Fingolimod hydrochloride oral soluble film and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a fingolimod hydrochloride oral soluble film and a preparation method thereof. The fingolimod hydrochloride oral soluble film provided by the invention is prepared from the following raw materials in parts by weight: 0.5 to 5 parts of fingolimod hydrochloride, 30 to 60 parts of a macromolecular film-forming material and 10 to 20 parts of a filling agent, the polymer film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol and hydroxyethyl cellulose; the filler is selected from one or more of mannitol, calcium carbonate, lactose, microcrystalline cellulose and pregelatinized starch. The oral soluble film preparation provided by the invention is smooth in surface, uniform in color and luster, free of gravel feeling in mouth feel, uniform in thickness and high in content uniformity, the tensile strength, the elongation at break and the folding strength meet the requirements, and the dissolution rate in 15 minutes is equivalent to that of a capsule; and the melting can be completed within 30 seconds at the temperature of about 37 DEG C, and the product can be stabilized for more than 6 months at normal temperature or under the daily high-temperature condition.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a fingolimod hydrochloride orodispersible film and a preparation method thereof. Background Art

[0002] Multiple Sclerosis (MS), a neurological disease, is an autoimmune disease that affects the white matter of the central nervous system (CNS) and causes multiple parts of myelin loss. It leaves local lesions in the nervous system, causing irreversible neurological dysfunction, affecting the cerebral hemispheres, brainstem, cerebellum, optic nerves and spinal cord, causing visual impairment, nystagmus, facial nerve paralysis, imbalance, limb weakness, intellectual impairment, aphasia, and severe hemiplegia, which seriously endangers life and health, greatly affects the quality of life of patients, and is characterized by easy relapse and high disability rate. In recent years, the incidence rate in my country has been on the rise. Fingolimod Hydrochloride is the first drug to treat multiple relapsing sclerosis, which can reduce the relapse rate and delay the progression of damage.

[0003] Fingolimod is an oral sphingosine 1-phosphate receptor (S1PR) modulator. Pharmacological studies have shown that fingolimod can act on sphingosine 1-phosphate receptors located on lymphocytes, causing circulating lymphocytes to remain in the lymph nodes, thereby reducing the chance of autoreactive lymphocytes re-entering the circulation and preventing these cells from infiltrating the central nervous system (CNS). The pharmacological action of fingolimod is reversible, and if the drug is stopped, the level of circulating lymphocytes will recover. Normal clinical phase II trial data showed that in the first six months of the trial, the group taking fingolimod hydrochloride once a day could reduce inflammation by 80% compared with the placebo control group (the experimental results were measured by magnetic resonance imaging), and could also reduce the relapse rate by at least 50%. In the next six months, the inflammatory activity and relapse rate of patients who continued to take fingolimod hydrochloride remained at a low level, and the same results were also seen in patients who switched from placebo to fingolimod hydrochloride in the later stage of the trial.

[0004] Orodispersible film is a new oral drug delivery system developed based on transdermal patch technology. It can be put into the mouth without drinking water or chewing, and can be decomposed or dissolved within 1 minute. As a kind of film, it can replace tablets, capsules and oral solutions, because it can avoid swallowing large amounts of liquid, especially suitable for pediatric and elderly people. The orodispersible film is placed on the patient's tongue or other oral mucosal tissue. Due to the presence of hydrophilic polymers and other excipients in the orodispersible film, the film will be immediately moistened by saliva, quickly hydrated and attached to the use site, and quickly dissolve to release the drug. It quickly decomposes or dissolves or decomposes to release the drug, part of which is used for mucosal absorption, and part of which is modified and quickly dissolved in the gastrointestinal tract for absorption. There are already mature fingolimod hydrochloride capsules for the treatment of relapsing multiple sclerosis in the prior art, but some patients have difficulty swallowing capsules. Developing an orodispersible film of fingolimod hydrochloride that is easy to swallow and takes medicine without or with less water can help improve patient medication compliance and facilitate the treatment and control of patients' diseases. Summary of the invention

[0005] The present invention provides a fingolimod hydrochloride orodispersible film and a preparation method thereof, which are used to solve the defect in the prior art that it is difficult to swallow fingolimod hydrochloride oral capsules, provide patients with a better medication experience, and improve patients' medication compliance.

[0006] The fingolimod hydrochloride orodispersible film provided by the present invention comprises, by weight, 0.5 to 5 parts of fingolimod hydrochloride, 30 to 60 parts of polymer film-forming materials and 10 to 20 parts of fillers; The polymer film-forming material is selected from one or more (two or more, such as two, three or four, etc., the same below) of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol and hydroxyethyl cellulose; the filler is selected from one or more of mannitol, calcium carbonate, lactose, microcrystalline cellulose and pregelatinized starch.

