A perampanel pharmaceutical composition, a pharmaceutical preparation containing the same, and a preparation method

Abstract

The present application provides a perampanel pharmaceutical composition, a pharmaceutical preparation containing the same, and a preparation method. The perampanel pharmaceutical composition comprises or consists of perampanel, poloxamer 188, and citric acid. The pharmaceutical preparation includes a perampanel suspension and a perampanel orally disintegrating film. The perampanel pharmaceutical composition or pharmaceutical preparation provided by the present invention has good dispersibility, uniform quality, good stability, and accurate dosage.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a perampanel pharmaceutical composition, a pharmaceutical preparation containing the same, and a preparation method. Background Art

[0002] Any discussion of the prior art throughout the specification should not be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0003] Epilepsy is a chronic brain disease caused by multiple causes, characterized by excessive discharge of brain neurons leading to recurrent, paroxysmal and transient central nervous system dysfunction. Epilepsy has serious negative impacts on individuals, families and society. Epileptic seizures cause great physical and psychological pain to patients, seriously affecting the quality of life of patients and their families. At the same time, there are misunderstandings about epilepsy and discrimination against epilepsy patients in society. The health care, education, employment, marriage and childbearing of epilepsy patients are also issues of concern to patients, their relatives and many sectors of society. Epilepsy is not only a medical problem, but also an important public health and social issue. WHO has listed epilepsy as one of the neurological and psychiatric diseases that require priority prevention and treatment. Epilepsy occurs in people of all ages, regions and races, especially in children and adolescents.

[0004] Perampanel is a new third-generation antiepileptic drug approved by the US FDA in 2012. It is a highly selective, non-competitive AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolidinone) glutamate receptor antagonist. It inhibits glutamate activity at postsynaptic AMPA receptors, reducing neuronal hyperexcitation and thereby preventing and treating epilepsy. Currently available dosage forms include tablets, fine granules, and suspension.

[0005] Oral fast-dissolving films offer numerous advantages: accurate drug loading, water-free administration, ease of use, and high compliance. They dissolve instantly on the tongue, resist spitting out once adhered, and prevent airway obstruction, making them particularly suitable for children. They are compact and portable, and their production process is simple, energy-efficient, and cost-effective. Formulating perampanel into an oral fast-dissolving film not only improves patient compliance and prevents medication refusal, drug hiding, and spitting, but also reduces patient awareness of medication administration, lowering psychological barriers and social stigma.

[0006] Due to the low solubility of perampanel in water, there are many problems in the preparation process of orally dissolving film. For example, when forming a suspension, the system is unstable, resulting in problems with the content uniformity of the finished product. Controlling the drug particle size and adding surfactants are common means of preparation. However, the hydrophobicity and easy aggregation characteristics of perampanel make it difficult for these two methods to achieve the desired effect. Currently, most practices increase the solubility of perampanel by adding organic solvents such as ethanol and acetonitrile to form a solution. However, the large-scale use of organic solvents not only increases the risk of environmental pollution, but the residue of organic solvents can also have adverse effects on the health of patients. Summary of the Invention

[0007] Therefore, the purpose of this application is to provide a perampanel pharmaceutical composition that is easy to carry and easy to use, a pharmaceutical preparation comprising the perampanel pharmaceutical composition, and a preparation method thereof, wherein the pharmaceutical preparation is particularly a perampanel suspension and a perampanel orally disintegrating film. The perampanel pharmaceutical composition provided by the present invention has good dispersibility, stability, and quality uniformity due to its specific composition, and accurate dosage. In particular, the perampanel orally disintegrating film provided by the present invention does not use an organic solvent during the preparation process, has a good improvement in drug administration compliance, can avoid patients from hiding medicine, spitting medicine, and at the same time diluting patients' awareness of drug administration, reducing patients' psychological barriers, and reducing social discrimination, and thus has good practical application value.

[0008] Specifically, the present invention provides the following technical solutions.

[0009] In a first aspect of the present invention, a perampanel pharmaceutical composition is provided, comprising or consisting of perampanel, poloxamer 188 and citric acid.

