A formulation of safinamide mesylate and a method for preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a sifentanil mesylate preparation and a preparation method thereof. The preparation contains sifentanil mesylate, a non-volatile solvent, a surfactant, a water-soluble base, a disintegrant and a flavoring agent. The obtained preparation can achieve good taste, high content uniformity, good stability, high bioavailability, and simple preparation process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a safenamide mesylate formulation and its preparation method. Background Technology

[0002] Safenamide mesylate, developed by Newron and its marketing partner Zambon, was approved by the EMA in February 2015. It is available as film-coated tablets under the brand name Xadago, in strengths of 50 mg and 100 mg. Safenamide mesylate is used to treat adult patients with mid-to-late-stage idiopathic Parkinson's disease experiencing fluctuating symptoms, as adjunctive therapy to stable-dose levodopa monotherapy or in combination with other Parkinson's disease medications. As a third-generation MAO-B inhibitor, safenamide mesylate exhibits stronger and more reversible inhibition of MAO-B than selegiline or rasagiline, resulting in fewer side effects. It is a highly selective, biocompatible, and effective new drug for treating Parkinson's disease, significantly reducing the frequency of tremor and motor dysregulation episodes, prolonging the duration of symptom-free periods, and improving patients' motor function.

[0003] The chemical name of safinamide mesylate is (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propionamide mesylate, and its structural formula is as follows:

[0004]

[0005] Safenamide methanesulfonate is a white or off-white crystalline powder with a pungent odor and a bitter, astringent taste. It is readily soluble in water, methanol, and dimethyl sulfoxide; slightly soluble in ethanol; and practically insoluble in ethyl acetate.

[0006] CN106361711B describes the preparation of safenamide mesylate tablets using a direct powder compression method, in which the raw materials are micronized to control the particle size to below 50 μm. However, due to the high proportion of raw materials in the formulation, the poor flowability of the mixed powders of raw materials and excipients, excessive differences in tablet weight, and prolonged disintegration time may affect efficacy and delay drug action.

[0007] CN106580900A discloses safenamide mesylate tablets and their preparation method, which employs direct powder compression or dry granulation. However, neither method can solve the problem of intra-batch and batch-to-batch dissolution differences, and the resulting safenamide mesylate tablets all suffer from defects such as poor powder flowability, large differences in tablet weight and hardness, and tablet cracking.

[0008] CN117919186A discloses a safenamide mesylate tablet and its preparation method. A premix is ​​prepared by surface treatment of the active pharmaceutical ingredient with colloidal silica. A diluent and a disintegrant are added to the premix, and the mixture is then stirred to obtain a final mixture. ++ Compress into blocks; add lubricant and mix, then tablet. By first surface-treating safenamide mesylate raw material with colloidal silica before adding other materials, the flowability of the material is improved and the risk of raw material adhesion is reduced.

[0009] CN109414404B relates to pharmaceutical compositions comprising saphenamide, taste-masked granules comprising the active ingredient or a pharmaceutically acceptable salt thereof, oral dosage forms comprising the granules, and methods for preparing the same. CN117752819A improves the taste of saphenamide mesylate through cyclodextrin inclusion.

[0010] In the existing technology, oral safenamide mesylate preparations still have problems such as complex preparation processes, uneven content, poor stability, and reliance on flavoring agents for taste masking. Further research is needed on formulations and preparation processes to provide a more clinically suitable and high-quality oral solid dosage form of safenamide mesylate. Summary of the Invention

[0011] In view of the deficiencies of the prior art, the present invention provides a safenamide mesylate formulation that can achieve good taste, high content uniformity, good stability, high bioavailability, and simple preparation process.

[0012] This invention is specifically achieved through the following technical solutions:

[0013] A safenamide methanesulfonate formulation comprising safenamide methanesulfonate, a non-volatile solvent, a surfactant, a water-soluble matrix, a disintegrant, and a flavoring agent.

[0014] Preferably, in the formulation, the non-volatile solvent is diethylene glycol monoethyl ether or propylene carbonate, propylene glycol didecanoate; more preferably, the non-volatile solvent is diethylene glycol monoethyl ether.

