Olpine sustained-release pellets

Abstract

The application provides opicapone sustained-release pellets, and relates to the technical field of drug release. The opicapone sustained-release pellets comprise, from inside to outside, a drug-containing sustained-release core layer, an isolation sustained-release layer and an enteric layer in sequence. The raw materials of the drug-containing sustained-release core layer at least comprise opicapone, a sustained-release material, a filler, a binder and a pH regulator, and the sustained-release material is selected from a combination of Eudragit L, Eudragit S and a cationic polymer. Preferably, the raw materials of the isolation sustained-release layer at least comprise a combination of Eudragit L and Eudragit S. The opicapone sustained-release pellets have good stability in a gastric acid environment, can realize smooth and long-acting slow release in an intestinal environment, and improve the safety and bioavailability of the drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug release and relates to opicapone sustained-release micropellets. Background Art

[0002] Opicapone is a third-generation catechol-O-methyltransferase (COMT) inhibitor with potent and long-lasting COMT inhibitory activity. By reducing levodopa metabolism, it allows more levodopa to enter the brain, thereby enhancing its efficacy and helping to improve motor symptom control in Parkinson's disease (PD) patients. Currently, opicapone formulations approved for marketing worldwide include tablets and capsules, clinically indicated for adjunctive therapy with levodopa / carbidopa, and are suitable for improving end-of-dose symptom fluctuations in PD patients.

[0003] Existing opicapone tablets and capsules suffer from low solubility, resulting in insufficient bioavailability and impaired efficacy. Prior art CN115335036A micronizes the opicapone API to obtain opicapone crystals with a specific primary particle size distribution, thereby improving opicapone's dissolution properties and achieving superior bioavailability compared to non-micronized opicapone. Prior art CN115105483A provides opicapone capsules and a preparation method thereof. By repeatedly granulating and sieving the opicapone API, the content of heavy opicapone particles with a mesh size of 20 to 60 is controlled to facilitate dissolution of opicapone in the body. Excipients are mixed at a constant rate to ensure high opicapone dissolution. Summary of the Invention

[0004] During their research, the inventors discovered that opicapone is unstable under acidic conditions and easily converts into impurity compounds, which can affect the drug's safety and efficacy. The aforementioned prior art only considers opicapone's dissolution properties, but fails to address issues such as its instability under gastric acid conditions and low bioavailability. Through extensive experimental research and analysis, the present inventors have discovered a method for improving opicapone's stability under gastric acid conditions (pH 1-2) and its high solubility in a neutral intestinal environment, while also achieving good sustained-release properties. Based on this, the present invention provides opicapone sustained-release micropellets.

[0005] The technical solutions of the present invention are as follows:

[0006] An opicapone sustained-release micropellet, comprising, from the inside to the outside, a drug-containing sustained-release core layer, an isolation sustained-release layer, and an enteric-coated layer;

[0007] The raw materials of the drug-containing sustained-release core layer at least include opicapone, sustained-release material, filler, adhesive and pH regulator, and the sustained-release material is selected from the combination of Eudragit L, Eudragit S and cationic polymer.

[0008] Preferably, the opicapone has a weight of 25-70 mg.

[0009] Preferably, the weight ratio of the Eudragit L to the Eudragit S is (2-3.5):1.

[0010] Preferably, the Eudragit L is selected from Eudragit L100, the Eudragit S is selected from Eudragit S100, and the cationic polymer is selected from chitosan.

[0011] Preferably, the weight ratio of the Eudragit L to the Eudragit S is (2-3.5):1.

[0012] Preferably, the weight ratio of the Eudragit L to the cationic polymer is (2-1):1.

[0013] Preferably, the filler is selected from one or a combination of two or more of soluble starch, lactose, mannitol, and microcrystalline cellulose.

[0014] More preferably, the filler has a weight ratio of (35-68)% in the drug-containing sustained-release core layer.

[0015] Preferably, the binder is selected from one or a combination of two or more of hypromellose, sodium hypromellose, ethyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone.

[0016] More preferably, the binder has a weight ratio of (1-10)% in the drug-containing sustained-release core layer.

[0017] Preferably, the pH adjuster is at least one of alkali metal hydroxide, alkaline earth metal hydroxide, carbonate, and bicarbonate, and the pH adjuster has a weight ratio of (5-20)% in the drug-containing sustained-release core layer.

[0018] Preferably, the raw material of the separation sustained-release layer at least comprises a combination of Eudragit L and Eudragit S.

[0019] More preferably, the weight ratio of the Eudragit L to the Eudragit S is (4-1):1.

[0020] More preferably, the Eudragit L is selected from Eudragit L100, and the Eudragit S is selected from Eudragit S100.

[0021] More preferably, the combination of the Eudragit L and Eudragit S has a weight ratio of not less than 60% in the separation sustained-release layer.

[0022] Preferably, the raw material of the enteric layer contains at least Eudragit FS30D.

[0023] More preferably, the weight proportion of the Eudragit FS30D in the enteric layer is not less than 80%.

[0024] Preferably, the weight ratio of the drug-containing sustained-release core layer, the isolation sustained-release layer and the enteric layer is (4-8):(1-2):1.

