Safinamide mesylate preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a safinamide mesylate preparation and a preparation method thereof. The preparation contains safinamide mesylate, a non-volatile solvent, a surfactant, a water-soluble matrix, a disintegrating agent and a flavoring agent, the obtained preparation can realize good taste, high content uniformity, relatively good stability and high bioavailability, and meanwhile, the preparation process is simple and convenient.

Description

Technical Field

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

[0002] Safinamide mesylate was developed by Newron and its marketing partner Zambon. It was approved by the 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.

[0003] The chemical name of Safinamide Mesylate is (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide mesylate, and the structural formula is as follows:

[0004]

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

[0006] CN106361711B uses a powder direct tableting method to prepare safinamide mesylate tablets, micronizing the raw materials to control the particle size below 50 μm. Since the raw materials account for a relatively high proportion in the prescription, the mixed powder of raw materials 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.

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

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

[0009] CN109414404B relates to a pharmaceutical composition containing safinamide, a taste-masking particle containing the active ingredient or a pharmaceutically acceptable salt thereof, an oral dosage form containing the particle, and a method for preparing the same. CN117752819A improves the taste of safinamide mesylate by cyclodextrin inclusion.

[0010] In the prior art, oral preparations of safinamide mesylate still have the problems of complex preparation process, uneven content, poor stability, and reliance on flavor correctives for taste masking. It is still necessary to continuously study the formulation and preparation process in order to provide a more clinically suitable, high-quality oral solid preparation of safinamide mesylate. Summary of the invention

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

[0012] The present invention is specifically implemented through the following technical solutions:

[0013] A safinamide methanesulfonate preparation contains safinamide methanesulfonate, a non-volatile solvent, a surfactant, a water-soluble matrix, a disintegrant and a flavoring agent.

[0014] Preferably, in the preparation, the non-volatile solvent is diethylene glycol monoethyl ether or propylene carbonate, propylene glycol dicaprate; further preferably, the non-volatile solvent is diethylene glycol monoethyl ether.

[0015] Preferably, in the preparation, the volume ratio of the non-volatile solvent to the weight ratio of safinamide methanesulfonate is 0.2 to 0.4:1, the volume is measured in mL, and the weight is measured in g.

[0016] Preferably, in the preparation, the surfactant is polyoxyethylene-32 stearate, stearoyl polyoxyethylene-32 glyceride or lauroyl polyoxyethylene-32 glyceride.

[0017] Preferably, in the preparation, the weight ratio of the surfactant to safinamide methanesulfonate is 0.4 to 0.6:1.

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

[0019] Preferably, in the preparation, the weight ratio of the water-soluble matrix to safinamide methanesulfonate is 1 to 1.5:1.

[0020] Preferably, in the preparation, the disintegrant is sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose.

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

[0022] Preferably, in the preparation, the flavoring agent is sucralose, steviol glycoside or xylitol.

[0023] Preferably, in the preparation, the weight ratio of the flavoring agent to safinamide methanesulfonate is 0.01 to 0.06:1.

[0024] Preferably, the safinamide methanesulfonate preparation of the present invention is a safinamide methanesulfonate orally disintegrating tablet.

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

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

[0027] Further 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 in 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 insulation temperature is 60-75°C.

[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 material. By dissolving or dispersing the drug in the solvent, the raw material is finally evenly dispersed in the preparation, solving the problem of poor uniformity caused by high viscosity and strong adsorption of the raw material;

[0033] 2. The present invention directly quantitatively fills the drug melt into the blister and cools it into tablets, thus avoiding problems such as sticking and splitting that occur in the ordinary tableting process;

[0034] 3. The orodisintegrating tablets obtained by the present invention have good taste, disintegrate rapidly in the oral cavity, have incomparable disintegration and dissolution properties compared with ordinary tablets, are quickly absorbed after taking, and have high bioavailability;

[0035] 4. 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 suitable for industrial production. DETAILED DESCRIPTION

[0036] 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.