[0015] Preferably, in the formulation, the volume ratio of the non-volatile solvent to the weight ratio of safenamide mesylate is 0.2 to 0.4:1, with the volume expressed in mL and the weight in g.

[0016] Preferably, in the formulation, the surfactant is polyoxyethylene-32 stearate, stearoyl polyoxyethylene-32 glycerol ester, or lauroyl polyoxyethylene-32 glycerol ester.

[0017] Preferably, in the formulation, the weight ratio of surfactant to safenamide mesylate is 0.4 to 0.6:1.

[0018] Preferably, in the formulation, the water-soluble matrix is ​​selected from one or more of polyoxyethylene stearate, polyethylene glycol 4000, polyethylene glycol 6000 and poloxamer.

[0019] Preferably, in the formulation, the weight ratio of the water-soluble matrix to safenamide mesylate is 1 to 1.5:1.

[0020] Preferably, in the formulation, the disintegrant is sodium carboxymethyl starch, crospovidone, or sodium crospovidone carboxymethyl cellulose.

[0021] Preferably, in the formulation, the weight ratio of the disintegrant to safenamide mesylate is 0.2 to 0.5:1.

[0022] Preferably, in the formulation, the flavoring agent is sucralose, steviol glycosides, or xylitol.

[0023] Preferably, in the formulation, the weight ratio of the flavoring agent to safenamide mesylate is 0.01 to 0.06:1.

[0024] Preferably, the safenamide mesylate formulation of the present invention is safenamide mesylate orally disintegrating tablets.

[0025] The present invention also provides a method for preparing safenamide mesylate formulation, comprising the following steps: adding safenamide mesylate, flavoring agent and disintegrant to a solvent and stirring until completely dissolved to obtain a mixture; heating and melting surfactant and water-soluble matrix, then adding the aforementioned mixture, stirring evenly, continuing to heat to remove part of the solvent, keeping warm, quantitatively filling the resulting drug solution into tablet inner packaging blister packs, rapidly cooling at 2-8°C, sealing, and obtaining the final product.

[0026] Preferably, in the preparation method, the solvent is a mixture of a non-volatile solvent and a volatile solvent.

[0027] More preferably, in the preparation method, the volume ratio of the non-volatile solvent to the volatile solvent is 1:100.

[0028] Preferably, in the preparation method, the volatile solvent is ethanol or methanol with a volume fraction.

[0029] Preferably, in the preparation method, the heating and melting temperature is 65-85°C.

[0030] Preferably, in the preparation method, the heat preservation temperature is 60-75℃.

[0031] Compared with the prior art, the present invention has the following outstanding advantages:

[0032] 1. In the preparation method of the present invention, there is no need to strictly control the particle size of the raw materials. By dissolving or dispersing the drug in a solvent, the raw drug is eventually uniformly dispersed in the formulation, which solves the problem of poor uniformity caused by the high viscosity and strong adsorption of the raw materials.

[0033] 2. This invention directly fills the molten drug into blister packs and cools them into tablets, avoiding problems such as sticking and cracking that occur during ordinary tableting processes;

[0034] 3. The orally disintegrating tablets obtained by this invention have a good taste and disintegrate rapidly in the oral cavity. They have unparalleled disintegration and dissolution properties compared to ordinary tablets, and are absorbed quickly and have high bioavailability after ingestion.

[0035] 4. The tablets obtained by this invention have high stability, the tablet preparation method is simple and easy to operate, and the production efficiency is high, making it suitable for industrial production. Detailed Implementation

[0036] The following specific embodiments 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 depart from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0037] Example 1

[0038] prescription:

[0039]

[0040] Preparation process:

[0041] Add the prescribed amounts of safenamide mesylate, sucralose, and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3L) and stir until completely dissolved to obtain a mixture. Melt polyoxyethylene-32 stearate and stearic acid polyoxyethylene ester at 80°C, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, keep warm at 70°C, and quantitatively fill the resulting drug solution into tablet inner packaging blister packs according to the specification of 100mg safenamide mesylate per tablet. Rapidly cool at 2-8°C and seal to obtain the final product.

