Edaravone oral instant film as well as preparation method and application thereof

Abstract

The invention relates to an edaravone oral instant film as well as a preparation method and application thereof, and belongs to the technical field of medicines. The invention relates to an edaravone oral instant film. The edaravone oral instant film is prepared from the following raw materials: edaravone, a film forming material and phospholipid, the phospholipid is one or more of soybean phospholipid, lecithin or hydrogenated soybean phospholipid, and the film-forming material is one or more of hydroxypropyl methyl cellulose, polyvinyl alcohol, polyethylene glycol or polyvinylpyrrolidone; the weight ratio of the edaravone to the film-forming material to the phospholipid is 1: (1-5): (1-5). The oral cavity instant film provided by the invention not only meets the requirement that the dissolution rate of the oral cavity instant film is greater than 30% under a non-leakage groove condition, but also can form nanoparticles which can remarkably penetrate through soft palate mucosa after meeting water, and is delivered into the brain through a trigeminal nerve path, so that the bioavailability and local drug concentration of edaravone are remarkably improved, and the oral cavity instant film is suitable for clinical application. Wide application prospects are realized in the application of treating nervous system diseases.

Description

Technical Field

[0001] This invention relates to an edaravone oral instant-dissolving film, its preparation method, and its application, belonging to the field of pharmaceutical technology. Background Technology

[0002] Edaravone (EDA) has the chemical name 3-methyl-1-phenyl-2-pyrazolin-5-one and the molecular formula C60. 10 H 10 N2O, with a molecular weight of 174.20, has the structural formula shown below. Developed by Mitsubishi Corporation of Japan, this drug is a potent free radical scavenger, commonly used to treat acute ischemic stroke and as an adjunct therapy for various neurological disorders. Edaravone primarily works by scavenging free radicals, inhibiting oxidative damage to lipids, nerve cells, and vascular endothelial cells, reducing brain tissue damage and cerebral edema, and ultimately preventing nerve cell death.

[0003]

[0004] Edaravone belongs to the BCS Class IV drugs and is characterized by low water solubility (≤ 3 mg / mL) and poor membrane permeability. Although it is readily soluble in methanol, ethanol, and acetic acid, its poor water solubility leads to low oral bioavailability, limiting the development of oral administration routes. Currently, edaravone is mainly administered intravenously in clinical practice; however, this route has problems such as inconvenience and poor patient compliance. Furthermore, due to its unstable nature, quality control during the preparation of intravenous solutions is difficult, further restricting its clinical application and the development of new dosage forms. In contrast, oral administration is the most common and convenient route of administration, offering advantages such as less pain, higher safety, and better patient compliance compared to other routes (intravenous, intramuscular, subcutaneous). Therefore, improving the oral bioavailability of edaravone and developing stable, orally suitable dosage forms have become important directions for expanding its clinical applications and promoting new drug development.

[0005] Patent WO2017157350A1 discloses a lipid-based drug delivery system for preparing drugs to treat oxidative stress-related diseases. While this invention significantly improves the bioavailability of edaravone, the surfactant used is toxic and has low safety. Patent RU2021115473A discloses an edaravone suspension for oral administration and for treating amyotrophic lateral sclerosis (ALS). This method significantly improves its bioavailability, but its physicochemical stability is poor, it is prone to sedimentation, and has a short shelf life. Patent WO2018134243A1 discloses an edaravone solution with excellent absorption properties. However, due to the low solubility of edaravone in water, the solution dosage provided by this invention, up to 100 mL, has the problems of large volume and poor patient dependence during treatment. Summary of the Invention

[0006] To address the problems of low oral bioavailability and poor patient compliance in existing technologies, this invention provides an edaravone oral fast-dissolving film, its preparation method, and its application. This significantly improves the dissolution and permeability of edaravone, enabling rapid release and thereby enhancing the accumulation of edaravone in brain tissue, providing a new formulation method for the treatment of neurological diseases.

[0007] An edaravone oral instant dissolving film, the oral instant dissolving film being prepared from the following raw materials: edaravone, film-forming material and phospholipid; the phospholipid (PC) is one or more of soybean phospholipid, lecithin or hydrogenated soybean phospholipid, the film-forming material is one or more of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP); the weight ratio of edaravone, film-forming material and phospholipid is 1:1~5:1~5.

