Oral dissolving film agent containing ropinirole hydrochloride and preparation method of oral dissolving film agent

Abstract

The invention relates to an oral dissolving film agent containing ropinirole hydrochloride and a preparation method of the oral dissolving film agent, and belongs to the technical field of pharmaceutical preparations. The ropinirole hydrochloride oral dissolving film agent comprises ropinirole hydrochloride, a composite film forming material and an ion exchange resin. The ropinirole hydrochloride oral soluble film agent can be quickly dissolved in an oral cavity, is good in taste and high in bioavailability, and overcomes the defects of short drug effect maintaining time, poor taking compliance and the like in the prior art; meanwhile, the invention further discloses a preparation process of the ropinirole hydrochloride oral membrane agent, and the preparation process is simple, easy to control and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically an orally disintegrating film containing ropinirole hydrochloride and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Parkinson's disease (PD), also known as shaking palsy, is the most common degenerative disease of the central nervous system in middle-aged and elderly people. PD has a slow onset and progresses gradually. One of the most common non-motor symptoms of PD is cognitive impairment, including mild cognitive impairment (MCI) and dementia. MCI has a high incidence and can appear in the early stages of PD. Epidemiological studies show that the prevalence of MCI is as high as 40%, reaching 30% in newly diagnosed PD patients. The annual progression rate of MCI to dementia is 6%–15%. When PD patients' cognitive impairment progresses to dementia, it severely impacts their social function and quality of life.

[0004] Ropinirone hydrochloride is a non-ergot dopamine receptor agonist. In vitro studies have shown high selectivity for dopamine receptors and intrinsic activity against dopamine D2 and D3 receptors. Its exact mechanism of action in treating Parkinson's disease is unclear, but it is believed to be related to the activation of postsynaptic D2 receptors in the caudate core of the brain. The chemical name of ropinirone hydrochloride is 4-[2-(di-n-propylamino)-ethyl]-1,3-dihydro-2H-indole-2-one hydrochloride (chemical structure shown below). This drug was developed by GlaxoSmithKline (GSK) in the United States for the treatment of symptoms and signs of primary Parkinson's disease.

[0005]

[0006] Currently, the only marketed ropinirole hydrochloride formulations are immediate-release tablets or extended-release tablets, all of which are oral tablets. Since the most prominent symptoms of Parkinson's disease are resting tremor, bradykinesia, and rigidity, patients in the middle and late stages often experience postural instability. They may also experience non-motor symptoms before and after the onset of the disease, as well as autonomic dysfunction and mental and cognitive impairments. Furthermore, most PD patients have varying degrees of swallowing problems and usually require long-term medication. All of these factors make tablet administration inconvenient for PD patients and their caregivers, and to some extent, affect patient adherence. Additionally, according to the review reports on marketed ropinirole hydrochloride tablets, ropinirole is rapidly absorbed orally, reaching peak absorption in about 1-2 hours. However, its bioavailability is relatively low, with an absolute bioavailability of only about 45%-55%, which affects the duration of ropinirole hydrochloride's efficacy. Therefore, it needs to be taken more frequently each day. In addition, ropinirole hydrochloride has a bitter taste. Although the drug is relatively water-soluble, with a solubility of about 133 mg / ml in water, the conventional oral solution form cannot mask the bitter taste of the drug, and the liquid preparation is not convenient to carry or take accurately.

[0007] Oral films, as a novel oral drug delivery system, can release drugs in a short time under the action of saliva in the mouth. They can be absorbed directly through the oral mucosa or swallowed and then absorbed through the gastrointestinal tract. They can quickly exert their effects and maintain a certain concentration. They have the advantages of tablets, such as accurate content and good stability, as well as liquid preparations, such as rapid absorption and good efficacy. At the same time, they have a novel appearance, small size, and are easy to transport and carry. They can be administered quickly and accurately anytime and anywhere without the need for water, and patients have good compliance.

[0008] Therefore, if ropinirole hydrochloride can be developed into an oral disintegrating film formulation suitable for Parkinson's patients in abnormal physical or mental states, it can effectively avoid problems such as inconvenience in medication administration or missed doses for Parkinson's patients.

[0009] For orally dissolving film formulations, the film-forming material is a key formulation component affecting drug dissolution behavior and the mechanical properties of the film. Commonly used orally dissolving film materials are composed of one or more water-soluble polymers with different properties, such as polyvinyl alcohol, hydroxypropyl methylcellulose, ethyl cellulose, hyaluronic acid, chitosan, and other synthetic or natural polymers. In the research and experiments of the inventors of this application, when using commonly used film-forming materials such as polyvinyl alcohol or hydroxypropyl methylcellulose, the resulting ropinirole hydrochloride orally dissolving film also showed good tensile strength and release properties, as well as high flexural strength. However, because ropinirole hydrochloride is highly water-soluble and has a bitter taste, the orally dissolving film prepared with conventional film-forming materials dissolves too quickly, instantly exceeding the drug's bitterness concentration threshold in the oral cavity, resulting in a poor taste. Furthermore, the rapid dissolution and entry of the drug into the gastrointestinal tract also prevents its full absorption.

