A film pharmaceutical composition containing remegapride

Abstract

The application discloses a film for oral dissolution of remegiprant and a preparation method thereof. The film for oral dissolution is prepared from a drug active ingredient remegiprant, a film forming agent, a plasticizer, a surfactant and other materials such as a flavoring agent and a solvent. The film forming agent, the plasticizer and the surfactant are selected from a combination of polyvinyl alcohol, polyethylene glycol and poloxamer, and the weight ratio is 57:20:1. It is found that the combination of polyvinyl alcohol, polyethylene glycol and poloxamer can overcome the problem of low drug loading capacity in the existing OTF technology, and can significantly improve the distribution of remegiprant in the film and accelerate the release of the drug.

Description

[0001] This invention belongs to the field of pharmaceutical preparations, and specifically relates to an orally disintegrating film pharmaceutical composition containing retamipine. Background Technology

[0002] Remdesivir is an oral calcitonin gene-related peptide (CGRP) receptor antagonist that exerts its clinical effect by blocking the binding of CGRP ligands to receptors. It is characterized by convenient administration, rapid onset of action, and long duration of effect. It was first launched in the United States in February 2020 for the acute treatment of migraines in adults. In May 2021, its use was expanded to include the prevention of episodic migraines in adults. In April 2022, Remdesivir was launched in the European Union for the acute treatment of migraines and the prevention of episodic migraines. Remegapan is the world's first and only innovative drug that can be used simultaneously for the acute treatment and preventative treatment of migraines; its chemical name is: [(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridin-9-yl]4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; its chemical formula is: C 28 H 28 The structure of F2N6O3 and Remepiride is:

[0003]

[0004] The method for preparing Rememe-Gram orally disintegrating tablets disclosed in Chinese Patent CN112153969A involves first forming a composition by combining raw materials and a fish gelatin carrier in a solvent, and then encapsulating the composition in a mold using a freeze-drying process to produce freeze-dried orally disintegrating tablets. This process is complex, energy-intensive, and costly, making it unsuitable for industrial production. Furthermore, the orally disintegrating tablets are prone to moisture absorption, brittleness, and poor stability. Therefore, optimizing the preparation process of Rememe-Gram is the primary key task for improving product quality.

[0005] Existing technologies for preparing Remdesivir require control of raw material particle size, followed by mixing with excipients to prepare suspensions or solutions, filling, quick-freezing, sublimation drying, desorption drying, and sealing, making the process complex. Furthermore, Remdesivir has poor solubility, and when prepared as a suspension, the raw materials easily precipitate, resulting in inconsistent formulation content and low in vitro disintegration of the prepared orally disintegrating tablets. Therefore, there is an urgent need for a Remdesivir formulation and its preparation process that is simple to operate, highly feasible for industrialization, produces stable product quality, and has high bioavailability. Summary of the Invention

[0006] In order to overcome the shortcomings of the prior art, the present invention aims to provide a method for preparing oral soluble films containing Remiglitol and their compositions that is simple in process, has good solubility and in vitro dissolution performance, high bioavailability, good content uniformity, does not require particle size control, and is suitable for industrial production.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] This invention provides a Remequat oral dissolving film composition, comprising Remequat and pharmaceutically acceptable pharmaceutical excipients, wherein the pharmaceutical excipients include one or more of pharmaceutically used film-forming agents, plasticizers, surfactants, stabilizers, flavoring agents, and saliva stimulants.

[0009] According to embodiments of the present invention, the film-forming agent is selected from one or more of polyvinyl alcohol, polyoxyethylene, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, pullulan.

[0010] Preferably, the film-forming agent is selected from polyvinyl alcohol, and the amount used, in w / w, is selected from 30%-70%.

[0011] According to embodiments of the present invention, the plasticizer is selected from one or more of glycerol, polyethylene glycol 200, polyethylene glycol 400, diethyl phthalate, triethyl citrate, triacetin, polyethylene glycol, and propylene glycol, or a mixture thereof.