[0008] Preferably, the weight ratio of edaravone, film-forming material, and phospholipid is 1:5:1.

[0009] Preferably, the film-forming material is PVP-K90.

[0010] Furthermore, the edaravone is crystalline edaravone, micronized edaravone, or other pharmaceutically acceptable forms.

[0011] Furthermore, the dissolution rate of edaravone in the oral instant film is 70%~90% under non-leaking conditions.

[0012] Another object of the present invention is to provide a method for preparing the above-mentioned edaravone oral quick-dissolving film, comprising the following steps: dissolving the film-forming material and edaravone in an ethanol-water solution to form solution A; dissolving phospholipid in an organic solvent to form solution B; adding solution B to solution A and continuously stirring until a transparent spinning solution is formed; and obtaining the edaravone oral quick-dissolving film by electrospinning the transparent spinning solution.

[0013] In the above technical solution, the concentration of edaravone in the transparent spinning solution is 15~20 mg / mL, and the weight ratio of edaravone, film-forming material and phospholipid is 1:1~5:1~5.

[0014] In the above technical solution, the electrospinning parameters are set as follows: voltage 10~25 kV, pushing speed 0.001~0.010 mm / s, motion swing amplitude 40 mm, and moving speed 5~10 mm / s.

[0015] Preferably, the electrospinning parameters are set as follows: voltage 16 kV, pushing speed 0.003 mm / s, motion amplitude 40.0 mm, and moving speed 10 mm / s.

[0016] In the above technical solution, the ethanol-water solution contains 95% to 100% ethanol.

[0017] In the above technical solution, the organic solvent is one or more of anhydrous ethanol, methanol, or acetone.

[0018] In the above technical solution, the spinning solution containing edaravone is solidified to form a solid dispersion by electrospinning technology.

[0019] Solid dispersions are dispersion systems in which drugs are dispersed in a solid dispersion material in a molecular, microcrystalline, or amorphous state. They can significantly improve the solubility and bioavailability of poorly soluble drugs.

[0020] Another object of the present invention is to provide the use of the above-mentioned edaravone oral instant film in the preparation of medicaments for treating central nervous system diseases.

[0021] Furthermore, the drug is administered via mucosal delivery.

[0022] Furthermore, the mucosa is the soft palate mucosa or the buccal mucosa.

[0023] More preferably, the mucosa is the soft palate mucosa.

[0024] The mucosal drug delivery method described in this invention can effectively avoid the first-pass effect of the liver and maximize the bioavailability of the drug.

[0025] This invention adds phospholipids to the existing binary system of edaravone and film-forming materials to form a novel ternary oral fast-dissolving film. The addition of phospholipids does not alter or affect the original binary system, but it significantly increases the dissolution rate after curing, especially under non-drainage conditions, where the dissolution rate is much higher than that of the binary system. This ensures the release and permeability of edaravone, thereby improving its bioavailability.

[0026] The beneficial effects of this invention are: 1. Compared with the binary edaravone oral instant dissolving film, the ternary edaravone oral instant dissolving film prepared by electrospinning in this invention exhibits the following advantages: Edaravone exists in an amorphous form, which significantly improves its dissolution rate under non-sinking conditions; In addition, the nanoparticles formed by the ternary oral dissolving film upon contact with water can significantly penetrate the soft palate mucosa and be delivered into the brain through the trigeminal nerve pathway, promoting the accumulation of edaravone in brain tissue and increasing the local drug concentration.

[0027] 2. The ternary oral fast-dissolving film provided by this invention is not only simple to prepare and inexpensive, but also meets the requirement of a dissolution rate of greater than 30% under non-leaking conditions, significantly improving the bioavailability of edaravone. Compared with traditional oral and injectable formulations, this formulation can achieve rapid drug release, enhance intracerebral delivery efficiency, reduce the pain and inconvenience caused by long-term injections, and thus improve patient compliance. Attached Figure Description

[0028] Figure 1 The figures show the morphology of the edaravone oral fast-dissolving film obtained in Examples 1-5. In Figures A and F, the weight ratio of EDA / PVP-K90 / PC is 1:5:1; in Figures B and G, the weight ratio of EDA / PVP-K90 / PC is 1:5:2; in Figures C and H, the weight ratio of EDA / PVP-K90 / PC is 1:5:3; in Figures D and I, the weight ratio of EDA / PVP-K90 / PC is 1:5:4; and in Figures E and J, the weight ratio of EDA / PVP-K90 / PC is 1:5:5.

