Pramipexole oral soluble film composition, preparation method therefor and use thereof

Abstract

A pramipexole oral soluble film composition, a preparation method therefor and the use thereof. A pramipexole oral soluble film composition containing an active drug, a film-forming material, a plasticizer and a flavoring agent, wherein the active drug is a hydrochloride and / or other pharmaceutically acceptable salt forms of S-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole as shown in formula I. The pramipexole oral soluble film composition has the advantages of a small thickness, rapid disintegration, no gritty sensation after dissolving in the oral cavity, improved drug taste, good mouth feel, improved patient compliance, instant dissolution in the oral cavity without the need to drink water, fast absorption after taking orally, uniform film appearance, strong tensile strength, good flexibility, convenient transportation and storage, etc. In addition, the composition has the advantages of readily available raw materials, a simple process, simple and convenient operation, a high drug-loading capacity, and good uniformity of drug content, and is suitable for industrial production.

Description

Pramipexole orally dissolving film composition, preparation method and application thereof

[0001] This application claims priority to 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 orally disintegrating film composition, preparation method and application thereof”. Technical Field

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

[0003] Pramipexole hydrochloride is a new generation of non-ergot dopamine receptor agonist developed by Boehringer Ingelheim in Germany. It can act highly selectively on dopamine D2 and D3 receptors, 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, and its molecular formula is C 10 H 17 N3S, relative molecular weight 211.33. Pramipexole hydrochloride is a white or off-white crystalline powder that is readily soluble in water, soluble in methanol, poorly soluble or slightly soluble in ethanol, and practically insoluble in dichloromethane. It is very stable in the solid state, but is photosensitized when in solution or mixed with other excipients. The chemical formula of pramipexole is as follows:

[0005] Currently, only regular tablets and extended-release tablets are available on the market. The regular tablets were approved by the US FDA in January 1997 and marketed under the trade name "Sifrol." In December 2005, the regular tablets were approved for market entry in China under the trade name "Senfuluo." The extended-release tablets were approved for marketing in the US in February 2010 and launched in China in August 2014.

[0006] Since Parkinson's patients often suffer from hand tremors, tablets are difficult to take and easy to scatter when used for medication. For those with dysphagia, especially the elderly, tablets are not easy to swallow, making medication difficult and compliance low. In addition, conventional tablets need to be taken with water for better medication, which is troublesome and cumbersome for Parkinson's patients.

[0007] 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.

[0008] Summary of the Invention

[0009] The present invention addresses the technical problem of overcoming the drawbacks of prior art pramipexole, such as limited dosage forms, low dosage accuracy, and low patient compliance, by providing a pramipexole orally disintegrating film composition, a preparation method, and applications thereof. The pramipexole orally disintegrating film composition of the present invention combines the advantages of a solid preparation, such as accurate dosage, easy portability, convenient transportation, and good stability, with the advantages of a liquid preparation, such as ease of administration and suitability for patients with swallowing difficulties. It also improves drug compliance, simplifies the process, and has promising market prospects.

[0010] The present invention provides a pramipexole orally disintegrating film composition, which comprises an active drug, a film-forming material, a plasticizer, and a flavoring agent; the active drug is the 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] 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 a number between any two of the foregoing values. The mass percentage refers to the percentage of the mass of the active drug to the total mass of the pramipexole orally disintegrating film composition.

[0012] According to an embodiment of the present invention, the film-forming material is a carrier of the active drug and is 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, polyethylene oxide, 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), exemplified by 1:3.8 or 3.8:1.

[0013] 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. The mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the pramipexole orally disintegrating film composition.

[0014] 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 (such as polyethylene glycol 6000), glycerol, propylene glycol, silicone oil, dimethicone, polypropylene glycol and hexylene glycol.

[0015] 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. The mass percentage refers to the percentage of the mass of the plasticizer to the total mass of the pramipexole orally dissolving film composition.

[0016] 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.

[0017] 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 percentage of the weight of the flavoring agent to the total weight of the pramipexole orally disintegrating film composition.

[0018] According to an embodiment of the present invention, the pramipexole orally disintegrating film composition may further comprise a filler. The filler is a substance that increases the weight of the film and makes the film stronger, and is selected from one or more of mannitol, dextrin, starch, pregelatinized starch, lactose, and microcrystalline cellulose.

[0019] 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 percentage of the mass of the filler to the total mass of the pramipexole orally disintegrating film composition.

[0020] According to an embodiment of the present invention, the pramipexole orally disintegrating film composition may further comprise a disintegrant. The disintegrant is an excipient that promotes 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.