[0012] Preferably, the plasticizer is selected from polyethylene glycol 400, and the amount used, in w / w, is selected from 5% to 40%.

[0013] According to embodiments of the present invention, the surfactant is selected from one or a mixture of several of poloxamer 407, sodium dodecyl sulfate, polyoxyethylene 40 hydrogenated castor oil, Tween 80, Tween 20, and polyethylene glycol glycerol castor oil.

[0014] Preferably, the surfactant is selected from poloxamer 407, and the amount used, on a w / w basis, is selected from 0.1% to 5%.

[0015] According to embodiments of the present invention, the stabilizer is selected from one or more mixtures of sodium bisulfite, disodium edetate, sodium thiosulfate, vitamin C, tert-butyl-p-hydroxyanisole, and vitamin E.

[0016] Preferably, the stabilizer is selected from sodium bisulfite, and the amount used, on a w / w basis, is selected from 0.5%-3%.

[0017] According to embodiments of the present invention, the flavoring agent is selected from one or more mixtures of mannitol, sorbitol, sucralose, aspartame, vanillin, acesulfame potassium, sodium saccharin and sucralose.

[0018] Preferably, the flavoring agent is selected from sucralose and mannitol, and the amount used is selected from 0.01% to 15% by w / w.

[0019] According to an embodiment of the present invention, the saliva stimulant is selected from one or more mixtures of citric acid, malic acid, and lactic acid.

[0020] Preferably, the saliva stimulant is selected from citric acid, and the dosage, on a w / w basis, is selected from 1% to 10%.

[0021] This invention also discloses a method for preparing a pharmaceutical composition containing Remdesivir orally soluble film. The method is selected from solution casting, hot melt extrusion, electrospinning, and 3D printing, with solution casting being preferred. Specifically:

[0022] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0023] ② Dissolving: Add the film-forming agent, plasticizer, surfactant, stabilizer, Remdesivir, saliva stimulant, and flavoring agent to purified water in sequence, and stir to dissolve;

[0024] ③ Vacuum degassing: The solution is stirred and degassed under vacuum conditions;

[0025] ④ Coating and drying: The degassed mixture is coated onto the backing material at a certain thickness, and then dried at 60°C to evaporate and remove the solvent water;

[0026] ⑤ Cutting: Place on the oral cavity instant molding machine and cut out 15cm pieces. 2 Oral dissolving film of a certain size.

[0027] The beneficial effects of this invention are as follows: This invention provides an orally disintegrating film drug composition containing retemapam. This invention unexpectedly discovered that the combination ratio of polyvinyl alcohol, polyethylene glycol 400 and poloxamer overcomes the problem of low drug loading in existing OTF technology. At the same time, it can significantly improve the distribution of retemapam in the film, accelerate drug release, increase drug loading, drug release rate and bioavailability, and increase drug stability, without the need to control the particle size of the raw materials. Attached Figure Description

[0028] Figure 1 For comparison of the content uniformity of the examples and comparative examples;

[0029] Figure 2 For comparison of dissolution curves of pH 6.8 phosphate buffer in the examples and comparative examples;

[0030] Figure 3 This is a comparison of the stability of accelerated tests in both the examples and comparative examples;

[0031] Figure 4 This is a comparison of the pharmacokinetic (typical chromatogram) of Example 1 and the comparative example. Detailed Implementation

[0032] Experimental materials: Remigelpam, polyvinyl alcohol (Merck KGaA), hydroxypropyl methylcellulose (Shin-Etsu Chemical Co., Ltd.), povidone (Anhui Shanhe Pharmaceutical Excipients Co., Ltd.), glycerin (Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.), polyethylene glycol (Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.), poloxamer (BASF SE), Tween 80 (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), disodium edetate (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), sodium bisulfite (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), citric acid (Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.), mannitol (Roquette Frere), sorbitol (Merck KGaA), vanillin (Jiaxing Zhonghua Chemical Co., Ltd.), sucralose (Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.).