[0007] The invention provides a fingolimod hydrochloride orodispersible film for treating relapsing multiple sclerosis. The orodispersible film has the characteristics of good appearance, uniform thickness, good toughness, non-irritating taste, uniform drug content, easy to take and carry, etc.

[0008] In some embodiments provided by the present invention, the polymer film-forming material is selected from one or two of hydroxypropyl methylcellulose and hydroxypropyl cellulose; Preferably, the hypromellose is one or two of hypromellose E15, hypromellose E5 and hypromellose E30; and / or the hydroxypropyl cellulose is hydroxypropyl cellulose LF; More preferably, the polymer film-forming material is composed of hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5 and hydroxypropyl cellulose LF, the weight ratio of hydroxypropyl methylcellulose E15 to hydroxypropyl methylcellulose E5 is 3-12:2-10, and the weight ratio of hydroxypropyl methylcellulose E15 to hydroxypropyl cellulose LF is 3-12:1-5; Or, the polymer film-forming material is a mixture of hydroxypropyl methylcellulose E15 and hydroxypropyl cellulose LF in a weight ratio of 12:3-7; Or, the polymer film-forming material is a mixture of hypromellose E15 and hypromellose E5 in a weight ratio of 12:3-7; Or, the polymer film-forming material is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl cellulose LF in a weight ratio of 5-9:6-10. Using the above polymer film-forming materials, the prepared fingolimod hydrochloride oral dissolving film has better film-forming properties, high content uniformity, good mechanical properties, fast dissolution and good stability.

[0009] In some embodiments provided by the present invention, the filler is selected from one or both of mannitol and calcium carbonate. The present invention uses mannitol and calcium carbonate as fillers to prepare fingolimod hydrochloride oral dissolving film with high content uniformity, good mechanical properties, fast dissolution and good stability.

[0010] By selecting suitable fillers and polymer film-forming materials, the orodispersible film preparation prepared by the present invention has a smooth surface, uniform color, no gritty taste, high content uniformity, good mechanical properties, can be completely dissolved within 30 seconds at about 37°C, and can be stable for more than 6 months at room temperature or under daily high temperature conditions.

[0011] Preferably, the raw materials include: 1-3 parts of fingolimod hydrochloride, 40-60 parts of polymer film-forming material and 11-19 parts of filler.

[0012] More preferably, the raw materials include: 1.3-1.9 parts of fingolimod hydrochloride, 48-58 parts of polymer film-forming material and 14-19 parts of filler. The fingolimod hydrochloride orodispersible film prepared by using this ratio has better quality.

[0013] According to the fingolimod hydrochloride orodispersible film provided by the present invention, the raw materials also include a plasticizer and a suspending agent; preferably, the plasticizer is selected from one or more of polyethylene glycol, glycerol, triethyl citrate and gelatin; and / or, the suspending agent is selected from one or more of microcrystalline cellulose-sodium carboxymethylcellulose complex, polyethylene oxide, xanthan gum, and carrageenan.

[0014] In some embodiments provided by the present invention, the plasticizer is one or both of glycerol and polyethylene glycol. And / or, the suspending agent is one or both of microcrystalline cellulose-sodium carboxymethylcellulose complex and polyethylene oxide.

[0015] In some embodiments provided by the present invention, the mass ratio of the polymer film-forming material to the plasticizer is 30-60:10-20; and / or the mass ratio of the polymer film-forming material to the suspending agent is 30-60:5-15.

[0016] In some embodiments of the present invention, the mass ratio of the polymer film-forming material to the plasticizer is further preferably 48-58:14-19; and / or, the mass ratio of the polymer film-forming material to the suspending agent is 40~60:6~15, so as to better improve the mechanical properties such as flexibility and strength of the orodissolving film, so that the orodissolving film of the present invention is not easily accidentally torn off during use.

[0017] According to the fingolimod hydrochloride orodispersible film provided by the present invention, the raw materials also include flavoring agents, and the flavoring agents are selected from one or more of sucralose, saccharin sodium, stevioside, maltitol, acesulfame potassium, and erythritol; the preferred flavoring agent is one or more of sucralose, saccharin sodium, and acesulfame potassium.

[0018] Preferably, the mass ratio of fingolimod hydrochloride to the flavoring agent is 0.5~5:0.05~1, more preferably 1~3:0.11~0.5, and even more preferably 1.3~1.9:0.11~0.3.