[0010] It is evident that how to prepare orally disintegrating film formulations containing ropinirole hydrochloride with good patient compliance and high bioavailability remains an unsolved problem. Summary of the Invention

[0011] To overcome the shortcomings of existing technologies, this invention provides an orally disintegrating film containing ropinirole hydrochloride and its preparation method. This orally disintegrating film features high bioavailability, convenient administration, long-lasting efficacy, and a simple and easy preparation process suitable for industrial production. The technical solution of this invention is as follows:

[0012] As a first aspect of the present invention, the present invention provides an orally disintegrating film containing ropinirole hydrochloride, comprising ropinirole hydrochloride, a composite film-forming material, and an ion exchange resin, wherein the mass percentage of ropinirole hydrochloride in the orally disintegrating film is 7.5-15%, the mass percentage of the composite film-forming material in the orally disintegrating film is 49-66%, and the mass percentage of the ion exchange resin in the orally disintegrating film is 12-21%; wherein the composite film-forming material is a mixture of hydroxypropyl methylcellulose and alginate; the mass ratio of hydroxypropyl methylcellulose to alginate is 4-6:1.

[0013] In an embodiment of the present invention, the active ingredient of the oral dissolving film is ropinirole hydrochloride, and each portion of the oral dissolving film contains 1 to 8 mg of ropinirole hydrochloride, preferably 2 mg and 4 mg.

[0014] Commonly used film-forming materials include polyvinyl alcohol-polyethylene glycol copolymer, xanthan gum, sodium alginate, sodium carboxymethyl cellulose, povidone, gum arabic, methylcellulose, and highly substituted hydroxypropyl methylcellulose. The inventors discovered that using conventional film-forming materials to prepare Pironil hydrochloride orally dissolving films resulted in excessively rapid dissolution. Adding other polymers to the film-forming materials, such as commonly used sodium carboxymethyl cellulose, xanthan gum, dextrin, and amylopectin, did not effectively slow down the dissolution rate of the drug in the orally dissolving film. During their research, the inventors inadvertently discovered that when using hydroxypropyl methylcellulose as the base film-forming material and adding an appropriate amount of alginate, the drug dissolution rate from the orally dissolving film decreased significantly, greatly reducing the bitterness of the drug in the orally dissolving film. The best effect was achieved when hydroxypropyl methylcellulose and alginate were mixed at a mass ratio of 4–5.5:1. This may be related to the fact that the addition of alginate reduces the drug exposure concentration in the oral cavity and, through its encapsulation effect, reduces contact with taste buds in the mouth.

[0015] However, although adding alginate to hydroxypropyl methylcellulose membranes significantly improves drug dissolution rate and taste, it still cannot effectively improve drug bioavailability. This results in a short duration of efficacy for the developed orally disintegrating membrane, requiring multiple daily doses. Through further exploration, the inventors unexpectedly discovered that when a certain amount of styrene-based strong acid cation exchange resin was added to ropinirole hydrochloride solution, the bitter taste of the orally disintegrating membrane almost completely disappeared. More importantly, the bioavailability of the orally disintegrating membrane containing styrene-based strong acid cation exchange resin was significantly improved, and because the amount of ion exchange resin added was small, it did not affect the drug loading rate or mechanical properties such as tensile strength of the orally disintegrating membrane.

[0016] Furthermore, the ropinirole hydrochloride oral dissolving film of the present invention contains a styrene strong acid cation exchange resin with a particle size of less than 15 μm, and the mass percentage of the ion exchange resin to ropinirole hydrochloride is 1.4 to 1.6:1, preferably 1.5:1.

[0017] Preferably, the ion exchange resin is DOWEX. TM HCR-S / S ion exchange resin.

[0018] To increase the elongation of the film, improve its mechanical properties, and facilitate its packaging and cutting, an appropriate amount of plasticizer needs to be added. In the embodiments of the present invention, the orally soluble film also contains a plasticizer selected from polyethylene glycol 400 or triethyl citrate or a combination thereof, and the mass ratio of the composite film-forming material to the plasticizer is 4.0 to 5.5:1, preferably 5:1.

[0019] In embodiments of the present invention, sweeteners, flavorings, and opacifiers may be selectively added; the sweetener is one or a combination of sucralose, aspartame, steviol glycosides, and high fructose syrup, preferably sucralose, and the sweetener accounts for 0.1-1% by mass in the oral dissolving film; the flavoring is one or a combination of standard fruit flavorings such as peach flavoring and orange flavoring, and the flavoring accounts for 0.1-2% by mass in the oral dissolving film; the opacifier is titanium dioxide, and the opacifier accounts for 0.5-2% by mass in the oral dissolving film.