[0025] Preferably, the opicapone sustained-release micropellets further comprise an excipient layer, and the excipient layer covers the enteric layer.

[0026] More preferably, the raw materials of the auxiliary material layer include at least one of magnesium stearate, talc and microcrystalline cellulose.

[0027] More preferably, the weight of the auxiliary material layer accounts for (0.1-2)% of the opicapone sustained-release pellets.

[0028] The present invention has the following beneficial effects: The enteric-coated sustained-release micropellets of opicapone provided by the present invention have the following structural design: 1) A pH-sensitive enteric coating is selected to achieve stability in gastric acid and targeted release in the intestine, thereby preventing opicapone from being destroyed or deteriorated under gastric acid conditions; 2) A combination of sustained-release materials Eudragit L100 and Eudragit S100 is preferably used in the isolation sustained-release layer and the drug-containing sustained-release core layer, which can avoid burst release and slowly release the drug in the intestinal environment; 3) Chitosan is added to the drug-containing sustained-release core layer to extend the retention time of the micropellets in the intestine, further improving the sustained-release performance and achieving longer-lasting and steady release performance. Through the above structural design, the enteric-coated sustained-release micropellets of the present invention can maintain drug stability in gastric acid and achieve steady and slow long-term release in the intestine, which is beneficial for improving the safety and absorption rate of opicapone, stabilizing blood drug concentrations, and enhancing the therapeutic effect of opicapone, and has great clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Schematic diagram of the structure of opicapone sustained-release micropellets in Example 1.

[0030] Figure 2 Schematic diagram of the structure of opicapone sustained-release micropellets in Example 10. DETAILED DESCRIPTION

[0031] The technical solution of the present invention is further illustrated and described below through specific implementation methods.

[0032] In order to solve the problems in the prior art of opicapone being unstable under acidic conditions and unable to achieve long-term, stable slow release in the intestinal environment, the present invention provides an opicapone sustained-release micropill, which comprises, from the inside to the outside, a drug-containing sustained-release core layer, an isolation sustained-release layer, and an enteric layer;

[0033] The raw materials of the drug-containing sustained-release core layer at least include opicapone, sustained-release material, filler, adhesive and pH regulator, and the sustained-release material is selected from the combination of Eudragit L, Eudragit S and cationic polymer.

[0034] Drug-containing sustained release core layer

[0035] In the present invention, the drug-containing sustained-release core layer is the innermost layer, and its raw materials include at least opicapone, a sustained-release material, a filler, a binder, and a pH adjuster. Opicapone is the active drug, and together with the sustained-release material, filler, binder, and pH adjuster, it provides excellent stability under acidic conditions and good long-term release under neutral conditions (the human intestine is a neutral environment). The sustained-release material is selected from a combination of Eudragit L, Eudragit S, and a cationic polymer. Eudragit L and Eudragit S are both acrylic resins that are insoluble at the pH of gastric fluid but soluble at a weakly acidic pH near neutral or higher. Cationic polymers are generally soluble in acidic conditions but have poor solubility under neutral or alkaline conditions. The cationic polymer adjusts the solubility and dissolution rate of the sustained-release material under different pH environments. The sustained-release material of the present invention is selected from a combination of Eudragit L, Eudragit S, and a cationic polymer. Combining the characteristics of these three materials, it can achieve slow dissolution in the intestinal environment while prolonging its residence time in the intestine, preventing excessive dissolution from causing excessive release of opicapone or incomplete release leading to excretion from the body, thereby improving the drug's effectiveness and safety. For example, Eudragit L can be Eudragit L100 or Eudragit L100-55, Eudragit S can be Eudragit S100, and the cationic polymer can be chitosan and its copolymers, polyamino acids and their copolymers, poly(N-isopropylacrylamide) (PINPAM) and its copolymers, etc.

[0036] The opicapone sustained-release micropellets of the present invention are provided with an isolation sustained-release layer to further protect the drug-containing sustained-release core layer, thereby further improving the stability of the micropellets under acidic conditions and the sustained-release performance in the intestinal environment.

[0037] In a preferred embodiment of the present application, the weight of opicapone is 25-70 mg. For example, the weight of opicapone in the drug-containing sustained-release core layer can be any value or any value between any of 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, etc., without particular limitation. More preferably, the weight of opicapone can be 40-55 mg. In the present application, the opicapone raw material can be micronized by airflow pulverization, with the D90 controlled to be 10-20 μm; the remaining raw materials can also be micronized, with the D90 controlled to be no more than 20 μm.

[0038] In a preferred embodiment of the present application, the weight ratio of the sustained-release material in the drug-containing sustained-release core layer is 15-35%. A weight ratio of the sustained-release material in the drug-containing sustained-release core layer that is too high or too low is not conducive to the slow release of opicapone. For example, the weight ratio of the sustained-release material in the drug-containing sustained-release core layer can be any value or any value between any of 15%, 17%, 18%, 20%, 21%, 23%, 25%, 27%, 28%, 30%, 32%, 33%, 35%, etc., without particular limitation.