[0037] Example 1

[0038] prescription:

[0039]

[0040] Preparation process:

[0041] Add the prescribed amount of safinamide methanesulfonate, sucralose and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3 L), stir until completely dissolved to obtain a mixture; heat polyoxyethylene-32 stearate and polyoxyl stearate at 80° C. to melt, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, and keep warm at 70° C. The obtained drug solution is quantitatively filled into the tablet inner package blister according to the specification of 100 mg of safinamide methanesulfonate per tablet, quickly cooled at 2-8° C., and sealed to obtain the product.

[0042] Example 2

[0043] prescription:

[0044]

[0045] Preparation process:

[0046] Add the prescribed amount of safinamide mesylate, stevioside and cross-linked polyvinylpyrrolidone to a mixed solvent of propylene carbonate and ethanol (2L), stir until completely dissolved to obtain a mixture; heat stearoyl polyoxyethylene-32 glyceride and polyethylene glycol 4000 at 75°C to melt, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, and keep warm at 75°C. The obtained drug solution is quantitatively filled into the tablet inner package blister according to the specification of 100 mg of safinamide mesylate per tablet, quickly cooled at 2-8°C, and sealed to obtain the product.

[0047] Example 3

[0048] prescription:

[0049]

[0050] Preparation process:

[0051] Add the prescribed amount of safinamide mesylate, xylitol and cross-linked sodium carboxymethyl cellulose to a mixed solvent of propylene glycol dicaprate and methanol (4 L), stir until completely dissolved to obtain a mixture; heat lauroyl polyoxyethylene-32 glyceride, polyethylene glycol 6000 and poloxamer at 65° C. to melt, then add the aforementioned mixture, stir evenly, continue heating to remove methanol, keep warm at 60° C., and quantitatively fill the obtained drug solution into the tablet inner package blister according to the specification of 100 mg of safinamide mesylate per tablet, quickly cool at 2-8° C., and seal to obtain the drug solution.

[0052] Example 4

[0053] prescription:

[0054]

[0055] Preparation process:

[0056] Add the prescribed amount of safinamide methanesulfonate, sucralose and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3 L), stir until completely dissolved to obtain a mixture; heat polyoxyethylene-32 stearate and polyoxyl stearate at 80° C. to melt, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, and keep warm at 70° C. The obtained drug solution is quantitatively filled into the tablet inner package blister according to the specification of 100 mg of safinamide methanesulfonate per tablet, quickly cooled at 2-8° C., and sealed to obtain the product.

[0057] Example 5

[0058] prescription:

[0059]

[0060] Preparation process:

[0061] Add the prescribed amount of safinamide methanesulfonate, sucralose and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3 L), stir until completely dissolved to obtain a mixture; heat polyoxyethylene-32 stearate and polyoxyl stearate at 80° C. to melt, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, and keep warm at 70° C. The obtained drug solution is quantitatively filled into the tablet inner package blister according to the specification of 100 mg of safinamide methanesulfonate per tablet, quickly cooled at 2-8° C., and sealed to obtain the product.

[0062] Example 6

[0063] prescription:

[0064]

[0065] Preparation process:

[0066] Add the prescribed amount of safinamide methanesulfonate, sucralose and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3 L), stir until completely dissolved to obtain a mixture; heat polyoxyethylene-32 stearate and polyoxyl stearate at 80° C. to melt, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, and keep warm at 70° C. The obtained drug solution is quantitatively filled into the tablet inner package blister according to the specification of 100 mg of safinamide methanesulfonate per tablet, quickly cooled at 2-8° C., and sealed to obtain the product.

[0067] Comparative Example 1

[0068] prescription:

[0069]

[0070] Preparation process:

[0071] Add the prescribed amount of safinamide mesylate, sucralose and sodium carboxymethyl starch into ethanol (3 L), stir until completely dissolved to obtain a mixture; heat polyoxyethylene-32 stearate and polyoxyl stearate at 80° C. to melt, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, keep warm at 70° C., and quantitatively fill the obtained drug solution into the tablet inner package blister according to the specification of 100 mg of safinamide mesylate per tablet, quickly cool at 2-8° C., and seal to obtain the product.

