A solifenacin succinate tablet composition and a preparation method thereof

Abstract

A solifenacin succinate pharmaceutical composition comprises solifenacin succinate 5mg, sodium hexametaphosphate 0.25-0.75mg, sorbitol 72-108mg, microcrystalline cellulose 36-72mg, magnesium stearate 0.75-2.25mg. The solifenacin succinate pharmaceutical composition has high stability, reduces the generation of impurity I, and has good total mixture material fluidity, effectively improving the content uniformity.

Description

Technical Field

[0001] This invention relates to a solifenacin succinate tablet composition and its preparation method, belonging to the field of pharmaceutical formulation technology. Background Technology

[0002] Solifenacin succinate tablets were developed by Astellas Pharma Inc. of Japan for the treatment of urinary incontinence and / or urinary frequency and urgency symptoms associated with overactive bladder. This product was approved by the US FDA on November 19, 2004; approved in Japan in June 2006; and approved by the my country CFDA on September 30, 2009.

[0003] Solifenacin is a competitive muscarinic cholinergic receptor antagonist. It is more selective for the bladder than the salivary glands. Muscarinic M3 receptors play important roles in several primarily cholinergic-mediated functions, including bladder smooth muscle contraction and stimulating saliva secretion. Solifenacin succinate inhibits detrusor overactivity by blocking muscarinic M3 receptors in bladder smooth muscle, thereby relieving symptoms of urge incontinence, urgency, and frequency associated with overactive bladder.

[0004] Solifenacin succinate crystals will largely transform into an amorphous state when the water content is high. The amorphous form of solifenacin succinate is easily degraded, producing a large number of degradation impurities, which affects its drug safety. The original patent CN101601673A chose a wet granulation process, which forces solifenacin to come into contact with water, resulting in a high amount of degradation impurities.

[0005] The powder direct pressing process can avoid contact between solifenacin succinate and water. However, after the solifenacin succinate raw material is crushed, the particle size becomes finer, the surface area increases, and the surface energy increases. Under the combined action of electrostatics, van der Waals forces, and molecular surface hydrogen bonds, the solifenacin succinate raw material is prone to agglomeration. The powder direct pressing process can easily lead to poor content uniformity, and the material is prone to adhering to the inner wall of the equipment or causing sticking and punching during tableting.

[0006] Patent WO 2010097243 A2 solved the problem of poor content uniformity in the direct compression process of powder, but its formulation dissolution was poor. The same is true for tablets prepared by the formulation process in patent EP2500013A. Summary of the Invention

[0007] To address the above problems, this invention provides a method for preparing solifenacin succinate tablets by direct powder compression.

[0008] The inventors accidentally discovered that mixing sodium hexametaphosphate with a particle size of less than 5 μm with solifenacin succinate API can improve the problems of agglomeration and clumping in solifenacin succinate API. The underlying principle is speculated to be that sodium hexametaphosphate can increase the absolute value of the particle surface potential, thereby generating a strong double-layer repulsive force. Simultaneously, the adsorption layer can also generate a strong steric repulsion effect, effectively preventing particle agglomeration. Furthermore, sodium hexametaphosphate is readily soluble in water and has no effect on dissolution rate, etc.

[0009] Furthermore, subsequent experiments unexpectedly revealed that the formulation with added sodium hexametaphosphate exhibited lower levels and rates of impurity I formation compared to the formulation without it.

[0010]

[0011] Figure 1. Structure of Solinena (left) and structure of Solinena impurity I (right).

[0012]

[0013] Figure 2. Structural formula of sodium hexametaphosphate

[0014] It is speculated that this is because the oxygen in sodium hexametaphosphate is negatively charged, and after solifenacin is premixed with sodium hexametaphosphate, it easily combines with the bridgehead N of solifenacin, thus preventing the oxidation of the bridgehead N.

[0015] The technical solution of this invention is:

[0016] A composition of solifenacin succinate tablets, each tablet containing 5 mg of solifenacin succinate, 0.25-0.75 mg of sodium hexametaphosphate, 72-108 mg of sorbitol, 36-72 mg of microcrystalline cellulose, and 0.75-2.25 mg of magnesium stearate, wherein the particle size D90 of sodium hexametaphosphate is < 5 μm.

[0017] Preferably, a solifenacin succinate tablet composition contains 5 mg of solifenacin succinate, 0.5 mg of sodium hexametaphosphate, 96 mg of sorbitol, 48 mg of microcrystalline cellulose, and 1.5 mg of magnesium stearate per tablet, wherein the particle size D90 of sodium hexametaphosphate is < 5 μm.