[0039] In a preferred embodiment of the present application, Eudragit L is selected from Eudragit L100, Eudragit S is selected from Eudragit S100, and the cationic polymer is selected from chitosan. Eudragit L100 starts to dissolve at pH 6.0, and Eudragit S100 starts to dissolve at pH 7.0. The use of Eudragit L100 and Eudragit S100 in combination is more conducive to achieving slow and long-acting release of the pellets in the intestinal environment. The use of chitosan as the cationic polymer has poor solubility in slightly neutral conditions, which can adjust the release rate of the sustained-release material and improve the adhesion to the intestinal tract, thereby achieving the effect of controllable slow and long-acting release.

[0040] In a preferred embodiment of the present application, the weight ratio of Eudragit L to Eudragit S is (2-3.5):1. By adjusting the weight ratio of Eudragit L to Eudragit S, the release performance of the pellets in the intestinal environment can be adjusted. For example, the weight ratio of Eudragit L to Eudragit S can be any value or any value between any of 2:1, 2.1:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.8:1, 3:1, 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, etc., without particular limitation.

[0041] In a preferred embodiment of the present invention, the weight ratio of Eudragit L to the cationic polymer is (2-1):1. The content of the cationic polymer in the sustained-release material should not be too high or too low. If it is too high, the solubility of the drug-containing sustained-release core layer in an acidic environment will be increased, and the adhesion in the intestine will be too strong, which will cause local irritation. If it is too low, it will not be conducive to adjusting the dissolution rate of the sustained-release material in the intestinal environment, and the adhesion in the intestine will be too weak, which will not have the effect of prolonging the residence time in the intestine. For example, the weight ratio of Eudragit L to the cationic polymer can be any value among 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, etc., or any value in between, without special restrictions.

[0042] In a preferred embodiment of the present invention, the filler is selected from one or a combination of two or more of soluble starch, lactose, mannitol and microcrystalline cellulose. More preferably, the filler is selected from soluble starch.

[0043] In a more preferred embodiment of the present invention, the weight proportion of the filler in the drug-containing sustained-release core layer is (35-68)%. For example, the weight proportion of the filler in the drug-containing sustained-release core layer can be 35%, 37%, 38%, 40%, 42%, 43%, 45%, 47%, 48%, 50%, 52%, 53%, 55%, 57%, 58%, 60%, 62%, 63%, 65%, 67%, 68%, etc., or any value therebetween, without particular limitation. More preferably, the weight proportion of the filler in the drug-containing sustained-release core layer is (35-50)%.

[0044] In a preferred embodiment of the present invention, the binder is selected from one or a combination of two or more of hypromellose, sodium hypromellose, ethyl cellulose, polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP). More preferably, the binder is PVP, which can be PVP K30, PVP K60, PVP K90, etc.

[0045] In a more preferred embodiment of the present invention, the weight proportion of the binder in the drug-containing sustained-release core layer is (1-10)%. For example, the weight proportion of the binder in the drug-containing sustained-release core layer can be any value among 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc. or any value in between, without particular limitation. More preferably, the weight proportion of the binder in the drug-containing sustained-release core layer can be (1.5-7)%.

[0046] In a preferred embodiment of the present invention, the pH regulator mainly plays a role in improving the stability of the drug. The pH regulator is at least one of an alkali metal hydroxide, an alkaline earth metal hydroxide, a carbonate and a bicarbonate. The weight proportion of the pH regulator in the drug-containing sustained-release core layer is (5-20)%. Furthermore, the pH regulator can be a bicarbonate, such as sodium bicarbonate. The weight proportion of the pH regulator in the drug-containing sustained-release core layer can be any value of 5%, 7%, 8%, 10%, 12%, 13%, 15%, 16%, 18%, 20%, etc., or any value in between, without special restrictions. More preferably, the weight proportion of the pH regulator in the drug-containing sustained-release core layer can be (6-10)%. For example, the weight proportion can be any value of 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, etc., or any value in between, without special restrictions.

[0047] Isolating sustained release layer

[0048] The isolation sustained-release layer is provided in the structure of the opicapone sustained-release micropellets of the present invention, which can further improve the stability in an acidic environment (such as gastric acid pH), further protect the drug-containing sustained-release core layer, and adjust the sustained-release performance in the intestinal environment, further improving the sustained-release performance of the opicapone sustained-release micropellets, and making the sustained-release more stable and long-lasting.

[0049] In a preferred embodiment of the present invention, the raw materials for the isolation sustained-release layer include at least a combination of Eudragit L and Eudragit S. The above technical solution can further enhance the resistance of the micropills to acidic conditions, improve their stability under acidic conditions, and provide a certain degree of solubility in the intestinal environment, further improving the sustained-release performance of the micropills.

[0050] In a more preferred embodiment of the present invention, the weight ratio of Eudragit L to Eudragit S is (4-1):1. For example, the weight ratio of Eudragit L to Eudragit S can be any value among 4:1, 3.5:1, 3:1, 2.5:1, 2.2:1, 2:1, 1.8:1, 1.5:1, 1:1, etc., or any value in between, without particular limitation. More preferably, the weight ratio of Eudragit L to Eudragit S is (3-1.8):1, and even more preferably, the weight ratio is (2.5-1.8):1.

