range.

[0030] In the present invention, the mixing temperature is 10-50°C, and can be 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C or a range formed by any two of the above values ​​and a value within the range.

[0031] In the present invention, the particle size of the pulverized product is 10-100 μm, and can be 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm or a range formed by any two of the above values ​​and a value within the range.

[0032] In the present invention, the method further comprises: tableting the mixed granulation product obtained in step (3) to obtain tablets.

[0033] In the present invention, in order to obtain tablets, the tableting pressure is 10-80N, which can be 10N, 20N, 30N, 40N, 50N, 60N, 70N, 80N or a range formed by any two of the above values ​​and a value within the range.

[0034] On the other hand, the present application provides a spironolactone-containing composition prepared by the above method.

[0035] In the present invention, the spironolactone-containing composition has been described above and will not be described in detail herein.

[0036] On the other hand, the present application provides the use of the above-mentioned spironolactone-containing composition in the preparation of medicines for pediatric patients.

[0037] In the present invention, the daily dosage of spironolactone is 0.5-3 mg / kg, which can be 0.5 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.3 mg / kg, 1.5 mg / kg, 1.7 mg / kg, 2 mg / kg, 2.2 mg / kg, 2.5 mg / kg, 2.7 mg / kg, 3 mg / kg or a range formed by any two of the above values ​​and a value within the range.

[0038] In the present invention, the age of the child is 1-144 months, and can be 1 month, 10 months, 12 months, 14 months, 16 months, 20 months, 30 months, 40 months, 50 months, 60 months, 70 months, 80 months, 90 months, 100 months, 110 months, 120 months, 130 months, 140 months, 144 months or a range formed by any two of the above values, and a value within the range.

[0039] In the present invention, the patient is a patient whose disease can be treated with spironolactone. The disease can be one that has been disclosed to be treatable with spironolactone, such as nephrotic syndrome, ascites due to liver cirrhosis, and congestive heart failure, or can be one that has not been disclosed.

[0040] The spironolactone microtablets of the present application have small specifications, are easy for children to take in divided doses, and have small individual differences; tableting after forming a dispersion can improve solubility and increase in vivo absorption and bioavailability; granulation and tableting after forming a dispersion can avoid sticking during the tableting process. DETAILED DESCRIPTION

[0041] raw material:

[0042] Fiberacetyl acetate Source: Shenzhen Eastman Pharmaceutical Co., Ltd. (Eastman);

[0043] Spironolactone source: Zhejiang Langhua Pharmaceutical Co., Ltd.;

[0044] Hydroxypropyl methylcellulose: Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0045] Croscarmellose sodium: JRS PHARMA;

[0046] Microcrystalline cellulose: Jiangsu Xidian Pharmaceutical Excipients Co., Ltd.;

[0047] Stearic acid: Huzhou Zhanwang Pharmaceutical Co., Ltd.

[0048] Magnesium stearate: Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0049] Octadecanol: Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.;

[0050] Beeswax: Henan Fumei Biotechnology Co., Ltd.;

[0051] Ethylcellulose: Ashland Specialty Ingredients GP.

[0052] Example 1

[0053] (1) dissolving celloacetate in organic solvents of ethanol and acetone (the weight ratio of ethanol to acetone is 1:5), adding spironolactone raw material to dissolve, wherein the content of spironolactone is 30% by weight, the weight ratio of spironolactone to celloacetate is 1:1, and the temperature is 10-20° C.;

[0054] (2) drying the solution of step (1) to volatilize and remove the organic solvent, and crushing the obtained solid, wherein the particle size of the crushed product is 10-100 μm;

[0055] (3) The pulverized product obtained in step (2) is mixed with hypromellose, croscarmellose sodium, and microcrystalline cellulose to prepare granules, and magnesium stearate is added and mixed evenly, wherein the weight ratio of spironolactone, hypromellose, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate is 1:0.4:0.3:2:0.1.

[0056] Example 2

[0057] (1) dissolving cellulose acetate in organic solvents of ethanol and acetone (the weight ratio of ethanol to acetone is 1:4), adding spironolactone raw material to dissolve, wherein the content of spironolactone is 10 weight %, the weight ratio of spironolactone to cellulose acetate is 1:3, and the temperature is 25-35° C.;

[0058] (2) drying the solution of step (1) to volatilize and remove the organic solvent, and crushing the obtained solid to obtain a particle size of 20-90 μm;

[0059] (3) The pulverized product obtained in step (2) is mixed with hypromellose, croscarmellose sodium, and microcrystalline cellulose to prepare granules, and magnesium stearate is added and mixed evenly, wherein the weight ratio of spironolactone, hypromellose, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate is 1:0.4:0.3:2:0.1.