[0072] Comparative Example 2

[0073] prescription:

[0074]

[0075] Preparation process:

[0076] Add the prescribed amount of safinamide methanesulfonate, sucralose and sodium carboxymethyl starch to a mixed solvent of diethylene glycol monoethyl ether and ethanol (3 L), stir until completely dissolved to obtain a mixture; heat polyoxyl stearate at 80° C. to melt, then add the aforementioned mixture, stir evenly, continue heating to remove ethanol, and keep warm at 70° C. The obtained drug solution is quantitatively filled into the tablet inner package blister according to the specification of 100 mg of safinamide methanesulfonate per tablet, quickly cooled at 2-8° C., and sealed to obtain the product.

[0077] Comparative Example 3

[0078] prescription:

[0079]

[0080] Preparation process: pass polyoxyethylene-32 stearate and polyoxyl stearate through a 60-mesh sieve; evenly mix the prescribed amount of safinamide methanesulfonate, sucralose, sodium carboxymethyl starch, and the sieved polyoxyethylene-32 stearate and polyoxyl stearate; add a mixed solvent of diethylene glycol monoethyl ether and ethanol (3L) to granulate, and pass through a 20-mesh sieve; dry under reduced pressure at 40°C; pass through a 20-mesh sieve to size the particles; compress the tablets into tablets according to the specification that each tablet contains 100 mg of safinamide methanesulfonate, and pack them in aluminum-plastic packaging to obtain the product.

[0081] Comparative Example 4

[0082] prescription:

[0083]

[0084]

[0085] Preparation process: The raw material of safinamide mesylate is crushed with a pulverizer, the prescribed amount of the raw material of safinamide mesylate is weighed, and then it is fully mixed 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 tableting is performed, and the hardness of the tablet is adjusted to 3-6kg, and the tablet weight difference is ±5.0%, and tableting is performed.

[0086] Verification Example

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

[0088] Taste testing method: 10 teenagers aged 18 to 22 years old will evaluate the taste. The assessors should be able to correctly taste orally disintegrating tablets of different fineness and hardness. Orally disintegrating tablets should have a smooth surface, a delicate taste without grit, moderate hardness and good taste.

[0089] Disintegration time determination: refer to the disintegration time method of orally disintegrating tablets in the 0921 disintegration time inspection method of the four general rules of the 2020 edition of the Chinese Pharmacopoeia. The instrument: the main structure is a lifting bracket and a stainless steel tube with a screen at the lower end. The lifting bracket moves up and down a distance of 30 times per minute. The disintegration basket stainless steel tube, the tube length is 30mm, the inner diameter is 13.0mm, and the stainless steel screen (set at the bottom of the stainless steel tube) has a mesh inner diameter of 710um. Inspection method: Fix the stainless steel tube on the bracket and immerse it in a 1000mL cup. The cup contains about 900mL of water at a temperature of 37℃±1℃. Adjust the water level so that the screen is 15mm±1mm below the water surface when the stainless steel tube is at the lowest position and start the instrument. Take 1 tablet of this product and place it in the above-mentioned stainless steel tube for inspection. It should be completely disintegrated and pass through the screen within 60 seconds. If there is a small amount of light floating or adhering to the inner wall of the stainless steel tube or the screen, but there is no hard core, it can be considered as meeting the regulations. Repeat the test for 6 pieces, and all pieces should meet the requirements. If one piece does not meet the requirements, take another 6 pieces for retest, and all pieces should meet the requirements.

[0090] Table 1 Measurement results of Examples and Comparative Examples

[0091] Example Appearance Taste Disintegration time Example 1 White and clean Slightly sweet, non-gritty 45s Example 2 White and clean Slightly sweet, non-gritty 46s Example 3 White and clean Slightly sweet, non-gritty 44s Example 4 White and clean Slightly sweet, non-gritty 53s Example 5 White and clean Slightly sweet, non-gritty 50s Example 6 White and clean Slightly sweet, non-gritty 55s Comparative Example 1 White and clean Obvious sense of gravel 65s Comparative Example 2 White and clean Slightly sweet, non-gritty 69s Comparative Example 3 White, rough surface Bitter taste, gritty feel 76s Comparative Example 4 White, slightly spotted - 12min

[0092] The results show that the orally disintegrating tablets obtained in each embodiment are white and smooth in appearance, have a good taste, and disintegrate quickly; in Comparative Example 1, no non-volatile solvent is added to the prescription, the dispersibility of the excipients is poor, and the resulting preparation has a distinct gritty feel; Comparative Example 3 adopts a preparation method different from that of the embodiments, and the resulting preparation has a rough surface, a bitter taste, and a distinct gritty feel; the ordinary tablets obtained in Comparative Example 4 have slightly spotted appearance and a longer disintegration time.

