Pramipexole oral soluble film composition as well as preparation method and application thereof

Abstract

The invention provides a pramipexole oral soluble film composition as well as a preparation method and application thereof. The invention provides a pramipexole oral soluble film composition. The pramipexole oral soluble film composition comprises an active medicine, a film-forming material, a plasticizer and a flavoring agent, the active drug is a hydrochloride of S-2-amino-4, 5, 6, 7-tetrahydro-6-(propylamino)-benzothiazole as shown in a formula I and / or other pharmaceutically acceptable salt forms of the hydrochloride of S-2-amino-4, 5, 6, 7-tetrahydro-6-(propylamino)-benzothiazole as shown in the formula I. The pramipexole oral soluble film composition has the advantages that the pramipexole oral soluble film composition is thin in thickness, fast in disintegration, free of grit feeling after being dissolved in the oral cavity, capable of improving the taste of a medicine and improving the compliance of a patient, capable of being instantly dissolved in the oral cavity without drinking water, fast in oral absorption speed, uniform in film appearance, high in tensile capacity, good in flexibility and long in service life. Meanwhile, the raw materials are easy to obtain, the process is simple, the operation is simple and convenient, the drug loading capacity is high, the drug content uniformity is good, and the preparation method is suitable for industrial production. # imgabs0 #

Description

[0001] This application claims the priority of the prior application with patent application number 202310969117.X filed with the State Intellectual Property Office of China on August 3, 2023, and invention name “Pramipexole hydrochloride orodispersible film composition, preparation method and application thereof”. Technical Field

[0002] The invention relates to a pramipexole orodissolving film composition, a preparation method and application thereof. Background Art

[0003] Pramipexole hydrochloride is a new generation of non-ergot dopamine receptor agonists developed by Boehringer Ingelheim in Germany. It can act on dopaminergic D2 and D3 receptors with high selectivity, stimulate the release of dopamine in the brain, and improve motor symptoms. It is a first-line drug for the treatment of Parkinson's disease.

[0004] The chemical name of Pramipexole is S-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole, with a molecular formula of C 10 H 17 N3S, relative molecular weight 211.33. Pramipexole hydrochloride is a white or off-white crystalline powder, easily soluble in water, soluble in methanol, poorly soluble or slightly soluble in ethanol, almost insoluble in dichloromethane, very stable in solid state, but photosensitivity when in solution or mixed with other excipients. The chemical formula of pramipexole is as follows:

[0005]

[0006] Currently, only regular tablets and sustained-release tablets exist on the market.

[0007] Since Parkinson's patients usually have symptoms of hand tremors, tablets are difficult to take and easy to scatter when they are given to patients. For those with dysphagia, especially the elderly, tablets are not easy to swallow, making it difficult to take the medicine and their compliance is not high. In addition, conventional tablets need to be taken with water for better medication, which is troublesome and cumbersome for Parkinson's patients.

[0008] Therefore, it is necessary to develop a new dosage form of pramipexole with good stability, good taste and good patient compliance to solve the problem of medication compliance in Parkinson's patients. Summary of the invention

[0009] The technical problem solved by the present invention is to provide a pramipexole orodispersible film composition, a preparation method and application thereof in order to overcome the defects of the prior art such as the small number of pramipexole dosage forms, low dosage accuracy and low patient compliance. The pramipexole orodispersible film composition of the present invention has the characteristics of a solid preparation, such as accurate dosage, convenient carrying, convenient transportation and good stability, and has the advantages of a liquid preparation, such as convenient administration, suitable for patients with swallowing difficulties, improved drug compliance and simple process, and good market prospects.

[0010] The present invention provides a pramipexole orally dissolving film composition, which comprises an active drug, a film-forming material, a plasticizer and a flavoring agent; the active drug is a hydrochloride of S-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole as shown in Formula I and / or other pharmaceutically acceptable salt forms thereof;

[0011]

[0012] According to an embodiment of the present invention, the mass percentage of the active drug can be 0.01% to 10.00%, for example, 9.00%, 8.33%, 8.00%, 7.00%, 6.00%, 5.00%, 4.00%, 3.00%, 2.00%, 1.91%, 1.52%, 1.51%, 1.00%, 0.50%, 0.33%, 0.16%, 0.03% or any number between any two of the foregoing values, and the mass percentage refers to the mass of the active drug as a percentage of the total mass of the pramipexole orodispersible film composition.