[0021] According to an embodiment of the present invention, the mass percentage of the disintegrant may be 0-8.00%, for example, 0-5.00%. The mass percentage refers to the mass percentage of the disintegrant to the total mass of the pramipexole orally disintegrating film composition.

[0022] According to an embodiment of the present invention, the pramipexole orally disintegrating film composition may further comprise a colorant. The colorant is a substance that can improve the 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 medication, and is selected from one or more of titanium dioxide, pigments, and lakes.

[0023] According to an embodiment of the present invention, the mass percentage of the colorant may be 0-1.00%, where the mass percentage refers to the percentage of the mass of the disintegrant to the total mass of the pramipexole orally disintegrating film composition.

[0024] According to one embodiment of the present invention, the pramipexole orally disintegrating film composition is composed of an active drug, a film-forming material, a plasticizer, and a flavoring agent;

[0025] 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%;

[0026] The film-forming material is selected from hydroxypropyl methylcellulose and / or polyvinyl alcohol, with a mass percentage of 40.00 to 95.00%;

[0027] The plasticizer is selected from glycerol and / or polyethylene glycol 6000, with a mass percentage of 2.00% to 30.00%.

[0028] According to one embodiment of the present invention, the pramipexole orally disintegrating film composition comprises at least an active drug, a film-forming material, a plasticizer, a filler, and a flavoring agent;

[0029] 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%;

[0030] The film-forming material is selected from hydroxypropyl methylcellulose and / or polyvinyl alcohol, with a mass percentage of 40.00% to 70.00% or 50.00% to 95.00%;

[0031] The plasticizer is selected from glycerol and / or polyethylene glycol 6000, with a mass percentage of 4.00% to 25.00% or 8.00% to 30.00%;

[0032] The filler is selected from pregelatinized starch and / or microcrystalline cellulose, with a mass percentage of 5.00% to 25.00%;

[0033] Alternatively, the pramipexole orally disintegrating film composition may further comprise a disintegrant and / or a colorant;

[0034] When the disintegrant is contained, the mass percentage of the disintegrant does not exceed 8%. In one embodiment, the disintegrant is cross-linked polyvinylpyrrolidone.

[0035] According to an embodiment of the present invention, the pramipexole orally disintegrating film composition may be any of the following formulations:

[0036] 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 mentioned refer to the mass percentage of each component to the total mass of the pramipexole orally disintegrating film composition;

[0037] 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 mentioned refer to the mass percentage of each component to the total mass of the pramipexole orally disintegrating film composition;

[0038] 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 mentioned refer to the mass percentage of each component to the total mass of the pramipexole orally disintegrating film composition;

[0039] 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 mentioned refer to the mass percentage of each component to the total mass of the pramipexole orally disintegrating film composition;

[0040] 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 mentioned refer to the mass percentage of each component to the total mass of the pramipexole orally disintegrating film composition;

[0041] Prescription 6: 0.16% pramipexole hydrochloride, 43.68% polyvinyl alcohol, 12.48% microcrystalline cellulose, 28.71% polyethylene glycol 6000, 9.98% steviol glycosides, and 4.99% cross-linked polyvinylpyrrolidone; the percentages mentioned refer to the mass percentage of each component to the total mass of the pramipexole orally disintegrating film composition;

[0042] 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 orally disintegrating film composition.

[0043] The present invention also provides a method for preparing the pramipexole orally disintegrating film composition, which comprises the following steps:

[0044] Step 1: Prepare a solution by mixing plasticizer, flavoring agent and water;

[0045] Step 2: adding the film-forming material to the solution obtained in step 1, stirring and dissolving, and then mixing with the active drug, or further adding a filler, a disintegrant and / or a colorant, to obtain a drug-containing gel;

[0046] Step 3: evenly coating the drug-containing glue obtained in step 2 on a polyester tape, drying, and cutting to obtain the pramipexole orally disintegrating film composition.

[0047] According to an embodiment of the present invention, the thickness of the pramipexole orally disintegrating film composition is 10 μm to 120 μm, for example, 50 μm, 70 μm, 73 μm or 60 μm.

[0048] According to an embodiment of the present invention, the pramipexole orally disintegrating 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.

[0049] The present invention also provides use of the pramipexole orally disintegrating film composition in preparing a drug for treating and / or preventing Parkinson's disease.

[0050] 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 orally disintegrating film composition to a patient in need.

[0051] The reagents and raw materials used in the present invention are commercially available.

