Opiapone sustained-release pellet

Abstract

The invention provides an omicapone sustained-release pellet, and relates to the technical field of drug release. The olpiapone sustained-release pellet sequentially comprises a drug-containing sustained-release core layer, an isolation sustained-release layer and an enteric-coated layer from inside to outside, the drug-containing sustained-release core layer at least comprises the following raw materials: olpicopone, a sustained-release material, a filler, an adhesive 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 slow release layer at least comprise a combination of Eudragit L and Eudragit S. The olpinapone sustained-release pellet disclosed by the invention has relatively good stability in a gastric acid environment, and can realize stable and long-acting slow release in an intestinal environment, so that the safety and the bioavailability of a medicine are improved.

Description

Technical Field

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

[0002] Opicapone is a third-generation catechol-O-methyltransferase (COMT) inhibitor with potent and persistent COMT inhibitory activity. It can reduce the metabolism of levodopa, allowing more levodopa to enter the brain, thereby better exerting its efficacy and helping to improve the control of motor symptoms in Parkinson's (PD) patients. Currently, the opicapone preparations approved for marketing worldwide include tablets and capsules, which are clinically used as adjuvant therapy for levodopa / carbidopa and are suitable for improving end-of-dose symptom fluctuations in PD patients.

[0003] The existing opicapone tablets and capsules have a low solubility, resulting in insufficient bioavailability, which affects the efficacy of the drug. Prior art CN115335036A micronizes the opicapone raw material to obtain opicapone crystals with a specific primary particle size distribution, thereby improving the dissolution performance of opicapone and obtaining a better bioavailability than non-micronized opicapone. Prior art CN115105483A provides an opicapone capsule and a preparation method thereof, which controls the content of opicapone heavy powder particles between 20 and 60 meshes by repeatedly granulating and sieving the opicapone raw material to facilitate the dissolution of opicapone in the body, and the excipients used are mixed at a constant speed, which is conducive to ensuring the high solubility of opicapone. Summary of the invention

[0004] The inventors found during the research that opicapone is unstable under acidic conditions and is easily converted into impurity compounds, which will affect the safety and effectiveness of the drug. The above-mentioned prior art only considers the dissolution performance of opicapone, and does not consider its instability under gastric acid conditions and low bioavailability. After a large number of experimental studies and analyses, the present invention has found a method for improving the stability of opicapone under gastric acid conditions (pH1-2) and high solubility in the intestinal environment (neutral), and has good sustained-release performance. Based on this, the present invention provides an opicapone sustained-release micropill.

[0005] The technical solution of the present invention is as follows:

[0006] An opicapone sustained-release micropellet, comprising, from inside to outside, a drug-containing sustained-release core layer, an isolation sustained-release layer and an enteric 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 weight of opicapone is 25-70 mg.

[0009] Preferably, the sustained-release material accounts for 15-35% by weight of the drug-containing sustained-release core layer.

[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 weight proportion of the filler in the drug-containing sustained-release core layer is (35-68)%.

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

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

[0017] Preferably, the pH regulator is at least one of alkali metal hydroxides, alkaline earth metal hydroxides, carbonates and bicarbonates, and the weight proportion of the pH regulator in the drug-containing sustained-release core layer is (5-20)%.

[0018] Preferably, the raw material of the isolation sustained-release layer comprises at least 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 weight proportion of the combination of Eudragit L and Eudragit S in the isolation sustained-release layer is not less than 60%.

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

[0023] More preferably, the weight proportion of 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 pellets 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 proportion of the auxiliary material layer in the opicapone sustained-release pellets is (0.1-2)%.