[0029] Figure 2 The images show the morphology of the edaravone oral instant films obtained in Comparative Examples 1-5. In Figures A and F, the EDA / PVP-K90 weight ratio is 1:1; in Figures B and G, the EDA / PVP-K90 weight ratio is 1:2; in Figures C and H, the EDA / PVP-K90 weight ratio is 1:3; in Figures D and I, the EDA / PVP-K90 weight ratio is 1:4; and in Figures E and J, the EDA / PVP-K90 weight ratio is 1:5.

[0030] Figure 3 The particle size distribution of the edaravone oral instant film obtained in Examples 1-5 after reconstitution is shown in the figure.

[0031] Figure 4 The X-ray diffraction patterns are those of the binary oral fast-dissolving membranes obtained in Comparative Examples 1-5.

[0032] Figure 5 Differential scanning calorimetry (DSC) of the binary oral quick-dissolving membrane (A) obtained in Comparative Examples 1-5 and the ternary oral quick-dissolving membrane (B) obtained in Examples 1-5.

[0033] Figure 6 Fourier transform infrared images of the binary oral quick-dissolving membrane (A) obtained in Comparative Example 1 and the ternary oral quick-dissolving membrane (B) obtained in Examples 1-5.

[0034] Figure 7 The dissolution results of the binary oral quick-dissolving film (A) obtained in Comparative Examples 1-5 and the ternary oral quick-dissolving film (B) obtained in Examples 1-5 under non-sinking conditions are shown in the figure. Pure EDA is edaravone active pharmaceutical ingredient powder.

[0035] Figure 8 The figures show the drug-time curves of the oral fast-dissolving films obtained in Example 1 and Comparative Example 1 after administration to the rat mucosa, where EDA Supension was administered by gavage and IV was administered by intravenous injection.

[0036] Figure 9 The figures show the distribution of edaravone in the body after administration of different prescriptions. A (trigeminal ganglion) and B (brain tissue) are small animal imaging images at different time points. C is the permeation curve of the orally dissolving film obtained in Example 1 and Comparative Example 1 on the nasal mucosa of sheep. D shows the distribution of edaravone in brain tissue under different prescriptions and administration methods. Among them, F1 is oral EDA suspension, F2 is oral orally dissolving film obtained in Example 1 administered to the soft palate mucosa, F3 is oral orally dissolving film obtained in Comparative Example 1 administered to the soft palate mucosa, and F4 is EDA solution injected via tail vein. Detailed Implementation

[0037] The following non-limiting embodiments are intended to enable those skilled in the art to more fully understand the invention, but do not limit the invention in any way.

[0038] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0039] Example 1 A method for preparing an edaravone ternary oral quick-dissolving film includes the following steps: dissolving 500 mg PVP-K90 and 100 mg EDA in 3 mL of 96% ethanol to form solution A; dissolving 100 mg hydrogenated soybean lecithin in 2 mL of anhydrous ethanol to form solution B; adding solution B to solution A and stirring continuously until a clear and transparent spinning solution is formed; using electrospinning technology, the spinning solution is spun into fibers under the conditions of 16 kV voltage, 0.003 mm / s push speed, 40.0 mm swing amplitude, and 10 mm / s moving speed; the spun sample is collected through aluminum foil to obtain the edaravone ternary oral quick-dissolving film.

[0040] Examples 2-5 The difference between Examples 2-5 and Example 1 is that the weight ratios of EDA, PVP-K90, and phospholipids are different, namely 1:5:2, 1:5:3, 1:5:4, and 1:5:5, respectively. All other operations are the same as in Example 1.

