Perampanel Orally Disintegrating Film and Its Preparation Method

Abstract

The present invention belongs to the field of pharmaceutical preparations, and in particular to a perampanel orally disintegrating film and a preparation method thereof. Its orally disintegrating film includes the following components in parts by weight: 1-10 parts of perampanel, 5-60 parts of film-forming agent, 5-50 parts of disintegrant and 1-30 parts of plasticizer. The preparation method includes first adding perampanel, film-forming agent, disintegrant and plasticizer to a solvent, then adding a flavoring agent to the solvent, stirring and mixing, and preparing a drug-containing slurry; then the drug-containing slurry is vacuum degassed, and finally the degassed slurry is coated on a substrate, dried, and film-formed, to obtain. The perampanel orally disintegrating film provided by the present invention has moderate strength and toughness, a smooth surface, uniform drug loading, good dissolution effect and good taste, and has a good application prospect.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a perampanel orally disintegrating film and a preparation method thereof. Background Art

[0002] Perampanel, chemically known as 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, has the following chemical structure. It is clinically indicated for the adjunctive treatment of partial-onset epileptic seizures with or without secondary generalized seizures, as well as primary generalized tonic-clonic seizures, in patients aged 12 years and older. The currently marketed dosage form is a standard tablet.

[0003] Since most patients with epileptic seizures experience sudden loss of consciousness and whole-body convulsions, or sudden loss of consciousness and muscle tone, or bilateral rhythmic myoclonic twitching mainly in the head and upper limb muscles, or status epilepticus, which is characterized by continuous or recurrent seizures with no recovery of consciousness during intermittent periods, tablets need to be swallowed with water, and patients have poor compliance with the medication, which may even cause tracheal obstruction and pose a potential risk.

[0004]

[0005] Currently, there is little research on perampanel orally disintegrating film. Chinese invention patent application CN109106696A discloses a perampanel orally disintegrating film and its preparation method. However, the particle size of the API was studied, and the limited particle size range was relatively wide, which is of no practical reference value. In addition, the patented formula contains the API, film-forming agent, disintegrant, and surfactant. After research, the design is unreasonable, and the compatibility of the drug excipients with the raw materials is very poor, making it unimplementable. After adjusting the formula, the resulting intermediate slurry contains a large amount of insoluble matter, the drug solution has poor uniformity, and the slurry has no viscosity, which causes the suspended API to easily settle, making it impossible to apply to obtain a uniform film.

[0006] Therefore, there is an urgent need to develop a perampanel orally disintegrating film with good excipient compatibility, moderate slurry viscosity, uniform drug solution, good coating, and good disintegration and solubility to meet the actual needs of patients. Summary of the Invention

[0007] In view of the shortcomings of the existing technology, the present invention provides a perampanel orally dissolving film with moderate strength and toughness, smooth surface, uniform drug loading, good dissolution effect and good taste, which has good application prospects.

[0008] In order to achieve the purpose of the present invention, the technical solutions adopted are as follows:

[0009] A perampanel orally disintegrating film comprises the following components in parts by weight: 1-10 parts of perampanel, 5-60 parts of a film-forming agent, 5-50 parts of a disintegrant, and 1-30 parts of a plasticizer.

[0010] Preferably, the orally disintegrating film comprises the following components in parts by weight: 3-8 parts of perampanel, 20-50 parts of film-forming agent, 20-40 parts of disintegrant and 5-20 parts of plasticizer.

[0011] Preferably, the orally disintegrating film comprises the following components in parts by weight: 6-7 parts of perampanel, 35-45 parts of film-forming agent, 30-40 parts of disintegrant and 10-20 parts of plasticizer.

[0012] Preferably, the film-forming agent is selected from one or any combination of hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene oxide, gelatin, xanthan gum, pectin, sodium alginate and corn starch, and is particularly preferably a mixture of hydroxyethyl cellulose and hydroxypropyl methylcellulose, wherein the weight ratio of hydroxyethyl cellulose to hydroxypropyl methylcellulose is 1:1-10, preferably 1:3-8, more preferably 1:4-6, and most preferably 1:5.

[0013] Preferably, the disintegrant is at least one selected from maltodextrin, sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium alginate, cross-linked polyvinyl pyrrolidone and microcrystalline cellulose.

