Enteric-coated duloxetine hydrochloride preparation, its active ingredient layer, its suspension, its barrier layer, its coating solution, and its preparation method

Abstract

The present invention discloses an enteric-coated duloxetine hydrochloride preparation, its main drug layer and its suspension, its isolating layer and its coating solution, and its preparation method. The present invention also discloses an enteric-coated duloxetine hydrochloride preparation, which comprises a specific main drug layer and / or an isolating layer, or is prepared by a specific method. The preparation method of the present invention well overcomes the problem of easy adhesion and granulation during the coating process of its preparation method, and the prepared enteric-coated duloxetine hydrochloride preparation greatly improves the drug stability while not affecting the drug release.

Description

[0001] This application is a divisional application of a patent application with the application number 201910821242.X, the invention name of "Enteric-coated Duloxetine Hydrochloride Preparation, Its Active Drug Layer and Its Suspension, Its Barrier Layer and Its Coating Solution, and Its Preparation Method", and the application date of August 30, 2019. Technical Field

[0002] The present invention belongs to the field of pharmaceutical preparations. Specifically, it relates to an enteric-coated duloxetine hydrochloride preparation, its active drug layer and its suspension, its barrier layer and its coating solution, and its preparation method. Background Art

[0003] Duloxetine Hydrochloride (API) is an effective dual serotonin and norepinephrine reuptake inhibitor for treating depression. Its chemical name is: (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine hydrochloride, and its structural formula is:

[0004]

[0005] Duloxetine Hydrochloride is a white or off-white crystalline powder, soluble in ethanol and also has a certain solubility in water. It is unstable under acidic conditions and is prone to degradation. Therefore, it is suitable to be made into enteric-coated preparations to resist the destruction of gastric juice on the drug. However, duloxetine hydrochloride reacts with acidic groups in many known enteric materials, forming a coating that dissolves slowly or even does not dissolve.

[0006] Generally speaking, in the pharmaceutical field, considering issues such as the cost of solvents, handling solvent vapors, and the difficulty of recovering evaporated solvents, there is no benefit in using organic solvents in pharmaceutical factories. Therefore, general process personnel do not use organic solvents in formulation design. In case of necessity, only ethanol solvents are considered.

[0007] When preparing enteric-coated duloxetine hydrochloride pellets, the duloxetine hydrochloride raw material is usually semi-dissolved in water and small drug-containing pellets are prepared by fluid bed coating, such as in US Patent US5508276. There are also patent literatures recording that the raw material is dissolved in an ethanol solution to prepare a solid dispersion and then prepared by fluid bed coating, such as in Chinese Patent CN100362996C.

[0008] However, in the above-mentioned prior arts, due to the relatively high viscosity after duloxetine hydrochloride is dissolved, it leads to situations such as easy adhesion and granulation during the coating process, further affecting the integrity of the barrier and enteric layers, resulting in a decline in the ability of the preparation to resist the destruction of gastric juice on the drug.

[0009] In addition, there are also some patent documents that record the preparation of drug-containing pellets by mixing raw materials with pharmaceutically acceptable excipients and then extruding and spheronizing them. For example, Chinese Patent CN104414993A.

[0010] However, in the above-mentioned prior art, in order to prepare good drug-containing pellets, the raw materials are wrapped in a large amount of skeleton materials, resulting in delayed drug release.

[0011] In addition, numerous studies have shown that duloxetine hydrochloride has obvious degradation with common enteric coating materials (Reference: Lu Zhenju, Gao Hao, Xiong Feng, Stability study of original research and generic capsules based on enteric-coated micro-pills of duloxetine hydrochloride [J]. Chinese Journal of Pharmaceuticals, 2016, 47(8): 1022-1027.). The weight gain of the isolation layer of duloxetine recorded in Chinese Patent CN100362996C is only 2%-10%, which greatly increases the impurities in the preparation; while an excellent isolation layer can improve the stability of the preparation. Chinese Patent CN105534949A added sorbitol to the isolation layer to make its quality stable, but the weight gain of the isolation layer coating on the basis of the pill core loaded with the drug is 10%-50%, thus having a certain impact on the drug release; for this reason, Chinese Patent CN104107169A divides the isolation layer into a collapse layer and a separation layer, so that 1) it plays a role in isolating the enteric coating layer and the drug-containing layer, protecting the active ingredient duloxetine hydrochloride to be stable in any enteric coating material, and 2) it plays a collapsing role to promote the release of duloxetine hydrochloride.

[0012] However, although the above technologies have achieved excellent protection effects and made the products have good chemical compatibility. However, the coating weight gain is high and the production cycle is long, which affects the patients' timely access to qualified products.

[0013] Therefore, in this field, for duloxetine hydrochloride drug preparations, there is an urgent need to seek a preparation method that can overcome the defects such as easy adhesion and granulation during the coating process of the existing preparation methods, and can ensure the integrity, dissolution and stability of duloxetine hydrochloride enteric preparations and other various properties and its efficient preparation method. Summary of the Invention

[0014] The technical problem to be solved by the present invention is to provide a duloxetine hydrochloride enteric preparation, its main drug layer and its suspension, its isolation layer and its coating solution, and its preparation method in order to overcome the technical problems such as easy adhesion and granulation during the coating process of the existing preparation method of duloxetine hydrochloride enteric preparations, poor integrity of the preparation, low release efficiency and low stability. The preparation method of the present invention well overcomes the above-mentioned technical problems existing in the prior art.