[0018] The method for preparing the solifenacin succinate composition of the present invention includes the following steps:

[0019] (1) Place 3mm, 5mm and 10mm 95% zirconia beads into the ball mill jar in a certain proportion, so that the 95% zirconia beads occupy about one-third of the ball mill jar. Then add sodium hexametaphosphate into the ball mill jar. After running at low speed for more than ten seconds without any abnormalities, increase the rotation speed of the planetary ball mill to 500 rpm. Take a sample once per minute and use a Malvern 2000 laser particle size analyzer to dry test the particle size. If D90≥5μm, continue to grind until D90<5μm, and then set aside.

[0020] (2) Use an acoustic resonance mixer to mix solifenacin succinate and pulverized sodium hexametaphosphate for 3 min;

[0021] (3) Add the materials obtained in (2) along with sorbitol and microcrystalline cellulose to a dual-motion mixer, set the tank speed to 15 rpm and the mixing paddle speed to 35 rpm, and mix for 5 min;

[0022] (4) Add magnesium stearate to the dual motion mixer and mix at a tank speed of 15 rpm and a mixing paddle speed of 35 rpm for 3 minutes to obtain the total mixture for later use.

[0023] (5) Press the total mixture obtained in (4) into sheets using a φ7.6mm die, with a hardness of not less than 45N.

[0024] Compared with the prior art, the present invention has at least the following advantages:

[0025] In the solifenacin succinate tablets of this invention, ultrafine sodium hexametaphosphate is mixed with the solifenacin succinate active pharmaceutical ingredient, allowing the sodium hexametaphosphate to encapsulate the solifenacin succinate. This effectively improves its flowability and avoids the problems of the active ingredient sticking to the walls and agglomerating, thus effectively improving the mixing uniformity of the total solifenacin succinate mixture and consequently improving the content uniformity of the solifenacin succinate tablets. Furthermore, sodium hexametaphosphate is readily soluble in water, has no effect on the dissolution of the tablets, and can reduce the formation of degradation impurities, thereby improving medication safety. Detailed Implementation

[0026] The prescription for the example is as follows.

[0027]

[0028] In the formulations of Examples 1-7 above, the particle size D90 of sodium hexametaphosphate is <5μm.

[0029] The preparation methods of Examples 1-7 above refer to the preparation process described in the technical solution section.

[0030] The comparative prescriptions are as follows:

[0031]

[0032] In Comparative Example 2 above, the particle size of sodium hexametaphosphate was approximately 10 μm (D90), while in the other formulations, D90 was less than 5 μm.

[0033] The preparation methods of the above comparative examples 1 and 3-6 refer to the preparation process described in the technical solution section.

[0034] The preparation method of Comparative Example 2 includes the following steps:

[0035] (1) Place three types of 95% zirconia beads of 3mm, 5mm and 10mm in a certain proportion into the ball mill jar, so that the 95% zirconia beads occupy about one-third of the ball mill jar. Then add sodium hexametaphosphate into the ball mill jar. After running at low speed for more than ten seconds without any problems, increase the self-rotation speed of the planetary ball mill to 300rpm. Take a sample once per minute and use a Malvern 2000 laser particle size analyzer to dry test the particle size. When D90≈10μm, it is ready for use.

[0036] (2) Use an acoustic resonance mixer to mix solifenacin succinate and pulverized sodium hexametaphosphate for 3 min;

[0037] (3) Add the materials obtained in (2) along with sorbitol and microcrystalline cellulose to a dual-motion mixer and set the tank speed to 15 rpm and the mixing paddle speed to 35 rpm for 5 min;

[0038] (4) Add magnesium stearate to the dual motion mixer and mix at a tank speed of 15 rpm and a mixing paddle speed of 35 rpm for 3 minutes to obtain the total mixture for later use.

[0039] (5) Press the total mixture obtained in (4) into sheets using a φ7.6mm die, with a hardness of not less than 45N.

[0040] Experimental Example 1: Powder Properties

[0041] According to the "Guidelines for Determination of Powder Flowability" (Draft for Comments) issued by the Chinese Pharmacopoeia Commission, the angle of repose and Hausner ratio should be tested.

[0042]

[0043]

[0044]

[0045] As can be seen from Tables 5 and 6, the angles of repose of Examples 1-7 are all in the "good - no help needed" range, and the Hausnerby angle is also in the "good" range; the angles of repose and Hausnerby angles of Comparative Examples 1, 2, and 4 are in the "acceptable - potential problems" range.