[0014] Preferably, the disintegrant is maltodextrin.

[0015] Preferably, the plasticizer is selected from at least one of glycerol, propylene glycol, triethyl citrate, sorbitol, dimethyl phthalate, diethyl phthalate, triacetin and castor oil, preferably glycerol, wherein the weight ratio of glycerol to perampanel is 1.5-3:1, preferably 2-2.5:1, more preferably 2:1.

[0016] Preferably, the orally dissolving film further comprises 0.1-10 parts of flavoring agent;

[0017] Preferably, the orally disintegrating film further comprises 0.1-5 parts of a flavoring agent, preferably 1-2 parts, more preferably 1-1.2 parts, wherein the flavoring agent is selected from one or any combination of sucralose, aspartame, stevioside, saccharin sodium, xylitol, sorbitol, lemon flavor and strawberry flavor, preferably sucralose.

[0018] Preferably, the weight ratio of sucralose to perampanel is 0.1-0.5:1.

[0019] Another object of the present invention is to provide a method for preparing an orally disintegrating film, comprising the steps of:

[0020] A. adding perampanel, a film-forming agent, a disintegrant, a plasticizer, and a flavoring agent into a solvent to prepare a slurry;

[0021] B. Vacuum degassing the slurry;

[0022] C. Apply the deaerated slurry on the substrate, dry it, and form a film.

[0023] Preferably, the solvent in step A is water and / or ethanol solution.

[0024] Preferably, before adding the solvent to the perampanel in step A, the perampanel should first be added to a mixed solution of water and ethanol to prepare a perampanel suspension.

[0025] Preferably, the mass ratio of the perampanel to the mixed solution is 1:25-35.

[0026] Preferably, the substrate in step C is an inert carrier material, and the drying temperature is 50-70°C.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] (1) The present invention prepares a perampanel orally disintegrating film by combining a specific film-forming agent, a plasticizer, and a disintegrant, and the perampanel orally disintegrating film has a good dissolution effect and a fast dissolution rate.

[0029] (2) The present invention found that the selection of plasticizers has a significant effect on the stability of the perampanel orally dissolving film. Under the formulation of the present invention, the drug content is stable under high temperature, high humidity and strong light, and the growth of related substances is not obvious, indicating good stability.

[0030] (3) The present invention uses a specific film-forming agent in combination with the main drug and other excipients, and the resulting perampanel orally dissolving film has moderate strength and toughness, a smooth surface, and uniform drug loading.

[0031] (4) After pilot-scale expansion, the performance of the drug is good and stable, making it suitable for industrial large-scale production and having good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the appearance of the orally disintegrating film sheet of Comparative Example 1;

[0033] Figure 2 1 is the dissolution curve diagram of Example 10 and Comparative Example 1. DETAILED DESCRIPTION

[0034] The present invention will be further described below with reference to specific embodiments.

[0035] Examples 1-3

[0036] The prescription is shown in Table 1.

[0037] Table 1

[0038]

[0039] Preparation method:

[0040] The preparation method is as follows:

[0041] Take 30g of purified water, heat it to above 85°C, add the prescribed amount of perampanel, film-forming agent, maltodextrin, PEG400, PEG4000 and sucralose, add water to 84g, and stir to obtain a drug-containing slurry; transfer the obtained drug-containing slurry to a vacuum degassing cup and degas using a vacuum degassing mixer; adjust the coating knife height to 600μm, apply the obtained degassed slurry on an inert carrier material, and place it in a 60°C oven to dry for 40 minutes to form a film.

[0042] Examples 4-9

[0043] The prescription is shown in Table 2.

[0044] Table 2

[0045]

[0046] The preparation method is as follows:

[0047] Take 30g of purified water, heat it to above 85°C, add the prescribed amount of hydroxypropyl methylcellulose E50, perampanel, hydroxyethyl cellulose 250g, maltodextrin, plasticizer and sucralose, add water to 84g, stir and mix to obtain a drug-containing slurry; transfer the obtained drug-containing slurry to a vacuum degassing cup and use a vacuum degassing mixer to degas; adjust the coating knife height to 600μm, apply the obtained degassed slurry on an inert carrier material, and place it in a 60°C oven to dry for 40min to form a film.

[0048] Example 10

[0049] The pilot batch formulation is shown in Table 3.