[0051] In a more preferred embodiment of the present invention, Eudragit L is selected from Eudragit L100, and Eudragit S is selected from Eudragit S100. As described above, Eudragit L100 begins to dissolve at pH 6.0, and Eudragit S100 begins to dissolve at pH 7.0. The combination of Eudragit L100 and Eudragit S100 is more conducive to achieving stability in gastric acid environment and sustained release in intestinal environment.

[0052] In a more preferred embodiment of the present invention, the weight proportion of the combination of Eudragit L and Eudragit S in the isolation sustained-release layer is not less than 60%. For example, the weight proportion of the combination of Eudragit L and Eudragit S in the isolation sustained-release layer can be any value among 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, etc., or any value in between, without particular limitation. When the weight proportion of the combination of Eudragit L and Eudragit S in the isolation sustained-release layer is not 100%, the remaining components can be other sustained-release materials or non-sustained-release materials. Other sustained-release materials can include Eudragit L100-55, PINPAM, and copolymers thereof, and non-sustained-release materials can include PVA, PVP, soluble starch, etc.

[0053] Enteric layer

[0054] In a preferred embodiment of the present invention, the enteric layer comprises at least Eudragit FS30D. Eudragit FS30D is a copolymer of an anionic polymer and methacrylic acid. It dissolves above pH 7.0 and is typically provided as a 30% aqueous dispersion. It exhibits excellent enteric solubility and is generally the preferred material for enteric-coated capsule formulations, control agents, and polymer coatings.

[0055] In a more preferred embodiment of the present invention, the weight proportion of Eudragit FS30D in the enteric layer is not less than 80%. For example, the weight proportion of Eudragit FS30D in the enteric layer can be any value among 80%, 82%, 83%, 85%, 86%, 87%, 88%, 90%, 92%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, etc., or any value in between, without particular limitation. When the weight proportion of Eudragit FS30D in the enteric layer is not 100%, the remaining raw material components can be PVP, PVA, polyethylene glycol PEG, etc.

[0056] In a preferred embodiment of the present invention, the weight ratio of the drug-containing sustained-release core layer, the isolation sustained-release layer, and the enteric layer is (4-8): (1-2): 1. By adjusting the weight ratio of the drug-containing sustained-release core layer, the isolation sustained-release layer, and the enteric layer, the stability of the sustained-release micropellets of the present invention in a gastric acid environment and the long-term sustained-release performance in an intestinal environment can be better adjusted. For example, the weight ratio can be any value among 4:1:1, 4:2:1, 6:1:1, 6:2:1, 8:1:1, 8:2:1, 5:1.5:1, 6:1.5:1, 7:1:1, 7:2:1, etc., or any value in between, without particular limitation.

[0057] In a preferred embodiment of the present invention, the opicapone sustained-release micropellets further comprise an excipient layer, which covers the enteric layer. More preferably, the raw material of the excipient layer comprises at least one of magnesium stearate, talc, and microcrystalline cellulose.

[0058] In a more preferred embodiment of the present invention, the weight proportion of the excipient layer in the opicapone sustained-release micropellets is (0.1-2)%. For example, the weight proportion of the excipient layer in the opicapone sustained-release micropellets can be 0.1%, 0.3%, 0.4%, 0.5%, 0.7%, 0.8%, 1%, 1.2%, 1.3%, 1.5%, 1.7%, 1.8%, 2%, etc., or any value therebetween, without particular limitation. More preferably, the weight proportion of the excipient layer in the opicapone sustained-release micropellets can be (0.5-1.5)%.

[0059] The outermost surface of the opicapone sustained-release micropellets of the present invention can be encapsulated and protected by a capsule shell to prepare a microcapsule. The capsule shell can be a pharmaceutical gelatin capsule shell, etc., without particular limitation.

[0060] The preparation method of the opicapone sustained-release micropellets of the present invention is not particularly limited. One preparation method may comprise the following steps:

[0061] (1) Raw material preparation: The opicapone API was micronized by air flow milling to control the D90 to be 10-20 μm; the remaining raw materials were also micronized to control the D90 to be no more than 20 μm and set aside.

[0062] (2) Preparation of drug-containing sustained-release core layer (extrusion spheronization method): The active ingredient opicapone of the drug-containing sustained-release core layer is uniformly mixed with the filler, binder (PVP aqueous solution is used as the binder), sustained-release material, and pH adjuster, and then wet granulated. The wet granules are used to prepare drug-containing pellet cores using an extrusion spheronizer, and then dried in a fluidized bed. After drying, drug-containing sustained-release pellet cores with a mesh size of 30-40 are selected.

[0063] (3) Preparation of the isolation sustained-release layer: The isolation sustained-release layer raw materials are prepared into an isolation sustained-release layer suspension with ethanol, and the isolation sustained-release layer suspension is sprayed onto the drug-containing sustained-release pellet cores using a fluidized bed to coat the pellets to prepare isolation sustained-release layer coated particles.

[0064] (4) Preparation of enteric layer: The enteric layer raw materials are prepared into an enteric layer coating solution with ethanol, and the enteric layer coating solution is applied to the outside of the isolated sustained-release layer coated particles to prepare the opicapone sustained-release micropellets of the present invention.