[0010] Perampanel API has low solubility and strong hydrophobicity. It is easy to aggregate into a bird's nest shape in the solution and thus suspend on the liquid surface. The present invention uses poloxamer 188 as a surfactant to reduce the surface tension of the solution and increase the wettability of the drug particle surface. However, the inventors found that the effect of using poloxamer 188 alone is not ideal, and increasing the dosage cannot improve the undesirable effect. This is manifested in that when its dosage is large, it is easy to increase the bubbles in the drug solution, thereby affecting the defoaming step and the appearance of the drug during subsequent coating. Perampanel has pH dependence and is slightly more soluble under acidic conditions. In addition, the inventors found that perampanel API and its preparations are generally stable, but when the prescription is acidic and metal ions or oxidizing substances are present at the same time, perampanel is easily oxidized and degraded into impurities. However, the inventors have also discovered that when poloxamer 188 and citric acid are used simultaneously to formulate a perampanel composition or preparation, the addition of citric acid not only alters the pH of the solution but also, surprisingly, acts as a chelating agent and antioxidant enhancer. In particular, the combined use of poloxamer 188 and citric acid can slow the aggregation of perampanel. This makes perampanel pharmaceutical compositions and pharmaceutical preparations containing such compositions more conducive to dispersion and the production of uniform quality products.

[0011] In particular, in some embodiments of the present invention, when the mass ratio of the perampanel, poloxamer 188, and citric acid is 4:(0.05-0.4):(0.6-1.8), the above function is very significant, especially in some embodiments of the present invention, when the mass ratio of the perampanel, citric acid, and poloxamer 188 is 4:(0.08-0.3):(0.6-1.7), and especially further 4:(0.1-0.3):(0.8-1.6), the above function is even more significant.

[0012] Furthermore, in some embodiments of the present invention, the particle size of the perampanel is d(0.9) / μm≤20. Control of the particle size is more conducive to obtaining a perampanel pharmaceutical composition with better dispersion and more uniform content and a pharmaceutical preparation containing the pharmaceutical composition.

[0013] In a second aspect of the present invention, a perampanel pharmaceutical preparation is provided, comprising a perampanel pharmaceutical composition and at least one pharmaceutically acceptable excipient, wherein the perampanel pharmaceutical composition comprises or consists of perampanel, poloxamer 188 and citric acid.

[0014] In some embodiments of the present invention, in the perampanel pharmaceutical composition, the mass ratio of perampanel, poloxamer 188, and citric acid is 4:(0.05-0.4):(0.6-1.8), preferably the mass ratio of perampanel, citric acid, and poloxamer 188 is 4:(0.08-0.3):(0.6-1.7), and more preferably 4:(0.1-0.3):(0.8-1.6).

[0015] In some embodiments of the present invention, in the perampanel pharmaceutical composition, the particle size of the perampanel is d(0.9) / μm≤20.

[0016] In some embodiments of the present invention, the pharmaceutically acceptable excipient is a solvent.

[0017] For example, in some embodiments of the present invention, the perampanel pharmaceutical preparation is a perampanel suspension, which consists of perampanel, poloxamer 188, citric acid, and a solvent.

[0018] In some embodiments, the solvent is water.

[0019] In some embodiments of the present invention, the pharmaceutically acceptable excipients may be a plasticizer and a film-forming material, or the pharmaceutically acceptable excipients may be a plasticizer, a film-forming material and a flavoring agent.

[0020] For example, in some embodiments of the present invention, the perampanel pharmaceutical preparation is a perampanel orally disintegrating film, which is composed of perampanel, poloxamer 188, citric acid, a plasticizer and a film-forming material; or is composed of perampanel, poloxamer 188, citric acid, a plasticizer, a film-forming material and a flavoring agent.

[0021] For example, in one embodiment of the present invention, the perampanel orally disintegrating film may be composed of the following raw materials, in parts by mass: 12.86-15.71 parts of perampanel, 3.86-4.71 parts of poloxamer 188, 0.64-0.79 parts of citric acid, 60.62-74.09 parts of film-forming material, 11.12-13.59 parts of plasticizer; and, optionally, 0.90-1.10 parts of flavoring agent.

[0022] In some embodiments of the present invention, the plasticizer is selected from a combination of one or more of sorbitol, mannitol, propylene glycol, glycerol, and polyethylene glycol, preferably sorbitol.

[0023] In some embodiments of the present invention, the film-forming material is selected from a combination of one or more of hypromellose, hydroxypropyl cellulose, pullulan and polyvinyl alcohol, preferably a combination of hypromellose and hydroxypropyl cellulose.