[0020] As a second aspect of the present invention, a method for preparing the aforementioned ropinirole hydrochloride oral dissolving film agent is provided, comprising:

[0021] Ion exchange resin was added to an aqueous solution of ropinirole hydrochloride and stirred continuously to prepare a drug-loaded resin. After the composite film-forming material was dissolved, the drug-loaded resin and plasticizer were added and stirred to form a drug-containing adhesive. After standing and degassing, the adhesive was coated, dried and cut using a coating machine to obtain the final product.

[0022] Furthermore, the preparation method includes the following steps:

[0023] (1) Preparation of drug-loaded resin: At room temperature, ion exchange resin was added to an aqueous solution of ropinirole hydrochloride with a concentration of 20-30 mg / ml and stirred continuously for 3-5 h;

[0024] (2) Preparation of drug-containing adhesive solution: Weigh the hydroxypropyl methylcellulose and seaweed gum composite film-forming material, add purified water and stir to dissolve for 2-3 hours; after stirring evenly, add the drug resin, plasticizer, sweetener, fragrance and opacifier, and continue stirring for more than 1 hour; finally, after vacuum degassing, let stand for later use.

[0025] (3) Coating, drying and cutting: The medicated adhesive liquid is coated onto the dimethyl silicone oil polyester film for plastering using a coating machine, dried at 70-80℃ and rolled up, and then cut into the required size using a cutting device.

[0026] As a third aspect of the invention, it is to provide the use of the ropinirole-containing oral disintegrating film in the preparation of a medicament for treating Parkinson's disease.

[0027] Compared with the prior art, the beneficial effects of the present invention are:

[0028] 1. This invention successfully developed an orally disintegrating film formulation of ropinirole hydrochloride, which is suitable for Parkinson's disease patients with autonomic dysfunction, mental and cognitive impairment, and varying degrees of dysphagia. It can effectively avoid problems such as inconvenience in administration or missed doses during the onset of Parkinson's disease, and improve patient medication adherence.

[0029] 2. Ropinirole hydrochloride is highly water-soluble and has a bitter taste. Oral dissolving films typically dissolve rapidly in the mouth, making it easy for the bitterness threshold to be exceeded, thus affecting the taste of the oral dissolving film. This invention, through screening film materials, developed a composite film-forming material with a specific ratio. While maintaining the normal mechanical characteristics of the film material, it improves the encapsulation of the drug, significantly reducing the bitter taste present in oral dissolving films.

[0030] 3. Conventional ropinirole hydrochloride oral tablets have low bioavailability and short duration of action, thus typically requiring a three-times-daily dosing frequency, further reducing adherence in Parkinson's disease patients. This invention, while maintaining normal dissolution time and mechanical properties of the orally disintegrating membrane, incorporates fine-particle styrene-based strong acid cation exchange resin. This not only further improves the drug's taste but also significantly enhances the duration of plasma concentration and bioavailability of ropinirole hydrochloride. This allows for a significant reduction in daily dosing frequency while maintaining the original dosage and therapeutic effect, and also improves patient safety. Attached Figure Description

[0031] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0032] Figure 1 This is a blood concentration-time curve of different ropinirole hydrochloride orally dissolving membranes in Experiment Example 3. Detailed Implementation

[0033] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. The reagents and raw materials used in this invention are readily available through conventional means, and unless otherwise specified, they are used in accordance with conventional methods in the art or as per the product instructions. Furthermore, any methods or materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0035] To better illustrate this invention, several examples from the research process are selected as demonstrations, as follows:

[0036] Example 1

[0037] Weigh 10.0g of ropinirole hydrochloride into a vacuum emulsification and degassing tank, add 400ml of purified water and stir until completely dissolved, then add 15.0g of DOWEX. TM HCR-S / S ion exchange resin was stirred continuously at room temperature for 4 hours to obtain a drug-loaded resin solution. 48.0 g of hydroxypropyl methylcellulose K4M and 12.0 g of alginate were mixed evenly and then slowly and evenly added to the drug-loaded resin solution. The mixture was stirred at 500 rpm for approximately 2.5 hours. Separately, 12.0 g of polyethylene glycol 400, 0.5 g of sucralose, 1.0 g of peach flavoring, and 1.5 g of titanium dioxide were dissolved and dispersed in 100 ml of purified water and then added to the drug-containing resin solution. Stirring was continued for at least 60 minutes. After thorough mixing and dehydration, stirring was stopped, and air bubbles were removed from the resin solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0038] Example 2