[0065] When the enteric layer is coated with an auxiliary material layer, the process may further include step (5) total mixing: after the enteric coating is completed, the auxiliary materials are added and mixed evenly to obtain the product.

[0066] The finally prepared opicapone sustained-release micropellets can be filled into hollow capsules (such as No. 2 hollow capsules) using a capsule filling machine to prepare opicapone sustained-release micropellet capsules, which can be stored more conveniently.

[0067] The technical solution of the present invention is further described and illustrated below based on various embodiments.

[0068] Comparative Example 1

[0069] Opicapone sustained-release micropellets, from the inside to the outside, include a drug-containing sustained-release core layer and an enteric-coated layer.

[0070] The drug-containing extended-release core layer consists of 50mg of opicapone, 94mg of soluble starch, 10mg of sodium bicarbonate, and 3mg of PVP K30, while the enteric layer consists of 30mg of Eudragit FS30D. The opicapone API was micronized using a jet milling method to a controlled D90 of 15μm; the remaining raw materials were similarly micronized to a controlled D90 of 9μm.

[0071] Opicapone was mixed evenly with soluble starch and sodium bicarbonate. 30 mg of PVP K30 was pre-dissolved in water and used as a binder for wet granulation. The wet granules were then extruded and spheronized to form drug-containing sustained-release pellet cores. These pellets were then dried in a fluidized bed and sieved to select drug-containing sustained-release pellet cores with a mesh size of 30-40. An enteric coating solution was prepared by mixing 300 mg of Eudragit FS30D with 80% ethanol. This was then coated onto the surface of the drug-containing sustained-release pellet cores to produce enteric-coated granules, the opicapone sustained-release pellets.

[0072] Comparative Example 2

[0073] Opicapone sustained-release micropellets, from the inside to the outside, include a drug-containing sustained-release core layer and an enteric-coated layer.

[0074] The drug-containing sustained-release core layer is composed of 50 mg of opicapone, 20 mg of Eudragit L100, 10 mg of Eudragit S100, 64 mg of soluble starch, 10 mg of sodium bicarbonate, and 3 mg of PVP K30. The preparation method of opicapone sustained-release micropellets is shown in Comparative Example 1.

[0075] Comparative Example 3

[0076] Opicapone sustained-release micropellets, from the inside to the outside, include a drug-containing sustained-release core layer and an enteric-coated layer.

[0077] The drug-containing sustained-release core layer is composed of 50 mg of opicapone, 20 mg of Eudragit L100, 10 mg of Eudragit S100, 15 mg of chitosan, 49 mg of soluble starch, 10 mg of sodium bicarbonate, and 3 mg of PVP K30. The preparation method of opicapone sustained-release micropellets is shown in Comparative Example 1.

[0078] Example 1

[0079] Opicapone sustained-release pellets, the structure of which is as shown in the attached Figure 1 As shown, from inside to outside, it comprises a drug-containing sustained-release core layer 1, an isolation sustained-release layer 2 and an enteric layer 3. The composition and preparation method of the drug-containing sustained-release core layer 1 and the enteric layer 3 are the same as those of Comparative Example 3.

[0080] The isolation sustained-release layer 2 is composed of 30 mg of hydroxypropyl cellulose and 17 mg of talc. Hydroxypropyl cellulose and talc are dispersed in 300 mg of water to prepare an isolation liquid. The isolation liquid is sprayed onto the drug-containing sustained-release pellet cores using a fluidized bed to coat the pellets, producing isolation sustained-release layer-coated granules.

[0081] Example 2

[0082] The difference between this embodiment and embodiment 1 is that in embodiment 1, the isolation sustained-release layer composed of 30 mg of hydroxypropyl cellulose and 17 mg of talc is adjusted to the isolation sustained-release layer composed of 47 mg of hypromellose E5.

[0083] Example 3

[0084] The difference between this embodiment and embodiment 1 is that in embodiment 1, the isolation sustained-release layer composed of 30 mg of hydroxypropyl cellulose and 17 mg of talc was adjusted to the isolation sustained-release layer composed of 20 mg of Eudragit L100, 10 mg of Eudragit S100 and 17 mg of soluble starch.

[0085] Comparative Example 4

[0086] The difference between the present comparative example and Example 3 is that the composition of the sustained-release material of the drug-containing sustained-release core layer in Example 3 is changed from 20 mg of Eudragit L100, 10 mg of Eudragit S100 and 15 mg of chitosan to 30 mg of Eudragit L100 and 15 mg of Eudragit S100. The remaining steps remain unchanged.

[0087] Dissolution performance test

[0088] 1. Preparation of dissolution medium:

[0089] (1) pH = 1.2 hydrochloric acid solution: 9 mL of concentrated hydrochloric acid was taken and added to purified water while stirring, and then diluted to 1000 mL to obtain a pH = 1.2 hydrochloric acid solution.

[0090] (2) pH = 6.8 phosphate buffer: 0.1 mol / L hydrochloric acid solution and 0.2 mol / L sodium phosphate solution were mixed in a ratio of 3:1, and then the pH value was adjusted to 6.8 using 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution to obtain the solution.