[0046] Experimental Example 2: Tableting Parameters and Tableting Smoothness

[0047]

[0048] As can be seen from Tables 5 and 6, when the tablet hardness is controlled between 45-50N, the tablet brittleness and main compressive strength are not significantly different, indicating that sodium hexametaphosphate has no significant effect on the compressibility of the material.

[0049] Comparative Example 1, which did not contain sodium hexametaphosphate, and Comparative Example 5, which did not contain magnesium stearate, both exhibited sticking and punching during tableting. Comparative Example 3, due to its high sorbitol content, showed tablet cracking during brittleness testing. The three batches of samples from Comparative Examples 1, 2, and 4, which had poor flowability, showed "mouse holes" during tableting and required auxiliary feeding.

[0050] Experimental Example 3: Content Uniformity

[0051] Content uniformity was determined according to the method under the Content Uniformity section of the imported registration standard for Solifenacin Succinate Tablets (JX20050264). Content uniformity was judged based on A+2.2S≤15, where the absolute value of the difference between the standard value and the average value is used. Standard deviation

[0052]

[0053] As can be seen from Tables 7 and 8, the A+2.2S values ​​of Examples 1-7 are all less than 8, which is not much different from the original product's 5.32. The A+2.2S values ​​of Comparative Examples 1 and 2 are higher, with Comparative Example 1 reaching 16.01, which exceeds the limit of 15 specified in the Chinese Pharmacopoeia.

[0054] Experimental Example 4: Accelerated Conditional Dissolution

[0055]

[0056] Among them, "original research" is prepared according to patent CN101601673A; "EP" is prepared according to patent EP2500013A; and "WO" is prepared according to patent WO 2010097243 A2.

[0057] As can be seen from Tables 11 and 12, under accelerated conditions, the dissolution rates of Examples 1-7 decreased to varying degrees with increasing time, but all remained above 90%, meeting the limit of greater than 80%, showing no significant difference from the original study. All were superior to the dissolution rates of samples prepared according to patents EP2500013A and WO 2010097243 A2 under the same medium. In Comparative Example 6, due to the larger amount of magnesium stearate and the use of a dual-motion mixer with greater mixing force for more uniform mixing, the excessive lubrication of magnesium stearate was more pronounced, resulting in a dissolution rate of Comparative Example 6 below 80% after two months of accelerated storage.

[0058] Experimental Example 5: Formation of Impurity I in the Degradation of Solifenacin Succinate under Accelerated Conditions

[0059]

[0060] As can be seen from Tables 13 and 14, under accelerated conditions, the amount and rate of impurity I generated in Examples 1-7 were much lower than those in the original formulation; in Comparative Example 1, since sodium hexametaphosphate was not used, the growth rate of impurity I was higher; in Comparative Example 2, since the particle size of sodium hexametaphosphate was larger, the effect of inhibiting impurity growth was poor, and impurity I also increased significantly.

[0061] In summary, based on the examination of powder properties, tableting parameters, tableting smoothness, content uniformity, dissolution rate, and the amount of impurity I generated, it was finally determined that solifenacin succinate tablets should be produced by direct powder compression. The formulation is: solifenacin succinate 5mg, sodium hexametaphosphate 0.25-0.75mg, sorbitol 72-108mg, microcrystalline cellulose 36-72mg, and magnesium stearate 0.75-2.25mg, wherein the particle size D90 of sodium hexametaphosphate is <5μm.

Claims

1. A pharmaceutical composition of solifenacin succinate suitable for direct compression of a powder, characterized in that, Each tablet contains 5 mg of solifenacin succinate, 0.25-0.75 mg of sodium hexametaphosphate, 72-108 mg of sorbitol, 36-72 mg of microcrystalline cellulose, and 0.75-2.25 mg of magnesium stearate. The particle size D90 of the sodium hexametaphosphate is < 5 μm. The preparation method of this composition is as follows: (1) Use a planetary ball mill to pulverize sodium hexametaphosphate to below 5 μm; (2) Solifenacin succinate and pulverized sodium hexametaphosphate are mixed evenly using an acoustic vibration mixer; (3) Add the materials obtained in (2) and sorbitol and microcrystalline cellulose to a double-motion mixer and mix evenly; (4) Add the material obtained in (3) to magnesium stearate and mix evenly to obtain a mixture; (5) Compress the mixture in (4) into tablets.

2. The pharmaceutical composition of claim 1, wherein, Each tablet contains 5mg of solifenacin succinate, 0.5mg of sodium hexametaphosphate, 96mg of sorbitol, 48mg of microcrystalline cellulose, and 1.5mg of magnesium stearate.

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