[0013] According to an embodiment of the present invention, the film-forming material is a carrier of the active drug, selected from one or more of gelatin, xanthan gum, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose E5), hydroxypropyl cellulose, polyvinyl alcohol, polyoxyethylene, acrylic acid copolymer, povidone, polylactic acid, and silicone rubber. In one embodiment, the film-forming material is hydroxypropyl methylcellulose and polyvinyl alcohol, for example, the mass ratio of hydroxypropyl methylcellulose to polyvinyl alcohol is (1-6): (6-1), such as (2-5): (5-2), exemplarily 1:3.8 or 3.8:1.

[0014] According to an embodiment of the present invention, the mass percentage of the film-forming material can be 30.00% to 95.00%, for example, 90.00%, 87.79%, 90.91%, 87.88%, 85.00%, 80.00%, 70.00%, 60.00%, 66.67%, 56.97%, 50.00%, 40.00%, 43.68%, 35.00% or a number between any two of the foregoing values, and the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the pramipexole orodispersible film composition.

[0015] According to an embodiment of the present invention, the plasticizer is a substance used to lower the glass transition temperature of the film, increase plasticity and toughness, and improve elongation, and is selected from one or more of polyethylene glycol (e.g., polyethylene glycol 6000), glycerol, propylene glycol, silicone oil, dimethicone, polypropylene glycol and hexylene glycol.

[0016] According to an embodiment of the present invention, the mass percentage of the plasticizer can be 0 to 30.00%, for example 2.00% to 30.00%, exemplified by 25.00%, 28.71%, 21.34%, 20.00%, 15.00%, 10.00%, 8.33%, 7.63%, 6.06%, 5.00%, 4.55%, 3.00%, 2.00%, 1.00% or a number between any two of the foregoing values, wherein the mass percentage refers to the mass of the plasticizer as a percentage of the total mass of the pramipexole orodispersible film composition.

[0017] According to an embodiment of the present invention, the flavoring agent is a substance that acts as a flavoring agent in the film, and is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavors (such as strawberry flavor), spices, saccharin and saccharin sodium.

[0018] According to an embodiment of the present invention, the weight percentage of the flavoring agent can be 1.00% to 50.00%, for example, 1.00% to 10.00%, exemplified by 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, 6.00%, 7.00%, 8.00%, 8.33%, 9.00%, 9.98%, 10.00%, 2.67%, 1.51%, 1.33% or 6.06%, wherein the weight percentage refers to the weight of the flavoring agent as a percentage of the total weight of the pramipexole orodispersible film composition.

[0019] According to an embodiment of the present invention, the pramipexole orodispersible film composition may further comprise a filler. The filler is a substance that increases the weight of the film and makes the film more solid, and is selected from one or more of mannitol, dextrin, starch, pregelatinized starch, lactose and microcrystalline cellulose.

[0020] According to an embodiment of the present invention, the mass percentage of the filler can be 0 to 30.00%, for example, 10.00% to 25.00%, exemplified by 5.00%, 8.34%, 10.00%, 12.48%, 15.00%, 20.00%, 25.00% or a number between any two of the foregoing values; the mass percentage refers to the mass of the filler as a percentage of the total mass of the pramipexole orodispersible film composition.

[0021] According to an embodiment of the present invention, the pramipexole orodispersible film composition may further comprise a disintegrant, which refers to an auxiliary material that promotes the rapid disintegration of the film into small particles in the oral cavity and gastrointestinal tract, and is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch.

[0022] According to an embodiment of the present invention, the mass percentage of the disintegrant may be 0-8.00%, such as 0-5.00%, and the mass percentage refers to the mass percentage of the disintegrant to the total mass of the pramipexole orodispersible film composition.