[0019] In some embodiments provided by the present invention, the raw materials of the fingolimod hydrochloride orodispersible film include, by weight: 1 to 3 parts of fingolimod hydrochloride, 40 to 60 parts of polymer film-forming material, 11 to 19 parts of filler, 11 to 19 parts of plasticizer and 6 to 15 parts of suspending agent; Preferably, the filler is calcium carbonate or mannitol; the polymer film-forming material is one or two of hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5 and hydroxypropyl cellulose LF; the plasticizer is glycerol or polyethylene glycol; the suspending agent is microcrystalline cellulose-sodium carboxymethylcellulose complex or polyethylene oxide; Preferably, the raw materials include, by weight: 1.3-1.9 parts of fingolimod hydrochloride, 48-58 parts of polymer film-forming material, 14-19 parts of filler, 14-19 parts of plasticizer and 8-15 parts of suspending agent.

[0020] In some embodiments provided by the present invention, the thickness of the fingolimod hydrochloride orodispersible film is 30-65 μm; and / or the water content of the fingolimod hydrochloride orodispersible film is less than 5%.

[0021] The present invention also provides a method for preparing the above-mentioned fingolimod hydrochloride orodispersible film, which comprises the following steps: (1) Preparing a gel solution: mixing raw materials other than fingolimod hydrochloride with water to prepare a gel solution; (2) Preparing a drug-containing solution: mixing fingolimod hydrochloride with water to prepare a drug-containing solution; (3) Preparing a drug-containing glue solution: adding the drug-containing solution to the glue solution to form a drug-containing glue solution; the solid content of the drug-containing glue solution is 20% to 30%; (4) Preparation of orally dissolving film: Apply the drug-containing adhesive solution onto the isolation film and dry until the moisture content is less than 5%.

[0022] The orally dissolving film prepared by the preparation method has better quality.

[0023] Preferably, in step (4), the coating rate is 20 mm / min to 50 mm / min; and / or the coating thickness is 30 to 65 μm.

[0024] Preferably, the preparation method provided by the present invention further comprises a vacuum degassing step when preparing the drug-containing gel solution; during the vacuum degassing, the vacuum degree is -0.08MPa~-0.05MPa, the degassing time is 1~3 hours, and the degassing temperature is 10~35°C.

[0025] In some embodiments of the present invention, the method for preparing the fingolimod hydrochloride orodispersible film comprises the following main steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: Add a certain amount of water into the liquid preparation tank, and then add the film-forming material, plasticizer, suspending agent, filler, and flavoring agent in sequence, and stir at high speed for 2 to 4 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add an appropriate amount of water, start stirring, add fingolimod hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gelatin: Add the drug-containing solution to the gelatin, add water to the prescribed amount, and continue stirring for 30 minutes; turn on the vacuum degassing, the vacuum degree is -0.08MPa~-0.05MPa, the degassing time is 1~3 hours, and the degassing temperature is 10~35℃; (5) Preparation of orodispersible film: Apply the prepared drug-containing gel solution onto the isolation film at a certain coating rate (20 mm / min~50 mm / min) and coating thickness (30~60 μm), and simultaneously dry (60°C) until the moisture content is less than 5%.

[0026] (6) Cutting: Cut according to a certain area and pack.

[0027] Preferably, in some embodiments of the present invention, the rotation speed of the high-speed stirring is 200-500 rpm. At this rotation speed, the prepared orally dissolving film is more uniform and stable.

[0028] The present invention has successfully developed a fingolimod hydrochloride orodispersible film for the first time after systematic and scientific research. Compared with the capsules already on the market, the present invention has the advantages of thin thickness, light weight, good palatability, and convenient administration and carrying by preparing fingolimod hydrochloride into an orodispersible film, and at least the following beneficial effects are achieved: (1) It has a good taste and a dissolution curve similar to that of capsules, which improves patients' medication compliance; (2) The dissolution rate after 15 minutes can reach more than 85%, which is equivalent to that of capsules; the content is uniform and the stability is good (it can be stored at room temperature for more than 6 months), which meets the requirements for clinical use; (3) The tensile strength, elongation at break and folding endurance meet the requirements, the film has good mechanical properties and uniform thickness; (4) The prescription and preparation process are simple, the production process is stable and controllable, and it is suitable for large-scale production. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0031] The microcrystalline cellulose-sodium carboxymethylcellulose complex in the following examples is produced by FMC Corporation of the United States, and the product model is RC-591.

[0032] In the method for preparing the orally dissolving film in the following example, the rotation speed of the high-speed stirring is in the range of 200-500 rpm.

[0033] Example 1

[0034] The present embodiment provides a fingolimod hydrochloride orodispersible film, the raw materials of which are 0.5g of fingolimod hydrochloride, 5g of calcium carbonate, 10g of hydroxypropyl methylcellulose E15, 5g of hydroxypropyl methylcellulose E5, 1.5g of hydroxypropyl cellulose LF, 5g of glycerol, 3g of microcrystalline cellulose-sodium carboxymethylcellulose complex, 0.05g of sucralose and 90g of purified water.