[0033] Experimental equipment: Electronic balance (Mettler-Toledo International Trading (Shanghai) Co., Ltd.), Fisco-1s-A complete reactor (Fluke), laboratory oral instant dissolution molding machine (Zhejiang Qisheng Technology Co., Ltd.), dissolution apparatus (Shenzhen Ruituo Instrument Equipment Co., Ltd. RT612), XLW (PC) intelligent electronic tensile testing machine (Jinan Langguang Electromechanical Technology Co., Ltd.).

[0034] Examples 1, 2, and 3

[0035] 1. Prescription

[0036]

[0037] 2. Preparation method

[0038] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0039] ② Dissolving: Add polyvinyl alcohol / hydroxypropyl methylcellulose / povidone, polyethylene glycol, poloxamer, sodium bisulfite, rimex, citric acid, mannitol, and sucralose to purified water in sequence, and stir to dissolve;

[0040] ③ Vacuum degassing: The solution is stirred and degassed under vacuum conditions;

[0041] ④ Coating and drying: The degassed mixture is coated onto the backing material at a certain thickness, and then dried at 60°C to evaporate and remove the solvent water;

[0042] ⑤ Cutting: Place on the oral cavity instant molding machine and cut out 15cm pieces. 2 Oral dissolving film of a certain size.

[0043] Examples 4, 5, and 6

[0044] 1. Prescription

[0045]

[0046] 2. Preparation method

[0047] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0048] ② Dissolving: Add polyvinyl alcohol, glycerol / polyethylene glycol, poloxamer, sodium bisulfite, rimex, citric acid, mannitol, and sucralose to purified water in sequence, and stir to dissolve;

[0049] ③ Vacuum degassing: The solution is stirred and degassed under vacuum conditions;

[0050] ④ Coating and drying: The degassed mixture is coated onto the backing material at a certain thickness, and then dried at 60°C to evaporate and remove the solvent water;

[0051] ⑤ Cutting: Place on the oral cavity instant molding machine and cut out 15cm pieces. 2 Oral dissolving film of a certain size.

[0052] Examples 7, 8, and 9

[0053] 1. Prescription

[0054]

[0055] 2. Preparation method

[0056] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0057] ② Dissolving: Add polyvinyl alcohol, polyethylene glycol, poloxamer / Tween 80, sodium bisulfite, remedypa, citric acid, mannitol, and sucralose to purified water in sequence, and stir to dissolve;

[0058] ③ Vacuum degassing: The solution is stirred and degassed under vacuum conditions;

[0059] ④ Coating and drying: The degassed mixture is coated onto the backing material at a certain thickness, and then dried at 60°C to evaporate and remove the solvent water;

[0060] ⑤ Cutting: Place on the oral cavity instant molding machine and cut out 15cm pieces. 2 Oral dissolving film of a certain size.

[0061] Examples 10, 11, and 12

[0062] 1. Prescription

[0063]

[0064] 2. Preparation method

[0065] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0066] ② Dissolving: Add polyvinyl alcohol, polyethylene glycol, poloxamer, disodium edetate / sodium bisulfite / sodium thiosulfate, rememepam, citric acid, mannitol, and sucralose to purified water in sequence, and stir to dissolve;

[0067] ③ Vacuum degassing: The solution is stirred and degassed under vacuum conditions;

[0068] ④ Coating and drying: The degassed mixture is coated onto the backing material at a certain thickness, and then dried at 60°C to evaporate and remove the solvent water;

[0069] ⑤ Cutting: Place on the oral cavity instant molding machine and cut out 15cm pieces. 2 Oral dissolving film of a certain size.

[0070] Examples 13 and 14

[0071] 1. Prescription

[0072]

[0073] 2. Preparation method

[0074] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0075] ② Dissolving: Add polyvinyl alcohol, polyethylene glycol, poloxamer, sodium bisulfite, remedypa, citric acid, mannitol, and sucralose to purified water in sequence and stir to dissolve;

[0076] ③ Vacuum degassing: The solution is stirred and degassed under vacuum conditions;

[0077] ④ Coating and drying: The degassed mixture is coated onto the backing material at a certain thickness, and then dried at 60°C to evaporate and remove the solvent water;

[0078] ⑤ Cutting: Place on the oral cavity instant molding machine and cut out 15cm pieces. 2 Oral dissolving film of a certain size.