[0039] Weigh 7.5g of ropinirole hydrochloride and place it in a vacuum emulsification and degassing tank. Add 300ml of purified water and stir until completely dissolved. Then add 12.0g of DOWEX. TM HCR-S / S ion exchange resin was stirred continuously at room temperature for 4 hours to obtain a drug-loaded resin solution. 55.0 g of hydroxypropyl methylcellulose K4M and 11.0 g of alginate were mixed evenly and then slowly and evenly added to the drug-loaded resin solution. The mixture was stirred at 500 rpm for approximately 2 hours. Separately, 12.0 g of triethyl citrate, 0.4 g of aspartame, 0.1 g of peach flavoring, and 2.0 g of titanium dioxide were dissolved and dispersed in 100 ml of purified water and added to the drug-containing resin solution. Stirring was continued for at least 60 minutes. After thorough mixing and dehydration, stirring was stopped, and air bubbles were removed from the resin solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 1mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0040] Example 3

[0041] Weigh 15.0g of ropinirole hydrochloride into a vacuum emulsification and degassing tank, add 500ml of purified water and stir until completely dissolved, then add 21.0g of DOWEX. TM HCR-S / S ion exchange resin was stirred continuously at room temperature for 4 hours to obtain a drug-loaded resin solution. 42.0 g of hydroxypropyl methylcellulose K4M and 7.0 g of alginate were mixed evenly and then slowly and evenly added to the drug-loaded resin solution. The mixture was stirred at 500 rpm for approximately 3 hours. Separately, 12.25 g of polyethylene glycol 400, 1.0 g of high fructose syrup, 0.8 g of orange flavoring, and 1.0 g of titanium dioxide were dissolved and dispersed evenly in 100 ml of purified water and then added to the drug-containing resin solution. Stirring was continued for at least 60 minutes. After thorough mixing and dehydration, stirring was stopped, and air bubbles were removed from the resin solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 8mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0042] Example 4

[0043] Weigh 8.0g of ropinirole hydrochloride and place it in a vacuum emulsification and degassing tank. Add 400ml of purified water and stir until completely dissolved. Then add 12.0g of DOWEX. TMHCR-S / S ion exchange resin was stirred continuously at room temperature for 4 hours to obtain a drug-loaded resin solution. 54.0 g of hydroxypropyl methylcellulose K4M and 12.0 g of alginate were mixed evenly and then slowly and evenly added to the drug-loaded resin solution. The mixture was stirred at 500 rpm for approximately 3 hours. Separately, 12.9 g of triethyl citrate, 0.1 g of steviol glycoside, 0.5 g of strawberry flavoring, and 0.5 g of titanium dioxide were dissolved and dispersed in 100 ml of purified water and added to the drug-containing resin solution. Stirring was continued for at least 60 minutes. After thorough mixing and dehydration, stirring was stopped, and air bubbles were removed from the solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 2mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0044] Comparative Example 1: Formulation of a conventional oral dissolving film

[0045] Weigh 15.0g of ropinirole hydrochloride and place it in a vacuum emulsification degassing vessel. Add 500ml of purified water and stir until completely dissolved to obtain a drug solution. Slowly and evenly add 65.0g of hydroxypropyl methylcellulose K4M to the above drug-containing solution and stir at 500rpm for about 3 hours. Separately, dissolve and disperse 16.0g of triethyl citrate, 1.5g of aspartame, 0.5g of strawberry flavoring, and 2.0g of titanium dioxide in 100ml of purified water, then add this to the above drug-containing gel and continue stirring for at least 60 minutes. After degassing and stirring until homogeneous, stop stirring and remove air bubbles from the gel under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0046] Comparative Example 2: Formulation of a conventional oral dissolving film

[0047] Weigh 11.0g of ropinirole hydrochloride and place it in a vacuum emulsification and degassing vessel. Add 500ml of purified water and stir until completely dissolved to obtain a drug solution. Slowly and evenly add 70.0g of polyvinyl alcohol to the above drug-containing solution and stir at 500rpm for about 3 hours. Separately, dissolve and disperse 16.0g of polyethylene glycol 400, 1.5g of aspartame, 0.5g of peach flavoring, and 1.0g of titanium dioxide in 100ml of purified water, then add this to the above drug-containing gel solution and continue stirring for at least 60 minutes. After dehydration and thorough stirring, stop stirring and remove air bubbles from the gel solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0048] Comparative Example 3: Preparation of composite membrane material using hydroxypropyl methylcellulose and sodium carboxymethyl cellulose

[0049] Weigh 9.0g of ropinirole hydrochloride and place it in a vacuum emulsification degassing vessel. Add 400ml of purified water and stir until completely dissolved to obtain a drug solution. Mix 65.0g of hydroxypropyl methylcellulose K4M and 12.0g of sodium carboxymethyl cellulose evenly, and slowly and evenly add them to the above drug-containing solution. Stir at 500rpm for about 3 hours. Separately, dissolve and disperse 12.9g of triethyl citrate, 0.1g of sucralose, 0.5g of peach flavoring, and 0.5g of titanium dioxide in 100ml of purified water, and add them to the above drug-containing gel solution. Continue stirring for at least 60 minutes. After dehydration and even mixing, stop stirring and remove air bubbles from the gel solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0050] Comparative Example 4: Preparation of composite membrane material using polyvinyl alcohol and xanthan gum