[0015] Through in-depth research, the inventor of the present invention unexpectedly found that using a specific organic solvent in the preparation of enteric-coated duloxetine hydrochloride preparations can overcome the sticking problem commonly existing in aqueous film coating, thereby significantly improving the integrity, dissolution and stability of enteric-coated duloxetine hydrochloride preparations. At the same time, the in vitro dissolution curve of the prepared enteric-coated duloxetine hydrochloride preparation is similar to that of the positive control drug (Cymbalta of Eli Lilly). The improvements brought by these advantages are far higher than the loss of treating solvent vapor.

[0016] At the same time, the inventor of the present invention also found that using a specific retarder in the preparation of enteric-coated duloxetine hydrochloride preparations can greatly reduce the amount of the isolating layer, effectively isolate duloxetine hydrochloride from the enteric material, but does not affect the release of the drug, greatly improves the stability of the drug, and ensures the safety, effectiveness and quality stability of drug use.

[0017] Specifically, the present invention solves the above technical problems through the following technical solutions.

[0018] The present invention provides a method for preparing a suspension of the main drug layer of an enteric-coated duloxetine hydrochloride preparation, which includes the following steps: suspending duloxetine hydrochloride and pharmaceutically acceptable excipients in an organic solvent.

[0019] In some embodiments of the present invention, the organic solvent is preferably selected from one or more of alkyl carboxylic acid solvents, ketone solvents, ether solvents, C 1-4 alcohol solvents, ester solvents, sulfone solvents and aromatic hydrocarbon solvents. 3-5 In some embodiments of the present invention, the organic solvent is further preferably a Class 3 solvent of ICH, for example, selected from one or more of formic acid, acetic acid, ethyl ether, acetone, anisole, propanol, isopropanol, 1-butanol, 2-butanol, pentanol, butyl acetate, tributylmethyl ether, isopropyl acetate, methyl ethyl ketone, dimethyl sulfoxide, cumene, ethyl acetate, ethyl formate, isobutyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol and propyl acetate.

[0020] In some embodiments of the present invention, the organic solvent preferably makes the duloxetine hydrochloride slightly soluble, very slightly soluble, almost insoluble or insoluble in the solvent.

[0021] In some embodiments of the present invention, the organic solvent is preferably selected from one or more of ethyl ether, propanol and isopropanol.

[0022]

[0023] ​In some embodiments of the present invention, in the duloxetine hydrochloride and the pharmaceutically acceptable excipients, the content of duloxetine hydrochloride preferably accounts for 50% to 95% by weight, more preferably 80% to 95% by weight, such as 89.7% by weight, 90% by weight or 90.9% by weight. The content of the pharmaceutically acceptable excipients preferably accounts for 5% to 50% by weight, more preferably 8% to 20% by weight, such as 10% by weight, 10.3% by weight or 10.4% by weight (that is, the % by weight refers to the weight percentage of duloxetine hydrochloride or the pharmaceutically acceptable excipients respectively accounting for the total weight of duloxetine hydrochloride and the pharmaceutically acceptable excipients). The solid content of duloxetine hydrochloride in the organic solvent is preferably 10% - 30% w / w, such as 10% - 25% w / w (such as 17.5%).

[0024] In the present invention, the duloxetine hydrochloride can be duloxetine hydrochloride of various particle sizes conventional in the art, for example, d90 is below 200 μm. The particle size d90 of the duloxetine hydrochloride is preferably below 40 μm (such as 38 μm, 25 μm, 24 μm or 11 μm), more preferably below 25 μm, and further preferably below 12 μm.

[0025] In some embodiments of the present invention, the pharmaceutically acceptable excipients can be the pharmaceutically acceptable excipients conventional in the main drug layer of the enteric-coated preparation of duloxetine hydrochloride in the art, preferably selected from one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone K30 (PVP K30), hydroxypropyl cellulose (HPC) and colloidal silicon dioxide; more preferably selected from one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone K30 (PVP K30) and colloidal silicon dioxide; further preferably selected from hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone K30, or a combination of hydroxypropyl methylcellulose (HPMC) and colloidal silicon dioxide (in this combination, the contents of HPMC and colloidal silicon dioxide may not be specifically limited, for example, the content of HPMC preferably accounts for 10.3%, and the content of colloidal silicon dioxide preferably accounts for 0.1%, and the definition of the content is as described above).

[0026] In another embodiment of the present invention, the pharmaceutically acceptable excipients can also be selected from one or more of poloxamer, sucrose and sodium bisulfite, such as poloxamer, sucrose and sodium bisulfite.

[0027] In some embodiments of the present invention, the pharmaceutically acceptable excipients may be the conventional pharmaceutically acceptable excipients in the active ingredient layer of duloxetine hydrochloride enteric-coated preparations in the art, and are preferably selected from one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone K30 (PVP K30), hydroxypropyl cellulose (HPC), microcrystalline silica, poloxamer, sucrose, and sodium bisulfite. For example, a combination of PVP K30 (content: 24.5%), poloxamer (content: 2.4%), sucrose (content: 12.2%), sodium bisulfite (content: 0.6%), and microcrystalline silica (content: 3.1%). The definition of the content is as described above.

[0028] The present invention provides a suspension of the active ingredient layer of a duloxetine hydrochloride enteric-coated preparation prepared by the preparation method as described above.

[0029] The suspension of the active ingredient layer of the duloxetine hydrochloride enteric-coated preparation provided by the present invention comprises duloxetine hydrochloride, pharmaceutically acceptable excipients, and an organic solvent; the duloxetine hydrochloride, pharmaceutically acceptable excipients, and organic solvent are as described above.