[0028] The beneficial effects of the present invention are as follows: the enteric-coated sustained-release micro-pellets of opicapone provided by the present invention have the following structural design: 1) pH-sensitive enteric coating is selected to achieve stability under gastric acid and fixed-point release in the intestine, thereby preventing opicapone from being destroyed or deteriorated under gastric acid conditions; 2) the combination of sustained-release materials Eudragit L100 and Eudragit S100 is preferably selected in the isolation sustained-release layer and the drug-containing sustained-release core layer, which can avoid the sudden release phenomenon and slowly release the drug under the intestinal environment; 3) chitosan is added to the drug-containing sustained-release core layer, which prolongs the retention time of the micro-pellets in the intestine, further improves the sustained-release performance, and has a longer-lasting and stable release performance. Through the above structural design, the enteric-coated sustained-release micro-pellets of the present invention can maintain the stability of the drug in gastric acid and the stable and slow long-term release in the intestine, which is conducive to improving the safety and absorption rate of opicapone, stabilizing the blood drug concentration, and enhancing the efficacy of opicapone, and has great clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is a 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 of 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 that opicapone is unstable under acidic conditions and cannot achieve long-term, stable and slow release under intestinal conditions, the present invention provides an opicapone sustained-release micro-pellet, 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 the raw materials at least include opicapone, sustained-release materials, fillers, binders and pH regulators. Opicapone is an active drug, and together with the sustained-release materials, fillers, binders and pH regulators, it has good stability under acidic conditions and good long-acting 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, wherein Eudragit L and Eudragit S are both acrylic resins, which are insoluble at the pH of gastric juice and soluble at a weakly acidic pH close to neutral or higher. Cationic polymers are generally soluble in acidic conditions, and their solubility will deteriorate 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, which combines the characteristics of these three materials, can achieve slow dissolution in the intestinal environment, and prolong the residence time in the intestine, avoiding too fast dissolution leading to too fast release of opicapone and incomplete release before excretion from the body, thereby improving the effectiveness and safety of the drug. 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 isolation sustained-release layer is provided in the opicapone sustained-release micropellets of the present invention to further protect the drug-containing sustained-release core layer, which can further improve the stability of the micropellets under acidic conditions and the sustained-release performance under intestinal environment.

[0037] In a preferred embodiment of the present invention, 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 of 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, etc. or any value in between, without special restrictions. More preferably, the weight of opicapone can be 40-55 mg. In the present invention, the opicapone raw material can be micronized by air flow milling to control D90 to 10-20 μm; the remaining raw materials can also be micronized to control D90 not exceeding 20 μm.

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

[0039] In a preferred embodiment of the present invention, Eudragit L is selected from Eudragit L100, Eudragit S is selected from Eudragit S100, and the cationic polymer is selected from chitosan. 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 slow and long-term release of micropills in the intestinal environment. The cationic polymer is chitosan, which has poor solubility under neutral conditions, and can adjust the release rate of the sustained-release material and improve the adhesion to the intestine, thereby achieving a controllable slow and long-term release effect.

[0040] In a preferred embodiment of the present invention, 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 micropellets in the intestinal environment can be adjusted. For example, the weight ratio of Eudragit L to Eudragit S can be 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., or any value therebetween, 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 reactions; 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, and it will not be able to prolong the stay in the intestine. For example, the weight ratio of Eudragit L to the cationic polymer can be any value of 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 in between, without special restrictions. 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 hydroxypropyl methylcellulose, sodium hydroxypropyl methylcellulose, 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 of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc. or any value in between, without special restrictions. 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, and the pH regulator is at least one of an alkali metal hydroxide, an alkaline earth metal hydroxide, a carbonate and a bicarbonate, and the weight proportion of the pH regulator in the drug-containing sustained-release core layer is (5-20)%. Further, 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 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 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, etc., or any value in between, without special restrictions.

[0047] Isolation 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 improve the sustained-release performance of the opicapone sustained-release micropellets, and make the sustained-release more stable and long-lasting.

[0049] In a preferred embodiment of the present invention, the raw material of the isolation sustained-release layer comprises at least a combination of Eudragit L and Eudragit S. The above technical solution can further improve the resistance of the micropills to acidic conditions, improve the stability under acidic conditions, and have a certain 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 of 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 therebetween, without particular limitation. More preferably, the weight ratio of Eudragit L to Eudragit S is (3-1.8):1, and further 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 of 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, etc. or any value in between, without special restrictions. 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 be Eudragit L100-55, PINPAM and its copolymers, etc., and non-sustained-release materials can be PVA, PVP, soluble starch, etc.

[0053] Enteric layer

[0054] In a preferred embodiment of the present invention, the raw material of the enteric layer comprises at least Eudragit FS30D. Eudragit FS30D is a copolymer of anionic polymer and methacrylic acid, which dissolves above pH 7.0 and is usually provided in the form of a 30% aqueous dispersion. It has excellent enteric solubility and is generally the preferred material for enteric capsule preparations, control agents and polymer encapsulation materials.

[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 80%, 82%, 83%, 85%, 86%, 87%, 88%, 90%, 92%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, etc., or any value in between, without special restrictions. 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 the gastric acid environment and the long-acting sustained-release performance in the intestinal environment can be better adjusted. For example, the weight ratio can be any value of 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 special restrictions.

[0057] In a preferred embodiment of the present invention, the opicapone sustained-release pellets further comprise an excipient layer, and the excipient layer 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 auxiliary material layer in the opicapone sustained-release micropellets is (0.1-2)%. For example, the weight proportion of the auxiliary material 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 in between, without special restrictions. More preferably, the weight proportion of the auxiliary material 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 special restrictions.

