A solid preparation of safinamide mesylate and its preparation method

Abstract

The present invention belongs to the field of pharmaceutical preparation technology, specifically relating to a solid formulation of safinamide mesylate and a preparation method thereof. The formulation comprises a solid dispersion of safinamide mesylate, a filler, a disintegrant, and a lubricant. The resulting formulation can achieve good dissolution of the active ingredient under low or high pH conditions, while also exhibiting good stability and a simple preparation process.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular 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]propionamide methanesulfonate, and its structural formula is as follows:

[0003]

[0004] Safinamide mesylate was developed by Newron and its marketing partner, Zambon, and was approved for marketing by the EMA in February 2015. It is marketed as a film-coated tablet under the trade name Xadago in 50mg and 100mg strengths. Safinamide mesylate is indicated for the treatment of adult patients with idiopathic Parkinson's disease (IDD) in the middle and late stages with fluctuating symptoms, as an adjunct to stable levodopa monotherapy or in combination with other Parkinson's medications. As a third-generation MAO-B inhibitor, safinamide mesylate exhibits stronger and reversible MAO-B inhibition than selegiline or rasagiline, resulting in fewer side effects. It is a highly selective, biosafe, and effective new drug for the treatment of Parkinson's disease. It also significantly reduces the frequency of tremor and dyskinesias, prolongs the duration of the symptom-free period, and improves patients' motor function.

[0005] Safinamide mesylate is a white or off-white crystalline powder with a pungent odor, bitter taste, and astringency. It is readily soluble in water, methanol, and dimethyl sulfoxide; slightly soluble in ethanol; and nearly insoluble in ethyl acetate. Its solubility is high at low pH, but low at high pH. Patients taking gastric acid suppressant medications such as antacids, H2 receptor blockers, and proton pump inhibitors can increase gastric pH. Increased gastric pH in the elderly due to physiological factors can affect the solubility and dissolution characteristics of safinamide mesylate, thereby altering its bioavailability and, consequently, its efficacy and safety. Therefore, addressing the dissolution problem of safinamide mesylate tablets under high pH conditions is particularly important.

[0006] CN106361711B uses a direct powder compression method to prepare safinamide mesylate tablets, micronizing the raw materials to control the particle size to below 50 μm. Because the raw materials account for a high proportion of the formula, the mixed raw and excipient powders have poor fluidity, tablet weights vary greatly, and disintegration time is long, which may affect drug efficacy and lead to delayed drug action. Dissolution is similar to the original formulation only under low pH conditions, failing to address the solubility issue under high pH conditions.

[0007] CN106580900A discloses safinamide mesylate tablets and their preparation methods, employing direct powder compression or dry granulation. However, neither method addresses the issue of intra-batch and inter-batch variability in product dissolution. The resulting safinamide mesylate tablets suffer from poor powder flowability, large variations in tablet weight and hardness, and flake cracking.

[0008] CN117919186A discloses a safinamide mesylate tablet and a preparation method thereof. The premix is ​​prepared by surface-treating the API with colloidal silica, adding a diluent and a disintegrant to the premix, mixing to obtain a mixture, and pressing the mixture into blocks. A lubricant is added, mixed, and tableted. By first surface-treating the safinamide mesylate API with colloidal silica before adding other materials, the material's fluidity is improved and the risk of API adhesion 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. In particular, the large amount of sodium lauryl sulfate used increases the irritation to the gastrointestinal tract.

[0010] CN109414404B relates to a pharmaceutical composition containing safinamide, taste-masked granules containing the active ingredient or a pharmaceutically acceptable salt thereof, oral dosage forms containing the granules, and methods for preparing the same. CN117752819A improves the mouthfeel of safinamide mesylate by inclusion in cyclodextrin. None of the above patent documents address the solubility of safinamide mesylate tablets under high pH conditions.

[0011] CN116327714A discloses a safinamide mesylate tablet. A mixture A containing safinamide mesylate and microcrystalline cellulose is granulated, mixed to obtain a mixture B, and then compressed into tablets. While this preparation method overcomes the problem of tableting easily causing tablets to split, the resulting tablets still suffer from incomplete dissolution in a pH 6.8 phosphate buffer.

[0012] Due to the complex pH changes in human gastric juice, excessive or insufficient gastric acid secretion can interfere with the normal dissolution process of safinamide mesylate. If gastric acid secretion is too low, the drug may not be fully dissolved, resulting in reduced bioavailability and affected efficacy. Conversely, excessive gastric acid secretion can cause the drug to dissolve too quickly, potentially leading to large amounts of absorption 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 existing technology, 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 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 better 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 contains 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 octenylsuccinate 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 the 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 micropowder 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 copovidone and sodium starch octenylsuccinate to 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 encapsulating.