[0030] The present invention provides an active ingredient layer of a duloxetine hydrochloride enteric-coated preparation, which can be obtained by drying the above-mentioned suspension of the active ingredient layer.

[0031] As is well known to those skilled in the art, the suspension of the active ingredient layer generally needs to be coated on a carrier and dried to obtain the active ingredient layer. In the present invention, the suspension of the active ingredient layer can be coated on blank pellets, dried, to obtain drug-containing pellets with an active ingredient layer.

[0032] The present invention provides a coating solution for the barrier layer of a duloxetine hydrochloride enteric-coated preparation.

[0033] In some embodiments of the present invention, the coating solution for the barrier layer comprises a retarder;

[0034] The retarder is preferably selected from one or more of talc, zein, carnauba wax, ethylcellulose, cetyl alcohol, and cetostearyl alcohol, more preferably from one or more of talc, zein, and cetyl alcohol, and further preferably from zein and / or cetyl alcohol.

[0035] In the present invention, the particle size of talc in the retarder may be 5 - 50 μm, preferably 6 - 25 μm (such as 6.5 μm, 10 μm, 13 μm, 23 μm), and more preferably 6.5 - 13 μm.

[0036] In some embodiments of the present invention, the coating solution for the barrier layer may further comprise one or more of a water-soluble gel material, a plasticizer, an antifoaming agent, an anti-adhesive agent, a sugar, and a light-shielding agent.

[0037] In the present invention, the water-soluble gel material may be one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and hydroxypropyl cellulose, and is preferably hydroxypropyl methylcellulose.

[0038] In the present invention, the sugar may be one or more of sucrose, lactose, mannitol, xylitol, maltitol, and sorbitol, and is preferably sucrose and / or lactose.

[0039] In the present invention, the anti-adhesive agent may be one or more of talc powder, ethyl cellulose, cetyl alcohol, cetostearyl alcohol, colloidal silica, glycerol monostearate, and magnesium stearate, and is preferably talc powder and / or colloidal silica. Among them, the anti-adhesive effect of talc powder is preferably greater than that of colloidal silica.

[0040] In the present invention, the light-shielding agent may be titanium dioxide and / or talc powder. Among them, the light-shielding effect of titanium dioxide is preferably greater than that of talc powder.

[0041] In a preferred embodiment of the present invention, the coating solution for the barrier layer more preferably comprises a retarder (such as zein), or, a retarder (such as talc powder), a water-soluble gel material (such as hydroxypropyl methylcellulose), and a sugar (such as sucrose), or, a retarder (such as cetyl alcohol or ethyl cellulose) and a water-soluble gel material (such as hydroxypropyl methylcellulose); wherein, the ethyl cellulose is preferably an ethyl cellulose aqueous dispersion with a solids content of 25%.

[0042] Those skilled in the art can understand that the coating solution for the barrier layer of the present invention may further comprise a solvent. The solvent may be a conventional solvent in the coating solution for the barrier layer of the duloxetine hydrochloride enteric-coated preparation. The present invention preferably uses water, such as purified water. In the coating solution for the barrier layer, the mass of the solvent is preferably 0.8 to 11 times the mass of the retarder.

[0043] In the coating solution for the barrier layer of the present invention, the contents of each component are the same as those of each component in the following barrier layer. Among them, the weight % refers to the weight percentage of each component respectively accounting for the total weight of the barrier coating solution.

[0044] The present invention also provides a barrier layer for a duloxetine hydrochloride enteric-coated preparation, which can be obtained by drying the above coating solution for the barrier layer.

[0045] As is well known to those skilled in the art, the coating solution for the barrier layer generally needs to be coated on the drug-containing pellets with a main drug layer, and after drying, a barrier layer is obtained. In the present invention, the coating solution for the barrier layer can be coated on the drug-containing pellets with a main drug layer, dried, to obtain drug-containing pellets with a barrier layer.

[0046] In the present invention, the barrier layer is wrapped on the surface of the drug-containing pellets with a main drug layer, and functions to prevent the drug from contacting the enteric layer containing acidic groups, thereby ensuring the stability of the drug.

[0047] The present invention also provides a separating layer for an enteric-coated duloxetine hydrochloride preparation, which comprises a retardant.

[0048] The retardant is preferably selected from one or more of talc, zein, carnauba wax, ethyl cellulose, cetyl alcohol and cetylstearyl alcohol, more preferably selected from one or more of talc, zein and cetyl alcohol, and further preferably selected from zein and / or cetyl alcohol.

[0049] In the present invention, the particle size of talc in the retardant can be 5 - 50 μm, preferably 6 - 25 μm (such as 6.5 μm, 10 μm, 13 μm, 23 μm), and more preferably 6.5 - 13 μm.

[0050] In some embodiments of the present invention, the separating layer may further comprise one or more of a water-soluble gel material, a plasticizer, an antifoaming agent, an anti-adhesive agent, a sugar and a light-shielding agent.

[0051] In the present invention, the water-soluble gel material can be one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone and hydroxypropyl cellulose, and is preferably hydroxypropyl methylcellulose.

[0052] In the present invention, the sugar can be one or more of sucrose, lactose, mannitol, xylitol, maltitol and sorbitol, and is preferably sucrose and / or lactose.

[0053] In the present invention, the anti-adhesive agent can be one or more of talc, ethyl cellulose, cetyl alcohol, cetylstearyl alcohol, microcrystalline silica, glycerol monostearate and magnesium stearate, and is preferably talc and / or microcrystalline silica, wherein the anti-adhesive effect of talc is greater than that of microcrystalline silica.