[0060] The preparation method of the opicapone sustained-release pellets of the present invention is not particularly limited. A preparation method may include 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 mixed with the filler, the binder (PVP aqueous solution is used as the binder), the sustained-release material and the 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 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 for coating 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 step (5) of total mixing may also be included: 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 according to various embodiments below.

[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 sustained-release core layer is composed of 50 mg of opicapone, 94 mg of soluble starch, 10 mg of sodium bicarbonate, and 3 mg of PVP K30, and the enteric layer is composed of 30 mg of Eudragit FS30D. The opicapone API is micronized by airflow milling to control the D90 to 15 μm; the other raw materials are also micronized to control the D90 to 9 μm.

[0071] Opicapone was mixed evenly with soluble starch and sodium bicarbonate. PVP K30 was pre-dissolved in water with 30 mg and used as a binder for wet granulation. The wet granules were used to prepare drug-containing sustained-release pellet cores using an extrusion spheronizer, and dried in a fluidized bed. After drying, the drug-containing sustained-release pellet cores with a mesh size of 30-40 were selected. Eudragit FS30D was prepared into an enteric layer coating solution with 300 mg 80% ethanol, and the surface of the drug-containing sustained-release pellet core particles was coated to prepare enteric-coated particles, namely, 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 pellets 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 pellets 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 includes 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, and the isolation liquid is sprayed onto the drug-containing sustained-release pellet core using a fluidized bed for coating to prepare isolation sustained-release layer coated particles.

[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 hydroxypropyl methylcellulose 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 hydroxypropyl cellulose and 17 mg talc is adjusted to the isolation sustained-release layer composed of 20 mg Eudragit L100, 10 mg Eudragit S100 and 17 mg soluble starch.

[0085] Comparative Example 4

[0086] The difference between this comparative example and Example 3 is that in Example 3, the composition of the sustained-release material of 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 Eudragit S100. The other steps remained unchanged.

[0087] Dissolution performance test

[0088] 1. Preparation of dissolution medium:

[0089] (1) pH = 1.2 hydrochloric acid solution: Take 9 mL of concentrated hydrochloric acid and add it into purified water while stirring, and make up to 1000 mL to obtain a pH = 1.2 hydrochloric acid solution.

[0090] (2) pH = 6.8 phosphate buffer: Take 0.1 mol / L hydrochloric acid solution and 0.2 mol / L sodium phosphate solution, mix them in a ratio of 3:1, and adjust the pH value to 6.8 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution.

[0091] 2. Dissolution determination:

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

[0093] (2) Dissolution liquid collection: Measure 900 mL of dissolution medium with different pH values ​​and place it in the dissolution cup. Wait until the temperature of the dissolution medium is constant at 37°C ± 0.5°C. Place the sample in the sinker first, and then in the dissolution cup. Set the speed to 75 rpm and start the timer. At the specified sampling time, take an appropriate amount of dissolution liquid, filter it through a 0.45 μm microporous filter membrane, and take the clarified filtrate for later use.

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

[0095] The dissolution rates of the opicapone sustained-release pellets of Comparative Examples 1-4 and Examples 1-3 change over time as shown in Tables 1 and 2 below.

[0096] Table 1 Dissolution / %

[0097]

[0098] Table 2 Dissolution / %

[0099]

[0100] In the above Tables 1 and 2, “-” indicates that the release of the active drug, opicapone, was not detected, and “ / ” indicates that no further detection was performed.

[0101] From the data in Table 1 and Table 2 above, it can be seen that the opicapone sustained-release pellets of Comparative Examples 1-3 are not provided with an isolation sustained-release layer, and there is a release phenomenon in an acidic environment (pH=1.2), indicating that the protection of the enteric layer alone cannot effectively resist the dissolution of the pellets 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 pellets in an acidic environment, and the raw materials of the isolation sustained-release layer include a combination of Eudragit L100 and Eudragit S100, which has better sustained-release performance in an environment of pH=6.8, and the release is slower and more stable, 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 in Example 3, the isolation sustained-release layer composed 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 other steps remained unchanged.

[0104] Example 5

[0105] The difference between this example and Example 3 is that in Example 3, the isolation sustained-release layer composed 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 other steps remained unchanged.

[0106] Example 6

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

[0108] Example 7

[0109] The difference between this example and Example 3 is that in Example 3, the isolation sustained-release layer composed 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 other steps remained unchanged.