[0024] In some embodiments of the present invention, the flavoring agent is a sweetener selected from a combination of one or more of sucralose, neotame, acesulfame potassium, and saccharin sodium, preferably sucralose.

[0025] In one embodiment of the present invention, the plasticizer in the perampanel orally disintegrating film is sorbitol, and the film-forming materials are hypromellose and hydroxypropyl cellulose. In another embodiment of the present invention, the perampanel orally disintegrating film further contains a flavoring agent selected from a combination of one or more of sucralose, neotame, acesulfame potassium, and saccharin sodium, preferably sucralose.

[0026] For example, in one embodiment of the present invention, the perampanel orally disintegrating film may be composed of the following raw materials, in parts by mass: 12.86-15.71 parts of perampanel, 3.86-4.71 parts of poloxamer 188, 0.64-0.79 parts of citric acid, 47.76-58.38 parts of hypromellose, 12.86-15.71 parts of hydroxypropyl cellulose, 11.12-13.59 parts of sorbitol, and, optionally, 0.90-1.10 parts of sucralose.

[0027] In a third aspect of the present invention, a method for preparing a perampanel pharmaceutical preparation is provided, comprising: preparing perampanel, citric acid, and poloxamer 188 into a suspension, and then adding pharmaceutical excipients to prepare a desired dosage form.

[0028] For example, in some embodiments of the present invention, the pharmaceutical preparation is a perampanel suspension, and the method comprises: dissolving poloxamer 188 and citric acid in a solvent, and adding perampanel to prepare the perampanel suspension.

[0029] In some typical embodiments, the method comprises: dissolving poloxamer 188 and citric acid in a solvent; adding perampanel under stirring, and dispersing using a disperser to obtain a uniform perampanel suspension.

[0030] In some typical embodiments, the particle size of perampanel used in the method is d(0.9) / μm≤20.

[0031] Alternatively, in some typical methods, the method includes a step of controlling the particle size of perampanel to satisfy a particle size of d(0.9) / μm ≤ 20. This step can be a step conventionally used in the art, particularly a step suitable for processing perampanel, such as a jet milling method.

[0032] For example, in some embodiments of the present invention, the pharmaceutical preparation is a perampanel orally disintegrating film, and the method comprises: preparing perampanel, citric acid, and poloxamer 188 into a suspension, then adding a plasticizer, a film-forming material, and optionally a flavoring agent, and stirring, applying the drug solution on a release film, and obtaining the perampanel film after drying; the film is cut into unit doses according to specification requirements to obtain the perampanel orally disintegrating film.

[0033] In some embodiments of the present invention, the release film for preparing the orally dissolving film is a thin film with separability on its surface, which can be non-adhesive or slightly adhesive to the orally dissolving film after contact under limited conditions, making it easy to peel off. The main function of the release film is to protect the integrity and stability of the orally dissolving film and to prevent adhesion and deformation between the orally dissolving film and the mold or equipment surface. According to different substrates and coatings, the release films for preparing the orally dissolving film are as follows: PET release film: with polyester (PET) as substrate, surface coating release agents such as silicone or fluoroplastics; PE release film: with polyethylene (PE) as substrate, surface coating release agents such as silicone or fluoroplastics; OPP release film: with stretched polypropylene (OPP) as substrate, surface coating release agents such as silicone or fluoroplastics; and composite release film: with a substrate composited with two or more materials, surface coating release agents such as silicone or fluoroplastics.

[0034] In some typical embodiments, the method comprises:

[0035] Dissolve poloxamer 188 and citric acid in a solvent;

[0036] Under stirring, add perampanel and disperse using a disperser to obtain a uniform suspension;

[0037] Adding a plasticizer, a film-forming material, and optionally a flavoring agent to the obtained suspension, and stirring to form a uniform liquid;

[0038] After defoaming, the drug solution is evenly coated on a release film (such as a PET release film) and dried. The dried sample is cut into unit doses to obtain the perampanel orally disintegrating film. Optionally, a polyester / aluminum / polyethylene composite film can be used for packaging.

[0039] In some embodiments of the present invention, when a disperser is used for dispersion, the rotation speed thereof is 8000 to 12000 rpm.

[0040] The various specific technical features described in the above embodiments of the present invention can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further explain various possible combinations.

