Safinamide mesylate solid preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a safinamide mesylate solid preparation and a preparation method thereof. The preparation contains safinamide mesylate solid dispersion, a filling agent, a disintegrating agent and a lubricating agent, active ingredients of the obtained preparation can be well dissolved out under the condition of low pH or high pH, meanwhile, the stability is good, and the preparation process is simple and convenient.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a safinamide mesylate solid preparation and a preparation method thereof. Background Art

[0002] The chemical name of Safinamide Mesylate is (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide mesylate, and the structural formula is as follows:

[0003]

[0004] Safinamide mesylate was developed by Newron and its marketing partner Zambon. It was approved by EMA for marketing in February 2015. The dosage form is a film-coated tablet with the trade name Xadago and specifications of 50mg and 100mg. Safinamide mesylate is used to treat adult patients with idiopathic Parkinson's disease with fluctuating symptoms in the middle and late stages, as an adjuvant to a stable dose of levodopa alone or in combination with other Parkinson's treatment drugs. As a third-generation MAO-B inhibitor, safinamide mesylate has a stronger and reversible inhibitory effect on MAO-B than selegiline or rasagiline, so it has fewer side effects. It is a new drug for the treatment of Parkinson's disease with high selectivity, good biosafety, and obvious therapeutic effect. It can also significantly reduce the frequency of tremor and dyskinesia, prolong the duration of the symptom-free period, and improve the patient's motor function.

[0005] Safinamide mesylate is a white or off-white crystalline powder with a pungent odor, bitter taste, and astringent taste. It is easily soluble in water, methanol, and dimethyl sulfoxide; slightly soluble in ethanol; almost insoluble in ethyl acetate; has a higher solubility under low pH conditions; and has a lower solubility under high pH conditions. Patients taking gastric acid-suppressing drugs such as antacids, H2 receptor blockers, and proton pump inhibitors will cause gastric acid pH to increase; the increase in gastric acid pH in the elderly due to physiological factors will affect the solubility and dissolution characteristics of safinamide mesylate, thereby changing the bioavailability, and further affecting its effectiveness and safety. Therefore, it is particularly important to solve the dissolution problem of safinamide mesylate tablets under high pH conditions.

[0006] CN106361711B uses a powder direct tableting method to prepare mesylate safinamide tablets, micronizing the raw materials to control the particle size below 50μm. Since the raw materials account for a high proportion in the prescription, the mixed powder of raw and auxiliary materials has poor fluidity, the tablet weight difference is too large, and the disintegration time is long, which may affect the efficacy and cause the drug to take effect later. The dissolution is similar to the original formulation only under low pH conditions, and the dissolution problem under high pH conditions is not solved.

[0007] CN106580900A discloses mesylate safinamide tablets and a preparation method thereof, which adopts a powder direct tableting method or a dry granulation method. However, both methods cannot solve the problem of intra-batch and inter-batch differences in product dissolution, and the prepared mesylate safinamide tablets have the defects of poor powder fluidity, large differences in tablet weight and hardness, and cracked tablets.

[0008] CN117919186A discloses a mesylate safinamide tablet and a preparation method thereof, wherein the raw material is surface treated with colloidal silica to obtain a premix, a diluent and a disintegrant are added to the premix, mixed to obtain a mixture, and pressed into blocks; a lubricant is added, mixed, and tableted. By first surface treating the mesylate safinamide raw material with colloidal silica and then adding other materials, the fluidity of the material is improved and the risk of adhesion of the raw material is reduced.

[0009] CN105456214A discloses a safinamide mesylate tablet and a preparation method thereof. The disclosed dissolution results show that the sample dissolution reaches 100% in 5 minutes, but the dissolution of the sample under high pH conditions is still not improved, especially the large amount of sodium dodecyl sulfate used increases the irritation to the gastrointestinal tract.