[0023] According to an embodiment of the present invention, the pramipexole orodispersible film composition may further comprise a colorant. The colorant refers to a substance that can improve the appearance color of the film, can be used to identify the concentration of the film, distinguish the application method, and reduce the patient's aversion to taking the medicine, and is selected from one or more of titanium dioxide, pigments, and lakes.

[0024] According to an embodiment of the present invention, the mass percentage of the colorant may be 0-1.00%, and the mass percentage refers to the mass percentage of the disintegrant to the total mass of the pramipexole orodispersible film composition.

[0025] According to one embodiment of the present invention, the pramipexole orodispersible film composition is composed of an active drug, a film-forming material, a plasticizer and a flavoring agent;

[0026] The active drug is the hydrochloride of S-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole as shown in Formula I, with a mass percentage of 0.01% to 10.00%;

[0027] The film-forming material is selected from hydroxypropyl methylcellulose and / or polyvinyl alcohol, and the mass percentage is 40.00-95.00%;

[0028] The plasticizer is selected from glycerol and / or polyethylene glycol 6000, and the mass percentage content is 2.00% to 30.00%.

[0029] According to one embodiment of the present invention, the pramipexole orodispersible film composition comprises at least an active drug, a film-forming material, a plasticizer, a filler and a flavoring agent;

[0030] The active drug is the hydrochloride of S-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole as shown in Formula I, with a mass percentage of 0.01% to 10.00%;

[0031] The film-forming material is selected from hydroxypropyl methylcellulose and / or polyvinyl alcohol, and the mass percentage is 40.00% to 70.00% or 50.00% to 95.00%;

[0032] The plasticizer is selected from glycerol and / or polyethylene glycol 6000, and the mass percentage is 4.00% to 25.00% or 8.00% to 30.00%;

[0033] The filler is selected from pregelatinized starch and / or microcrystalline cellulose, and the mass percentage is 5.00% to 25.00%;

[0034] Alternatively, the pramipexole orodispersible film composition may further comprise a disintegrant and / or a colorant;

[0035] When the disintegrant is contained, the mass percentage of the disintegrant does not exceed 8%; in one embodiment, the disintegrant is cross-linked polyvinylpyrrolidone.

[0036] According to an embodiment of the present invention, the pramipexole orodispersible film composition may be any of the following formulations:

[0037] Prescription 1: 1.91% pramipexole hydrochloride, 87.79% hydroxypropyl methylcellulose E5, 7.63% polyethylene glycol 6000, 2.29% aspartame and 0.38% strawberry flavor; the percentages refer to the percentage of the mass of each component to the total mass of the pramipexole orodispersible film composition;

[0038] Prescription 2: 1.52% pramipexole hydrochloride, 90.91% hydroxypropyl methylcellulose E5, 6.06% polyethylene glycol 6000, 1.21% aspartame and 0.30% strawberry flavor; the percentages refer to the percentage of the mass of each component to the total mass of the pramipexole orodispersible film composition;

[0039] Prescription 3: 1.51% pramipexole hydrochloride, 69.70% hydroxypropyl methylcellulose E5, 18.18% polyvinyl alcohol, 4.55% polyethylene glycol 6000, 3.03% aspartame and 3.03% strawberry flavor; the percentages refer to the percentage of the mass of each component to the total mass of the pramipexole orodispersible film composition;

[0040] Prescription 4: 1.51% pramipexole hydrochloride, 69.70% polyvinyl alcohol, 18.18% hydroxypropyl methylcellulose E5, 4.55% polyethylene glycol 6000, 3.03% aspartame and 3.03% strawberry flavor; the percentages refer to the percentage of the mass of each component to the total mass of the pramipexole orodispersible film composition;

[0041] Prescription 5: 0.33% pramipexole hydrochloride, 56.97% polyvinyl alcohol, 20.00% pregelatinized starch, 21.34% glycerol, 1.33% sucralose and 0.03% lake; the percentages refer to the percentage of the mass of each component to the total mass of the pramipexole orodispersible film composition;

[0042] Prescription 6: 0.16% pramipexole hydrochloride, 43.68% polyvinyl alcohol, 12.48% microcrystalline cellulose, 28.71% polyethylene glycol 6000, 9.98% stevioside and 4.99% cross-linked polyvinylpyrrolidone; the percentages refer to the percentage of the mass of each component to the total mass of the pramipexole orodispersible film composition;

[0043] Prescription 7: 8.33% pramipexole hydrochloride, 66.67% polyvinyl alcohol, 8.34% microcrystalline cellulose, 8.33% glycerol and 8.33% sucralose; the percentages refer to the percentage of the mass of each component to the total mass of the pramipexole orosoluble film composition.