[0110] Example 8

[0111] The difference between this example and Example 3 is that in Example 3, the isolation sustained-release layer composed 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 other steps remain unchanged.

[0112] Example 9

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

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

[0115] Table 3 Dissolution / %

[0116]

[0117] From the data results in Table 3 above, it can be seen that when the ratio of Eudragit L100 in the isolation sustained-release layer is large, the micropills release faster in the early stage in the pH=6.8 release medium; and when the ratio of Eudragit S100 is large, the micropills are difficult to dissolve and release very slowly. When the weight ratio of Eudragit L100 and Eudragit S100 is within a more appropriate ratio range (such as 2:1 in Examples 3 and 8, and 11:4 in Example 7), the micropills can be released slowly, long-actingly and stably in the pH=6.8 release medium.

[0118] Example 10

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

[0120] Embodiment 11

[0121] The difference between this embodiment and embodiment 3 is that in embodiment 3, the sustained-release material in the drug-containing sustained-release core layer is adjusted from 20 mg Eudragit L100, 10 mg Eudragit S100, and 15 mg chitosan to 30 mg Eudragit S100 and 15 mg chitosan. An auxiliary material layer composed of magnesium stearate is added outside the enteric layer, and the weight of the auxiliary material layer is 1 mg. The obtained opicapone sustained-release microcapsules are then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remain unchanged.

[0122] Example 12

[0123] The difference between this embodiment and embodiment 3 is that in embodiment 3, the sustained-release material in the drug-containing sustained-release core layer is 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 auxiliary material layer composed of magnesium stearate is added outside the enteric layer, and the weight of the auxiliary material layer is 1 mg. The obtained opicapone sustained-release microcapsules are then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remain unchanged.

[0124] Embodiment 13

[0125] The difference between this embodiment and embodiment 3 is that in embodiment 3, the sustained-release material in the drug-containing sustained-release core layer is 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 auxiliary material layer composed of magnesium stearate is added outside the enteric layer, and the weight of the auxiliary material layer is 1 mg. The obtained opicapone sustained-release microcapsules are then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remain unchanged.

[0126] Embodiment 14

[0127] The difference between this embodiment and embodiment 3 is that in embodiment 3, the sustained-release material in the drug-containing sustained-release core layer is 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 auxiliary material layer composed of magnesium stearate is added outside the enteric layer, and the weight of the auxiliary material layer is 1 mg. The obtained opicapone sustained-release microcapsules are then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remain unchanged.

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

[0129] 1. Preparation of test samples: opicapone sustained-release micropellets capsules 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 groups: Beagle dogs, male, weighing 8-10 kg, were randomly divided into groups, 3 in each group.

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

[0132] 4. Collection and processing of plasma samples: 4 mL of blood was collected from the forelimb vein before administration and 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 for testing.

[0133] 5. Content determination: Take the plasma samples at different time points mentioned above into a centrifuge tube, add 200 μL of acetonitrile solution, vortex for 60 seconds, centrifuge at 1500×g for 10 minutes at 4°C, and take 20 μL of the supernatant for injection. The absorbance at a wavelength of 272 nm was determined by UV-visible spectrophotometry, the concentration of opicapone was calculated, and a time-blood drug concentration curve was drawn. The results are shown in Table 4 below.

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

[0135]

[0136] From the data in Table 4 above, it can be seen that the opicapone sustained-release pellets of Examples 3 and 13 can maintain the drug efficacy for up to about 16 hours (blood drug concentration is not less than 0.3 μg / ml). In Example 14, the opicapone sustained-release pellets are released relatively quickly, maintaining the drug efficacy for about 12 hours, and the opicapone sustained-release pellets of Examples 10-12 are released relatively faster, maintaining a lower drug efficacy of only about 9 hours. The above illustrates that the opicapone sustained-release pellets of the present invention have a more stable and long-lasting sustained-release performance, can achieve a more stable blood drug concentration and a longer-lasting action time, and are more conducive to improving the effect of the drug.

[0137] Embodiment 15

[0138] The difference between this embodiment and embodiment 3 is that in embodiment 3, the sodium bicarbonate is adjusted from 10 mg to 15 mg. An auxiliary material layer composed of magnesium stearate is added outside the enteric layer, and the weight of the auxiliary material layer is 1 mg. The obtained opicapone sustained-release microcapsules are then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remain unchanged.