[0035] This embodiment also provides a method for preparing the fingolimod hydrochloride orodispersible film, wherein 1000 pieces of fingolimod hydrochloride orodispersible film are prepared by the following method, which comprises the following steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: Add 80 g of water to the liquid preparation tank, and add hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose LF, glycerol, microcrystalline cellulose-sodium carboxymethylcellulose complex, calcium carbonate and sucralose in sequence, and stir at high speed for 3 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add 5 g of water, start stirring, add fingolimod hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gelatin: Add the drug-containing solution to the gelatin, add 5 g of water to the prescribed amount, and continue stirring for 30 min; turn on the vacuum degassing, the vacuum degree is -0.08 MPa~-0.05 MPa, the degassing time is 2 hours, and the degassing temperature is 20~30°C; (5) Preparation of orally dissolving film: The prepared adhesive solution is coated on the isolation film at a coating rate of 20 mm / min and a coating thickness of 30 μm, and simultaneously dried (60°C) until the moisture content is less than 5%.

[0036] (6) Cutting: Cut according to a certain area and pack.

[0037] Example 2

[0038] The present embodiment provides a fingolimod hydrochloride orodispersible film, the raw materials of which include 0.5g of fingolimod hydrochloride, 5g of mannitol, 5g of hydroxypropyl methylcellulose E15, 8.5g of hydroxypropyl methylcellulose E5, 3g of hydroxypropyl cellulose LF, 5g of glycerol, 3g of microcrystalline cellulose-sodium carboxymethylcellulose complex, 0.05g of saccharin sodium and 90g of purified water.

[0039] This embodiment also provides a method for preparing the fingolimod hydrochloride orodispersible film. Every 1000 pieces of fingolimod hydrochloride orodispersible film are prepared by the following method, which comprises the following steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: Add 80 g of water to the liquid preparation tank, and then add hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose LF, glycerol, microcrystalline cellulose-sodium carboxymethylcellulose complex, mannitol, and saccharin sodium, and stir at high speed for 2.5 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add 5 g of water, start stirring, add fingolimod hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gel solution: Add the drug-containing solution to the gel solution, add 5 g of water to the prescribed amount, and continue stirring for 30 min; turn on the vacuum degassing, the vacuum degree is -0.08 MPa ~ -0.05 MPa, the degassing time is 2 hours, and the degassing temperature is 20~30℃.

[0040] (5) Preparation of orally dissolving film: The prepared adhesive solution is coated on the isolation film at a coating rate of 30 mm / min and a coating thickness of 40 μm, and then dried simultaneously (60°C) until the moisture content is less than 5%.

[0041] (6) Cutting: Cut according to a certain area and pack.

[0042] Example 3

[0043] The present embodiment provides a fingolimod hydrochloride orodispersible film, the raw materials of which include 0.5g of fingolimod hydrochloride, 5g of calcium carbonate, 10g of hydroxypropyl methylcellulose E15, 5g of hydroxypropyl methylcellulose E5, 1.5g of hydroxypropyl cellulose LF, 5g of polyethylene glycol, 3g of polyoxyethylene, 0.05g of saccharin sodium and 90g of purified water.

[0044] This embodiment also provides a method for preparing the fingolimod hydrochloride orodispersible film. Every 1000 pieces of fingolimod hydrochloride orodispersible film are prepared by the following method, which comprises the following steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: add 80 g of water to the liquid preparation tank, and add hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose LF, polyethylene glycol, polyoxyethylene, calcium carbonate, and saccharin sodium in sequence, and stir at high speed for 2.5 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add 5 g of water, start stirring, add fingolimod hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gel solution: Add the drug-containing solution to the gel solution, add 5 g of water to the prescribed amount, and continue stirring for 30 min; turn on the vacuum degassing, the vacuum degree is -0.08 MPa ~ -0.05 MPa, the degassing time is 2.5 hours, and the degassing temperature is 20~30℃.

[0045] (5) Preparation of orally dissolving film: The prepared glue solution is coated on the isolation film at a coating rate of 50 mm / min and a coating thickness of 50 μm, and then dried simultaneously (60°C) until the moisture content is less than 5%; (6) Cutting: Cut according to a certain area and pack.

[0046] Example 4

[0047] The present embodiment provides a fingolimod hydrochloride orodispersible film, the raw materials of which include 0.5g of fingolimod hydrochloride, 5g of mannitol, 12g of hydroxypropyl methylcellulose E15, 4.5g of hydroxypropyl cellulose LF, 5g of glycerol, 3g of microcrystalline cellulose-sodium carboxymethylcellulose complex, 0.05g of sucralose and 90g of purified water.