[0060] Example 3

[0061] (1) dissolving cellulose acetate in organic solvents of ethanol and acetone (the weight ratio of ethanol to acetone is 1:6), adding spironolactone raw material to dissolve, wherein the content of spironolactone is 20% by weight, the weight ratio of spironolactone to cellulose acetate is 1:2, and the temperature is 40-50° C.;

[0062] (2) drying the solution of step (1) to volatilize and remove the organic solvent, and crushing the obtained solid to obtain a particle size of 20-90 μm;

[0063] (3) The pulverized product obtained in step (2) is mixed with hypromellose, croscarmellose sodium, and microcrystalline cellulose to prepare granules, and magnesium stearate is added and mixed evenly, wherein the weight ratio of spironolactone, hypromellose, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate is 1:0.4:0.3:2:0.1.

[0064] Example 4

[0065] The method of Example 1 is followed, except that the weight ratio of spironolactone to cellolacetate is 1:4.

[0066] Example 5

[0067] The method of Example 1 was followed, except that the weight ratio of spironolactone to cellulose acetate was 1:0.5

[0068] Example 6

[0069] The method of Example 1 is followed, except that the cellulose acetate is replaced with stearic acid.

[0070] Example 7

[0071] The method of Example 1 is followed, except that cellulose acetate is replaced with octadecyl alcohol.

[0072] Example 8

[0073] The method of Example 1 is followed, except that the cellulose acetate is replaced with beeswax.

[0074] Example 9

[0075] The method of Example 1 is followed, except that cellulose acetate is replaced by cellulose acetate phthalate.

[0076] Comparative Example 1

[0077] The method of Example 1 was followed, except that cellulose acetate was replaced with ethyl cellulose.

[0078] Comparative Example 2

[0079] The method of Example 1 is followed, except that the weight ratio of spironolactone to cellulose acetate is 1:0.25

[0080] Comparative Example 3

[0081] (1) heating stearic acid to 80° C. to melt, adding spironolactone raw material to disperse, wherein the content of spironolactone is 50% by weight, the weight ratio of spironolactone to cellulose acetate is 1:1, and the temperature is 10-20° C.;

[0082] (2) then cooling the solution of step (1) to room temperature to obtain a solid, and crushing the solid to obtain a particle size of 10-100 μm;

[0083] (3) The pulverized product obtained in step (2) is mixed with hypromellose, cross-linked sodium carboxymethyl cellulose, and microcrystalline cellulose to prepare granules, and then stearic acid is added and mixed evenly, wherein the weight ratio of spironolactone, hypromellose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate is 1:0.4:0.3:2:0.1.

[0084] Comparative Example 4

[0085] The method of Comparative Example 3 is followed, except that stearic acid is replaced with octadecyl alcohol.

[0086] Comparative Example 5

[0087] The method of Comparative Example 3 is followed, except that stearic acid is replaced with beeswax.

[0088] Comparative Example 6

[0089] The method of Example 1 is followed, except that steps (1) and (2) are not performed, and spironolactone is directly mixed with hypromellose, croscarmellose sodium, and microcrystalline cellulose to prepare granules.

[0090] Test Case

[0091] The products obtained in the above examples and comparative examples were compressed using a micro tablet press (pressure of 50 N) and a common tablet press (pressure of 50 N), and the obtained spironolactone micro tablets had a diameter of 2.5 mm, a thickness of 2.5 mm, and a tablet weight of 12 mg / tablet; the obtained spironolactone large tablets had a diameter of 8.5 mm, a thickness of 3.5 mm, and a tablet weight of 400 mg / tablet. The commercially available spironolactone large tablets (Pfizer Labs) had a diameter of 8.5 mm, a thickness of 3.5 mm, a tablet weight of 400 mg / tablet, and a specification of 25 mg / tablet.

[0092] In vitro dissolution

[0093] The dissolution and release rate were determined according to the dissolution and release rate determination method (Chinese Pharmacopoeia 2020 General Rules 0931 Second Method). The dissolution conditions were pH 6.8 phosphate buffer (containing 0.1% sodium dodecyl sulfate) 1000 ml as the dissolution medium, the rotation speed was 75 revolutions per minute, and the operation was carried out according to the law. Samples were taken at specific times (the sampling time points of the dissolution curve were 5, 10, 15, 30, 45, 60, 90, and 120 minutes). The dissolution curves of each embodiment are shown in Table 1.

[0094] Table 1

[0095]

[0096]

[0097] Note: The unit is %

[0098] The results showed that the dissolution rates of the examples were faster than those of the commercially available preparations, while the dissolution rates of the comparative examples were slower than those of the commercially available preparations.