[0044] The present invention also provides a method for preparing the pramipexole orodispersible film composition, which comprises the following steps:

[0045] Step 1: Add plasticizer, flavoring agent and water to prepare a solution;

[0046] Step 2: adding the film-forming material to the solution obtained in step 1, stirring and dissolving, and then adding the active drug, or further adding a filler, a disintegrant and / or a colorant, mixing evenly to obtain a drug-containing gel solution;

[0047] Step 3: evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain the pramipexole orodispersible film composition.

[0048] According to an embodiment of the present invention, the thickness of the pramipexole orosoluble film composition is 10 μm to 120 μm, such as 50 μm, 70 μm, 73 μm or 60 μm.

[0049] According to an embodiment of the present invention, the pramipexole orosoluble film composition can completely disintegrate in 900 ml of 37±1° C. simulated saliva within 60 seconds, such as 13 seconds, 20 seconds, 26 seconds, 27 seconds, 34 seconds, 30 seconds or 35 seconds.

[0050] The present invention also provides the use of the pramipexole orodispersible film composition in preparing a drug for treating and / or preventing Parkinson's disease.

[0051] The present invention also provides a method for treating and / or preventing Parkinson's disease, which comprises administering a therapeutically effective amount of the pramipexole orodispersible film composition to a patient in need.

[0052] The reagents and raw materials used in the present invention are commercially available.

[0053] The term "plurality" used herein refers to more than two kinds, for example, two, three or more kinds.

[0054] The beneficial effects of the present invention are as follows: the pramipexole orodispersible film composition of the present invention has the advantages of thin thickness, fast disintegration, no gritty feeling after dissolving in the oral cavity, good taste and improved taste of the drug, increased patient compliance, instant dissolution in the oral cavity without drinking water, fast oral absorption rate, uniform film appearance, strong tensile strength, good flexibility, convenient transportation and storage, etc., and at the same time, the raw materials are easily available, the process is simple, the operation is simple, the drug loading capacity is high, the drug content uniformity is good, and it is suitable for industrial production. DETAILED DESCRIPTION

[0055] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0056] Example 1 Prescription 1

[0057] name mg / tablet Proportion (%) Function Pramipexole Hydrochloride 0.25 1.91 Active ingredients Hydroxypropyl methylcellulose (E5) 11.5 87.79 Film-forming materials Polyethylene glycol 6000 1 7.63 Plasticizers Aspartame 0.30 2.29 Flavoring agents Strawberry flavor 0.05 0.38 Flavoring agents water 25 / Solvents Total weight (mg / tablet) 13.1 100.00 /

[0058] Preparation steps:

[0059] Step 1: Stir and dissolve polyethylene glycol 6000, aspartame, strawberry flavor and water to obtain a solution;

[0060] Step 2: Add hydroxypropyl methylcellulose (E5) to the aqueous solution prepared in step 1, stir until the hydroxypropyl methylcellulose (E5) is dissolved, add pramipexole hydrochloride and stir for 20 minutes until it is evenly dispersed to obtain a drug-containing gel solution;

[0061] Step 3: Use a scraper to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain a pramipexole hydrochloride orodispersible film-forming preparation.

[0062] Example 2

[0063] Prescription 2

[0064]

[0065]

[0066] Preparation steps:

[0067] Step 1: Stir and dissolve polyethylene glycol 6000, aspartame, strawberry flavor and water to obtain a solution;

[0068] Step 2: Add hydroxypropyl methylcellulose (E5) to the aqueous solution prepared in step 1 and stir until the hydroxypropyl methylcellulose (E5) is dissolved, then add pramipexole hydrochloride and stir for 20 minutes until it is evenly dispersed to obtain a drug-containing gel solution;

[0069] Step 3: The drug-containing gel obtained in step 2 is evenly coated on a polyester tape with a scraper, dried, and cut to obtain a pramipexole hydrochloride orodispersible film-forming agent.