[0091] 2. Dissolution determination:

[0092] (1) Test sample preparation: the opicapone sustained-release pellets to be tested.

[0093] (2) Collection of dissolution liquid: 900 mL of dissolution medium of different pH was placed in a dissolution cup, and the temperature of the dissolution medium was kept constant at 37°C ± 0.5°C. The test sample was first placed in a sinker and then placed in the dissolution cup. The rotation speed was set to 75 rpm, and the time was counted. At the specified sampling time, an appropriate amount of dissolution liquid was taken, filtered through a 0.45 μm microporous filter, and the clear filtrate was taken for standby.

[0094] (3) Content determination: the filtrate was diluted with a solvent, and the absorbance at a wavelength of 272 nm was determined by ultraviolet-visible spectrophotometry, and the dissolution rate (%) of opicapone was calculated.

[0095] The dissolution rate of the opicapone sustained-release pellets of Comparative Examples 1-4 and Example 1-3 with time is shown in Tables 1 and 2 below.

[0096] Table 1 Dissolution rate (%)

[0097]

[0098] Table 2 Dissolution rate (%)

[0099]

[0100] In the above Tables 1 and 2, "-" indicates that no active drug, opicapone, was detected, and " / " indicates that the detection was not continued.

[0101] As can be seen from the data in Tables 1 and 2 above, the opicapone sustained-release micropellets of Comparative Examples 1-3 are not provided with an isolation sustained-release layer, and release occurs in an acidic environment (pH = 1.2), indicating that the protection of the enteric layer alone cannot effectively resist the dissolution of the micropellets by gastric acid. In Examples 1-3, a sustained-release isolation layer is provided between the drug-containing sustained-release core layer and the enteric layer, which significantly improves the stability of the sustained-release micropellets in an acidic environment. Moreover, the combination of Eudragit L100 and Eudragit S100, the raw materials of the isolation sustained-release layer, has better sustained-release performance in an environment of pH = 6.8, with a slower and more stable release, indicating that it is very suitable for sustained release in an intestinal environment. When the sustained-release material of the drug-containing sustained-release core layer does not contain a cationic polymer, the release is significantly faster, and the long-term effect and stability are relatively poor.

[0102] Example 4

[0103] The difference between this example and Example 3 is that the isolation sustained-release layer in Example 3, which consisted of 20 mg Eudragit L100, 10 mg Eudragit S100, and 17 mg soluble starch, was adjusted to 30 mg Eudragit L100 and 17 mg soluble starch. The remaining steps remained unchanged.

[0104] Example 5

[0105] The difference between this example and Example 3 is that the isolation sustained-release layer in Example 3, which consisted of 20 mg Eudragit L100, 10 mg Eudragit S100, and 17 mg soluble starch, was adjusted to 30 mg Eudragit S100 and 17 mg soluble starch. The remaining steps remained unchanged.

[0106] Example 6

[0107] The difference between this example and Example 3 is that the isolation sustained-release layer in Example 3, which consisted of 20 mg Eudragit L100, 10 mg Eudragit S100, and 17 mg soluble starch, was adjusted to consist of 15 mg Eudragit L100, 15 mg Eudragit S100, and 17 mg soluble starch. The remaining steps remained unchanged.

[0108] Example 7

[0109] The difference between this example and Example 3 is that the isolation sustained-release layer in Example 3, which consisted of 20 mg Eudragit L100, 10 mg Eudragit S100, and 17 mg soluble starch, was adjusted to 22 mg Eudragit L100, 8 mg Eudragit S100, and 17 mg soluble starch. The remaining steps remained unchanged.

[0110] Example 8

[0111] The difference between this example and Example 3 is that the isolation sustained-release layer in Example 3, which consisted of 20 mg Eudragit L100, 10 mg Eudragit S100, and 17 mg soluble starch, was adjusted to 26 mg Eudragit L100, 13 mg Eudragit S100, and 8 mg soluble starch. The remaining steps remained unchanged.

[0112] Example 9

[0113] The difference between this example and Example 3 is that the isolation sustained-release layer in Example 3, which consisted of 20 mg Eudragit L100, 10 mg Eudragit S100, and 17 mg soluble starch, was adjusted to consist of 10 mg Eudragit L100, 20 mg Eudragit S100, and 17 mg soluble starch. The remaining steps remained unchanged.

[0114] The dissolution rate of the opicapone sustained-release pellets of Examples 3-9 was tested over time in a phosphate buffer solution at pH 6.8 according to the above dissolution performance test method. The results are shown in Table 3 below.

[0115] Table 3 Dissolution / %

[0116]

[0117] The data in Table 3 show that when the proportion of Eudragit L100 in the isolation sustained-release layer is high, the pellets release rapidly in the early stage in a pH 6.8 release medium. However, when the proportion of Eudragit S100 is high, the pellets are difficult to dissolve and release very slowly. When the weight ratio of Eudragit L100 to Eudragit S100 is within a suitable range (e.g., 2:1 in Examples 3 and 8, and 11:4 in Example 7), the pellets can achieve slow, long-lasting, and stable release in a pH 6.8 release medium.