[0042] Example 2

[0043] prescription:

[0044]

[0045] Preparation process:

[0046] Add the prescribed amounts of safenamide mesylate, steviol glycosides, and crospovidone to a mixed solvent of propylene carbonate and ethanol (2L) and stir until completely dissolved to obtain a mixture. Melt stearoyl polyoxyethylene-32 glycerol ester and polyethylene glycol 4000 at 75°C, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, keep warm at 75°C, and quantitatively fill the resulting drug solution into tablet inner packaging blister packs according to the specification of 100mg safenamide mesylate per tablet. Rapidly cool at 2-8°C and seal to obtain the final product.

[0047] Example 3

[0048] prescription:

[0049]

[0050] Preparation process:

[0051] The prescribed amounts of safenamide mesylate, xylitol, and croscarmellose sodium were added to a mixed solvent of propylene glycol didecanoate and methanol (4L) and stirred until completely dissolved to obtain a mixture. Lauroyl polyoxyethylene-32 glyceryl ester, polyethylene glycol 6000, and poloxamer were heated and melted at 65°C, and then the aforementioned mixture was added. The mixture was stirred evenly, and the methanol was removed by heating. The mixture was kept at 60°C. The resulting drug solution was quantitatively filled into tablet inner packaging blister packs according to the specification of 100mg safenamide mesylate per tablet. The tablets were rapidly cooled at 2-8°C and sealed to obtain the final product.

[0052] Example 4

[0053] prescription:

[0054]

[0055] Preparation process:

[0056] Add the prescribed amounts of safenamide mesylate, sucralose, and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3L) and stir until completely dissolved to obtain a mixture. Melt polyoxyethylene-32 stearate and stearic acid polyoxyethylene ester at 80°C, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, keep warm at 70°C, and quantitatively fill the resulting drug solution into tablet inner packaging blister packs according to the specification of 100mg safenamide mesylate per tablet. Rapidly cool at 2-8°C and seal to obtain the final product.

[0057] Example 5

[0058] prescription:

[0059]

[0060] Preparation process:

[0061] Add the prescribed amounts of safenamide mesylate, sucralose, and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3L) and stir until completely dissolved to obtain a mixture. Melt polyoxyethylene-32 stearate and stearic acid polyoxyethylene ester at 80°C, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, keep warm at 70°C, and quantitatively fill the resulting drug solution into tablet inner packaging blister packs according to the specification of 100mg safenamide mesylate per tablet. Rapidly cool at 2-8°C and seal to obtain the final product.

[0062] Example 6

[0063] prescription:

[0064]

[0065] Preparation process:

[0066] Add the prescribed amounts of safenamide mesylate, sucralose, and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3L) and stir until completely dissolved to obtain a mixture. Melt polyoxyethylene-32 stearate and stearic acid polyoxyethylene ester at 80°C, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, keep warm at 70°C, and quantitatively fill the resulting drug solution into tablet inner packaging blister packs according to the specification of 100mg safenamide mesylate per tablet. Rapidly cool at 2-8°C and seal to obtain the final product.

[0067] Comparative Example 1

[0068] prescription:

[0069]

[0070] Preparation process:

[0071] Add the prescribed amounts of safenamide mesylate, sucralose, and sodium carboxymethyl starch to ethanol (3L) and stir until completely dissolved to obtain a mixture. Melt polyoxyethylene-32 stearate and polyoxyethylene stearate at 80°C, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, keep warm at 70°C, and quantitatively fill the resulting drug solution into tablet inner packaging blister packs according to the specification of 100mg safenamide mesylate per tablet. Rapidly cool at 2-8°C and seal to obtain the final product.

[0072] Comparative Example 2

[0073] prescription:

[0074]

[0075] Preparation process:

[0076] Add the prescribed amounts of safenamide mesylate, sucralose, and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3L) and stir until completely dissolved to obtain a mixture. Melt stearic acid polyoxyethylene at 80°C, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, keep warm at 70°C, and quantitatively fill the resulting drug solution into tablet inner packaging blister packs according to the specification of 100mg safenamide mesylate per tablet. Rapidly cool at 2-8°C and seal to obtain the final product.