[0048] This embodiment also provides a method for preparing the fingolimod hydrochloride orodispersible film. Every 1000 pieces of fingolimod hydrochloride orodispersible film are prepared by the following method, which comprises the following steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: Add 80 g of water to the liquid preparation tank, and add hydroxypropyl methylcellulose E15, hydroxypropyl cellulose LF, glycerol, microcrystalline cellulose-sodium carboxymethylcellulose, mannitol, and sucralose in sequence, and stir at high speed for 4 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add 5 g of water, start stirring, add fingolimod hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gelatin: Add the drug-containing solution to the gelatin, add 5 g of water to the prescribed amount, and continue stirring for 30 min; turn on the vacuum degassing, the vacuum degree is -0.08 MPa ~ -0.05 MPa, the degassing time is 2.5 hours, and the degassing temperature is 20~30°C; (5) Preparation of orally dissolving film: The prepared adhesive solution is coated on the isolation film at a coating rate of 30 mm / min and a coating thickness of 40 μm, and then dried simultaneously (55°C) until the moisture content is less than 5%.

[0049] (6) Cutting: Cut according to a certain area and pack.

[0050] Example 5

[0051] The present embodiment provides a fingolimod hydrochloride orodispersible film, the raw materials of which include 0.5g of fingolimod hydrochloride, 5g of calcium carbonate, 12g of hypromellose E15, 5g of hypromellose E5, 5g of polyethylene glycol, 3g of polyoxyethylene, 0.05g of sucralose and 90g of purified water.

[0052] This embodiment also provides a method for preparing the fingolimod hydrochloride orodispersible film. Every 1000 pieces of fingolimod hydrochloride orodispersible film are prepared by the following method, which comprises the following steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: Add 80 g of water to the liquid preparation tank, and add hypromellose E15, hypromellose E5, polyethylene glycol, polyoxyethylene, calcium carbonate, and sucralose in sequence, and stir at high speed for 4 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add 5 g of water, start stirring, add fingolimod hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gel solution: Add the drug-containing solution to the gel solution, add 5 g of water to the prescribed amount, and continue stirring for 30 min; turn on the vacuum degassing, the vacuum degree is -0.08 MPa ~ -0.05 MPa, the degassing time is 2.5 hours, and the degassing temperature is 20~30℃.

[0053] (5) Preparation of orally dissolving film: The prepared glue solution is coated on the isolation film at a certain coating rate of 40 mm / min and a coating thickness of 60 μm, and simultaneously dried (60°C) until the moisture content is less than 5%; (6) Cutting: Cut according to a certain area and pack.

[0054] Example 6

[0055] The present embodiment provides a fingolimod hydrochloride orodispersible film, the raw materials of which include 0.5g of fingolimod hydrochloride, 5g of calcium carbonate, 7g of hydroxypropyl methylcellulose E5, 8g of hydroxypropyl cellulose LF, 5g of polyethylene glycol, 4.5g of polyoxyethylene and 90g of purified water.

[0056] This embodiment also provides a method for preparing the fingolimod hydrochloride orodispersible film. Every 1000 pieces of fingolimod hydrochloride orodispersible film are prepared by the following method, which comprises the following steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: Add 80 g of water to the liquid preparation tank, and add hydroxypropyl methylcellulose E5, hydroxypropyl cellulose LF, polyethylene glycol, polyoxyethylene, calcium carbonate, and sucralose in sequence, and stir at high speed for 4 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add 5 g of water, start stirring, add fingolimod hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gel solution: Add the drug-containing solution to the gel solution, add 5 g of water to the prescribed amount, and continue stirring for 30 min; turn on the vacuum degassing, the vacuum degree is -0.08 MPa ~ -0.05 MPa, the degassing time is 3 hours, and the degassing temperature is 20~30℃.

[0057] (5) Preparation of orally dissolving film: The prepared glue solution is coated on the isolation film at a certain coating rate of 30 mm / min and a coating thickness of 40 μm, and simultaneously dried (60°C) until the moisture content is less than 5%; (6) Cutting: Cut according to a certain area and pack.

[0058] Comparative Example 1

[0059] This comparative example provides a tamsulosin hydrochloride orosoluble film, the raw materials of which are 0.5g tamsulosin hydrochloride, 5g calcium carbonate, 10g hydroxypropyl methylcellulose E15, 5g hydroxypropyl methylcellulose E5, 1.5g hydroxypropyl cellulose LF, 5g glycerol, 3g microcrystalline cellulose-sodium carboxymethylcellulose, 0.05g sucralose and 90g purified water.