[0041] Unless otherwise specified, the numerical ranges described in the present invention include all values within this range, and include ranges consisting of any two values within this range. For example, 0.8-1.6 includes all values between 0.8 and 1.6, and includes ranges consisting of any two values within this range (e.g., 0.81, 1.5, etc.); different values of the same indicator appearing in all embodiments of the present invention can be arbitrarily combined to form a range value.

[0042] Compared with the prior art, the advantages of the present invention include:

[0043] The present invention provides a perampanel pharmaceutical composition and a pharmaceutical preparation containing the composition, and a preparation method thereof. The composition contains perampanel, poloxamer 188, and citric acid. By simultaneously adding poloxamer 188 and citric acid, the present invention improves the problems of excessively high surface tension, poor surface wettability of drug particles, poor solubility, poor dispersibility (easy aggregation), and uneven drug content during the preparation process. It also improves the problems of stability problems and susceptibility to oxidative degradation impurities caused by improving solubility by lowering the pH during the preparation process. The invention also avoids the use of organic solvents, reduces the risk of environmental pollution and the threat to patient health caused by residual organic solvents. Most importantly, the perampanel pharmaceutical composition of the present invention and the pharmaceutical preparation containing the composition have the advantages of good dispersibility, uniform drug content, high stability, and the like.

[0044] Specifically, the combination of citric acid and poloxamer 188 improves the wettability of the API particles and the surface tension of the solvent while appropriately increasing the API solubility, significantly slowing down the aggregation of perampanel, thereby obtaining a suspension of uniform quality and avoiding stability issues caused by a biased acidic formulation. For example, when the formulation is biased acidic and metal ions or oxidizing substances are present at the same time, perampanel is easily oxidized and degraded into impurities.

[0045] In addition, the pharmaceutical preparation provided by the present invention, such as the perampanel orally disintegrating film, contains a therapeutically effective amount of an active drug, has good mechanical properties and taste, the perampanel is evenly distributed in the preparation, and the drug has good stability; it does not contain organic solvents such as ethanol and acetonitrile, and is safer.

[0046] In particular, the orodissolving film preparation of perampanel provided by the present invention is convenient to administer and does not require water compared to existing tablets and fine granules. It is accurate in dosage and does not require the use of a syringe for administration compared to existing suspensions. When administering the orodissolving film preparation, one only needs to tear open the package and place it on the tongue, which greatly facilitates the administration of the orodissolving film preparation for children, the elderly, and patients with difficulty swallowing, avoids the phenomenon of patients vomiting the medicine, improves the compliance of the administration, and has good medical and industrial value.

[0047] Of course, any product implementing the present invention does not necessarily need to achieve all of the advantages described above at the same time, but the present invention is in the best state when it can achieve all of the advantages described above at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The drawings constituting part of the present application are provided to provide a further understanding of the present application. The illustrative embodiments and their descriptions of the present application are provided to explain the present application and do not constitute an undue limitation on the present application. The following describes the implementation scheme of the present application in detail in conjunction with the drawings, wherein:

[0049] Figure 1 This is an electron microscope image of the particle size d(0.9) / μm≤20 of the raw material drug perampanel after air flow grinding.

[0050] Figure 2 The dissolution curves of the perampanel orally dissolving film products prepared in Examples 1-3 of the present invention and commercially available tablets are shown. DETAILED DESCRIPTION

[0051] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or as recommended by the manufacturer.

[0052] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. The reagents or raw materials used in this application can be purchased through conventional channels. Unless otherwise specified, the reagents or raw materials used in this application are used in a conventional manner in this area or in accordance with the product instructions. In addition, any methods and materials similar to or equivalent to those described herein can be applied to the present method. The preferred embodiments and materials described herein are for demonstration purposes only.

[0053] Unless otherwise specified, the API perampanel used in the examples of the present invention was milled by airflow to control the particle size to d(0.9) / μm ≤ 20. d(0.9) / μm ≤ 20 means that 90% of the particles have a diameter of less than or equal to 20 μm.