[0077] Comparative Example 3

[0078] prescription:

[0079]

[0080] Preparation process: Polyoxyethylene-32 stearate and stearic acid polyoxyethylene ester are passed through a 60-mesh sieve; the prescribed amounts of safenamide methanesulfonate, sucralose, sodium carboxymethyl starch, and the sieved polyoxyethylene-32 stearate and stearic acid polyoxyethylene ester are mixed evenly; a mixed solvent of diethylene glycol monoethyl ether and ethanol (3L) is added to granulate the mixture, which is then passed through a 20-mesh sieve; the mixture is dried under reduced pressure at 40℃; the granules are then sieved through a 20-mesh sieve for granulation; each tablet is compressed to contain 100mg of safenamide methanesulfonate and packaged in aluminum-plastic packaging.

[0081] Comparative Example 4

[0082] prescription:

[0083]

[0084]

[0085] Preparation process: The safenamide mesylate raw material is pulverized using a pharmaceutical pulverizer. The prescribed amount of safenamide mesylate raw material is weighed and then thoroughly mixed with crospovidone, microcrystalline cellulose, magnesium stearate, and colloidal silica in sequence. After testing the content of the mixed material, the corresponding tablet weight is calculated based on the content, and tablets are compressed. The tablet hardness is adjusted to 3-6 kg, with a tablet weight difference of ±5.0%.

[0086] Verification of Examples

[0087] Experimental Example 1: Examination of the appearance, taste, and disintegration time of the obtained formulation

[0088] The method for testing the texture is as follows: Ten teenagers aged 18-22 will evaluate the product. The evaluators should be able to correctly taste the different fineness and hardness of the oral-breakable tablets. The oral-breakable tablets should have a smooth surface, a delicate texture without any gritty feeling, a moderate softness and hardness, and a good taste.

[0089] Disintegration Time Test: Refer to the disintegration time test method for orally disintegrating tablets in General Chapter 0921 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. The instrument consists of a liftable support and a stainless steel tube with a sieve at the lower end. The liftable support moves up and down at a frequency of 30 times per minute. The disintegration basket is a 30mm long stainless steel tube with an inner diameter of 13.0mm. The stainless steel sieve (embedded at the bottom of the tube) has an inner diameter of 710µm. The test method involves fixing the stainless steel tube to the support and immersing it in approximately 900mL of water at 37℃ ± 1℃. The water level is adjusted so that the sieve is 15mm ± 1mm ​​below the water surface when the stainless steel tube is at its lowest position. One tablet of the product is placed in the stainless steel tube for testing. It should completely disintegrate and pass through the sieve within 60 seconds. If a small amount of light material floats to the top or adheres to the inner wall of the stainless steel tube or the sieve, but there is no hard core, it is considered compliant. Six tablets should be tested repeatedly, and all should meet the requirements. If one tablet fails to meet the requirements, six more tablets should be tested again, and all should meet the requirements.

[0090] Table 1. Measurement results of the examples and comparative examples.

[0091] Example Appearance taste Disintegration Time Example 1 White gloss Slightly sweet, without any gritty texture 45s Example 2 White gloss Slightly sweet, without any gritty texture 46s Example 3 White gloss Slightly sweet, without any gritty texture 44s Example 4 White gloss Slightly sweet, without any gritty texture 53s Example 5 White gloss Slightly sweet, without any gritty texture 50s Example 6 White gloss Slightly sweet, without any gritty texture 55s Comparative Example 1 White gloss The gritty texture is obvious. 65s Comparative Example 2 White gloss Slightly sweet, without any gritty texture 69s Comparative Example 3 White, rough surface It tastes bitter and has a noticeable gritty texture. 76s Comparative Example 4 White with slight spots - 12min

[0092] The results showed that the orally disintegrating tablets obtained in each example were white and smooth in appearance, had a good taste, and disintegrated rapidly. In contrast, the formulation of Example 1 did not contain a non-volatile solvent, resulting in poor dispersibility of the excipients and a noticeable gritty texture. In contrast, Example 3 used a different preparation method than the examples, resulting in a rough surface, a bitter taste, and a noticeable gritty texture. In contrast, the ordinary tablets obtained in Example 4 had slightly spotted appearance and a longer disintegration time.