[0070] Example 3

[0071] Prescription 3

[0072] name mg / tablet Proportion (%) Function Pramipexole Hydrochloride 0.25 1.51 Active ingredients Hydroxypropyl methylcellulose (E5) 11.5 69.70 Film-forming materials Polyvinyl alcohol 3 18.18 Film-forming materials Polyethylene glycol 6000 0.75 4.55 Plasticizers Strawberry flavor 0.5 3.03 Flavoring agents Aspartame 0.5 3.03 Flavoring agents Purified water 16.5 / Solvents total 100 /

[0073] Preparation steps:

[0074] Step 1: adding polyethylene glycol 6000, aspartame and strawberry flavor to the aqueous solution containing polyvinyl alcohol, stirring to dissolve, and then adding hydroxypropyl methylcellulose and stirring until dissolved to obtain a solution;

[0075] Step 2: adding pramipexole hydrochloride to the solution obtained in step 1 and stirring for 20 minutes until uniform, to obtain a drug-containing gel solution;

[0076] Step 3: Use a scraper to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain a pramipexole hydrochloride orodispersible film-forming preparation.

[0077] Example 4

[0078] Prescription 4

[0079] name mg / tablet Proportion (%) Function Pramipexole Hydrochloride 0.25 1.51 Active ingredients Hydroxypropyl methylcellulose (E5) 3 18.18 Film-forming materials Polyvinyl alcohol 11.5 69.70 Film-forming materials Polyethylene glycol 6000 0.75 4.55 Plasticizers Strawberry flavor 0.5 3.03 Flavoring agents Aspartame 0.5 3.03 Flavoring agents Purified water 16.5 / Solvents total 16.5 100 /

[0080] Preparation steps:

[0081] Step 1: adding polyethylene glycol 6000, aspartame and strawberry flavor to the aqueous solution containing polyvinyl alcohol, stirring to dissolve, and then adding hydroxypropyl methylcellulose and stirring until dissolved to obtain a solution;

[0082] Step 2: adding pramipexole hydrochloride to the solution obtained in step 2 and stirring for 20 minutes until uniform, to obtain a drug-containing gel solution;

[0083] Step 3: Use a scraper to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain a pramipexole hydrochloride orodispersible film-forming agent.

[0084] Example 5

[0085] Prescription 5

[0086]

[0087]

[0088] Preparation steps:

[0089] Step 1: adding glycerol and sucralose to an aqueous solution containing polyvinyl alcohol, stirring and dissolving to obtain a solution;

[0090] Step 2: adding pramipexole hydrochloride, pregelatinized starch and lake to the solution obtained in step 2 and stirring for 20 minutes until uniform, to obtain a drug-containing gelatin solution;

[0091] Step 3: Use a scraper to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain a pramipexole hydrochloride orodispersible film-forming agent.

[0092] Example 6

[0093] Prescription 6

[0094] name mg / tablet Proportion (%) Function Pramipexole Hydrochloride 0.125 0.16 Active ingredients Polyvinyl alcohol 35.00 43.68 Film-forming materials Microcrystalline Cellulose 10.00 12.48 Fillers Polyethylene glycol 6000 23.00 28.71 Plasticizers Stevioside 8.00 9.98 Flavoring agents Crospovidone 4.00 4.99 Disintegrants Purified water 100.00 / Solvents total 80.125 100.00 /

[0095] Preparation steps:

[0096] Step 1: adding polyethylene glycol 6000 and stevioside to an aqueous solution containing polyvinyl alcohol, stirring and dissolving to obtain a solution;

[0097] Step 2: adding pramipexole hydrochloride, microcrystalline cellulose and cross-linked polyvinylpyrrolidone to the solution obtained in step 2 and stirring for 20 minutes until uniform, to obtain a drug-containing gel solution;

[0098] Step 3: Use a scraper to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain a pramipexole hydrochloride orodispersible film-forming agent.