[0054] Example 1

[0055] This embodiment provides a unit dose formula of perampanel orally disintegrating film-forming agent as follows:

[0056]

[0057] This embodiment also provides a method for preparing the perampanel orally disintegrating film-forming agent, comprising:

[0058] 1) Dissolve poloxamer 188 and citric acid in purified water;

[0059] 2) Add perampanel while stirring, and disperse using a disperser at a speed of 10,000 rpm to obtain a uniform suspension;

[0060] 3) adding sucralose, sorbitol, hypromellose and hydroxypropyl cellulose to the suspension obtained in step 2) and stirring to form a uniform solution;

[0061] 4) After vacuum defoaming, the drug solution is evenly coated on a PET release film and dried. The dried sample is cut into a certain size (specification: 4 mg, area: 2.0×3.3 cm) and packaged with a polyester / aluminum / polyethylene composite film.

[0062] Example 2

[0063] This embodiment provides a perampanel orally disintegrating film-forming agent, and the formula of the unit dose is as follows:

[0064]

[0065] The preparation method is the same as that of Example 1.

[0066] Example 3

[0067] This embodiment provides a perampanel orally disintegrating film-forming agent, and the formula of the unit dose is as follows:

[0068]

[0069] The preparation method is the same as that of Example 1.

[0070] Example 4

[0071] This example provides a perampanel orally disintegrating film-forming agent, the formulation of which differs from that of Example 1 only in that citric acid is not contained and the amount of poloxamer 188 is increased to 1.40 mg. The preparation method is the same as that of Example 1.

[0072] Example 5

[0073] This example provides a perampanel orally disintegrating film-forming agent, the formulation of which differs from that of Example 1 only in that poloxamer 188 is not contained and the amount of citric acid is increased to 1.40 mg. The preparation method is the same as that of Example 1.

[0074] Example 6

[0075] This example provides a perampanel orally disintegrating film-forming agent, the formula of which differs from that of Example 1 only in that citric acid is replaced with glacial acetic acid, and the preparation method is the same as that of Example 1.

[0076] Example 7

[0077] This example provides a perampanel orally disintegrating film-forming agent. The formula thereof differs from that of Example 1 only in that poloxamer 188 is replaced with Tween 80. The preparation method is the same as that of Example 1.

[0078] Example 8

[0079] This embodiment provides a perampanel orally disintegrating film-forming agent. The difference between the formulation of the perampanel and that of the embodiment 1 is only that the particle size of the perampanel is d(0.9) / μm=31.16. The preparation method is the same as that of the embodiment 1.

[0080] Example 9

[0081] This embodiment provides a perampanel orally disintegrating film-forming agent, the formulation of which is the same as that of Example 1.

[0082] This embodiment also provides a method for preparing the perampanel orally disintegrating film-forming agent, comprising:

[0083] 1) While stirring, add citric acid, poloxamer 188, sorbitol, and sucralose to purified water and dissolve;

[0084] 2) adding perampanel to the material obtained in step 1) according to the formulation direction and stirring to disperse;

[0085] 3) adding hypromellose and hydroxypropyl cellulose to the material obtained in step 2) and stirring to dissolve;

[0086] 4) After vacuum defoaming, the drug solution was evenly coated on a PET release film and dried. The dried sample was cut into a certain size (specification: 4 mg, area: 2.0 × 3.3 cm) and packaged with a polyester / aluminum / polyethylene composite film.

[0087] Experimental Example 1

[0088] The above examples and comparative examples were respectively subjected to properties, related substances, content uniformity, dissolution rate, disintegration time, content, thickness, tensile strength, strain, and folding resistance tests.

[0089] Test method:

[0090] Properties: Visual observation.

[0091] Related Substances: Take 10 tablets of this product and place them in a 200ml volumetric flask. Add an appropriate amount of 2g / L ammonium acetate solution-acetonitrile (50:50). Dissolve the perampanel by sonication. Dilute to the mark with 2g / L ammonium acetate solution-acetonitrile (50:50). Shake well. Centrifuge. The supernatant is used as the test solution. Separately, accurately weigh an appropriate amount of perampanel reference substance. Dissolve it in 2g / L ammonium acetate solution-acetonitrile (50:50). Quantitatively dilute to a solution containing approximately 0.2mg per 1ml. This is used as the reference solution. Accurately measure 1ml of the reference solution and place it in a 20ml volumetric flask. Dilute to the mark with 2g / L ammonium acetate solution-acetonitrile (50:50). Shake well. This is used as the sensitivity solution.