[0060] This comparative example also provides a method for preparing the tamsulosin hydrochloride orodispersible film. Every 1000 tablets of tamsulosin hydrochloride orodispersible film are prepared by the following method, which comprises the following steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: Add 80 g of water to the liquid preparation tank, and add hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose LF, glycerol, microcrystalline cellulose-sodium carboxymethylcellulose, calcium carbonate and sucralose in sequence, and stir at high speed for 3 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add 5 g of water, start stirring, add tamsulosin hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gelatin: Add the drug-containing solution to the gelatin, add 5 g of water to the prescribed amount, and continue stirring for 30 min; turn on the vacuum degassing, the vacuum degree is -0.08 MPa~-0.05 MPa, the degassing time is 2 hours, and the degassing temperature is 20~30°C; (5) Preparation of orally dissolving film: The prepared glue solution is coated on the isolation film at a coating rate of 20 mm / min and a coating thickness of 30 μm, and then dried simultaneously (60°C) until the moisture content is less than 5%; (6) Cutting: Cut according to a certain area and pack.

[0061] Comparative Example 2

[0062] This comparative example provides a fingolimod hydrochloride orodispersible film, the raw materials of which are 0.5g fingolimod hydrochloride, 5g calcium hydrogen phosphate, 10g hydroxypropyl methylcellulose E15, 5g hydroxypropyl methylcellulose E5, 1.5g hydroxypropyl cellulose LF, 5g glycerol, 3g microcrystalline cellulose-sodium carboxymethylcellulose, 0.05g sucralose and 90g purified water.

[0063] This comparative example also provides a method for preparing the fingolimod hydrochloride orodispersible film. Every 1000 pieces of fingolimod hydrochloride orodispersible film are prepared by the following method, which comprises the following steps: (1) Weighing: Weigh the raw and auxiliary materials according to the prescription amount and set aside; (2) Preparation of glue solution: Add 80 g of water to the liquid preparation tank, and add hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose LF, glycerol, microcrystalline cellulose-sodium carboxymethylcellulose, calcium hydrogen phosphate and sucralose in sequence, and stir at high speed for 3 hours; (3) Preparation of drug-containing solution: Take another solution preparation bucket, add 5 g of water, start stirring, add fingolimod hydrochloride, and stir to dissolve; (4) Preparation of drug-containing gelatin: Add the drug-containing solution to the gelatin, add 5 g of water to the prescribed amount, and continue stirring for 30 min; turn on the vacuum degassing, the vacuum degree is -0.08 MPa~-0.05 MPa, the degassing time is 2 hours, and the degassing temperature is 20~30°C; (5) Preparation of orally dissolving film: The prepared glue solution is coated on the isolation film at a coating rate of 20 mm / min and a coating thickness of 30 μm, and then dried simultaneously (60°C) until the moisture content is less than 5%; (6) Cutting: Cut according to a certain area and pack.

[0064] Experimental Example 1 Oral Dissolving Film Properties and Content Test

[0065] Content uniformity test method: The content uniformity was determined according to the chromatographic conditions and content uniformity inspection method (General Rules 0941 of the 2020 edition of the Chinese Pharmacopoeia) in the content determination of Experimental Example 3 of the present invention.

[0066] Table 1 Test results of properties and content uniformity of fingolimod hydrochloride orodispersible films of Examples 1 to 6

[0067] Conclusion: According to the above results, the appearance, taste and content uniformity of the fingolimod hydrochloride oral dissolving films of Examples 1 to 6 are all good, the taste of the tamsulosin hydrochloride oral dissolving film of Comparative Example 1 meets the requirements, but the content uniformity does not meet the requirements, and the taste and content uniformity of the fingolimod hydrochloride oral dissolving film of Comparative Example 2 do not meet the requirements.

[0068] Experimental Example 2: Test of mechanical properties of oral dissolving film and determination of dissolution time

[0069] Film thickness: The film thickness of the orally soluble films in Examples 1-6 and Comparative Examples 1-2 was measured using a film thickness tester and read directly; Folding resistance: The folding resistance of the oral dissolving film of the embodiment is measured by using an MIT folding resistance tester, and the reading is directly taken; Tensile strength and elongation: The test was conducted using a texture analyzer. The test method for tensile strength and elongation at break was conducted in accordance with GB / T1040-2006 "Determination of tensile properties of plastics". Specifically, the film was cut into 5 samples with a length of 3 cm and a width of 2 cm. Each sample was tested using the above texture analyzer, with the "tensile strength" mode selected and a stretching speed of 10 mm / min until the film broke. The instrument automatically calculated the tensile strength and elongation at break. The test results of the samples were averaged, and the results are as follows: Determination of the time limit for dissolving the orodissolving film: Take 6 pieces of each of Examples 1 to 6 and Comparative Examples 1 to 2, and measure the time limit for dissolving the orodissolving film. The test method is as follows: 100 ml of artificial saliva is added to 6 150 ml beakers respectively, and heated to 37±1° C. The 6 pieces of orodissolving film are gently placed in the 6 beakers at the same time, and the time for all the 6 pieces of orodissolving film of each example to dissolve is recorded while they are left to stand.