[0099] Example 7

[0100] Prescription 7

[0101] name mg / tablet Proportion (%) Function Pramipexole Hydrochloride 1.0 8.33 Active ingredients Polyvinyl alcohol 8.0 66.67 Film-forming materials Microcrystalline Cellulose 1.0 8.34 Fillers glycerin 1.0 8.33 Plasticizers Sucralose 1.0 8.33 Flavoring agents Purified water 20.0 / Solvents total 12.0 100.00 /

[0102] Preparation steps:

[0103] Step 1: adding glycerol and sucralose to an aqueous solution containing polyvinyl alcohol, stirring and dissolving to obtain a solution;

[0104] Step 2: adding pramipexole hydrochloride and microcrystalline cellulose to the solution obtained in step 2 and stirring for 20 minutes until uniform, to obtain a drug-containing gel solution;

[0105] Step 3: Use a scraper to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain a pramipexole hydrochloride orodispersible film-forming agent.

[0106] Experimental Example 1

[0107] The samples prepared in Examples 1 to 7 of the present invention were taken to test film thickness, disintegration time (test conditions: 900 ml, 37±1° C. in simulated saliva), moisture content and mechanical strength.

[0108] Mechanical strength test method:

[0109] Use a texture analyzer (Model: Rapid TA + , manufacturer: Shanghai Tengba Instrument Technology Co., Ltd.) The mechanical strength test of the pramipexole hydrochloride orosoluble film preparations of Examples 1 to 7 was performed, and the maximum mechanical strength force and the maximum mechanical strength distance were recorded.

[0110] Folding endurance testing method:

[0111] Take the pramipexole hydrochloride orodispersible film preparations of Examples 1 to 7, fold the orodispersible film 180 degrees in the middle and unfold it, repeat the folding 5 times, and observe whether the orodispersible film is broken.

[0112] The test results are shown in Table 1.

[0113] Table 1 Test results of film thickness, disintegration time, moisture content and mechanical strength of samples prepared in Examples 1 to 7

[0114]

[0115]

[0116] The above results of the mechanical strength of the film show that the pramipexole hydrochloride orodispersible films prepared in Examples 1 to 7 have a certain degree of tensile strength and flexibility, which can overcome the external pressure during cutting, packaging and transportation. The disintegration time is short (within 35 seconds), and the appearance and taste are good.

[0117] Experimental Example 2

[0118] Take 10 portions of the samples prepared in Examples 1 to 7 of the present invention (about 90 mg / portion) respectively, and test the mixing uniformity of the samples. The test method is:

[0119] Octadecylsilane bonded silica gel was used as filler (SHIMADZU Shim-pack GIST C18-AQ, 4.6 mm × 250 mm, 5 μm or a chromatographic column of equivalent performance was recommended); ammonium formate solution (18.9 g of ammonium formate was dissolved in 1000 ml of water and the pH was adjusted to 5.0 with formic acid)-methanol (75:25) was used as mobile phase; the flow rate was 1.0 ml per minute; the column temperature was 40°C; the detection wavelength was 264 nm; and the injection volume was 20 μl.

[0120] The test results are shown in Table 2.

[0121] Table 2 Content uniformity test results of samples prepared in Examples 1 to 7

[0122]

[0123]

[0124] The above content uniformity results show that the pramipexole hydrochloride orodispersible films prepared in Examples 1 to 7 have good mixing uniformity and good preparation uniformity.

[0125] Experimental Example 3

[0126] The samples prepared in Example 5 of the present invention were respectively packaged in polyester / aluminum / cast polyethylene pharmaceutical composite film bags and placed under high temperature 50°C, high humidity 92.5%RH, strong light irradiation conditions, accelerated test (40°C±2°C / 75%RH+5%RH), and long-term test (25°C±2°C / 60%RH±5%RH) to investigate the dissolution, content, and related substances of the preparations.