[0050] Table 3

[0051] Raw materials Dosage / g Perampanel 8 Hydroxypropyl methylcellulose E50 40 Hydroxyethylcellulose 250G 8 maltodextrin 40 glycerin 16 Sucralose 1.2 ethanol 80 water Add water to a total weight of 672

[0052] Preparation method:

[0053] (1) Purified water and anhydrous ethanol in a ratio of 2:1 were placed in a beaker and mixed to obtain a mixed solution, and perampanel (wherein the mass ratio of perampanel to the mixed solution was 1:30) was added, and homogenized for 16 minutes using a homogenizer until uniform dispersion was obtained to obtain a perampanel suspension; the remaining purified water was heated to 88°C, and hydroxypropyl methylcellulose E50, perampanel suspension, hydroxyethyl cellulose 250g, maltodextrin, glycerol and sucralose were added in sequence, and stirred to obtain a drug-containing slurry;

[0054] (2) Transfer the obtained drug-containing slurry into a vacuum degassing cup and use a vacuum degassing mixer to degas;

[0055] (3) Adjust the coating knife height to 600 μm, apply the degassed drug-containing slurry onto an inert carrier material, and dry it in an oven at 50°C for 40 minutes.

[0056] Comparative Example 1

[0057] An orally disintegrating film was prepared according to the recipe and method of Example 4 of patent CN109106696A.

[0058] In the prescription (based on 1000 tablets), adding 40 mg of a mixed solvent of ethanol and water was unable to dissolve any material and was even unable to wet the material.

[0059] The prescription of patent CN109106696A is adjusted and studied according to 40g ethanol and water, but there are still problems in the subsequent process. Polyvinyl alcohol and sodium alginate are added to the system, and both do not dissolve. The system does not show any viscosity. After stirring for about 120-150min at high temperature, there is no sign of any dissolution. There are a large amount of insolubles in the obtained intermediate slurry, and the liquid homogeneity is poor. And the slurry does not have any viscosity, causing the API in the suspended state to easily settle, and it is impossible to apply a uniform film.

[0060] The prescription and process of patent CN109106696A are further optimized: the prescription is as shown in Table 4 below:

[0061] Table 4

[0062] Raw materials Dosage / g Perampanel 2 Pluronic F68 1.23 polyvinyl alcohol 6.92 Sodium alginate 2.92 polyethylene glycol 400 0.77 polyethylene glycol 4000 0.77 Aspartame 0.31 ethanol 20 water 40

[0063] The preparation method is as follows:

[0064] Perampanel was micronized to obtain perampanel particles with a particle size (D90) of 9.98 μm. The prescribed amount of purified water was added with polyvinyl alcohol, heated to above 80°C, and stirred to dissolve. Sodium alginate was added and stirred to obtain matrix A, which was set aside. The prescribed amount of anhydrous ethanol was added with Pluronic F68 and ultrasonically dissolved. Perampanel was added and ultrasonically stirred. The API did not dissolve but was evenly dispersed. The obtained matrix A was transferred to the suspension of the API and stirred to mix. Polyethylene glycol 4000, polyethylene glycol 400, and aspartame were added and stirred to mix. The mixture was vacuum degassed, coated, and dried at 65°C for approximately 45 minutes to obtain a dry film. The film was cut according to the intermediate content.

[0065] The optimized product can form a film, but the film surface is uneven, there are granular insolubles, and the properties are unqualified. Figure 1 .

[0066] Experiment 1: Film forming performance test

[0067] Comparing the film-forming effects of Examples 1-10, it is found that the film-forming effect of Example 3 is significantly better than that of Examples 1-2. The film-forming effects of Examples 4-10 are the best, and the results are shown in Table 5.

[0068] Table 5: Film composition

[0069] Grouping Film-forming effect Example 1 The surface of the membrane is uniform, with a small amount of granular insoluble matter Example 2 The surface of the membrane is uniform, with a small amount of granular insoluble matter Example 3 Off-white diaphragm with uniform color Examples 4-10 Off-white diaphragm with uniform color

[0070] Test 2: Product quality determination

[0071] The quality of the products of Example 3-4 was measured after 0 days and after 4 days of exposure, and the results are shown in Table 6 below.