[0139] Example 16

[0140] The difference between this embodiment and embodiment 3 is that in embodiment 3, the sodium bicarbonate is adjusted from 10 mg to 45 mg. An auxiliary material layer composed of magnesium stearate is added outside the enteric layer, and the weight of the auxiliary material layer is 1 mg. The obtained opicapone sustained-release microcapsules are then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remain unchanged.

[0141] Embodiment 17

[0142] The difference between this embodiment and embodiment 3 is that in embodiment 3, the sodium bicarbonate is adjusted from 10 mg to 5 mg. An auxiliary material layer composed of magnesium stearate is added outside the enteric layer, and the weight of the auxiliary material layer is 1 mg. The obtained opicapone sustained-release microcapsules are then filled into No. 2 hollow capsules to prepare opicapone sustained-release microcapsules. The remaining steps remain 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: Take the test sample and place it at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Take samples once at the first month, third month, and sixth month of the test to observe the properties of the enteric-coated sustained-release micropellets in the capsules and determine the drug content of opicapone in the capsules. The experimental 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 microcapsules has a great influence on the appearance of the final preparation microcapsules and the stability of the drugs in the microcapsules. When the amount of sodium bicarbonate used in the microcapsules / microcapsules is 10 mg, that is, the weight percentage in the drug-containing sustained-release core layer is 5.3%, the appearance of the obtained microcapsules 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 in the accelerated test is worse, and the drug content decreases more significantly. When the amount of sodium bicarbonate is 45 mg, that is, the weight percentage is 20%, it was found in the accelerated test that the microcapsules were adhered after 1 month, and the drug content decreased slightly. It may be that sodium bicarbonate is hygroscopic, and when the amount is added is large, it attracts moisture and causes drug instability. When the amount of sodium bicarbonate is 15 mg, that is, the weight percentage is 7.8%, the resulting microcapsules are complete in appearance, stable in the accelerated test, and no significant changes in drug content were found.

[0149] As described above, the basic principles, main features and advantages of the present invention are shown and described. Those skilled in the art should understand that the present invention is not limited by the above embodiments, which are only preferred embodiments of the present invention and cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the scope of the present invention and the contents of the specification should still be within the scope of the present invention. The scope of protection claimed by the present invention is defined by the attached 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 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.

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 Eudragit L is selected from Eudragit L100, the Eudragit S is selected from Eudragit S100, and the cationic polymer is selected from chitosan.

5. The opicapone sustained-release pellets according to claim 1, characterized in that: The weight ratio of the Eudragit L to the Eudragit S is (2-3.5):

1.

6. The opicapone sustained-release pellets according to claim 1, characterized in that: The weight ratio of the Eudragit L to the cationic polymer is (2-1):

1.

7. 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.

8. The opicapone sustained-release pellets according to claim 7, characterized in that: The weight proportion of the filler in the drug-containing sustained-release core layer is (35-68)%.

9. 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 hydroxypropyl methylcellulose, sodium hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl alcohol and polyvinyl pyrrolidone.

10. The opicapone sustained-release pellets according to claim 9, characterized in that: The weight proportion of the binder in the drug-containing sustained-release core layer is (1-10)%.

11. The opicapone sustained-release pellets according to claim 1, characterized in that: The pH regulator is at least one of alkali metal hydroxides, alkaline earth metal hydroxides, carbonates and bicarbonates, and the weight proportion of the pH regulator in the drug-containing sustained-release core layer is (5-20)%.

12. The opicapone sustained-release pellets according to claim 1, characterized in that: The material of the isolation sustained-release layer at least comprises a combination of Eudragit L and Eudragit S.

13. The opicapone sustained-release pellets according to claim 12, characterized in that: The weight ratio of the Eudragit L to the Eudragit S is (4-1):

1.

14. The opicapone sustained-release pellets according to claim 12, characterized in that: The Eudragit L is selected from Eudragit L100, and the Eudragit S is selected from Eudragit S100.

15. The opicapone sustained-release pellets according to claim 12, characterized in that: The weight of the combination of Eudragit L and Eudragit S in the isolation sustained-release layer is not less than 60%.

16. The opicapone sustained-release pellets according to claim 1, characterized in that: The raw material of the enteric layer at least comprises Eudragit FS30D.

17. The opicapone sustained-release pellets according to claim 16, characterized in that: The weight proportion of Eudragit FS30D in the enteric layer is not less than 80%.

18. The opicapone sustained-release pellets according to claim 1, characterized in that: 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.

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

20. The opicapone sustained-release pellets according to claim 19, characterized in that: The raw materials of the auxiliary material layer include at least one of magnesium stearate, talc and microcrystalline cellulose.

21. The opicapone sustained-release pellets according to claim 19, 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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