[0051] Weigh 9.0g of ropinirole hydrochloride and place it in a vacuum emulsification degassing vessel. Add 400ml of purified water and stir until completely dissolved to obtain a drug solution. Mix 59.9g of polyvinyl alcohol and 15.0g of xanthan gum evenly, and slowly and evenly add the mixture to the above drug-containing solution. Stir at 500rpm for about 3 hours. Separately, dissolve and disperse 15.0g of triethyl citrate, 0.1g of sucralose, 0.5g of peach flavoring, and 0.5g of titanium dioxide in 100ml of purified water, and add this mixture to the above drug-containing gel solution. Continue stirring for at least 60 minutes. After dehydration and thorough stirring, stop stirring and remove air bubbles from the gel solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0052] Comparative Example 5

[0053] Weigh 14.0g of ropinirole hydrochloride and place it in a vacuum emulsification degassing vessel. Add 400ml of purified water and stir until completely dissolved to obtain a drug solution. Mix 60.0g of hydroxypropyl methylcellulose K4M and 6.0g of alginate thoroughly, and slowly and evenly add them to the above drug-containing solution. Stir at 500rpm for about 3 hours. Separately, dissolve and disperse 16.5g of triethyl citrate, 1.0g of sucralose, 0.5g of peach flavoring, and 2.0g of titanium dioxide in 100ml of purified water, and add this to the above drug-containing gel solution. Continue stirring for at least 60 minutes. After dehydration and thorough mixing, stop stirring and remove air bubbles from the gel solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0054] Comparative Example 6

[0055] Weigh 14.0g of ropinirole hydrochloride and place it in a vacuum emulsification degassing vessel. Add 400ml of purified water and stir until completely dissolved to obtain a drug solution. Mix 52.0g of hydroxypropyl methylcellulose K4M and 20.0g of alginate thoroughly, and slowly and evenly add the mixture to the above drug-containing solution. Stir at 500rpm for about 3 hours. Separately, dissolve and disperse 10.5g of triethyl citrate, 1.0g of aspartame, 0.5g of peach flavoring, and 2.0g of titanium dioxide in 100ml of purified water, and add this mixture to the above drug-containing gel solution. Continue stirring for at least 60 minutes. After dehydration and thorough mixing, stop stirring and remove air bubbles from the gel solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0056] Comparative Example 7

[0057] Weigh 14.0g of ropinirole hydrochloride and place it in a vacuum emulsification degassing vessel. Add 500ml of purified water and stir until completely dissolved to obtain a drug solution. Mix 53.0g of hydroxypropyl methylcellulose K4M and 12.0g of alginate thoroughly, and slowly and evenly add them to the above drug-containing solution. Stir at 500rpm for about 3 hours. Separately, dissolve and disperse 16.0g of polyethylene glycol 400, 1.5g of sucralose, 1.5g of peach flavoring, and 2.0g of titanium dioxide in 100ml of purified water, and add this to the above drug-containing gel solution. Continue stirring for at least 60 minutes. After dehydration and thorough stirring, stop stirring and remove air bubbles from the gel solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0058] Comparative Example 8

[0059] Weigh 12.0g of ropinirole hydrochloride into a vacuum emulsification and degassing tank, add 500ml of purified water and stir until completely dissolved, then add 3.0g of DOWEX. TMHCR-S / S ion exchange resin was stirred continuously at room temperature for 4 hours to obtain a drug-loaded resin solution. 53.0 g of hydroxypropyl methylcellulose K4M and 11.0 g of alginate were mixed evenly and then slowly and evenly added to the drug-loaded resin solution. The mixture was stirred at 500 rpm for approximately 3 hours. Separately, 16.0 g of polyethylene glycol 400, 1.5 g of sucralose, 1.5 g of peach flavoring, and 2.0 g of titanium dioxide were dissolved and dispersed evenly in 100 ml of purified water and then added to the drug-containing resin solution. Stirring was continued for at least 60 minutes. After thorough mixing and dehydration, stirring was stopped, and air bubbles were removed from the resin solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0060] Comparative Example 9