[0010] CN109414404B relates to a pharmaceutical composition comprising safinamide, a taste-masking particle comprising the active ingredient or a pharmaceutically acceptable salt thereof, an oral dosage form comprising the particle, and a method for preparing the same. CN117752819A improves the mouthfeel of safinamide mesylate by cyclodextrin inclusion. None of the above patent documents solves the problem of the solubility of safinamide mesylate tablets under high pH conditions.

[0011] CN116327714A discloses a mesylate safinamide tablet, which is obtained by granulating and mixing a mixture A containing mesylate safinamide and microcrystalline cellulose to obtain a mixture B, and then tableting. Although this preparation method overcomes the problem of tabletting easily causing tablet splitting, the obtained tablet still has the defect of incomplete dissolution in pH 6.8 phosphate buffer.

[0012] Due to the complex changes in the pH of human gastric juice, excessive or insufficient gastric acid secretion will interfere with the normal dissolution process of safinamide mesylate. If gastric acid secretion is too little, the drug may not be fully dissolved, resulting in reduced bioavailability and affecting drug efficacy; conversely, excessive gastric acid secretion will cause the drug to dissolve too quickly and may be absorbed in large quantities in the stomach, increasing the risk of adverse gastric reactions or causing the drug to be metabolized prematurely before reaching the site of action.

[0013] In the prior art, the oral solid preparation of safinamide mesylate still has dissolution problems and cannot adapt to large changes in gastric juice pH. It is still necessary to continuously study the prescription and preparation process in order to provide a more clinically suitable, high-quality oral solid preparation of safinamide mesylate. Summary of the invention

[0014] In view of the defects of the prior art, the present invention provides a solid preparation of safinamide mesylate, which can achieve good dissolution of the active ingredient under low pH or high pH conditions, and has good stability and a simple preparation process.

[0015] The present invention is specifically implemented through the following technical solutions:

[0016] A solid preparation of safinamide mesylate, comprising a solid dispersion of safinamide mesylate, a filler, a disintegrant and a lubricant.

[0017] Preferably, the safinamide mesylate solid dispersion consists of safinamide mesylate, copovidone and sodium starch glycolate.

[0018] Further preferably, in the solid dispersion of the preparation, the weight ratio of safinamide mesylate to copovidone and sodium starch octenyl succinate is 1:1-2:0.2-0.4.

[0019] Preferably, in the preparation, the filler is selected from one or more of spray-dried lactose, xylitol, sorbitol, maltitol, and maltodextrin.

[0020] Preferably, in the preparation, the weight ratio of safinamide mesylate to filler is 1:0.8-1.3.

[0021] Preferably, in the preparation, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose.

[0022] Preferably, in the preparation, the weight ratio of safinamide mesylate to disintegrant is 1:0.1-0.2.

[0023] Preferably, in the preparation, the lubricant is selected from one or more of calcium stearate, sodium stearate fumarate, magnesium stearate and micro powder silica gel.

[0024] Preferably, in the preparation, the weight ratio of safinamide mesylate to lubricant is 1:0.01 to 0.04.

[0025] Preferably, the solid preparation of the present invention is safinamide mesylate tablets or capsules.

[0026] The present invention also provides a method for preparing a solid preparation of safinamide mesylate, comprising the following steps: adding copolyvidone and sodium starch octenyl succinate into purified water, heating and stirring until completely dissolved, then adding safinamide mesylate, and continuing to stir and mix; spray drying to obtain a solid dispersion of safinamide mesylate; mixing the solid dispersion with a filler and a disintegrant, adding a lubricant and mixing, and tableting or loading into a capsule.

[0027] Preferably, in the preparation method, the temperature of heating and stirring is 40-55°C.

[0028] Compared with the prior art, the present invention has the following outstanding advantages:

[0029] 1. The solid preparation obtained by the present invention has good taste and good solubility. It can be well dissolved not only at a lower pH, but also at a high pH, ​​which is beneficial to improve the absorption and bioavailability of the drug and provide more effective drugs for clinical use.