[0092] Chromatographic conditions: octadecyl bonded silica gel as filler (4.6×150 mm, 5 μm); column temperature, 35°C; detection wavelength, 290 nm; flow rate, 1.0 ml / min; mobile phase A, 2 g / L ammonium acetate solution (adjusted to pH 3.9 with glacial acetic acid), mobile phase B, acetonitrile, gradient elution according to the following table:

[0093]

[0094] Measure 25 μL of the sensitivity test solution and inject it into the liquid chromatograph. The main peak area should be 3.5% to 6.5% of the average main peak area of the reference solution. Accurately measure 25 μL each of the test solution and the reference solution and inject them into the liquid chromatograph. Record the chromatogram. Calculate the peak area using the external standard method. No single impurity should exceed 0.2% of the labeled amount of perampanel, and the total amount of impurities should not exceed 1.0% of the labeled amount (impurity peaks with an area smaller than the main peak of the sensitivity solution can be ignored).

[0095] Content Uniformity: Take one tablet and place it in a 50ml volumetric flask. Add an appropriate amount of 2g / L ammonium acetate solution-acetonitrile (50:50). Dissolve the perampanel by sonication. Dilute to the mark with 2g / L ammonium acetate solution-acetonitrile (50:50), shake well, centrifuge, and use the supernatant as the test solution. Separately, take an appropriate amount of perampanel reference substance and dissolve it in 2g / L ammonium acetate solution-acetonitrile (50:50). Quantitatively dilute to a solution containing 80μg per 1ml to serve as the reference solution. Test according to the HPLC method (Chinese Pharmacopoeia 2020 Edition, General Chapter 0512). Calculate the content of each tablet by peak area using the external standard method, which should comply with the regulations (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0941).

[0096] Dissolution: Dissolution and release were determined according to the second method of the dissolution and release method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931). Using 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium and a rotation speed of 50 rpm, the dissolution was performed according to the procedure. After 30 minutes, a sample was taken, filtered, and the filtrate was tested according to high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512). The amount of perampanel dissolved in each tablet was calculated using the peak area using the external standard method.

[0097] Assay: Perform according to the HPLC method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The test solution and chromatographic conditions are the same as those for related substances. Separately, dissolve an appropriate amount of perampanel reference substance in 2g / L ammonium acetate solution-acetonitrile (50:50) and quantitatively dilute to a solution containing 80μg per 1ml. This serves as the reference solution. Accurately measure the test solution and reference solution and calculate the peak area using the external standard method.

[0098] Disintegration: Take one tablet from any six orally disintegrating film tablets. Use forceps to hold one end of the film and immerse half of the film in purified water at 37°C ± 1°C. Record the time it takes for the film to break. Thickness: Measure using a thickness gauge (C640, Labthink International).

[0099] Tensile strength and strain were measured using an intelligent electronic tensile testing machine (C610m, Languang International).

[0100] Folding resistance: Take 6 pieces of oral dissolving film at random, take 1 piece each time, fold it in half along the center, then open it, fold it in half in the opposite direction and open it again, record it as one time, and repeat until the film breaks.

[0101] The experimental results are recorded in the table below.

[0102]

[0103]

[0104] Examples 1 to 9 were all off-white films, while Examples 5 and 8-9 all had agglomerated particles and the thickness measurements were too large. The content uniformity of Examples 4-5 and 8-9 did not meet the requirements.

[0105] The above examples showed no significant differences in the relevant substances, dissolution rates, and contents, and all had good tensile strength (39.889-52.232 MPa) and strain (5.2%-10.4%), and were folded more than 10 times, indicating good folding resistance. All of the above examples disintegrated within 30 seconds.

[0106] Test results indicate that the use of a surfactant in the formulation of the present invention reduces the surface tension of the solvent and increases the wettability of the particles, enabling good dispersion of perampanel. Furthermore, the use of citric acid in the formulation, controlled particle size of perampanel, and the use of a disperser during the preparation process also facilitate dispersion.

[0107] Experimental Example 2

[0108] Stability tests were performed on Examples 1 to 9 and Perampanel Tablets (specification: 4 mg; batch number: 211190; manufacturer: Eisai (China) Pharmaceutical Co., Ltd.).

[0109] Test method:

[0110] The samples were placed under 40°C ± 2°C and 75% ± 5% RH for 6 months and tested for related substances. The data were compared with the data from day 0.