[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 a good taste and good solubility. It can be dissolved well not only at a lower pH, but also at a high pH, ​​which is beneficial to improving the absorption and bioavailability of the drug and providing 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, overcoming the defects of poor fluidity of the raw material drug and easy fragmentation during powder 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 embodiments 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 copovidone and sodium starch octenylsuccinate to 3 L of purified water, heat and stir at 50°C until completely dissolved, then add safinamide mesylate and continue stirring to mix thoroughly. Spray dry to obtain a solid dispersion of safinamide mesylate, which is then passed through a 100-mesh sieve. Mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, then add calcium stearate and mix thoroughly. The powder content is tested, and the theoretical tablet weight is calculated based on the specification of 100 mg of safinamide mesylate per tablet. Tablets are compressed to a hardness of 70 to 110 N. The resulting 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 copovidone and sodium starch octenylsuccinate to 3 L of purified water, heat and stir at 40°C until completely dissolved, then add safinamide mesylate and continue stirring to mix thoroughly. Spray dry to obtain a solid dispersion of safinamide mesylate, which is then passed through a 100-mesh sieve. Mix the solid dispersion with xylitol, maltitol, and sodium carboxymethyl starch, then add sodium stearate fumarate and mix thoroughly. The powder content is tested, and the theoretical tablet weight is calculated based on the specification of 100 mg of safinamide mesylate per tablet. Tablets are compressed to a hardness of 70 to 110 N. The resulting tablets are white to off-white in appearance and have a smooth surface.

[0043] Example 3

[0044] prescription:

[0045]

[0046] Preparation process:

[0047] The prescribed amount of copovidone and sodium starch octenylsuccinate was added to 3 L of purified water and heated with stirring at 55°C until completely dissolved. Safinamide mesylate was then added and stirred until thoroughly dissolved. Spray drying was performed to obtain a solid dispersion of safinamide mesylate, which was then passed through a 100-mesh sieve. The solid dispersion was then mixed with sorbitol, maltodextrin, crospovidone, and croscarmellose sodium. Magnesium stearate and micro-powdered silica gel were then added and mixed thoroughly. The powder content was determined, and the theoretical tablet weight was calculated based on the specification of 100 mg of safinamide mesylate per tablet. The tablets were then compressed to a hardness of 70 to 110 N. The resulting tablets were white to off-white in appearance and had a smooth surface.

[0048] Example 4

[0049] prescription:

[0050]

[0051] Preparation process:

[0052] Add the prescribed amount of copovidone and sodium starch octenylsuccinate to 3 L of purified water, heat and stir at 50°C until completely dissolved, then add safinamide mesylate and continue stirring to mix thoroughly. Spray dry to obtain a solid dispersion of safinamide mesylate, which is then passed through a 100-mesh sieve. Mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, then add calcium stearate and mix thoroughly. The powder content is tested, and the theoretical tablet weight is calculated based on the specification of 100 mg of safinamide mesylate per tablet. Tablets are compressed to a hardness of 70 to 110 N. The resulting 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 copovidone and sodium starch octenylsuccinate to 3 L of purified water, heat and stir at 50°C until completely dissolved, then add safinamide mesylate and continue stirring to mix thoroughly. Spray dry to obtain a solid dispersion of safinamide mesylate, which is then passed through a 100-mesh sieve. Mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, then add calcium stearate and mix thoroughly. The powder content is tested, and the theoretical tablet weight is calculated based on the specification of 100 mg of safinamide mesylate per tablet. Tablets are compressed to a hardness of 70 to 110 N. The resulting tablets are white to off-white in appearance and have a smooth surface.

[0059] Example 6

[0060] prescription:

[0061]

[0062] Preparation process:

[0063] The prescribed amount of safinamide mesylate, copovidone, and sodium starch octenylsuccinate were added to 3 L of purified water and heated at 50°C with stirring until completely dissolved. The solid dispersion of safinamide mesylate was spray-dried to obtain the solution and passed through a 100-mesh sieve. The solid dispersion was then mixed with spray-dried lactose and low-substituted hydroxypropyl cellulose, followed by calcium stearate. The powder content was determined, and the theoretical tablet weight was calculated based on a specification of 100 mg of safinamide mesylate per tablet. The tablets were compressed to a hardness of 70 to 110 N. The resulting tablets were white to off-white in appearance and had a smooth surface.

[0064] Comparative Example 1

[0065] prescription:

[0066]

[0067] Preparation process:

[0068] Add the prescribed amount of copovidone to 3 L of purified water, heat and stir at 50°C until completely dissolved, then add safinamide mesylate and continue stirring to mix thoroughly. Spray dry to obtain a solid dispersion of safinamide mesylate, which is then passed through a 100-mesh sieve. Mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, then add calcium stearate and mix thoroughly. The powder content is tested, and the theoretical tablet weight is calculated based on the specification of 100 mg of safinamide mesylate per tablet. Tablets are compressed to a hardness of 70 to 110 N. The resulting tablets are white to off-white with slightly spotted surfaces.