[0127] (1) Dissolution test method:

[0128] Experimental device: "Chinese Pharmacopoeia" 2020 edition Part IV 0931 Dissolution and Release Determination Method 2 (Paddle Method + Sinking Basket), speed is 50rpm

[0129] Dissolution medium: pH 1.0 hydrochloric acid solution, medium volume 500ml, medium temperature 37℃±0.5℃

[0130] Sampling time: 15min

[0131] Detection method:

[0132] Octadecylsilane bonded silica gel was used as the filler (SHIMADZU Shim-pack GIST C18-AQ, 4.6 mm × 250 mm, 5 μm was recommended); ammonium formate solution (18.9 g of ammonium formate was dissolved in 1000 ml of water and the pH was adjusted to 5.0 with formic acid)-methanol (75:25) was used as the mobile phase; the flow rate was 1.0 ml per minute; the column temperature was 40°C; the detection wavelength was 264 nm; and the injection volume was 100 μl.

[0133] (2) Content detection method:

[0134] Octadecylsilane bonded silica gel was used as filler (SHIMADZU Shim-pack GIST C18-AQ, 4.6 mm × 250 mm, 5 μm or a chromatographic column of equivalent performance was recommended); ammonium formate solution (18.9 g of ammonium formate was dissolved in 1000 ml of water and the pH was adjusted to 5.0 with formic acid)-methanol (75:25) was used as mobile phase; the flow rate was 1.0 ml per minute; the column temperature was 40°C; the detection wavelength was 264 nm; and the injection volume was 20 μl.

[0135] (3) Detection methods for related substances:

[0136] Chromatographic conditions: Octadecylsilane bonded silica gel was used as filler (CAPCELL PAKMGIIC 184.6 mm × 250 mm, 5 μm was recommended); ammonium formate buffer (31.5 g of ammonium formate was dissolved in water and diluted to 1000 ml, and the pH value was adjusted to 5.0 with formic acid) was used as mobile phase A; methanol was used as mobile phase B; gradient elution was performed according to the table below (Table 3), and the detection wavelengths were 264 nm, 240 nm, and 326 nm, respectively; the flow rate was 1.0 ml per minute; the column temperature was 30°C; and the injection volume was 50 μl.

[0137] Table 3 Gradient elution program

[0138]

[0139] The test results are shown in Table 4 below:

[0140] Table 4 Test results of influencing factors test, accelerated test and long-term test of Example 5

[0141]

[0142]

[0143] According to the above results, the solubility, content and related substances of the pramipexole hydrochloride orodispersible film prepared according to Example 5 did not change significantly under the influencing factor test, accelerated test and long-term test conditions, and the preparation had good stability.

[0144] The above examples are used to illustrate the specific implementation of the present invention. However, the protection scope of the present invention is not limited to the above exemplary implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. An orally dissolving film composition, characterized in that: The invention comprises: an active drug, a film-forming material, a plasticizer and a flavoring agent; the active drug is S-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole hydrochloride and / or other pharmaceutically acceptable salt forms thereof as shown in Formula I; 2. The orodispersible film composition according to claim 1, wherein: The mass percentage of the active drug is 0.01% to 10.00%, and the mass percentage refers to the percentage of the mass of the active drug to the total mass of the orodispersible film composition; and / or, the film-forming material is selected from one or more of gelatin, xanthan gum, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyoxyethylene, acrylic acid copolymer, povidone, polylactic acid and silicone rubber; and / or, The plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, silicone oil, dimethicone, polypropylene glycol and hexylene glycol; and / or, The flavor corrector is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycoside, glycyrrhizin, flavor, spice, saccharin and saccharin sodium.

3. The orodispersible film composition according to claim 1, wherein: The mass percentage of the film-forming material is 30.00% to 95.00%, and the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the orally dissolving film composition; and / or, The mass percentage of the plasticizer is 0 to 30.00%, and the mass percentage refers to the mass percentage of the plasticizer to the total mass of the orodispersible film composition; and / or, The mass percentage of the flavoring agent is 1.00% to 50.00%, and the mass percentage refers to the percentage of the mass of the flavoring agent to the total mass of the orodispersible film composition.

4. The orodispersible film composition according to claim 1, wherein: The orally disintegrating film composition further comprises one or more of a filler, a disintegrant and a colorant.