[0030] 2. In the preparation method of the present invention, there is no need to strictly control the particle size or crystal form of the raw material drug safinamide mesylate. By preparing a solid dispersion, the raw material drug is evenly dispersed in the product, thereby overcoming the defects of poor fluidity of the raw material drug and easy cracking of the powder during tableting.

[0031] 3. The tablets obtained by the present invention have high stability, the preparation method of the tablets is simple and easy to operate, the production efficiency is high, and it is more suitable for industrial production. DETAILED DESCRIPTION

[0032] The following specific implementation modes are listed to further illustrate the present invention, but do not limit the scope of the present invention in any way. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0033] Example 1

[0034] prescription:

[0035]

[0036] Preparation process:

[0037] Add the prescribed amount of copolyvidone and sodium starch octenyl succinate to 3L purified water, heat and stir at 50°C until completely dissolved, then add safinamide mesylate, continue to stir and mix; spray dry to obtain safinamide mesylate solid dispersion, pass through a 100-mesh sieve; then mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, add calcium stearate and mix, test the mixed powder content, calculate the theoretical tablet weight according to the specification of 100 mg of safinamide mesylate per tablet, press the tablet, and control the hardness to 70N to 110N. The obtained tablets are white to off-white in appearance and have a smooth surface.

[0038] Example 2

[0039] prescription:

[0040]

[0041] Preparation process:

[0042] Add the prescribed amount of copolyvidone and sodium starch octenyl succinate to 3L purified water, heat and stir at 40°C until completely dissolved, then add safinamide mesylate, continue to stir and mix; spray dry to obtain a solid dispersion of safinamide mesylate, pass through a 100-mesh sieve; then mix with xylitol, maltitol, and sodium carboxymethyl starch, add sodium stearate fumarate and mix, test the mixed powder content, calculate the theoretical tablet weight according to the specification of 100 mg of safinamide mesylate per tablet, press the tablet, and control the hardness to 70N to 110N. The obtained tablets are white to off-white in appearance and have a smooth surface.

[0043] Example 3

[0044] prescription:

[0045]

[0046] Preparation process:

[0047] Add the prescribed amount of copolyvidone and sodium starch octenyl succinate to 3L purified water, heat and stir at 55°C until completely dissolved, then add safinamide mesylate, continue to stir and mix; spray dry to obtain a solid dispersion of safinamide mesylate, pass through a 100-mesh sieve; then mix with sorbitol, maltodextrin, cross-linked polyvidone, and cross-linked sodium carboxymethyl cellulose, add magnesium stearate and micro-powdered silica gel, mix, test the mixed powder content, calculate the theoretical tablet weight according to the specification of 100 mg of safinamide mesylate per tablet, press the tablet, and control the hardness to 70N to 110N. The obtained tablets are white to off-white in appearance and have a smooth surface.

[0048] Example 4

[0049] prescription:

[0050]

[0051] Preparation process:

[0052] Add the prescribed amount of copolyvidone and sodium starch octenyl succinate to 3L purified water, heat and stir at 50°C until completely dissolved, then add safinamide mesylate, continue to stir and mix; spray dry to obtain safinamide mesylate solid dispersion, pass through a 100-mesh sieve; then mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, add calcium stearate and mix, test the mixed powder content, calculate the theoretical tablet weight according to the specification of 100 mg of safinamide mesylate per tablet, press the tablet, and control the hardness to 70N to 110N. The obtained tablets are white to off-white in appearance and have a smooth surface.

[0053] Example 5

[0054] prescription:

[0055]

[0056]

[0057] Preparation process:

[0058] Add the prescribed amount of copolyvidone and sodium starch octenyl succinate to 3L purified water, heat and stir at 50°C until completely dissolved, then add safinamide mesylate, continue to stir and mix; spray dry to obtain safinamide mesylate solid dispersion, pass through a 100-mesh sieve; then mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, add calcium stearate and mix, test the mixed powder content, calculate the theoretical tablet weight according to the specification of 100 mg of safinamide mesylate per tablet, press the tablet, and control the hardness to 70N to 110N. The obtained tablets are white to off-white in appearance and have a smooth surface.