[0054] In the present invention, the light-shielding agent can be titanium dioxide and / or talc, wherein the light-shielding effect of titanium dioxide is greater than that of talc.

[0055] In a preferred embodiment of the present invention, the separating layer coating solution more preferably comprises a retardant (such as zein), or a retardant (such as talc), a water-soluble gel material (such as hydroxypropyl methylcellulose) and a sugar (such as sucrose), or a retardant (such as cetyl alcohol or ethyl cellulose) and a water-soluble gel material (such as hydroxypropyl methylcellulose); wherein, the ethyl cellulose is preferably an ethyl cellulose aqueous dispersion with a solids content of 25%.

[0056] In the separating layer, the content of the retardant accounts for 0 wt% - 100 wt% and is not 0, preferably accounts for 25 wt% - 100 wt%, such as 50 wt%, 57.9 wt%, 61.6 wt%, 83.3 wt% or 100 wt%.

[0057] When the barrier layer comprises a water-soluble gel material, in the barrier layer, the content of the water-soluble gel material preferably accounts for 0 wt% - 60 wt% and is not 0, more preferably 9 wt% - 58 wt%, such as 9.8 wt%, 10.0 wt%, 16.7 wt%, 25 wt%, 30.8 wt%, 57.1 wt% or 25 wt%. When the barrier layer comprises a plasticizer, in the barrier layer, the content of the plasticizer preferably accounts for 0 wt% - 20 wt% and is not 0. When the barrier layer comprises an antifoaming agent, in the barrier layer, the content of the antifoaming agent preferably accounts for 0 wt% - 3 wt% and is not 0. When the barrier layer comprises sugar, in the barrier layer, the content of the sugar preferably accounts for 0 wt% - 50 wt% and is not 0, more preferably 3 wt% - 42 wt%, such as 14.3 wt%, 40 wt%, 3.8 wt%, 25 wt% or 32.3 wt%. When the barrier layer comprises an anti-adhesive agent, in the barrier layer, the content of the anti-adhesive agent preferably accounts for 0 wt% - 85 wt% and is not 0, more preferably 3 wt% - 60 wt%, such as 3.8 wt%, 50 wt%, 57.9 wt% or 83.3 wt%. When the barrier layer comprises a light-shielding agent, in the barrier layer, the content of the light-shielding agent preferably accounts for 0 wt% - 70 wt% and is not 0, more preferably 20 wt% - 65 wt%, such as 28.6 wt%, 50 wt%, 57.9 wt% or 61.6 wt%.

[0058] In some embodiments of the present invention, the barrier layer preferably comprises a retarder, and one or more of a water-soluble gel material, sugar, a light-shielding agent and an anti-adhesive agent. Among them, in the barrier layer, the content of the retarder preferably accounts for 25 wt% - 100 wt%, but not 100%; in the barrier layer, the content of the water-soluble gel material preferably accounts for 9 wt% - 58 wt%; in the barrier layer, the content of the sugar preferably accounts for 3 wt% - 42 wt%; in the barrier layer, the content of the light-shielding agent preferably accounts for 20 wt% - 65 wt%; in the barrier layer, the content of the anti-adhesive agent preferably accounts for 3 wt% - 60 wt%.

[0059] In some embodiments of the present invention, the barrier layer preferably consists of a retarder.

[0060] In some embodiments of the present invention, the barrier layer preferably consists of a retarder, and one or more of a water-soluble gel material, sugar, a light-shielding agent and an anti-adhesive agent. For example: the barrier layer coating solution more preferably consists of a retarder (such as zein), or consists of a retarder (such as talc), a water-soluble gel material (such as hydroxypropyl methylcellulose) and sugar (such as sucrose), or consists of a retarder (such as cetyl alcohol or ethylcellulose) and a water-soluble gel material (such as hydroxypropyl methylcellulose).

[0061] The weight percentages described above refer to the weight percentages of the respective components accounting for the total weight of the isolation layer.

[0062] In the present invention, the component contents of the water-soluble gel material, plasticizer, defoaming agent, retarder, anti-adhesive, sugar, and light-shielding agent can be appropriately selected according to the defined ranges of conventional contents in the art.

[0063] An enteric-coated duloxetine hydrochloride preparation provided by the present invention comprises the above-mentioned active ingredient layer and / or isolation layer.

[0064] The enteric-coated duloxetine hydrochloride preparation provided by the present invention may further comprise an enteric layer.

[0065] In the present invention, the enteric layer is wrapped on the surface of the isolation layer, and the enteric layer comprises a pharmaceutically acceptable enteric material and a pharmaceutically acceptable auxiliary material, mainly functioning to prevent the drug from being released in the stomach and thus being destroyed by gastric acid.

[0066] Among them, the pharmaceutically acceptable auxiliary materials in the enteric layer preferably include one or more of a plasticizer, a defoaming agent, an anti-adhesive, and a light-shielding agent.

[0067] In some embodiments of the present invention, the pharmaceutically acceptable enteric material preferably includes one or more of pharmaceutical acrylic resin, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), polyvinyl alcohol phthalate (PVAP), and cellulose acetate trimellitate (CAT).

[0068] In some embodiments of the present invention, the main function of the plasticizer in the enteric layer is to lower the glass transition temperature of the coating material and increase its toughness. Specifically, it can be selected from one or more of triethyl citrate (TEC), tributyl citrate, triacetin, and tributyl acetyl citrate, preferably triethyl citrate (TEC). The anti-adhesive in the enteric layer can make the coating layer thicker, enhance its strength, reduce static charges, and lower the adhesiveness of particles. Specifically, it can be selected from one or more of talc powder (Talc), microcrystalline silica gel, and glyceryl monostearate, preferably talc powder (Talc).