[0099] Pharmacokinetic parameters

[0100] Pharmacokinetics of spironolactone in beagle dog plasma after intragastric administration of 50 mg / dog. Plasma samples were collected from all animals at 13 time points, including 5 min, 15 min, 30 min, 45 min, 1 h, 1.25 h, 1.5 h, 2 h, 2.5 h, 3.5 h, 5 h, 8 h, and 12 h after administration; the samples were analyzed by LC-MS / MS to obtain the plasma concentration data of spironolactone. The canine pharmacokinetic parameters are shown in Table 2. Among them, C max Indicates the maximum blood drug concentration after administration; AUC 0-t AUC represents the area of ​​the blood drug concentration curve from the start of drug administration to the last point on the time axis, which is used to evaluate the degree of drug absorption; 0-inf It represents the area of ​​the blood drug concentration curve on the time axis during the 0-infinity period, which is used to predict the degree of drug absorption. max Indicates the time when the blood drug concentration is the highest, T 1 / 2 It indicates the time required for the blood drug concentration in the terminal phase to drop by half. This parameter directly reflects the elimination rate of the drug from the body. The bioavailability is: AUC of the embodiment or comparative example 0-t / AUC of commercially available 0-t .

[0101] Table 2

[0102]

[0103] The results in Table 2 show that the bioavailability of the spironolactone microtablets obtained using the matrix of the present invention is not lower than that of the commercially available spironolactone large tablets, while the bioavailability of the spironolactone microtablets obtained using the method of the present invention is much higher than that of the commercially available spironolactone large tablets.

[0104] Reversion

[0105] After the microchips were ground, X-ray diffraction was used to detect whether there was any crystalline form. The test results are shown in Table 3.

[0106] Table 3

[0107]

[0108] The results in Table 3 show that the spironolactone composition obtained by the method of the present invention does not appear in a crystalline state after preparing micro-tablets, while although comparative examples 1 and 2 do not appear in a crystalline state in the initial state, they still appear in a crystalline state after 6 months, and comparative examples 3-6 still appear in a crystalline state after being prepared into micro-tablets.

[0109] Sticking phenomenon

[0110] When tableting into micro-tablets and large tablets, observe whether there is sticking phenomenon on the tablet press. The observation results are shown in Table 4.

[0111] Table 4

[0112]

[0113]

[0114] The results in Table 4 show that the spironolactone composition of the present invention has no sticking phenomenon whether it is prepared into microtablets or large tablets, while Comparative Examples 3-6 have no sticking phenomenon when prepared into large tablets, but have sticking phenomenon when prepared into microtablets.

[0115] Impurities

[0116] The microtablets, large tablets and commercially available large tablets were tested for impurities by liquid chromatography. The results are shown in Tables 5 and 6.

[0117] Table 5

[0118]

[0119]

[0120] Note: The unit is % Table 6

[0121]

[0122]

[0123] Note: The unit is %

[0124] It can be seen from Tables 5 and 6 that the impurity content of the microtablets and large tablets prepared by the method of the present invention of the spironolactone composition does not change, and is lower than that of the commercially available product, while the impurity content of the microtablets prepared by the spironolactone composition obtained by other methods is higher than that of the large tablets, and is higher than that of the commercially available product.

[0125] It can be seen from the above results that the spironolactone composition of the present invention has a faster dissolution rate and higher bioavailability when prepared into tablets. The spironolactone composition obtained by the method of the present invention has no significant re-crystallization phenomenon and sticking phenomenon whether it is prepared into micro-tablets or large tablets, and the impurities will not increase.

Claims

1. A method for preparing a pharmaceutical composition containing spironolactone, characterized in that: The method comprises: (1) mixing and dissolving spironolactone and celloacetate in the presence of an organic solvent; the organic solvent is ethanol and acetone; the content of spironolactone in the mixed system is 10-40 wt %; the weight ratio of spironolactone to celloacetate is 1:1-1:3; and the mixing temperature is 10-50° C.; (2) removing the organic solvent from the mixed product obtained in step (1), and pulverizing the mixed product to obtain a pulverized product; (3) mixing the pulverized product obtained in step (2) with hypromellose, croscarmellose sodium, and microcrystalline cellulose to prepare granules, and then adding magnesium stearate to mix evenly; the weight ratio of spironolactone, hypromellose, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate is 1:0.4:0.3:2:0.1; The method further comprises: tableting the mixed granulation product obtained in step (3) to obtain tablets.

2. The method according to claim 1, wherein the particle size of the pulverized product obtained in step (2) is 10-100 μm.

3. The method according to claim 1, wherein: The tabletting pressure is 10-80N.

4. A pharmaceutical composition containing spironolactone prepared using the method according to any one of claims 1 to 3.

5. The spironolactone-containing pharmaceutical composition according to claim 4, wherein the tablet has a diameter of 1-3 mm and a thickness of 1-3 mm; And / or, the weight of the tablet is 10-15 mg / tablet; and / or, the impurity content in the tablet is less than 0.3% by weight; And / or, the dissolution amount of the tablet after in vitro dissolution for 30 minutes is higher than 80%.

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