[0059] Example 6

[0060] prescription:

[0061]

[0062] Preparation process:

[0063] Add the prescribed amount of safinamide mesylate, copolyvidone, and sodium starch octenyl succinate to 3L purified water, heat and stir at 50°C until completely dissolved; spray dry to obtain a solid dispersion of safinamide mesylate, pass through a 100-mesh sieve; then mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, add calcium stearate and mix, test the mixed powder content, calculate the theoretical tablet weight according to the specification of 100mg safinamide mesylate per tablet, press the tablet, and control the hardness to 70N to 110N. The obtained tablets are white to off-white in appearance and have a smooth surface.

[0064] Comparative Example 1

[0065] prescription:

[0066]

[0067] Preparation process:

[0068] Add the prescribed amount of copolyvidone to 3L purified water, heat and stir at 50℃ until completely dissolved, then add safinamide mesylate, continue to stir and mix; spray dry to obtain safinamide mesylate solid dispersion, pass through a 100-mesh sieve; then mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, add calcium stearate and mix, test the mixed powder content, calculate the theoretical tablet weight according to the specification of 100mg safinamide mesylate per tablet, press the tablet, and control the hardness to 70N~110N. The appearance of the obtained tablet is white to off-white, with slight spots on the surface.

[0069] Comparative Example 2

[0070] prescription:

[0071]

[0072] Preparation process:

[0073] Add the prescribed amount of sodium starch octenyl succinate to 3L purified water, heat and stir at 50℃ until completely dissolved, then add safinamide mesylate, continue to stir and mix; spray dry to obtain safinamide mesylate solid dispersion, pass through a 100-mesh sieve; then mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, add calcium stearate and mix, test the mixed powder content, calculate the theoretical tablet weight according to the specification of 100mg safinamide mesylate per tablet, press the tablet, and control the hardness to 70N~110N. The appearance of the obtained tablet is white to off-white, with spots on the surface.

[0074] Comparative Example 3

[0075] prescription:

[0076]

[0077] Preparation process:

[0078] The prescribed amount of safinamide mesylate, copovidone, sodium starch octenyl succinate, spray-dried lactose, and low-substituted hydroxypropyl cellulose were mixed, and then calcium stearate was added and mixed. The mixed powder content was tested, and the theoretical tablet weight was calculated according to the specification that each tablet contained 100 mg of safinamide mesylate, and the tablets were pressed to control the hardness to 70N to 110N. The appearance of the obtained tablets was white to off-white, and there were cracks on the surface.

[0079] Comparative Example 4

[0080] prescription:

[0081]

[0082] Preparation process: crush the raw material of safinamide mesylate with a pulverizer, weigh the prescribed amount of safinamide mesylate raw material, and then fully mix it with cross-linked polyvinylpyrrolidone, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide in sequence; after the content of the mixed material is tested, it is converted into the corresponding tablet weight according to the content, and tablets are pressed, and the hardness of the tablets is adjusted to 3-6kg, and the tablet weight difference is ±5.0%, and tablets are pressed. The appearance of the obtained tablets is white to off-white, with slight spots on the surface.

[0083] Verification Example

[0084] Experimental Example 1: Determination of dissolution of the obtained preparation

[0085] The dissolution curve of safinamide mesylate is affected by solubility, and the solubility changes greatly with the change of pH. It is easily soluble in purified water, but extremely difficult to dissolve in a buffer medium of pH 6.8. Therefore, it is necessary to examine a variety of dissolution media when testing the dissolution.