[0070] Table 2 Test results of mechanical properties and melting time of Examples 1 to 6

[0071] Conclusion: The mechanical properties and dissolution time of the oral dissolving films of Comparative Examples 1 and 2 are inferior to those of the oral dissolving films of Examples 1 to 6.

[0072] Experimental Example 3 Long-term stability test of orally dissolving film

[0073] 1. Content determination: Determine by high performance liquid chromatography (General Rule 0512 of the 2020 edition of the Chinese Pharmacopoeia).

[0074] Chromatographic conditions: octadecylsilane bonded silica gel as filler; 0.1% phosphoric acid as mobile phase A, acetonitrile as mobile phase B; gradient elution according to the table below, detection wavelength at 215 nm; injection volume 5 μl.

[0075]

[0076] Solvent: Mobile phase A: acetonitrile (1:1) was used as solvent.

[0077] Test solution: Take an appropriate amount of the product, dissolve it in solvent and quantitatively dilute it to make a solution containing about 0.6 mg of fingolimod hydrochloride per 1 ml, filter it and take the filtrate.

[0078] Reference solution: Take an appropriate amount of fingolimod hydrochloride reference substance, dissolve it in solvent and quantitatively dilute it to make a solution containing approximately 0.6 mg per 1 ml.

[0079] Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate by peak area according to the external standard method.

[0080] 2. Related substances: Determined by high performance liquid chromatography (General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia).

[0081] Chromatographic conditions: octadecylsilane bonded silica gel as filler; 0.1% phosphoric acid as mobile phase A, acetonitrile as mobile phase B; gradient elution according to the table below, detection wavelength at 215 nm; injection volume 5 μl.

[0082]

[0083] Solvent: Mobile phase A: acetonitrile (1:1) was used as solvent.

[0084] Test solution: Take an appropriate amount of the product, dissolve it in solvent and quantitatively dilute it to make a solution containing about 0.6 mg of fingolimod hydrochloride per 1 ml, filter it and take the filtrate.

[0085] Reference solution: Add 1 ml of the test solution to a 200 ml volumetric flask, add solvent to the constant volume mark, filter, and take the filtrate as the reference solution.

[0086] The relative retention times of impurity A and impurity D are 0.82 and 1.23. If there are impurity peaks in the chromatogram of the test solution, calculate the content of each impurity by the self-control method.

[0087] 3. Dissolution: Determined according to the dissolution and release method (General Rules 0931 Method 1 of the 2020 edition of the Chinese Pharmacopoeia).

[0088] Dissolution conditions: Use water as the dissolution medium, rotate at 50 revolutions per minute, operate according to the law, after 30 minutes, take the dissolution liquid, filter it, and keep the filtrate for use.

[0089] Determination method: Determine the dissolution rate according to the method under content determination.

[0090] Stability study: The orodissolving film samples of Examples 1 to 6 and Comparative Example 2 were packaged and placed under conditions of 25°C ± 2°C and 60% ± 5% relative humidity. Samples were taken and analyzed after 0 month, 3 months, and 6 months to check properties, dissolution, moisture, related substances, and content. The results are shown in Table 3.

[0091] Table 3 Long-term stability test results of orally dissolving films of Examples 1 to 6 and Comparative Example 2

[0092] Conclusion: According to the above results, the quality of the orodissolving films in Examples 1 to 6 met the quality standards for a long period of 6 months, indicating that the stability of the orodissolving films was good. The solubility and content of the orodissolving film in Comparative Example 2 decreased, and the related substances increased, and the stability was worse than that of the orodissolving films in Examples 1 to 6.

[0093] Experimental Example 4 Results of accelerated stability test of orally dissolving film

[0094] Stability study: The orodissolving film samples in Examples 1 to 6 and Comparative Example 2 were packaged and placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. Samples were taken and analyzed after 0 month, 3 months, and 6 months. The properties, solubility, moisture, related substances, and content were checked using the relevant test methods in Experimental Example 3 of the present invention. The results are shown in Table 4.

[0095] Table 4 Accelerated stability test results of Examples 1 to 6

[0096] Conclusion: According to the above results, the quality of the orodissolving films in Examples 1 to 6 met the quality standards when accelerated for 6 months, indicating that the stability of the orodissolving films was good. The solubility and content of the orodissolving film in Comparative Example 2 decreased, and the related substances increased, and the stability was worse than that of the orodissolving films in Examples 1 to 6.