[0072] Table 6 Product quality measurement results

[0073]

[0074] From the above test results, it can be seen that in Example 3, polyethylene glycol (a mixture of PEG400 and PEG4000) is used as a plasticizer. The properties and content of the product change significantly under light conditions, indicating that polyethylene glycol has a certain effect on the stability of the product; in Example 4, glycerol is used as a plasticizer. The content and properties of the prepared preparation do not change significantly under light exposure conditions. Glycerol is the most preferred plasticizer in the present invention.

[0075] Test 3: Product flexibility test

[0076] The effect of the amount of glycerol used in Examples 4-9 on the flexibility of the products was tested, and the results are shown in Table 7.

[0077] Table 7 Flexibility of orally dissolving film

[0078]

[0079]

[0080] The test results show that the products of Examples 5-8 have good flexibility, among which Example 6 has the best effect. That is, when the ratio of glycerol to the main drug is 2:1, the finished preparation has sufficient toughness and is not easy to break when bent, which is the most preferred solution.

[0081] Test 4: Dissolving film performance test

[0082] The orally dissolving film of Example 10 of the present invention was tested for properties, film thickness, and content uniformity. The content uniformity was determined according to the Chinese Pharmacopoeia 2020 General Chapter 0941. The results are shown in Table 8.

[0083] Table 8 Oral dissolving film performance

[0084] Inspection indicators Example 10 Traits Off-white flake film with smooth appearance content 101.2％ Related substances Maximum single impurity 0.05%, total impurity 0.10% Film thickness 60±1μm Content uniformity (A+2.2S) 5 Folding strength Bend 10 times without breaking the diaphragm Tensile strength Measured three times, the average value is 15.5N Moisture 7.0 Melting time 1.5min Residual solvent (ethanol) 0.02％

[0085] From the above results, it can be seen that the obtained film is in the form of off-white flaky film with a smooth appearance and a film thickness of about 60 μm. It is easy and fast to dissolve in the mouth, and the content uniformity meets A+2.2S<15, which meets the requirements.

[0086] The dissolution time determination method involves cutting orally disintegrating film into predetermined sizes (e.g., six tablets of this product) and clamping them between two layers of stainless steel mesh with an inner diameter of 2.0 mm. Disintegration time is determined according to the disintegration time test method for tablets (Chinese Pharmacopoeia General Chapter 0921). The time it takes for the sample to completely dissolve and pass through the mesh is recorded. The results show that the film-forming agent of the present invention exhibits outstanding dissolution performance, with the resulting film rapidly dissolving in water and releasing the drug.

[0087] The tensile performance test method is as follows: take an appropriate amount of uncut perampanel orally disintegrating film, and cut 3 samples of appropriate size for measurement. Place the film in the upper and lower clamps of the tensile strength tester, so that the center line connecting the sample and the upper and lower clamps coincides, the clamps are appropriately tight, and the distance between the two clamps is 60mm. Start the testing machine at a speed of 100±10mm / min. After the sample breaks, read the tensile strength. Each sample is tested three times and the average value is taken. The three samples were tested for folding resistance, and each sample was bent 10 times. The results showed that the obtained film did not break after being bent 10 times, and the measured tensile strength was greater than 10N. The tensile value was in line with the relevant provisions of the National Pharmacopoeia. The film was not easy to break and had high tensile strength.

[0088] Experiment 5: Stability investigation

[0089] Samples from Example 10 were stored at 60°C for 30 days, with samples taken for testing on the 30th day. Samples were then stored at high humidity for 10 days, with samples taken for testing on the 10th day. The long-term stability of the formulation was evaluated by comparing the data from day 0 with the data from day 0, using properties, content, related substances, dissolution rate, and dissolution time as primary indicators. The results are shown in Table 9 below.

[0090] Table 9 Stability of orally dissolving film

[0091]

[0092] As can be seen from the table above, when the product is placed at 60°C for 30 days and at high humidity for 10 days, its properties, content, related substances, solubility and melting time all meet the requirements, and there is no significant difference compared with 0 days.