[0052] The term "plurality" used herein refers to more than two kinds, for example, two, three or more kinds.

[0053] The present invention has the following beneficial effects: The pramipexole orally disintegrating film composition of the present invention has the advantages of thin thickness, fast disintegration, no gritty feeling after dissolving in the oral cavity, can improve the taste of the drug and have a good mouthfeel, increase patient compliance, can dissolve instantly in the oral cavity without drinking water, has a fast oral absorption rate, has a uniform film appearance, strong tensile strength, good flexibility, and is convenient for transportation and storage. In addition, the raw materials are readily available, the process is simple, the operation is easy, the drug loading capacity is high, the drug content uniformity is good, and it is suitable for industrial production. DETAILED DESCRIPTION

[0054] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0055] Example 1 Prescription 1

[0056] Preparation steps:

[0057] Step 1: Stir and dissolve polyethylene glycol 6000, aspartame, strawberry flavor and water to obtain a solution;

[0058] Step 2: Add hydroxypropyl methylcellulose (E5) to the aqueous solution prepared in step 1, stir until the hydroxypropyl methylcellulose (E5) is dissolved, then add pramipexole hydrochloride and stir for 20 minutes until uniformly dispersed to obtain a drug-containing gel;

[0059] Step 3: The drug-containing glue obtained in step 2 is evenly coated on a polyester tape with a spatula, dried, and cut to obtain a pramipexole hydrochloride orally disintegrating film.

[0060] Example 2

[0061] Prescription 2

[0062] Preparation steps:

[0063] Step 1: Stir and dissolve polyethylene glycol 6000, aspartame, strawberry flavor and water to obtain a solution;

[0064] 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 uniformly dispersed to obtain a drug-containing gel;

[0065] Step 3: The drug-containing glue obtained in step 2 is evenly coated on a polyester tape with a spatula, dried, and cut to obtain a pramipexole hydrochloride orally disintegrating film.

[0066] Example 3

[0067] Prescription 3

[0068] Preparation steps:

[0069] Step 1: Add polyethylene glycol 6000, aspartame, and strawberry flavor to an aqueous solution containing polyvinyl alcohol, stir to dissolve, and then add hydroxypropyl methylcellulose and stir until dissolved to obtain a solution;

[0070] Step 2: Add pramipexole hydrochloride to the solution obtained in step 1 and stir for 20 minutes until uniform to obtain a drug-containing gel;

[0071] Step 3: The drug-containing glue obtained in step 2 is evenly coated on a polyester tape with a spatula, dried, and cut to obtain a pramipexole hydrochloride orally disintegrating film.

[0072] Example 4

[0073] Prescription 4

[0074] Preparation steps:

[0075] Step 1: Add polyethylene glycol 6000, aspartame, and strawberry flavor to an aqueous solution containing polyvinyl alcohol, stir to dissolve, and then add hydroxypropyl methylcellulose and stir until dissolved to obtain a solution;

[0076] Step 2: Add pramipexole hydrochloride to the solution obtained in step 2 and stir for 20 minutes until uniform to obtain a drug-containing gel;

[0077] Step 3: Use a spatula to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain the pramipexole hydrochloride orally disintegrating film-forming agent.

[0078] Example 5

[0079] Prescription 5

[0080] Preparation steps:

[0081] Step 1: adding glycerol and sucralose to an aqueous solution containing polyvinyl alcohol, stirring and dissolving to obtain a solution;

[0082] 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;

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

[0084] Example 6

[0085] Prescription 6

[0086] Preparation steps:

[0087] Step 1: adding polyethylene glycol 6000 and steviol glycoside to an aqueous solution containing polyvinyl alcohol, stirring and dissolving to obtain a solution;

[0088] Step 2: adding pramipexole hydrochloride, microcrystalline cellulose and crospovidone to the solution obtained in step 2 and stirring for 20 minutes until uniform, to obtain a drug-containing gel;

[0089] Step 3: Use a spatula to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain the pramipexole hydrochloride orally disintegrating film-forming agent.

[0090] Example 7

[0091] Prescription 7

[0092] Preparation steps:

[0093] Step 1: adding glycerol and sucralose to an aqueous solution containing polyvinyl alcohol, stirring and dissolving to obtain a solution;

[0094] 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;

[0095] Step 3: Use a spatula to evenly apply the drug-containing glue obtained in step 2 onto a polyester tape, dry it, and cut it to obtain the pramipexole hydrochloride orally disintegrating film-forming agent.