[0093] Experimental Example 2: Investigation of the content uniformity and stability of the obtained formulation

[0094] Content uniformity determination: The content uniformity test was performed according to the content uniformity test method in General Chapter 0941 of Part IV of the Chinese Pharmacopoeia. The standard is A+2.2S≤15.

[0095] Accelerated stability test: The sample was placed at a temperature of 40±2℃ and a relative humidity of 75±5% (accelerated) for 6 months. Samples were taken at the end of the 0th, 3rd and 6th months, and the related substances (total impurities, %) were determined.

[0096] Table 2. Measurement results of the examples and comparative examples.

[0097]

[0098]

[0099] The results showed that, compared with the comparative examples, the oral disintegrating tablets obtained in each example had uniform content and low content of related substances.

[0100] Experimental Example 3: Pharmacokinetic Study

[0101] Pharmacokinetic experiments were conducted on the formulations prepared in the embodiments and comparative embodiments of this invention (denoted as test formulation T). A commercially available 100mg Xadago formulation (denoted as reference formulation R) was used as the reference formulation in a single-dose, two-period crossover study. Eight Beagle dogs were used as test subjects in each embodiment and comparative embodiment, and these eight Beagle dogs were divided into two groups. After a high-fat meal, the dogs were administered the corresponding T and R formulations, respectively, to investigate pharmacokinetics and bioequivalence between the two formulations.

[0102] Table 3. Measurement results of the examples and comparative examples.

[0103]

[0104] The results showed that all examples were equivalent to the reference formulation, with slightly higher AUC. Comparative Example 1 did not contain a non-volatile solvent, Comparative Example 2 did not contain a surfactant, and Comparative Example 3 used a different preparation method than the examples, resulting in a formulation with a lower AUC than the reference formulation. Comparative Example 4 used existing formulations and preparation methods, and the resulting formulation had a significantly lower AUC than the reference formulation.

Claims

1. A safenamide mesylate formulation, characterized in that, The formulation contains safinamide methanesulfonate, a non-volatile solvent, a surfactant, a water-soluble matrix, a disintegrant, and a flavoring agent. The surfactant is polyoxyethylene-32 stearate, stearoyl polyoxyethylene-32 glycerol ester, or lauroyl polyoxyethylene-32 glycerol ester, with a surfactant-to-safinamide methanesulfonate weight ratio of 0.4-0.6:

1. The water-soluble matrix is ​​selected from one or more of polyoxyethylene stearate, polyethylene glycol 4000, polyethylene glycol 6000, and poloxamer, with a water-soluble matrix-to-safinamide methanesulfonate weight ratio of 1-1.5:

1. The non-volatile solvent is diethylene glycol monoethyl ether or propylene glycol carbonate, propylene glycol didecanoate, with the volume ratio of the non-volatile solvent to... The weight ratio of safenamide mesylate is 0.2~0.4:1, with volume in mL and weight in g; the disintegrant is sodium carboxymethyl starch, crospovidone, or crospovidone carboxymethyl cellulose; the preparation method of the formulation includes the following steps: adding safenamide mesylate, flavoring agent, and disintegrant to a solvent and stirring until completely dissolved to obtain a mixture; heating and melting the surfactant and water-soluble matrix, then adding the aforementioned mixture, stirring evenly, continuing to heat to remove part of the solvent, keeping warm, quantitatively filling the resulting drug solution into tablet inner packaging blister packs, rapidly cooling at 2~8℃, and sealing to obtain the final product; in the preparation method, the solvent is a mixture of non-volatile solvent and volatile solvent, and the volatile solvent is ethanol or methanol.

2. The formulation according to claim 1, characterized in that, In the formulation, the non-volatile solvent is diethylene glycol monoethyl ether.

3. The formulation according to claim 1, characterized in that, In the formulation, the flavoring agent is sucralose, steviol glycosides, or xylitol.

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