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

[0094] Determination of content uniformity: According to the content uniformity inspection method 0941 of Part IV of the Chinese Pharmacopoeia, the standard is A+2.2S≤15.

[0095] Accelerated stability test: Place the product under the conditions of temperature 40±2℃ 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 (total impurities, %) etc.

[0096] Table 2 Measurement results of Examples and Comparative Examples

[0097]

[0098]

[0099] The results show that compared with the comparative example, the orally disintegrating tablets obtained in each example have uniform content and low content of related substances.

[0100] Experimental Example 3: Pharmacokinetic Study

[0101] The preparations prepared in the examples of the present invention and the comparative examples (referred to as the test preparation T) were used for pharmacokinetic experiments, and the commercially available 100 mg Xadago (referred to as the reference preparation R) was used as the reference preparation, and a single-dose, two-period crossover test was performed. In each example and comparative example, 8 Beagle dogs were used as test subjects, wherein the 8 Beagle dogs were divided into two groups, and the corresponding T and R were given after a high-fat meal, respectively, to investigate the pharmacokinetics and bioequivalence between the two preparations.

[0102] Table 3 Measurement results of Examples and Comparative Examples

[0103]

[0104] The results show that: each embodiment is equivalent to the reference preparation, and the AUC is slightly higher than the reference preparation; no non-volatile solvent is added to the prescription of Comparative Example 1, no surfactant is added to the prescription of Comparative Example 2, and Comparative Example 3 adopts a preparation method different from that of the embodiments, and the AUC of the obtained preparation is lower than that of the reference preparation; Comparative Example 4 adopts the existing prescription and preparation method, and the AUC of the obtained preparation is significantly lower than that of the reference preparation.

Claims

1. A safinamide methanesulfonate preparation, characterized in that: The preparation contains safinamide mesylate, a non-volatile solvent, a surfactant, a water-soluble matrix, a disintegrant and a flavoring agent.

2. The preparation according to claim 1, characterized in that In the preparation, the surfactant is polyoxyethylene-32 stearate, stearoyl polyoxyethylene-32 glyceride or lauroyl polyoxyethylene-32 glyceride.

3. The preparation according to claim 1, characterized in that In the preparation, the weight ratio of the surfactant to the safinamide methanesulfonate is 0.4 to 0.6:

1.

4. The preparation according to claim 1, characterized in that In the preparation, the water-soluble matrix is ​​selected from one or more of polyoxyl stearate, polyethylene glycol 4000, polyethylene glycol 6000 and poloxamer.

5. The preparation according to claim 1, characterized in that In the preparation, the weight ratio of the water-soluble matrix to the safinamide mesylate is 1 to 1.5:

1.

6. The preparation according to claim 1, characterized in that In the preparation, the non-volatile solvent is diethylene glycol monoethyl ether or propylene carbonate, propylene glycol dicaprate; preferably, the non-volatile solvent is diethylene glycol monoethyl ether.

7. The preparation according to claim 1, characterized in that In the preparation, the volume ratio of the non-volatile solvent to the weight ratio of safinamide methanesulfonate is 0.2 to 0.4:1, the volume is measured in mL, and the weight is measured in g.

8. The preparation according to claim 1, characterized in that In the preparation, the disintegrant is sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose.

9. The preparation according to claim 1, characterized in that In the preparation, the flavoring agent is sucralose, steviol glycoside or xylitol.

10. A method for preparing the preparation according to claim 1, characterized in that: The preparation method comprises the following steps: adding safinamide mesylate, a flavoring agent and a disintegrant into a solvent and stirring until the mixture is completely dissolved; heating and melting a surfactant and a water-soluble matrix, adding the aforementioned mixture, stirring evenly, continuing to heat to remove part of the solvent, keeping the temperature, quantitatively filling the obtained drug solution into the blister of the tablet inner package, rapidly cooling at 2-8°C, and sealing to obtain the product.

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