[0111] The results are recorded in the table below.

[0112]

[0113]

[0114] The test results show that glacial acetic acid has no stabilizer effect, the use of Tween 80 will produce more peroxides, and when citric acid and poloxamer 188 are used to prepare samples together, the changes of related substances during the stability process are not obvious.

[0115] Experimental Example 3

[0116] The dissolution curves of Examples 1-3 and Perampanel tablets (specification: 4 mg; batch number: 211190; manufacturer: Eisai (China) Pharmaceutical Co., Ltd.) were investigated respectively.

[0117] The paddle method was used at 50 rpm, with 0.1 M hydrochloric acid solution as the dissolution medium, and the results were determined according to the method. The results showed that the in vitro dissolution of the perampanel orally dissolving film prepared in Examples 1-3 of the present invention was consistent with that of the commercially available tablets, with the dissolution reaching more than 85% within 15 minutes. Figure 2 The dissolution curves of the orally dissolving film products prepared in Examples 1-3 and commercially available tablets are shown.

[0118] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art may still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included within the scope of protection of the present application.

Claims

1. A perampanel pharmaceutical preparation, characterized in that: The perampanel pharmaceutical preparation is a perampanel orally disintegrating film, which is made of perampanel, poloxamer 188, citric acid, a plasticizer and a film-forming material; The mass ratio of perampanel, citric acid, and poloxamer 188 is 4:(0.1-0.3):(0.8-1.6); The particle size of the perampanel is d(0.9) / μm≤20; The plasticizer is sorbitol, and the film-forming materials are hypromellose and hydroxypropyl cellulose; The perampanel orally disintegrating film-forming agent is composed of the following raw materials in parts by mass: Perampanel 12.86-15.71 parts, Poloxamer 188 3.86-4.71 parts, citric acid 0.64-0.79 parts, hypromellose 47.76-58.38 parts, hydroxypropyl cellulose 12.86-15.71 parts, sorbitol 11.12-13.59 parts; The preparation method of the perampanel pharmaceutical preparation comprises: preparing perampanel, citric acid and poloxamer 188 into a suspension, and then adding pharmaceutical excipients to prepare a desired dosage form.

2. The perampanel pharmaceutical preparation according to claim 1, wherein The perampanel orally disintegrating film further contains 0.90-1.10 parts by weight of a flavoring agent, wherein the flavoring agent is selected from a combination of one or more of sucralose, neotame, acesulfame potassium and saccharin sodium.

3. The perampanel pharmaceutical preparation according to claim 2, wherein The flavoring agent is sucralose.

4. A method for preparing the perampanel pharmaceutical preparation according to any one of claims 1 to 3, comprising: Perampanel, citric acid and poloxamer 188 are prepared into a suspension, and then pharmaceutical excipients are added to prepare the desired dosage form.

5. The method according to claim 4, characterized in that The pharmaceutical preparation is a perampanel orally disintegrating film, and its preparation method comprises: preparing perampanel, citric acid, and poloxamer 188 into a suspension, then adding a plasticizer and a film-forming material and stirring, coating the drug solution on a release film, and obtaining the perampanel film after drying.

6. The method according to claim 5, characterized in that The method further comprises adding a flavoring agent to the suspension, wherein the flavoring agent is selected from a combination of one or more of sucralose, neotame, acesulfame potassium and saccharin sodium.

7. The method according to claim 6, characterized in that The flavoring agent is sucralose.

8. The method according to claim 5, characterized in that The dried sample is cut into unit doses according to specification requirements to obtain the perampanel orally disintegrating film.

9. The method according to claim 4, comprising: Dissolve poloxamer 188 and citric acid in a solvent; Under stirring, add perampanel and disperse using a disperser to obtain a uniform suspension; Adding plasticizer and film-forming material to the obtained suspension and stirring to form a uniform liquid; After the drug solution is defoamed, it is evenly coated on the release film and dried. The dried sample is cut into unit doses to obtain the perampanel orally disintegrating film.

10. The method according to claim 9, characterized in that The method further comprises adding a flavoring agent to the obtained suspension, wherein the flavoring agent is selected from a combination of one or more of sucralose, neotame, acesulfame potassium and saccharin sodium.

11. The method according to claim 10, characterized in that The flavoring agent is sucralose.

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