[0096] Experimental Example 1

[0097] The samples prepared in Examples 1 to 7 of the present invention were tested for film thickness, disintegration time (test conditions: 900 ml, 37±1° C. in simulated saliva), moisture content, and mechanical strength.

[0098] Mechanical strength test method:

[0099] Use a texture analyzer (Model: Rapid TA + , Manufacturer: Shanghai Tengba Instrument Technology Co., Ltd.) The mechanical strength test of the pramipexole hydrochloride orally dissolving film preparations of Examples 1 to 7 was performed, and the maximum mechanical strength force and the maximum mechanical strength distance were recorded.

[0100] Folding endurance testing method:

[0101] Take the orally disintegrating film preparations of pramipexole hydrochloride of Examples 1 to 7, fold the orally disintegrating film 180° in the middle and unfold it, repeat the folding process 5 times, and observe whether the orally disintegrating film is broken.

[0102] The test results are shown in Table 1.

[0103] Table 1 Test results of film thickness, disintegration time, moisture content and mechanical strength of samples prepared in Examples 1 to 7

[0104] The above film mechanical strength results show that the pramipexole hydrochloride orally disintegrating films prepared in Examples 1 to 7 all have a certain degree of tensile strength and flexibility, which can withstand external pressure during cutting, packaging, and transportation. They also have a short disintegration time (within 35 seconds) and good appearance and taste.

[0105] Experimental Example 2

[0106] Ten portions of the samples prepared in Examples 1 to 7 of the present invention (about 90 mg / portion) were taken respectively, and the mixing uniformity of the samples was tested. The testing method was as follows:

[0107] Use octadecylsilane bonded silica gel as the filler (SHIMADZU Shim-pack GIST C18-AQ, 4.6 mm × 250 mm, 5 μm or equivalent performance column is recommended); use ammonium formate solution (18.9 g of ammonium formate is dissolved in 1000 ml of water and the pH is adjusted to 5.0 with formic acid)-methanol (75:25) as the mobile phase; the flow rate is 1.0 ml / min; the column temperature is 40°C; the detection wavelength is 264 nm; and the injection volume is 20 μl.

[0108] The test results are shown in Table 2.

[0109] Table 2 Content uniformity test results of samples prepared in Examples 1 to 7

[0110] The above content uniformity results show that the pramipexole hydrochloride orally disintegrating films prepared in Examples 1 to 7 have good mixing uniformity and good preparation uniformity.

[0111] Experimental Example 3

[0112] Samples prepared in Example 5 of the present invention were sealed in polyester / aluminum / cast polyethylene pharmaceutical composite film bags and placed under high temperature (50°C), high humidity (92.5% RH), strong light exposure, accelerated testing (40°C ± 2°C / 75% RH + 5% RH), and long-term testing (25°C ± 2°C / 60% RH ± 5% RH). The dissolution, content, and related substance content of the formulations were investigated.

[0113] (1) Dissolution test method:

[0114] Experimental apparatus: Dissolution and release rate determination method 2 (paddle method + sinker method) of Part IV of the 2020 edition of the Chinese Pharmacopoeia, 0931, with a rotation speed of 50 rpm

[0115] Dissolution medium: pH 1.0 hydrochloric acid solution, medium volume 500ml, medium temperature 37℃±0.5℃

[0116] Sampling time: 15 minutes

[0117] Detection method:

[0118] 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.

[0119] (2) Content detection method:

[0120] Use octadecylsilane bonded silica gel as the filler (SHIMADZU Shim-pack GIST C18-AQ, 4.6 mm × 250 mm, 5 μm or equivalent performance columns are recommended); use ammonium formate solution (18.9 g of ammonium formate is dissolved in 1000 ml of water and the pH is adjusted to 5.0 with formic acid)-methanol (75:25) as the mobile phase; the flow rate is 1.0 ml / min; the column temperature is 40°C; the detection wavelength is 264 nm; and the injection volume is 20 μl.

[0121] (3) Detection methods for related substances:

[0122] Chromatographic conditions: Octadecylsilane bonded silica gel was used as the filler (CAPCELL PAK MGIIC 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 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.

[0123] Table 3 Gradient elution program

[0124] The test results are shown in Table 4 below:

[0125] Table 4 Test results of influencing factors test, accelerated test and long-term test of Example 5

[0126] According to the above results, the solubility, content and related substances of the pramipexole hydrochloride orally dissolving 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.

[0127] The above examples illustrate the specific embodiments of the present invention. However, the scope of protection of the present invention is not limited to the above-mentioned exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection 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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