[0093] Test 6: Dissolution Study

[0094] The dissolution determination method refers to the fourth method of paddle-disc method in General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia. Take the samples of Example 10 and Comparative Example 1, and use pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and 900 ml of purified water as dissolution media, respectively. The measurement temperature is 37 ° C, the rotation speed is 50 rpm, and the sampling time is 5 min, 10 min, 20 min, 30 min, 45 min, 60 min and 90 min, respectively. The same volume of dissolution medium is supplemented to determine the cumulative dissolution of the orally dissolving film in different media, as shown in Table 10 below. The cumulative dissolution curves of Example 10 and Comparative Example 1 in pH 1.0 hydrochloric acid medium are shown in Table 10. Figure 2 shown.

[0095] Table 10 Dissolution test of orally dissolving film

[0096]

[0097]

[0098] Dissolution test results showed that the orally dissolving film of Example 10 exhibited excellent dissolution at pH 1.0, pH 4.5, and pH 6.8 in aqueous media. Specifically, at pH 1.0, the dissolution rate of the sample of Example 10 within 10 minutes was above 95%, while the dissolution rate of the sample of Comparative Example 1 within 10 minutes was below 71%. Therefore, the dissolution effect of Example 10 was significantly superior to that of Comparative Example 1.

[0099] The above detailed description is a specific description of one feasible embodiment of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not depart from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A perampanel orally disintegrating film, characterized in that: The orally disintegrating film comprises the following components in parts by weight: 3-8 parts of perampanel, 20-50 parts of a film-forming agent, 20-40 parts of a disintegrant, and 5-20 parts of a plasticizer; the film-forming agent is a mixture of hydroxyethyl cellulose and hydroxypropyl methylcellulose, and the weight ratio of hydroxyethyl cellulose to hydroxypropyl methylcellulose is 1:1-10; the disintegrant is maltodextrin; the plasticizer is selected from glycerol, and the weight ratio of glycerol to perampanel is 1.5-3:1; the orally disintegrating film further comprises 0.1-5 parts of a flavoring agent.

2. The orally dissolving film according to claim 1, wherein The orally disintegrating film comprises the following components in parts by weight: 6-7 parts of perampanel, 35-45 parts of film-forming agent, 30-40 parts of disintegrant and 10-20 parts of plasticizer.

3. The orally dissolving film according to any one of claims 1 to 2, characterized in that: The weight ratio of the hydroxyethyl cellulose to the hypromellose is 1:3-8.

4. The orally dissolving film according to any one of claims 1 to 2, characterized in that: The weight ratio of the hydroxyethyl cellulose to the hypromellose is 1:4-6.

5. The orally dissolving film according to any one of claims 1 to 2, characterized in that: The weight ratio of the hydroxyethyl cellulose to the hypromellose is 1:

5.

6. The orally dissolving film according to any one of claims 1-2, characterized in that: The weight ratio of the glycerol to perampanel is 2-2.5:

1.

7. The orally dissolving film according to any one of claims 1 to 2, characterized in that: The weight ratio of the glycerol to perampanel is 2:

1.

8. The orally dissolving film according to any one of claims 1 to 2, characterized in that: The orally disintegrating film further comprises 1-2 parts of flavoring agent, wherein the flavoring agent is selected from one or more of sucralose, aspartame, stevioside, saccharin sodium, xylitol, sorbitol, lemon essence and strawberry essence.

9. The orally dissolving film according to any one of claims 1 to 2, characterized in that: The orally disintegrating film further comprises 1-1.2 parts of a flavoring agent, and the flavoring agent is selected from sucralose.

10. A method for preparing the perampanel orally disintegrating film according to any one of claims 1 to 9, characterized in that: The steps include: A. adding perampanel, a film-forming agent, a disintegrant, a plasticizer, and a flavoring agent into a solvent to prepare a slurry; B. Vacuum degassing the slurry; C. Apply the deaerated slurry on the substrate, dry it, and form a film. The solvent in step A is water and / or ethanol solution.

11. The preparation method according to claim 10, characterized in that: Before adding the solvent to the perampanel in step A, the perampanel must first be added to a mixed solution of water and ethanol to prepare a perampanel suspension; the mass ratio of the perampanel to the mixed solution is 1:25-35.

12. The preparation method according to claim 10, characterized in that The substrate in step C is an inert carrier material, and the drying temperature is 50-70°C.

13. Use of the perampanel orosoluble film according to any one of claims 1 to 9 or the perampanel orosoluble film prepared by the preparation method according to any one of claims 10 to 12 in preparing a drug for treating epilepsy.

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