[0041] Comparative Example 1 A method for preparing an edaravone binary oral quick-dissolving film includes the following steps: dissolving 500 mg PVP-K90 and 100 mg EDA in 3 mL of 96% ethanol to form solution A; electrospinning solution A using electrospinning technology under conditions of 16 kV voltage, 0.003 mm / s push speed, 40.0 mm swing amplitude, and 10 mm / s moving speed; collecting the spun sample through aluminum foil to obtain the edaravone binary oral quick-dissolving film.

[0042] Comparative Examples 2-5 The difference between Comparative Examples 2-5 and Comparative Example 1 is that the weight ratios of EDA and PVP-K90 are different, namely 1:1, 1:2, 1:3, and 1:4 respectively. All other operations are the same as Comparative Example 1.

[0043] The morphology of the oral quick-dissolving films obtained in Examples 1-5 and Comparative Examples 1-5 is studied, and the results are shown in [the table below]. Figure 1 and Figure 2 . Figure 1 and Figure 2 To observe the oral fast-dissolving films obtained in Examples 1-5 and Comparative Examples 1-5 using a scanning electron microscope (Zeiss SIGMA30, Zeiss) at a voltage of 15.0 kV and a magnification of 500-10000, it can be seen that different drug-carrier ratios affect the spinning morphology. The spun fibers prepared with different drug / carrier ratios have smooth and uniform surfaces.

[0044] The particle size study of the reconstituted oral instant films obtained in Examples 1-5 is shown in the following figures. Figure 3 . Figure 3 The particle size distribution of the oral instant dissolving films obtained in Examples 1-5 after redispersing in water was determined using a Malvern laser particle size analyzer (Nano-ZS90 Malvern) at 25°C. Each sample was measured in triplicate. It can be seen that the particle size of the edaravone ternary oral instant dissolving film gradually increases with the increase of the phospholipid ratio, from approximately 100 nm to approximately 300 nm. The smallest particle size, approximately 100 nm, was observed when the edaravone to phospholipid mass ratio was 1:1.

[0045] The state of edaravone in the edaravone oral instant films obtained in Examples 1-5 and Comparative Examples 1-5 was studied. The crystallinity of the drug in the edaravone oral instant films obtained in Comparative Examples 1-5 was measured using an X-ray diffractometer (X'Pert PRO X, PANalytical) with Cu-Kα radiation generated at 40 mA and 35 KV. The samples were analyzed in the range of 5° to 50°, with a step size of 0.033° and a counting time of 0.6 s / step. The results are shown in [Figure number missing]. Figure 4 Edaravone exhibits distinct diffraction peaks at 11.13°, 13.44°, 14.66°, 19.69°, 21.37°, 23.28°, and 24.29°. From... Figure 4 As can be seen, in the binary oral instant-dissolving film system, when the mass ratio of edaravone to PVP-K90 is 1:5, the diffraction peaks of the drug completely disappear, indicating that the drug exists in an amorphous form. Differential scanning calorimetry (DSC-1, METTLER) was used to detect the melting points of the oral instant-dissolving films obtained in Examples 1-5 and Comparative Examples 1-5 within the range of 30 to 300 °C at a heating rate of 10 °C / min. The results are shown in […]. Figure 5 Edaravone exhibits a distinct melting point peak at 129.36℃, and the drug exists in a crystalline state. From Figure 5 As can be seen, in the edaravone binary system oral instant dissolving film, when the mass ratio of drug to PVP-K90 is 1:5, the edaravone crystallization peak disappears, and it exists in an amorphous form. In the ternary system oral instant dissolving film with added phospholipids, no edaravone crystallization peak appears, indicating that edaravone exists in an amorphous form in the edaravone ternary oral instant dissolving film. Therefore, edaravone exists in an amorphous form in the oral instant dissolving film described in this invention.