[0079] Comparative Example 1

[0080] Remdesivir reference formulation, marketed under the brand name Nurtec Odt, is an orally disintegrating tablet in 75mg form. It is licensed by Pfizer Inc. and is a drug marketed in the United States.

[0081] I. Physical property testing

[0082] 1. Membrane tensile strength test:

[0083] Referring to GB / T 1040-2006 "Determination of Tensile Properties of Plastics": the film agent was cut into three samples with a length of 3 cm and a width of 2 cm. Longitudinal tension was performed, selecting the "tensile strength and elongation" mode, with a tensioning speed of 25 mm / min, until the film agent broke. The test was repeated three times, and the tensile strength of the film in different embodiments was recorded to evaluate the rationality of the selection of film-forming agent and plasticizer.

[0084] Calculate tensile strength and elongation using the following formulas: Tensile strength (N·mm) 2 = Tensile stress / cross-sectional area; Elongation (%) = Tensile length / initial length × 100%.

[0085] 2. Taste test

[0086] Volunteers evaluated the effectiveness of sweeteners and flavorings in masking the bitterness of Remegpan. Ten healthy adult volunteers tested the formulation and categorized the masking ability of the sweeteners and flavorings into four levels: weak (-), average (+), good (+), and very good (++).

[0087]

[0088] As can be seen from the table, the films prepared in Examples 1, 7, 8, 9, 10, 11, and 12, containing the same proportions of film-forming agent, plasticizer, and surfactant, have sufficient toughness and strength.

[0089] 3. For each example, 6 tablets of Remegapan film and 6 tablets of the comparative example orally disintegrating tablets were dissolved in 100 mL of simulated saliva (phosphate buffer containing sodium chloride) at pH 6.8, and the solutions were continuously shaken for 30 minutes to obtain homogeneous solutions. The content of each tablet was measured to evaluate the homogeneity of the Remegapan film.

[0090]

[0091] As can be seen from the table, the films prepared in Examples 1, 7, 8, 10, 11, 12, and 14, which contain the same proportions of film-forming agent, plasticizer, and surfactant, have good content uniformity and are more uniform in content compared with the comparative examples.

[0092] II. Dissolution Test

[0093] Dissolution curves were determined for Examples 1-14 and Comparative Example 1. The experimental method followed the dissolution assay, using the rotating basket method, pH 6.8 phosphate buffer medium, 500 ml volume, 50 rpm rotation speed, n=12. Samples were taken at 3, 5, 10, 15, and 20 minutes to determine the cumulative dissolution amount. The results are as follows:

[0094]

[0095] As can be seen from the table, in the pH 6.8 phosphate buffer medium, the cumulative dissolution of samples 1, 2, 3, 4, 5, 6, 10, 11, 12, 13, and 14 was significantly better than that of Comparative Example 1 in the first 5 minutes.

[0096] III. Stability Testing

[0097] For stability comparison, samples from Examples 1-14 and Comparative Example 1 of the present invention were placed under accelerated conditions (40℃±2℃ / 75%RH±5%RH) for preliminary stability testing.

[0098]

[0099] Compared with Comparative Example 1, the total impurity level of the samples prepared in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 13, and 14 was significantly lower than that of Comparative Example 1 under accelerated conditions. The samples prepared in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 13, and 14 showed better stability than the reference formulation.