[0061] Weigh 10.0g of ropinirole hydrochloride into a vacuum emulsification and degassing tank, add 500ml of purified water and stir until completely dissolved, then add 15.0g of DOWEX. TM HCR-S / S ion exchange resin was stirred continuously at room temperature for 4 hours to obtain a drug-loaded resin solution. 54.0 g of polyvinyl alcohol was slowly and evenly added to the drug-loaded resin solution, and the mixture was stirred at 500 rpm for approximately 3 hours. Separately, 16.0 g of polyethylene glycol 400, 1.5 g of sucralose, 1.5 g of peach flavoring, and 2.0 g of titanium dioxide were dissolved and dispersed in 100 ml of purified water, and then added to the drug-containing adhesive solution. Stirring was continued for at least 60 minutes. After dehydration and thorough stirring, stirring was stopped, and air bubbles were removed from the adhesive solution under vacuum. A coating machine was turned on, and the coating drying temperature was set to 70–80°C. After the temperature reached the set value for 15 minutes, the drug-containing adhesive solution was coated onto a dimethyl silicone oil-coated polyester film for plaster application, maintaining a coating speed of 0.5 m / min. After drying, the film was rolled up, and finally cut into films with an effective dose of 4 mg per piece and packaged to obtain ropinirole hydrochloride orally dissolving film.

[0062] Comparative Example 10

[0063] Weigh 10.0g of ropinirole hydrochloride and place it in a vacuum emulsification degassing vessel. Add 400ml of purified water and stir until completely dissolved. Then add 15.0g of polacolin potassium resin and stir continuously at room temperature for 4 hours to obtain a drug-loaded resin solution. Mix 48.0g of hydroxypropyl methylcellulose K4M and 12.0g of alginate evenly and slowly add it to the above drug-loaded resin solution. Stir at 500rpm for about 2.5 hours. Separately, dissolve and disperse 12.0g of polyethylene glycol 400, 0.5g of sucralose, 1.0g of peach flavoring, and 1.5g of titanium dioxide in 100ml of purified water and add it to the above drug-containing gel solution. Continue stirring for at least 60 minutes. After dehydration and stirring until homogeneous, stop stirring and remove air bubbles from the gel solution under vacuum. Turn on the coating machine and set the coating drying temperature to 70-80℃. After the temperature reaches the set value for 15 minutes, apply the medicated adhesive liquid to the dimethyl silicone oil-coated polyester film for plasters. Maintain the coating speed at 0.5m / min. After drying, roll it up and finally cut each film with an effective dose of 4mg and package it to obtain ropinirole hydrochloride oral dissolution film.

[0064] Taste evaluation of Experiment Example 1

[0065] To evaluate the taste of ropinirole hydrochloride orally dissolving films with different formulations in the oral cavity, a protocol was designed and a taste experience test was conducted on volunteers. The masking effect of different formulations was appropriately evaluated, as detailed below:

[0066] Experimental protocol: Ten male and female volunteers aged 20-40 years were selected and randomly assigned to the example and comparative examples for taste testing. Taste scores were given based on the quality of the taste.

[0067] Scoring criteria: 85-100 samples have no bitterness or almost no bitterness.

[0068] 70-85 points: Slightly bitter, still acceptable.

[0069] It's bitter to the point of being 55-70, but not intense.

[0070] <55 points: Strong bitterness, unacceptable.

[0071] The specific taste test results are as follows:

[0072]

[0073] The results show that, under conventional film-forming material conditions, the taste of ropinirole hydrochloride oral dissolving film after melting is poor, while the taste of oral dissolving film is slightly improved after adding different proportions of composite film-forming materials; at the same time, the taste of oral dissolving film prepared by adding a certain amount of ion exchange resin during the preparation process is also more obvious.

[0074] Each embodiment uses a suitable ratio of strong acid cation exchange resin and composite film-forming agent to prepare an oral dissolving film that has almost no bitter taste after dissolving in the oral cavity and has a significant taste-masking effect.

[0075] Although the taste-masking score of the oral film prepared by Comparative Example 10 using weak acid anion exchange resin and composite film-forming agent was slightly lower, the taste-masking effect was still relatively good.

[0076] Experimental Example 2: Determination of Mechanical Properties and Melting Time

[0077] For the tensile strength test, take an appropriate amount of uncut ropiniril hydrochloride orthosol film prepared in each example and comparative example, cut it to a size of 10cm × 2cm, and then test its tensile properties on a tensile strength tester. Place the film in the upper and lower clamps of the tensile strength tester, so that the center of the sample is connected to the center of the upper and lower clamps, the clamps are appropriately tight, the distance between the two clamps is 60mm, start the tester at a speed of 100mm / min, and read the tensile strength after the sample breaks.

[0078] For the dissolution time test, take the dissolution film samples from each test port, clamp them with two layers of stainless steel wire with an inner diameter of 1.5 mm, and observe the time it takes for the dissolution film to completely dissolve, referring to the disintegration time test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0921).

[0079] For the bending test, each test film was placed in a packaging bag. The packaging bag containing the film was folded together and placed on a flat plate. A 500g weight was added and held for 3 seconds. The operation was repeated 5 times. Six tablets were tested for each sample. The oral dissolving film was observed to see if there was any breakage or indentation at the bend.