[0046] The interaction between edaravone and PVP-K90 in the edaravone oral instant films obtained in Examples 1-5 and Comparative Example 1 was studied. Fourier transform infrared spectroscopy (IFS-55, Bruker) was used to analyze the possible molecular interactions between edaravone and PVP-K90. The scanning range was 400-4000 cm⁻¹. -1 The resolution is 4 cm. -1With a signal-to-noise ratio of 50,000:1 and 32 scans, spectral analysis was performed on the active pharmaceutical ingredient edaravone, PVP-K90, and the prepared oral fast-dissolving film samples. The results are shown in [Figure number missing]. Figure 6 Idarabon is 1783.3 cm tall. -1 There is a C=O stretching vibration peak at 1600.7 cm⁻¹. -1 A stretching vibration peak at C=N was found. Figure 6 As can be seen from the spectrum of PVP-K90, a depth of 3413.8 cm⁻¹ can be observed. -1 A peak of NH stretching vibration appears at 1735.09 cm⁻¹; in the spectrum of hydrogenated soybean lecithin, a peak can be seen at 1735.09 cm⁻¹. -1 A C=O stretching vibration peak was observed at 3437.6 cm⁻¹; in the oral quick-dissolving film obtained in Comparative Example 1, the peak was observed at 3437.6 cm⁻¹. -1 It exhibits a distinct characteristic absorption peak; compared to PVP-K90 and edaravone, its NH stretching vibration peak is 3413.8 cm⁻¹. -1 The displacement reached 3437.6 cm. -1 At this point, the stretching vibration peak of the carbonyl group in edaravone disappeared; in the ternary oral instant films obtained in Examples 1-5, the carbonyl peaks all shifted, indicating that there is a hydrogen bond interaction between the carbonyl group of edaravone and the amino group of PVP-K90.

[0047] The dissolution behavior of edaravone oral instant-dissolving films obtained in Examples 1-5 and Comparative Examples 1-5 under non-leaking conditions was studied. Edaravone active pharmaceutical ingredient, edaravone binary and ternary oral instant-dissolving films (equivalent to containing 30 mg of edaravone), were accurately weighed. 20 mL of distilled water was used as the dissolution medium, and the dissolution speed was 50 rpm. The procedure was followed, and after 5, 10, 15, 30, 60, 90, and 120 min, the filtrate was collected to determine the edaravone concentration in the solution. The results are as follows: Figure 7 As shown in the figure, edaravone active pharmaceutical ingredient initially dissolves slowly, reaching a maximum dissolution rate of 30% at 30 minutes. In contrast, the oral fast-dissolving films obtained in Comparative Examples 1-5 dissolve rapidly in the medium, reaching their maximum release rate in about 5 minutes. The highest dissolution rate, reaching 65%, is achieved when the weight ratio of edaravone to PVP-K90 is 1:5. The addition of phospholipids significantly improves the drug's dissolution rate, with the maximum release rate reaching approximately 90% and the minimum release rate reaching approximately 60%. The improvement in dissolution rate is most significant when the weight ratio of edaravone to hydrogenated soybean phospholipids is 1:1, providing strong support for maintaining the drug's original release behavior in the complex environment of the gastrointestinal tract.

[0048] In vivo pharmacokinetic studies of the edaravone oral fast-dissolving membranes obtained in Example 1 and Comparative Example 1. Male SD rats, weighing 180-220 g, were used. They were fasted for 12 hours the day before the experiment, and the experiment was reviewed by the Animal Ethics Committee of Shenyang Pharmaceutical University. No other drugs were administered for two weeks prior to and during the experiment. The drug was administered via the upper jaw and buccal mucosa. Blood was collected from the rat's orbital cavity. Blank plasma was collected before the experiment. After drug administration, 0.5 mL of blood was collected at 0.08, 0.25, 0.5, 1, 2, 4, and 6 hours in heparin-coated tubes, immediately centrifuged, and the supernatant plasma was frozen for storage. The plasma was processed and the concentration of edaravone in the plasma was determined by liquid chromatography-mass spectrometry. The results are shown in the figure below. Figure 8 See Table 1. It can be seen that, compared to the active pharmaceutical ingredient (API), both binary and ternary oral instant-dissolving films of edaravone significantly improved its oral absorption rate and bioavailability. The time to peak concentration after administration via the soft palate mucosa was 0.17 h, and after administration via the buccal mucosa, it was 0.50 h. The average peak concentration of the ternary system was significantly higher than that of the binary system, and the peak concentrations after administration via the soft palate mucosa were all higher than those after administration via the buccal mucosa. From a bioavailability perspective, the AUC0-∞ values ​​of the ternary oral instant-dissolving film were higher than those of the binary oral instant-dissolving film after different administration methods, indicating that the addition of phospholipids significantly improved the dissolution rate of edaravone, thus significantly increasing its peak concentration and bioavailability.