[0097] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A fingolimod hydrochloride orodispersible film, characterized in that: The raw materials include, by weight: 0.5-5 parts of fingolimod hydrochloride, 30-60 parts of polymer film-forming material and 10-20 parts of filler; The polymer film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol and hydroxyethyl cellulose; the filler is selected from one or more of mannitol, calcium carbonate, lactose, microcrystalline cellulose and pregelatinized starch.

2. The fingolimod hydrochloride orodispersible film according to claim 1, characterized in that The polymer film-forming material is selected from one or two of hydroxypropyl methylcellulose and hydroxypropyl cellulose; Preferably, the hypromellose is one or two of hypromellose E15, hypromellose E5 and hypromellose E30; and / or the hydroxypropyl cellulose is hydroxypropyl cellulose LF; More preferably, the polymer film-forming material is composed of hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5 and hydroxypropyl cellulose LF, the weight ratio of hydroxypropyl methylcellulose E15 to hydroxypropyl methylcellulose E5 is 3-12:2-10, and the weight ratio of hydroxypropyl methylcellulose E15 to hydroxypropyl cellulose LF is 3-12:1-5; Or, the polymer film-forming material is a mixture of hydroxypropyl methylcellulose E15 and hydroxypropyl cellulose LF in a weight ratio of 12:3-7; Or, the polymer film-forming material is a mixture of hypromellose E15 and hypromellose E5 in a weight ratio of 12:3-7; Alternatively, the polymer film-forming material is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl cellulose LF in a weight ratio of 5-9:6-10.

3. The fingolimod hydrochloride orodispersible film according to claim 1 or 2, characterized in that: The filler is selected from one or both of mannitol and calcium carbonate.

4. The fingolimod hydrochloride orodispersible film according to claim 1 or 2, characterized in that: The raw materials also include plasticizers and suspending agents; Preferably, the plasticizer is selected from one or more of polyethylene glycol, glycerol, triethyl citrate and gelatin; and / or, the suspending agent is selected from one or more of microcrystalline cellulose-sodium carboxymethylcellulose complex, polyethylene oxide, xanthan gum and carrageenan.

5. The fingolimod hydrochloride orodispersible film according to claim 1 or 2, characterized in that: The raw materials also include flavoring agents, and preferably the flavoring agents are selected from one or more of sucralose, saccharin sodium, stevioside, maltitol, acesulfame potassium, and erythritol.

6. The fingolimod hydrochloride orodispersible film according to any one of claims 1 to 5, characterized in that The raw materials include, by weight: 1-3 parts of fingolimod hydrochloride, 40-60 parts of polymer film-forming material, 11-19 parts of filler, 11-19 parts of plasticizer and 6-15 parts of suspending agent; Preferably, the filler is calcium carbonate or mannitol; the polymer film-forming material is one or two of hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5 and hydroxypropyl cellulose LF; the plasticizer is glycerol or polyethylene glycol; and the suspending agent is microcrystalline cellulose-sodium carboxymethylcellulose complex or polyoxyethylene.

7. The fingolimod hydrochloride orodispersible film according to claim 6, characterized in that The raw materials include, by weight: 1.3-1.9 parts of fingolimod hydrochloride, 48-58 parts of polymer film-forming materials, 14-19 parts of fillers, 14-19 parts of plasticizers and 8-15 parts of suspending agents.

8. The fingolimod hydrochloride orodispersible film according to any one of claims 1 to 7, characterized in that The thickness of the fingolimod hydrochloride orodispersible film is 30-65 μm; and / or the water content of the fingolimod hydrochloride orodispersible film is less than 5%.

9. The method for preparing the fingolimod hydrochloride orodispersible film according to any one of claims 1 to 8, characterized in that: The following steps are involved: (1) Preparing a gel solution: mixing raw materials other than fingolimod hydrochloride with water to prepare a gel solution; (2) Preparing a drug-containing solution: mixing fingolimod hydrochloride with water to prepare a drug-containing solution; (3) preparing a drug-containing glue solution: adding the drug-containing solution to the glue solution to form a drug-containing glue solution; The solid content of the drug-containing glue is 20% to 30%; (4) Preparation of orally dissolving film: Apply the drug-containing adhesive solution onto the isolation film and dry until the moisture content is less than 5%.

10. The method for preparing the fingolimod hydrochloride orodispersible film according to claim 9, characterized in that: The preparation of the drug-containing glue solution also includes a vacuum degassing step; During the vacuum degassing, the vacuum degree is -0.08MPa~-0.05MPa, the degassing time is 1~3 hours, and the degassing temperature is 10~35°C.

Images