[0118] Example 10

[0119] The difference between this example and Example 3 is that in Example 3, the sustained-release material in the drug-containing sustained-release core layer was adjusted from 20 mg Eudragit L100, 10 mg Eudragit S100, and 15 mg chitosan to 30 mg Eudragit L100 and 15 mg chitosan. An excipient layer of magnesium stearate was added outside the enteric layer, and the excipient layer weight was 1 mg. The obtained opicapone sustained-release microcapsules were then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remained unchanged. The structure of the sustained-release microcapsules is shown in the attached figure. Figure 2 As shown, from the inside out, it includes a drug-containing sustained-release core layer 1, an isolation sustained-release layer 2, an enteric layer 3 and an excipient layer 4.

[0120] Example 11

[0121] This example differs from Example 3 in that the sustained-release material composition of the drug-containing sustained-release core layer in Example 3 was adjusted from 20 mg Eudragit L100, 10 mg Eudragit S100, and 15 mg chitosan to 30 mg Eudragit S100 and 15 mg chitosan. An excipient layer of 1 mg magnesium stearate was added to the outside of the enteric layer. The resulting opicapone sustained-release micropellets were then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remained unchanged.

[0122] Example 12

[0123] This example differs from Example 3 in that the sustained-release material composition of the drug-containing sustained-release core layer in Example 3 was adjusted from 20 mg Eudragit L100, 10 mg Eudragit S100, and 15 mg chitosan to 30 mg Eudragit L100 and 15 mg Eudragit S100. An excipient layer of magnesium stearate weighing 1 mg was added to the outer surface of the enteric layer. The resulting opicapone sustained-release micropellets were then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remained unchanged.

[0124] Example 13

[0125] This example differs from Example 3 in that the sustained-release material composition of the drug-containing sustained-release core layer in Example 3 was adjusted from 20 mg Eudragit L100, 10 mg Eudragit S100, and 15 mg chitosan to 24 mg Eudragit L100, 9 mg Eudragit S100, and 12 mg chitosan. An excipient layer of 1 mg magnesium stearate was added to the outside of the enteric layer. The resulting opicapone sustained-release micropellets were then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remained unchanged.

[0126] Example 14

[0127] This Example differs from Example 3 in that the sustained-release material composition of the drug-containing sustained-release core layer in Example 3 was adjusted from 20 mg Eudragit L100, 10 mg Eudragit S100, and 15 mg chitosan to 30 mg Eudragit L100, 10 mg Eudragit S100, and 5 mg chitosan. An excipient layer of 1 mg magnesium stearate was added to the outside of the enteric layer. The resulting opicapone sustained-release micropellets were then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remained unchanged.

[0128] Performance test--drug-time curve determination

[0129] 1. Sample preparation: opicapone sustained-release micropellets prepared in Example 3 and Examples 10-14; opicapone sustained-release micropellets obtained in Example 3 were prepared into opicapone sustained-release microcapsules according to the method of Example 10.

[0130] 2. Experimental Animals and Grouping: Male beagle dogs, weighing 8-10 kg, were randomly divided into groups of 3.

[0131] 3. Administration: Each group of dogs was fed 1 tablet (grain) of the test sample 12 hours after eating.

[0132] 4. Plasma Sample Collection and Processing: 4 mL of blood was collected from the forelimb vein before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 10 h, 24 h, and 72 h after administration. The blood was anticoagulated with 1% heparin, centrifuged at 800 × g for 10 min, and the plasma was separated and stored at -80°C until testing.

[0133] 5. Content Assay: Plasma samples collected at the aforementioned different time points were placed in centrifuge tubes, 200 μL of acetonitrile solution was added, the samples were vortexed for 60 seconds, and centrifuged at 1500 × g for 10 minutes at 4°C. 20 μL of the supernatant was injected. The absorbance at 272 nm was measured using UV-visible spectrophotometry to calculate the opicapone concentration. Time-dependent plasma concentration curves were then plotted. The results are shown in Table 4 below.

[0134] Table 4 Blood drug concentration / μg / ml

[0135]

[0136] As can be seen from the data in Table 4 above, the opicapone sustained-release micropellets of Examples 3 and 13 can maintain their efficacy for approximately 16 hours (with a blood concentration of no less than 0.3 μg / ml). In Example 14, the opicapone sustained-release micropellets release relatively quickly, maintaining their efficacy for approximately 12 hours. The opicapone sustained-release micropellets of Examples 10-12 release relatively quickly, maintaining their efficacy for only approximately 9 hours. This demonstrates that the opicapone sustained-release micropellets of the present invention have a more stable and long-lasting sustained-release performance, achieving a more stable blood concentration and a longer duration of action, which is more conducive to improving the drug's efficacy.

[0137] Example 15

[0138] This example differs from Example 3 in that the sodium bicarbonate dosage in Example 3 was adjusted from 10 mg to 15 mg. An excipient layer of magnesium stearate weighing 1 mg was added to the outside of the enteric layer. The resulting opicapone sustained-release micropellets were then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remained unchanged.