[0049] Table 1. Pharmacokinetic parameters of edaravone binary and ternary oral fast-dissolving films in rats.

[0050] The distribution of edaravone in brain tissue was investigated after administration of the edaravone oral instantaneous films obtained in Example 1 and Comparative Example 1 via different routes. Male SD rats, weighing 180-220 g, were used. They were fasted for 12 h the day before the experiment, and the experiment was reviewed by the Animal Ethics Committee of Shenyang Pharmaceutical University. No other drugs were administered for two weeks prior to and during the experiment. The drugs were administered via the soft palate mucosa and buccal mucosa. Brain tissue was collected in 5 mL test tubes at 0.08, 0.25, 0.5, 1, 2, 4, 6, and 8 h after administration. The brain tissue was rinsed multiple times with physiological saline, dried, and weighed. An equal mass of physiological saline was added, and the tissue was homogenized at 10000 r / min for 10 min. The homogenate was then processed, and the intracranial concentration of edaravone was determined by mass spectrometry. The results are shown below. Figure 9 .Depend on Figure 9As shown in A (trigeminal ganglion) and B (brain tissue), compared with oral EDA suspension (F1) and tail vein injection of EDA solution (F4), the ternary electrospun membrane, after administration via the soft palate mucosa, has a higher distribution in brain tissue and trigeminal ganglion. This indicates that the nanoparticles formed by the ternary electrospun membrane provided by this invention when exposed to water can significantly penetrate the soft palate mucosa and be delivered into the brain via the trigeminal nerve pathway. Figure 9 Data on brain tissue distribution in D also reflect a significant increase in brain concentration after administration of the ternary orally disintegrating membrane system. Figure 9 As shown in C, ternary electrospinning significantly improves nasal mucosal permeability compared to binary electrospinning.

Claims

1. An oral fast dissolving film of Edaravone, characterized in that: The oral fast-dissolving film is prepared from edaravone, a film-forming material and phospholipid; the phospholipid is one or more of soybean phospholipid, lecithin or hydrogenated soybean phospholipid, and the film-forming material is one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene glycol or polyvinylpyrrolidone; the weight ratio of the edaravone, film-forming material and phospholipid is 1:1-5:1-5.

2. The oral film of edaravone according to claim 1, characterized in that: The weight ratio of the edaravone, film-forming material and phospholipid is 1:5:

1. 3.The oral dissolving film of edaravone according to claim 1, characterized in that: The edaravone is in the form of crystalline edaravone, micronized edaravone or other pharmaceutically acceptable forms. 4.The oral dissolving film of edaravone according to claim 1, characterized in that: The dissolution rate of the edaravone in the oral fast-dissolving film under non-leakage conditions is 70-90%.

5. The preparation method of the edaravone oral dissolving film according to any one of claims 1-4, characterized in that: The film-forming material and edaravone are dissolved in an ethanol-water solution to form solution A; The phospholipid is dissolved in an organic solvent to form solution B; solution B is added to solution A, and stirring is continued until a transparent spinning solution is formed; the transparent spinning solution is used to prepare the edaravone oral fast-dissolving film by electrospinning technology.

6. The method of claim 5, wherein: The concentration of the edaravone in the transparent spinning solution is 15-20 mg / mL, and the weight ratio of the edaravone, film-forming material and phospholipid is 1:1-5:1-5.

7. The method of claim 5, wherein: The electrospinning parameters are set as follows: voltage 10-25 kV, push speed 0.001-0.010 mm / s, movement swing 40.0 mm, and movement speed 5-10 mm / s.

8. The method of claim 5, wherein: The organic solvent is one or more of anhydrous ethanol, methanol or acetone.

9. Use of the edaravone oral fast-dissolving film of claim 1 in the preparation of a medicament for treating central nervous system diseases.

10. Use according to claim 9, characterized in that: The drug administration mode is soft palate mucosa administration or buccal mucosa administration.

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