[0069] In the enteric-coated layer, the content of the pharmaceutically acceptable enteric material preferably accounts for 0 wt% - 100 wt% and is not 0, more preferably accounts for 60 wt% - 75 wt%, for example, 67.3 wt%, 60.5 wt%, 68.9 wt%, 71.1 wt% or 66.7 wt%. When the enteric-coated layer includes a plasticizer, in the enteric-coated layer, the content of the plasticizer preferably accounts for 0 wt% - 30 wt% and is not 0, more preferably accounts for 7 wt% - 15 wt%, for example, 7.2 wt%, 8.2 wt%, 9.2 wt%, 10.4 wt% or 12.6 wt%. When the enteric-coated layer includes an antifoaming agent, in the enteric-coated layer, the content of the antifoaming agent preferably accounts for 0 wt% - 3 wt% and is not 0. When the enteric-coated layer includes an anti-adhesive agent, in the enteric-coated layer, the content of the anti-adhesive agent preferably accounts for 0 wt% - 40 wt%, more preferably accounts for 20 wt% - 32 wt%, for example, 20.1 wt%, 20.7 wt%, 21.7 wt%, 25.1 wt% or 30.3 wt%. When the enteric-coated layer includes a light-shielding agent, in the enteric-coated layer, the content of the light-shielding agent preferably accounts for 0 wt% - 10 wt% and is not 0. The wt% mentioned above refers to the weight percentage of each component accounting for the total weight of the enteric-coated layer respectively.

[0070] In some embodiments of the present invention, the enteric-coated layer preferably comprises the following components: an enteric material, an anti-adhesive agent, and a plasticizer; wherein, in the enteric-coated layer, the content of the enteric material preferably accounts for 60 wt% - 75 wt%, and the content of the anti-adhesive agent preferably accounts for 20 wt% - 32 wt%.

[0071] In some embodiments of the present invention, the enteric-coated layer consists of an enteric material (such as HPMCAS), an anti-adhesive agent (such as talc powder), and a plasticizer (such as TEC).

[0072] In the present invention, the preparation method of the enteric-coated layer comprises the following steps: drying the enteric-coated layer coating solution, wherein the enteric-coated layer coating solution comprises the materials (pharmaceutically acceptable enteric materials and pharmaceutically acceptable excipients) and solvents in the enteric-coated layer as described above.

[0073] Those skilled in the art all know that the enteric-coated layer coating solution generally needs to be coated on the drug-containing pellets with a separating layer, and after drying, an enteric-coated layer is obtained. In the present invention, the enteric-coated layer coating solution can be coated on the drug-containing pellets with a separating layer, dried, to obtain drug-containing pellets with an enteric-coated layer.

[0074] In the present invention, the enteric-coated layer coating solution can be a conventional enteric-coated layer coating solution in the enteric-coated duloxetine hydrochloride preparation, and can comprise an enteric material, and one or more of a plasticizer, an antifoaming agent, an anti-adhesive agent, and a light-shielding agent, and a solvent.

[0075] In some embodiments of the present invention, the enteric coating material preferably comprises one or more of pharmaceutical acrylic resins, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), polyvinyl alcohol phthalate (PVAP), and cellulose acetate trimellitate (CAT).

[0076] In some embodiments of the present invention, the main function of the plasticizer in the enteric coating solution is to lower the glass transition temperature of the coating material and increase its toughness. Specifically, it can be selected from one or more of triethyl citrate (TEC), tributyl citrate, triacetin, and tributyl acetylcitrate, preferably triethyl citrate (TEC); the anti-sticking agent in the enteric coating solution can make the coating layer thicker, enhance its strength, reduce static charges, and lower the adhesiveness of particles. Specifically, it can be selected from one or more of talc, colloidal silica, and glyceryl monostearate, preferably talc; the solvent in the enteric coating solution is an ethanol aqueous solution or water.

[0077] The pH value of the enteric coating solution can be adjusted according to needs using a conventional pH regulator in the art. Preferably, the pH value is adjusted to about 7.0. The pH regulator can be ammonia water.

[0078] Those skilled in the art can understand that the enteric coating solution of the present invention may further comprise a solvent. The solvent can be a conventional solvent in the enteric coating solution of the duloxetine hydrochloride enteric preparation. The present invention preferably uses an alcohol-aqueous solution, such as an ethanol aqueous solution. The amounts of alcohol and water in the alcohol-aqueous solution may not be particularly limited, and 80% V / V is preferred, where % V / V refers to the volume percentage of alcohol in the total volume of alcohol and water.

[0079] In the enteric coating solution described above, when the enteric material is included, the content preferably accounts for 0 wt% - 100 wt% and is not 0, more preferably 60 wt% - 75 wt%, for example, 67.3 wt%, 60.5 wt%, 68.9 wt%, 71.1 wt% or 66.7 wt%; when a plasticizer is included, the content preferably accounts for 0 wt% - 30 wt% and is not 0, more preferably 7 wt% - 15 wt%, for example, 7.2 wt%, 8.2 wt%, 9.2 wt%, 10.4 wt% or 12.6 wt%; when an antifoaming agent is included, the content preferably accounts for 0 wt% - 3 wt% and is not 0; when an anti-adhesive agent is included, the content preferably accounts for 0 wt% - 40 wt%, more preferably 20 wt% - 32 wt%, for example, 20.1 wt%, 20.7 wt%, 21.7 wt%, 25.1 wt% or 30.3 wt%; when a light-blocking agent is included, the content preferably accounts for 0 wt% - 10 wt% and is not 0; the wt% described above refers to the weight percentage of each component respectively accounting for the total weight of the enteric layer.