[0080] The tensile strength, melting time, and bending test results for each embodiment and comparative example are as follows:

[0081] Test sample Tensile strength (N) Melting time (s) Bending test Example 1 15 48 No fractures were observed, and the indentations were not obvious. Example 2 17 45 No fractures were observed, and the indentations were not obvious. Example 3 14 51 No fractures were observed, and the indentations were not obvious. Example 4 16 47 No fractures were observed, and the indentations were not obvious. Comparative Example 1 6 14 Completely broken Comparative Example 2 8 16 Completely broken Comparative Example 3 11 43 One piece broke, and the indentation on the unbroken piece showed a distinct white line. Comparative Example 4 12 39 No breakage, but a distinct white line appears at the indentation site. Comparative Example 5 12 47 Four pieces were broken, and the unbroken pieces showed obvious indentations. Comparative Example 6 11 43 No fractures were observed, and the indentations were not obvious. Comparative Example 7 16 49 No fractures were observed, and the indentations were not obvious. Comparative Example 8 14 35 No fractures were observed, and the indentations were not obvious. Comparative Example 9 8 13 Completely broken Comparative Example 10 15 38 No fractures were observed, and the indentations were not obvious.

[0082] Typically, the tensile strength of orally dissolving films needs to be above 10N, and they should also possess good flexural strength to ensure smooth cutting and packaging during film production and good flexural strength during use. Experimental results show that Comparative Examples 1, 2, and 9 have tensile strengths below 10N, indicating relatively poor tensile strength in orally dissolving films prepared using only hydroxypropyl methylcellulose or polyvinyl alcohol, and the resulting films are easily broken and brittle. In contrast, Comparative Examples 3 and 4 show varying degrees of increase in tensile strength and flexural strength after adding a certain proportion of other film-forming materials or thickeners to hydroxypropyl methylcellulose or polyvinyl alcohol. From the other examples and comparative examples, adding an appropriate proportion of alginate to hydroxypropyl methylcellulose yields the best results in terms of tensile strength and flexural strength. Furthermore, under conditions that increase the mechanical strength of the orally dissolving film, the films prepared in all examples can melt rapidly within 1 minute, demonstrating good melting performance.

[0083] Experimental Example 3: Pharmacokinetics in Beagle Dogs

[0084] Thirty healthy adult beagles (weighing 9–11 kg) were fasted for 12 hours before the experiment and randomly divided into 5 groups, half male and half female. Blood was collected from the hind limb veins, and the dosage of ropinirole hydrochloride was 4 mg. Ropinirole hydrochloride oral films prepared in Example 1 and Comparative Examples 1, 7, 8, and 10 were placed on the tongue and held in the mouth for about 1 minute after administration. 2 ml of blood was collected at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 3.0, 4.0, 6.0, 10, 12, 16, 20, 24, and 36 hours and placed into 5 ml heparin sodium blood collection tubes. Whole blood was centrifuged at 5000 rpm for 10 minutes. 100 μl of the supernatant was transferred to a 7 ml centrifuge tube, 50 μl of internal standard solution was added, followed by 5 ml of extraction buffer (acetonitrile). The mixture was vortexed for 10 minutes, then centrifuged at 10000 rpm for 10 minutes. The supernatant was transferred, and 1 ml of extraction buffer was added. The mixture was vortexed for 3 minutes, then centrifuged at 10000 rpm for 10 minutes. The two extracts were combined and dried in a vacuum oven at 35°C to evaporate the solvent. 250 μl of mobile phase was added to the evaporated residue for resuspending, and the mixture was vortexed for 3 minutes. The solution was filtered through a 0.22 μm filter membrane into a 200 μl inner-lined tube for analysis.

[0085] Chromatographic conditions: Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS) was used for determination. The column was Waters ACQUITYUPLC BEH Amide Cl8 (50 mm × 2.1 mm, 1.7 μm); the mobile phase was 0.1% formic acid-acetonitrile (85:15); the column temperature was 40℃; the flow rate was 0.3 ml / min; the injection volume was 5 μL; electrospray ionization (ESI) was used with positive ion scanning in multiple reaction monitoring (MRM) mode. The ion pairs used for quantitative analysis were m / z 261.2 → m / z 114.1 (ropinirole) and m / z 267.2 → m / z 145.0 (atenolol, internal standard).

[0086] Experimental Results: Pharmacokinetic parameters for each group were calculated using DAS 3.0 software and the statistical moment method of non-compartmental models. The results are shown in the table below:

[0087]

[0088] The plasma concentration-time curve of ropinirole hydrochloride is as follows: Figure 1 As shown, the ropinirole hydrochloride orally disintegrating film of the present invention has a significantly longer time to peak concentration in beagle dogs compared to orally disintegrating film preparations prepared by conventional formulations, suggesting that the drug release in vivo is relatively slow. This may be due to a certain drug exchange process in vivo involving the drug-loaded resin.