[0086] Dissolution test: Take the tablets obtained in each example and comparative example and the reference preparation (trade name Xadago, licensed by Zambon SpA), and follow the dissolution and release test method (Chinese Pharmacopoeia 2020 Edition, Part Four, General Rules 0931, Method 1), respectively using pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer solution and 900 mL of purified water as dissolution media, the speed is 100 rpm, operate according to the law, take samples after 5, 10, 15, 20, 30 min, and 60 min, discard 5 mL of the initial filtrate, and take the subsequent filtrate as the test solution; take an appropriate amount of mesylate safinamide reference substance, accurately weigh it, dissolve it with the dissolution medium and dilute it to make a solution containing approximately 0.11 mg of safinamide per 1 mL, as the reference substance solution.

[0087] Octadecylsilane bonded silica gel was used as filler; 0.05mol / L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid)-acetonitrile-methanol (60:20:20) was used as mobile phase; flow rate was 1.0mL per minute; column temperature was 30℃; detection wavelength was 230nm; injection volume was 20μl. Accurately measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the dissolution amount of each tablet by peak area according to the external standard method. The test results are shown in Table 1.

[0088] Table 1 Appearance and dissolution test results of Examples and Comparative Examples

[0089]

[0090]

[0091] The results show that in the dissolution medium of pH 1.0 hydrochloric acid solution and pH 4.5 acetate buffer solution, the dissolution of the tablets obtained in each example and the comparative example is good; while in purified water, the dissolution of the tablets obtained in comparative examples 1 to 2 is significantly reduced, which may be related to the prescription, and the synergistic effect of copovidone and sodium starch octenyl succinate is not formed; in the pH 6.8 phosphate buffer solution, the dissolution of the tablets obtained in comparative examples 3 to 4 and the reference preparation is also significantly reduced, which may be related to the phosphate buffer salt system, which is not conducive to its dissolution.

[0092] Experimental Example 2: Investigation of the stability of the obtained preparation

[0093] Accelerated stability test: Place the product under the conditions of temperature 40±2°C and relative humidity 75±5% (accelerated) for 6 months, take samples at the end of the 0th, 3rd and 6th month, and measure the related substances (%) of the obtained preparation. The structures of related substances A and B are shown below:

[0094] Related substance A:

[0095]

[0096] Related substance B:

[0097]

[0098] Table 2 Stability test results of the preparations obtained in Examples and Comparative Examples

[0099]

[0100]

[0101] The results show that the stability of the tablets obtained in the examples is better, while the stability of the comparative examples is relatively poor.

Claims

1. A solid preparation of safinamide mesylate, characterized in that: The preparation contains safinamide mesylate solid dispersion, a filler, a disintegrant and a lubricant.

2. The preparation according to claim 1, characterized in that In the preparation, the solid dispersion consists of safinamide mesylate, copovidone and sodium starch glycolate.

3. The preparation according to claim 2, characterized in that In the preparation, the weight ratio of safinamide mesylate to copovidone and sodium starch octenylsuccinate is 1:1-2:0.2-0.

4.

4. The preparation according to claim 1, characterized in that In the preparation, the filler is selected from one or more of spray-dried lactose, xylitol, sorbitol, maltitol, and maltodextrin.

5. The preparation according to claim 4, characterized in that In the preparation, the weight ratio of safinamide mesylate to the filler is 1:0.8-1.

3.

6. The preparation according to claim 1, characterized in that In the preparation, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose.

7. The preparation according to claim 6, characterized in that In the preparation, the weight ratio of safinamide mesylate to disintegrant is 1:0.1-0.

2.

8. The preparation according to claim 1, characterized in that The preparation method of the preparation comprises the following steps: adding copovidone and sodium starch octenyl succinate into purified water, heating and stirring until completely dissolved, then adding safinamide mesylate, and continuing to stir and mix; spray drying to obtain a solid dispersion of safinamide mesylate; mixing the solid dispersion with a filler and a disintegrant, adding a lubricant and mixing, and tableting or loading into a capsule.

9. The preparation according to claim 8, characterized in that In the method, the temperature of heating and stirring is 40-55°C.

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