[0080] In some embodiments of the present invention, the enteric coating solution preferably comprises the following components: an enteric material, an anti-adhesive agent and a plasticizer; wherein, in the enteric layer, the content of the enteric material preferably accounts for 60 wt% - 75 wt%, and the content of the anti-adhesive agent preferably accounts for 20 wt% - 32 wt%.

[0081] As appropriate, further, the duloxetine hydrochloride enteric preparation of the present invention may further comprise a modifying layer.

[0082] In the present invention, the modifying layer is formed by spraying a polymer material on the surface of the enteric layer. The polymer material is preferably hydroxypropyl methylcellulose and / or polyvinylpyrrolidone. The polymer material may further comprise a light-blocking agent and / or a bulking agent, and a commercially available film coating premix may also be used; the bulking agent is such as talc and / or a colorant; the colorant can be appropriately selected according to the routine in the art.

[0083] The modifying layer may further comprise excipients, and the excipients may be conventional excipients for the modifying layer in the pharmaceutical field, preferably one or more of talc, hydroxypropyl methylcellulose and titanium dioxide, more preferably talc and hydroxypropyl methylcellulose, or hydroxypropyl methylcellulose and titanium dioxide.

[0084] In addition, the modifying layer can also be directly mixed with the enteric-coated drug pellets with a small amount of the above materials; the components and contents of the above materials can be appropriately selected according to the conventional defined ranges in the art.

[0085] In the present invention, the enteric-coated duloxetine hydrochloride preparation may further include other pharmaceutically active ingredients as needed. The other pharmaceutically active ingredients can be selected according to conventional methods in the art, as long as they do not produce antagonistic effects with duloxetine hydrochloride.

[0086] The enteric-coated duloxetine hydrochloride preparation provided by the present invention is selected from any one of the following three:

[0087] Preparation (I):

[0088] (1) The above-mentioned main drug layer;

[0089] (2) A separating layer without a retarder;

[0090] (3) An enteric layer;

[0091] Preparation (II):

[0092] (1) The main drug layer (the main drug layer conventional in the prior art);

[0093] (2) The above-mentioned separating layer;

[0094] (3) An enteric layer;

[0095] Preparation (III):

[0096] (1) The above-mentioned main drug layer;

[0097] (2) The above-mentioned separating layer;

[0098] (3) An enteric layer;

[0099] In some embodiments of the present invention, in Preparation (II), the main drug layer may be the main drug layer conventional in the enteric-coated duloxetine hydrochloride preparation.

[0100] In some embodiments of the present invention, in Preparations (I) to (III), the enteric layer may be the enteric layer conventional in the enteric-coated duloxetine hydrochloride preparation, preferably the above-mentioned enteric layer.

[0101] In some embodiments of the present invention, in Preparations (I) to (III), the enteric-coated duloxetine hydrochloride preparation further includes a modifying layer outside the drug-containing pellets having an enteric layer.

[0102] In the present invention, the enteric-coated duloxetine hydrochloride preparation may be a capsule or a multi-particle pellet tablet.

[0103] The present invention also provides an enteric-coated duloxetine hydrochloride preparation and a method for preparing the same, and the preparation method is selected from any one of the following three methods:

[0104] Method (I):

[0105] (1) Prepare the suspension of the active ingredient layer of the duloxetine hydrochloride enteric-coated preparation according to the aforementioned method, and coat the obtained suspension of the active ingredient layer onto the blank pellets to obtain the medicated pellets with the active ingredient layer.

[0106] (2) Coat the separating layer coating solution without retarder onto the surface of the medicated pellets with the active ingredient layer obtained in step (1) to obtain the medicated pellets with the separating layer.

[0107] (3) Coat the enteric layer coating solution onto the surface of the medicated pellets with the separating layer obtained in step (2) to obtain the medicated pellets with the enteric layer.

[0108] Method (II):

[0109] (1) Coat the active ingredient layer coating solution onto the blank pellets to obtain the medicated pellets with the active ingredient layer.

[0110] (2) Coat the separating layer coating solution prepared according to the aforementioned method onto the surface of the medicated pellets with the active ingredient layer obtained in step (1) to obtain the medicated pellets with the separating layer.

[0111] (3) Coat the enteric layer coating solution onto the surface of the medicated pellets with the separating layer obtained in step (2) to obtain the medicated pellets with the enteric layer.

[0112] Method (III):

[0113] (1) Prepare the suspension of the active ingredient layer of the duloxetine hydrochloride enteric-coated preparation according to the aforementioned method, and coat the obtained suspension of the active ingredient layer onto the blank pellets to obtain the medicated pellets with the active ingredient layer.

[0114] (2) Coat the separating layer coating solution prepared according to the aforementioned method onto the surface of the medicated pellets with the active ingredient layer obtained in step (1) to obtain the medicated pellets with the separating layer.

[0115] (3) Coat the enteric layer coating solution onto the surface of the medicated pellets with the separating layer obtained in step (2) to obtain the medicated pellets with the enteric layer.

[0116] In some embodiments of the present invention, in the preparation method of the duloxetine hydrochloride enteric-coated preparation, after step (3), it further includes an operation of coating a modifying layer onto the medicated pellets with the enteric layer by a conventional method to obtain the medicated pellets with the modifying layer.