[0089] Compared with conventional oral disintegrating film formulations, the maximum blood drug concentration (C) in Example 1 was [missing information]. max While the AUC decreased slightly, the in vivo drug retention time of this film-coated formulation significantly increased, maintaining a relatively long duration and exhibiting a degree of sustained-release properties, which also significantly improved drug bioavailability. (From AUC) 0-36 and AUC 0-∞ As can be seen, although the area under the drug-time curve of the orally disintegrating membrane prepared in Comparative Example 10 was significantly increased compared with the other comparative examples, it was still far lower than that of the orally disintegrating membrane prepared in Example 1. This may be because the potassium polacrine used in Comparative Example 10 is a weak acid cation exchange resin, while the resin in Example 1 is a strong acid cation exchange resin. Ropinirole has a stronger binding force with the strong acid cation exchange resin, which makes the exchange and release of the drug in vivo slower and more prolonged, and effectively improves the bioavailability of the drug.

[0090] Based on the disclosure of this invention, those skilled in the art can apply this invention to the fullest extent. Therefore, the above preferred embodiments are merely illustrative and are not intended to limit the scope of this invention in any way.

Claims

1. A salted ropinirole-containing orally dissolving film formulation, characterized in that, The oral dissolving film comprises ropinirole hydrochloride, a composite film-forming material, and an ion exchange resin. The mass percentage of the ropinirole hydrochloride in the oral dissolving film is 7.5-15%. The mass percentage of the composite film-forming material in the oral dissolving film is 49-66%. The mass percentage of the ion exchange resin in the oral dissolving film is 12-21%. The composite film-forming material is a mixture of hypromellose and algin, and the mass ratio of the hypromellose to the algin is 4-6:

1.

2. The oral film containing ropinirole hydrochloride according to claim 1, characterized in that, Each portion of the oral dissolving film contains 1-8 mg of ropinirole hydrochloride.

3. The oral film containing ropinirole hydrochloride according to claim 1, characterized in that, The mass ratio of the hypromellose to the algin is 4-5.5:

1.

4. The oral film containing ropinirole hydrochloride according to claim 1, characterized in that, The ion exchange resin is a strong acid cation exchange resin of styrene, and the mass percentage of the ion exchange resin to the ropinirole hydrochloride is 1.4-1.6:

1.

5. The oral film containing ropinirole hydrochloride according to claim 1, wherein, The ion exchange resin is DOWEX TM HCR-S / S ion exchange resin.

6. The oral film containing ropinirole hydrochloride according to claim 1, wherein, The oral dissolving film further comprises a plasticizer selected from one or a combination of polyethylene glycol 400 or triethyl citrate, and the mass ratio of the composite film-forming material to the plasticizer is 4-5.5:

1.

7. The oral film containing ropinirole hydrochloride according to claim 1, wherein, The oral dissolving film further comprises a sweetener, a flavoring agent, and an opacifying agent; the sweetener is one or a combination of sucralose, aspartame, stevioside, and high fructose syrup, and the mass percentage of the sweetener in the oral dissolving film is 0.1-1%; the flavoring agent is one or a combination of peach flavoring agent and orange flavoring agent, and the mass percentage of the flavoring agent in the oral dissolving film is 0.1-2%; and the opacifying agent is titanium dioxide, and the mass percentage of the opacifying agent in the oral dissolving film is 0.5-2%.

8. A process for the preparation of a film containing ropinirole hydrochloride according to any one of claims 1 to 7, comprising: The ion exchange resin is added to an aqueous solution of the ropinirole hydrochloride, and stirring is continuously performed to prepare a drug-loaded resin; after the composite film-forming material is dissolved, the drug-loaded resin and a plasticizer are added and stirred to form a drug-containing glue solution; after standing and degassing, a coating machine is used for coating, drying, and cutting to obtain the oral dissolving film.

9. A preparation method of the oral dissolving film containing ropinirole hydrochloride according to claim 8, comprising the following steps: (1) preparation of a drug-loaded resin: under room temperature conditions, the ion exchange resin is added to an aqueous solution of the ropinirole hydrochloride with a concentration of 20-30 mg / ml, and stirring is continuously performed for 3-5 h; (2) preparation of a drug-containing glue solution: the composite film-forming material of hypromellose and algin is weighed, purified water is added and stirred to dissolve for 2-3 h; after uniform stirring, the drug-loaded resin, a plasticizer, and a sweetener, a flavoring agent, and an opacifying agent are loaded, and stirring is continuously performed for more than 1 h; finally, vacuum degassing is performed, and standing is performed for standby; (3) coating, drying, and cutting: a coating machine is used to coat the drug-containing glue solution on a dimethyl silicone oil-polyester film for a plaster, drying and drying are performed at 70-80°C, and then cutting equipment is used to cut into the required size to obtain the oral dissolving film.

10. Use of the oral dissolving film containing ropinirole hydrochloride according to any one of claims 1-7 in the preparation of a drug for treating Parkinson's disease.

Images