[0139] Example 16

[0140] This example differs from Example 3 in that the sodium bicarbonate dosage in Example 3 was adjusted from 10 mg to 45 mg. An excipient layer of magnesium stearate weighing 1 mg was added to the outside of the enteric layer. The resulting opicapone sustained-release micropellets were then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remained unchanged.

[0141] Example 17

[0142] This example differs from Example 3 in that the sodium bicarbonate content in Example 3 was adjusted from 10 mg to 5 mg. An excipient layer of magnesium stearate weighing 1 mg was added to the outside of the enteric layer. The resulting opicapone sustained-release micropellets were then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remained unchanged.

[0143] Performance test--stability inspection

[0144] 1. Sample preparation: opicapone sustained-release pellets prepared in Example 3 and Examples 15-17; opicapone sustained-release pellets obtained in Example 3 were prepared into opicapone sustained-release microcapsules according to the method of Example 15.

[0145] 2. Accelerated Test: The test sample was placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples were collected at 1, 3, and 6 months to observe the properties of the enteric-coated sustained-release pellets and determine the opicapone content in the capsules. The results are shown in Table 5.

[0146] Table 5 Accelerated test for drug stability

[0147]

[0148] The results show that the amount of sodium bicarbonate used in the drug-containing sustained-release pellets has a great influence on the appearance of the final preparation pellets and the stability of the drug in the pellets. When the amount of sodium bicarbonate in the pellets / microcapsules is 10 mg, i.e., the weight percentage in the drug-containing sustained-release core layer is 5.3%, the appearance of the obtained pellets is complete, but the drug stability is poor in the accelerated test, and the drug content decreases. When the amount of sodium bicarbonate is 5 mg, the drug stability is worse in the accelerated test, and the drug content decreases more obviously. When the amount of sodium bicarbonate is 45 mg, i.e., the weight percentage is 20%, it is found that the pellets are adhered and the drug content slightly decreases in the accelerated test for 1 month. It is possible that sodium bicarbonate is hygroscopic, and when the added amount is large, it can cause moisture absorption, leading to unstable drug. When the amount of sodium bicarbonate is 15 mg, i.e., the weight percentage is 7.8%, the obtained pellets have complete properties, and the stability is good in the accelerated test, and no obvious change in the drug content is found.

[0149] The basic principles, main features and advantages of the present application are shown and described above. It should be understood by those skilled in the art that the present application is not limited by the above examples, and the above examples are only preferred embodiments of the present application, and cannot limit the scope of the present application. Equivalent changes and modifications made in accordance with the scope and content of the present patent are still within the scope of the present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. An opicapone sustained-release pellet, characterized in that: From the inside to the outside, it includes a drug-containing sustained-release core layer, an isolation sustained-release layer, and an enteric layer; The raw materials of the drug-containing sustained-release core layer are composed of opicapone, a sustained-release material, a filler, a binder, and a pH regulator. The sustained-release material is selected from a combination of Eudragit L100, Eudragit S100, and chitosan. The weight ratio of Eudragit L100 to Eudragit S100 is (2-3.5):1, and the weight ratio of Eudragit L100 to chitosan is (2-1):

1. The pH regulator is sodium bicarbonate, and the weight proportion of the pH regulator in the drug-containing sustained-release core layer is 9.26%; The material of the isolation sustained-release layer is composed of Eudragit L100, Eudragit S100 and soluble starch, the weight ratio of the combination of Eudragit L100 and Eudragit S100 in the isolation sustained-release layer is not less than 60%, and the weight ratio of Eudragit L100 to Eudragit S100 is (4-1):1; The raw material of the enteric layer is Eudragit FS30D; The weight ratio of the drug-containing sustained-release core layer, the isolation sustained-release layer and the enteric layer is (4-8):(1-2):

1.

2. The opicapone sustained-release pellets according to claim 1, characterized in that: The weight of opicapone is 25-70 mg.

3. The opicapone sustained-release pellets according to claim 1, characterized in that: The weight proportion of the sustained-release material in the drug-containing sustained-release core layer is 15-35%.

4. The opicapone sustained-release pellets according to claim 1, characterized in that: The filler is selected from one or a combination of two or more of soluble starch, lactose, mannitol and microcrystalline cellulose.

5. The opicapone sustained-release pellets according to claim 4, characterized in that: The weight proportion of the filler in the drug-containing sustained-release core layer is (35-68)%.

6. The opicapone sustained-release pellets according to claim 1, characterized in that: The binder is selected from one or a combination of two or more of hypromellose, hypromellose sodium, ethyl cellulose, polyvinyl alcohol and polyvinyl pyrrolidone.

7. The opicapone sustained-release pellets according to claim 6, characterized in that: The weight proportion of the binder in the drug-containing sustained-release core layer is (1-10)%.

8. The opicapone sustained-release pellets according to claim 1, characterized in that: The opicapone sustained-release pellets further comprise an excipient layer, which covers the enteric layer.

9. The opicapone sustained-release pellets according to claim 8, characterized in that: The raw materials of the auxiliary material layer include at least one of magnesium stearate, talc and microcrystalline cellulose.

10. The opicapone sustained-release pellets according to claim 8, characterized in that: The weight proportion of the auxiliary material layer in the opicapone sustained-release pellets is (0.1-2)%.

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