5. The orodispersible film composition according to claim 4, wherein: The filler is selected from one or more of mannitol, dextrin, starch, pregelatinized starch, lactose and microcrystalline cellulose; and / or, The disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch; and / or, The colorant is one or more of titanium dioxide, pigment and lake.

6. The orodispersible film composition according to claim 4 or 5, characterized in that: The mass percentage of the filler is 0-30.00%, and the mass percentage refers to the percentage of the mass of the filler to the total mass of the orodispersible film composition. and / or, The mass percentage of the disintegrant is 0-8.00%, for example 0-5.00%, and the mass percentage refers to the percentage of the mass of the filler to the total mass of the orodispersible film composition. and / or, The mass percentage of the colorant is 0-1.00%, and the mass percentage refers to the percentage of the mass of the filler to the total mass of the orodispersible film composition.

7. The orodispersible film composition according to claim 1, wherein: The orodispersible film composition may be any of the following formulations: Prescription 1: 1.91% pramipexole hydrochloride, 87.79% hydroxypropyl methylcellulose E5, 7.63% polyethylene glycol 6000, 2.29% aspartame and 0.38% strawberry flavor; the percentages refer to the percentage of the mass of each component to the total mass of the orodispersible film composition; Prescription 2: 1.52% pramipexole hydrochloride, 90.91% hydroxypropyl methylcellulose E5, 6.06% polyethylene glycol 6000, 1.21% aspartame and 0.30% strawberry flavor; the percentages refer to the percentage of the mass of each component to the total mass of the orodispersible film composition; Prescription 3: 1.51% pramipexole hydrochloride, 69.70% hydroxypropyl methylcellulose E5, 18.18% polyvinyl alcohol, 4.55% polyethylene glycol 6000, 3.03% aspartame and 3.03% strawberry flavor; the percentages refer to the percentage of the mass of each component to the total mass of the orodispersible film composition; Prescription 4: 1.51% pramipexole hydrochloride, 69.70% polyvinyl alcohol, 18.18% hydroxypropyl methylcellulose E5, 4.55% polyethylene glycol 6000, 3.03% aspartame and 3.03% strawberry flavor; the percentages refer to the percentage of the mass of each component to the total mass of the orodispersible film composition; Prescription 5: 0.33% pramipexole hydrochloride, 56.97% polyvinyl alcohol, 20.00% pregelatinized starch, 21.34% glycerol, 1.33% sucralose and 0.03% lake; the percentages refer to the percentage of the mass of each component to the total mass of the orodispersible film composition; Prescription 6: 0.16% pramipexole hydrochloride, 43.68% polyvinyl alcohol, 12.48% microcrystalline cellulose, 28.71% polyethylene glycol 6000, 9.98% stevioside and 4.99% cross-linked polyvinylpyrrolidone; the percentages refer to the percentage of the mass of each component to the total mass of the orodispersible film composition; Prescription 7: 8.33% pramipexole hydrochloride, 66.67% polyvinyl alcohol, 8.34% microcrystalline cellulose, 8.33% glycerol and 8.33% sucralose; the percentages refer to the percentage of the mass of each component to the total mass of the orosoluble film composition.

8. The method for preparing the orally dissolving film composition according to any one of claims 1 to 7, characterized in that: The following steps are involved: Step 1: Add plasticizer, flavoring agent and water to prepare a solution; Step 2: adding the film-forming material to the solution obtained in step 1, stirring and dissolving, and then adding the active drug, or further adding a filler, a disintegrant and / or a colorant, mixing evenly to obtain a drug-containing gel solution; Step 3: evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain the orally dissolving film composition.

9. The orodispersible film composition according to any one of claims 1 to 7, characterized in that: The thickness of the orally dissolving film composition is 10 μm to 120 μm; and / or, The orally disintegrating film composition can be completely disintegrated within 60 seconds in 900 ml of simulated saliva at 37±1°C.

10. Use of the orodispersible film composition according to any one of claims 1 to 7 in the preparation of a medicament for treating and / or preventing Parkinson's disease.

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