[0117] In some embodiments of the present invention, the excipients in the modifying layer can be conventional excipients for the modifying layer in the pharmaceutical field, preferably selected from one or more of talc powder, HPMC, and TiO2, more preferably talc powder and HPMC, or HPMC and TiO2.

[0118] In some embodiments of the present invention, in method (I), in step (2), the barrier-free layer coating solution can be a conventional barrier-free layer coating solution for enteric-coated duloxetine hydrochloride preparations, such as the barrier-free layer coating solutions disclosed in US5508276, CN100362996C, CN105534949A, and CN104107169A mentioned in the background art.

[0119] In some embodiments of the present invention, in method (II), in step (1), the drug layer coating solution can be a conventional drug layer coating solution for enteric-coated duloxetine hydrochloride preparations, such as the drug layer coating solutions disclosed in US5508276, CN100362996C, CN105534949A, and CN104107169A mentioned in the background art.

[0120] In some embodiments of the present invention, in methods (I) to (III), in step (3), the enteric layer coating solution can be a conventional enteric layer coating solution for enteric-coated duloxetine hydrochloride preparations (such as the enteric layer coating solutions disclosed in US5508276, CN100362996C, CN105534949A, and CN104107169A mentioned in the background art) or the enteric layer coating solution mentioned in the present invention.

[0121] In some embodiments of the present invention, in methods (I) to (III), in step (1), the blank pellets can be blank pellets conventional in the pharmaceutical field, preferably selected from one or more of sugar pellets, starch pellets, lactose pellets, lactose-starch pellets, sucrose-starch pellets, silica pellets, and microcrystalline cellulose pellets, more preferably sugar pellets and / or microcrystalline cellulose pellets.

[0122] In some embodiments of the present invention, the particle size of the blank pellets can be the conventional particle size of blank pellets conventional in the pharmaceutical field, preferably 150 - 1100 μm, more preferably 170 - 750 μm, such as 180 - 250 μm, 250 - 300 μm, 500 - 600 μm, 600 - 710 μm.

[0123] In some embodiments of the present invention, in methods (I) to (III), in step (1), the dosage of the drug layer can be the conventional dosage in the pharmaceutical field, preferably such that the resulting drug-containing pellets with a drug layer have a weight gain of 2% - 80% w / w, preferably 15% - 80% w / w, more preferably 60% - 80% w / w, compared to the blank pellets, such as 19.6%, 44%, 59.52%, 60%, 70%, 78%, 78.1%.

[0124] In some embodiments of the present invention, in methods (I) to (III), in step (1), the coating operation can be a conventional coating operation in the pharmaceutical field. A bottom spray coater can be selected for the coating operation, such as a Glatt GPCG2 fluid bed or similar equipment. The present invention preferably includes the following steps: when using a Glatt GPCG2 fluid bed, the atomization pressure is 0.2 Mpa, and other equipment can be adjusted accordingly. When using method I or III, the material temperature is controlled at about 35°C, and when using method II, the material temperature is controlled at about 40°C. The inlet air volume is adjusted according to the flow condition of the pellets, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature.

[0125] In some embodiments of the present invention, in methods (I) to (III), after the coating operation in step (1), a drying operation may further be included. The drying operation can be a conventional drying operation in the pharmaceutical field. The drying time is preferably 10 min.

[0126] In some embodiments of the present invention, in methods (I) to (III), in step (2), the coating can be a conventional coating operation in the pharmaceutical field, such as sugar coating pan coating or fluid bed coating. After the coating operation, a drying operation may further be included. The drying operation can be a conventional drying operation in the pharmaceutical field. The amount of the isolating layer can be a conventional amount in the pharmaceutical field. Preferably, the weight gain of the medicated pellets with the isolating layer compared to the medicated pellets with the main drug layer is preferably 2% - 50% w / w, more preferably 2% - 40% w / w, and most preferably 2% - 6% w / w.

[0127] In the present invention, the enteric layer is wrapped on the surface of the isolating layer. The enteric layer includes a pharmaceutically acceptable enteric material and a pharmaceutically acceptable excipient, mainly serving to prevent the drug from being released in the stomach and being destroyed by gastric acid.

[0128] In some embodiments of the present invention, in modes (I) to (III), in step (3), the enteric coating solution of the drug-containing pellets with an enteric layer can be a conventional enteric coating solution in duloxetine hydrochloride enteric preparations, and can include an enteric material, and one or more of a plasticizer, an antifoaming agent, an anti-adhesive agent, and a light-shielding agent, as well as a solvent, and the solvent is an aqueous ethanol solution or water. The enteric coating solution can be adjusted to a pH value according to needs by using a conventional pH regulator in the art. Preferably, the pH value is adjusted to about 7.0. The pH regulator can be ammonia water. The coating can be a conventional coating operation in the pharmaceutical field. After the coating operation is completed, a drying operation can also be included. The drying can be a conventional drying in the pharmaceutical field. The dosage of the enteric layer can be a conventional dosage in the pharmaceutical field. Preferably, the obtained drug-containing pellets with an enteric layer have a weight gain of preferably 15%-40% w / w, more preferably 20%-30% w / w, compared with the drug-containing pellets with a barrier layer.