[0069] Comparative Example 2

[0070] prescription:

[0071]

[0072] Preparation process:

[0073] Add the prescribed amount of sodium starch octenylsuccinate to 3 L of purified water, heat and stir at 50°C until completely dissolved, then add safinamide mesylate and continue stirring to mix thoroughly. Spray dry to obtain a solid dispersion of safinamide mesylate, which is then passed through a 100-mesh sieve. Mix with spray-dried lactose and low-substituted hydroxypropyl cellulose, then add calcium stearate and mix thoroughly. The powder content is tested, and the theoretical tablet weight is calculated based on the specification of 100 mg of safinamide mesylate per tablet. Tablets are compressed to a hardness of 70 to 110 N. The resulting tablets are white to off-white with speckled surfaces.

[0074] Comparative Example 3

[0075] prescription:

[0076]

[0077] Preparation process:

[0078] Mix the prescribed amount of safinamide mesylate, copovidone, sodium starch octenylsuccinate, spray-dried lactose, and low-substituted hydroxypropyl cellulose. Then add calcium stearate and mix thoroughly. Test the powder content. Calculate the theoretical tablet weight based on the specification of 100 mg of safinamide mesylate per tablet. Press the tablets to a hardness of 70 to 110 N. The resulting tablets are white to off-white with cracks on the surface.

[0079] Comparative Example 4

[0080] prescription:

[0081]

[0082] Preparation process: The raw material of safinamide mesylate is pulverized in a pharmaceutical grinder. The prescribed amount of safinamide mesylate is weighed and then thoroughly mixed with crospovidone, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide. The mixed material is tested for content and converted to a corresponding tablet weight. Tablets are then compressed, with the tablet hardness adjusted to 3-6 kg and a tablet weight variance of ±5.0%. The resulting tablets are white to off-white in appearance with slightly spotted surfaces.

[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, which changes significantly with pH. It is easily soluble in purified water but extremely difficult to dissolve in a buffer medium with a pH of 6.8. Therefore, multiple dissolution media need to be examined when testing the dissolution rate.

[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 IV, General Rules 0931, Method 1), 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, respectively, at a speed of 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 safinamide mesylate reference substance, accurately weighed, dissolved and diluted with the dissolution medium to prepare a solution containing approximately 0.11 mg of safinamide per 1 mL, as the reference solution.

[0087] Octadecylsilane-bonded silica gel was used as the filler; the mobile phase consisted of 0.05 mol / L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid)-acetonitrile-methanol (60:20:20); the flow rate was 1.0 mL / min; the column temperature was 30°C; the detection wavelength was 230 nm; and the injection volume was 20 μl. The reference solution and the test solution were accurately measured and injected into the liquid chromatograph. The chromatograms were recorded, and the dissolution amount per tablet was calculated based on the peak area using 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 showed that in the dissolution media of pH 1.0 hydrochloric acid solution and pH 4.5 acetate buffer solution, the dissolution of the tablets obtained in each example and comparative example was good; however, in purified water, the dissolution of the tablets obtained in Comparative Examples 1 to 2 was significantly reduced, which may be related to the prescription and the synergistic effect of copovidone and sodium starch octenylsuccinate was not formed; in pH 6.8 phosphate buffer solution, the dissolution of the tablets obtained in Comparative Examples 3 to 4 and the reference preparation was also significantly reduced, which may be related to the phosphate buffer salt system, which is not conducive to their dissolution.

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

[0093] Accelerated stability test: The preparation was placed under conditions of 40±2°C and 75±5% (accelerated) for 6 months. Samples were taken at the end of the 0th, 3rd, and 6th month, and the content of related substances (%) in the resulting preparation was determined. 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 showed that the stability of the tablets obtained in the examples was better, while the stability of the comparative examples was relatively poor.

Claims

1. A solid preparation of safinamide mesylate, characterized in that The preparation contains a solid dispersion of safinamide mesylate, a filler, a disintegrant, and a lubricant. The solid dispersion is composed of safinamide mesylate, copovidone, and sodium starch octenylsuccinate. The weight ratio of safinamide mesylate to copovidone and sodium starch octenylsuccinate is 1:1-2:0.2-0.

4. The filler is selected from one or more of spray-dried lactose, xylitol, sorbitol, maltitol, and maltodextrin. 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. The preparation method of the preparation comprises the following steps: adding copovidone and sodium starch octenylsuccinate to 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 the filler and disintegrant, adding a lubricant and mixing, and tableting or encapsulating.

2. The preparation according to claim 1, wherein In the preparation, the weight ratio of safinamide mesylate to the filler is 1:0.8-1.

3.

3. The preparation according to claim 1, wherein In the preparation, the weight ratio of safinamide mesylate to disintegrant is 1:0.1-0.

2.

4. The preparation according to claim 1, wherein In the method, the temperature of heating and stirring is 40-55°C.

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