[0100] IV. Pharmacokinetic Studies

[0101] Experimental Methods: Based on a dosage of 2 mg / kg, the orally disintegrating film (Example 1) was pre-cut into appropriate sizes for later use. One tablet of Remdesivir was dissolved in 100 mL of purified water to prepare a 0.75 mg / mL Remdesivir tablet solution. The tablet group was administered orally via gavage, while the film group was administered directly via oral administration. After each administration, blood was collected from the rat's orbit at 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 24 h using a capillary tube. The blood volume was preferably between 0.5 and 1.0 mL. The obtained samples were then centrifuged at 40,000 rpm for 5 min in a low-temperature centrifuge. After centrifugation, the rat plasma was collected as plasma samples. The drug content in the plasma at different time points was determined by LC-MS, and pharmacokinetic parameters were calculated accordingly.

[0102] Experimental Results: The experiment showed that the Tmax of the film-coated group was 0.95 h, while that of the tablet group was 1.5 h, indicating a significantly earlier peak time for the film-coated group compared to the tablet group. The relative bioavailability of the film-coated group compared to the tablet group was 130.9%, indicating that the film-coated group had higher bioavailability than the tablet group. These experiments demonstrate that the oral dissolving film formulation of Remegpam has a faster onset of action and a higher AUC compared to the tablet formulation, significantly improving the bioavailability of Remegpam.

[0103]

Claims

1. A remdesivir oral dissolving film composition, characterized in that, The composition comprises Remigra and pharmaceutically acceptable excipients, wherein the excipients include one or more of pharmaceutically used film-forming agents, plasticizers, surfactants, stabilizers, flavoring agents, and saliva stimulants.

2. The oral dissolving film composition of Remdesivir according to claim 1, characterized in that, The film-forming agent is selected from one or more of polyvinyl alcohol, polyoxyethylene, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, pullulan, and a mixture thereof, preferably polyvinyl alcohol, and the amount used, in w / w, is selected from 30%-70%.

3. The oral dissolving film composition of Remdesivir according to claim 1, characterized in that, The plasticizer is selected from one or more of glycerol, polyethylene glycol 200, polyethylene glycol 400, diethyl phthalate, triethyl citrate, triacetin, polyethylene glycol and propylene glycol, preferably polyethylene glycol 400, and the amount used, in w / w, is selected from 5% to 40%.

4. The oral dissolving film composition of Remdesivir according to claim 1, characterized in that, The surfactant is selected from one or a mixture of several of poloxamer 407, sodium dodecyl sulfate, polyoxyethylene 40 hydrogenated castor oil, Tween 80, Tween 20, and polyethylene glycol glycerol ricinoleate, preferably poloxamer 407, and the amount used, in w / w, is selected from 0.1% to 5%.

5. The oral dissolving film composition of Remdesivir according to claim 1, characterized in that, The stabilizer is selected from one or more of sodium bisulfite, disodium edetate, sodium thiosulfate, vitamin C, tert-butyl-p-hydroxyanisole, and vitamin E, preferably sodium bisulfite, and the amount used is selected from 0.5% to 3% by w / w.

6. The oral dissolving film composition of Remdesivir according to claim 1, characterized in that, The flavoring agent is selected from one or more of mannitol, sorbitol, sucralose, aspartame, vanillin, acesulfame potassium, sodium saccharin and sucralose, preferably mannitol, and the amount used is selected from 0.01% to 15% by weight.

7. The oral dissolving film composition of Remdesivir according to claim 1, characterized in that, The saliva stimulant is selected from one or more of citric acid, malic acid, and lactic acid, preferably citric acid, and the amount used, on a w / w basis, is selected from 1% to 10%.

8. A method for preparing the Remdesivir oral dissolving film composition according to any one of claims 1-7, characterized in that, The method described is a solution casting method, which includes: ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount; ② Dissolving: Add the film-forming agent, plasticizer, surfactant, stabilizer, Remdesivir, saliva stimulant, and flavoring agent to purified water in sequence, and stir to dissolve; ③ Vacuum degassing: The solution is stirred and degassed under vacuum conditions; ④ Coating and drying: The degassed mixture is coated onto the backing material at a certain thickness, and then dried at 60°C to evaporate and remove the solvent water; ⑤ Cutting: Place on the oral cavity instant molding machine and cut out 15cm pieces. 2 Oral dissolving film of a certain size.

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