[0129] In some embodiments of the present invention, in modes (I) to (III), in step (3), when the enteric layer includes an enteric material, in the enteric layer, the content of the enteric material preferably accounts for 0 wt%-100 wt% and is not 0, more preferably accounts for 60 wt%-75 wt%, for example, 67.3 wt%, 60.5 wt%, 68.9 wt%, 71.1 wt% or 66.7 wt%; when the enteric layer includes a plasticizer, in the enteric layer, the content of the plasticizer preferably accounts for 0 wt%-30 wt% and is not 0, more preferably accounts for 7 wt%-15 wt%, for example, 7.2 wt%, 8.2 wt%, 9.2 wt%, 10.4 wt% or 12.6 wt%; when the enteric layer includes an antifoaming agent, in the enteric layer, the content of the antifoaming agent preferably accounts for 0 wt%-3 wt% and is not 0; when the enteric layer includes an anti-adhesive agent, in the enteric layer, the content of the anti-adhesive agent preferably accounts for 0 wt%-40 wt%, more preferably accounts for 20 wt%-32 wt%, for example, 20.1 wt%, 20.7 wt%, 21.7 wt%, 25.1 wt% or 30.3 wt%; when the enteric layer includes a light-shielding agent, in the enteric layer, the content of the light-shielding agent preferably accounts for 0 wt%-10 wt% and is not 0; the above-mentioned wt% refers to the weight percentage of each component accounting for the total weight of the enteric layer.

[0130] In some embodiments of the present invention, in modes (I) to (III), in step (3), the enteric coating solution preferably includes the following components: an enteric material, an anti-adhesive agent, and a plasticizer; wherein, in the enteric layer, the content of the enteric material preferably accounts for 60 wt%-75 wt%, and the content of the anti-adhesive agent preferably accounts for 20 wt%-32 wt%.

[0131] In the present invention, the modifying layer is formed by spraying a polymer material on the surface of the enteric coating layer. The polymer material is preferably hydroxypropyl methylcellulose and / or polyvinylpyrrolidone. The polymer material may also include a light-blocking agent and / or a bulking agent, and may also use a commonly available commercial film coating premix; the bulking agent is such as talc powder and / or a colorant; the colorant can be appropriately selected according to the routine in the art. The drug-containing pellets with the modifying layer preferably have a weight gain of 1%-10% w / w compared to the drug-containing pellets with the enteric coating layer.

[0132] The modifying layer may also include excipients, and the excipients may be the conventional excipients for the modifying layer in the pharmaceutical field, preferably one or more of talc powder, hydroxypropyl methylcellulose and titanium dioxide, more preferably talc powder and hydroxypropyl methylcellulose, or hydroxypropyl methylcellulose and titanium dioxide.

[0133] In addition, the modifying layer can also be directly mixed with the drug-containing pellets of the enteric coating layer with a small amount of the above materials; the components and contents of the above materials can be appropriately selected according to the conventional defined range in the art.

[0134] In the present invention, the enteric-coated duloxetine hydrochloride preparation may further include other pharmaceutically active ingredients as needed. The other pharmaceutically active ingredients can be selected according to the conventional methods in the art as long as they do not produce an antagonistic effect with duloxetine hydrochloride.

[0135] As needed, the enteric-coated duloxetine hydrochloride preparation can be prepared into a capsule or a multi-particle pellet tablet. For example, by using the well-known methods in the art, the drug-containing pellets can be prepared into a capsule, or can be mixed with other excipients and pressed into an enteric-coated multi-particle pellet tablet.

[0136] In the Chinese Pharmacopoeia, "very soluble, freely soluble, soluble, sparingly soluble, slightly soluble, very slightly soluble, practically insoluble or insoluble" is used to describe the dissolution properties of drugs in different solvents, and the specific reference standards are as follows:

[0137] Very soluble It means that 1 g (ml) of solute can dissolve in less than 1 ml of solvent Freely soluble It means that 1 g (ml) of solute can dissolve in 1 - less than 10 ml of solvent Soluble It means that 1 g (ml) of solute can dissolve in 10 - less than 30 ml of solvent Sparingly soluble It means that 1 g (ml) of solute can dissolve in 30 - less than 100 ml of solvent Slightly soluble It means that 1 g (ml) of solute can dissolve in 100 - less than 1000 ml of solvent Very slightly soluble It means that 1 g (ml) of solute can dissolve in 1000 - less than 10000 ml of solvent Practically insoluble or insoluble It means that 1 g (ml) of solute cannot completely dissolve in 10000 ml of solvent

[0138] When those skilled in the art want to detect the solubility of raw materials in different solvents, as long as the raw materials are sparingly soluble or less in the solvent, they are all better solvents. The test method for the solubility of raw materials is as follows:

[0139] Unless otherwise specified, weigh the powdered test sample or measure the liquid test sample, place it in a certain volume of solvent at 25°C ± 2°C, shake it strongly for 30 s every 5 min, and observe the dissolution situation within 30 min. If there are no visually visible solute particles or droplets, it is regarded as completely dissolved.

[0140] The selection of the organic solvent can refer to the classification and residual limits of commonly used organic solvents in ICH. Since residual solvents have no therapeutic effect, all residual solvents should be removed as much as possible to meet product specifications, GMP or other basic quality requirements. The level of residual solvents contained in the preparation should not be higher than the safety value. It is known that some solvents can cause unacceptable toxicity (Class 1). Unless it is proven to be particularly reasonable, they should be avoided in the production of the active ingredient, excipients and preparations. Some solvents with relatively low toxicity (Class 2) should be used restrictively to prevent potential adverse reactions in patients. It is more desirable to use low-toxic solvents (Class 3).

[0141] On the basis of not violating the common knowledge in this field, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0142] The reagents and raw materials used in the present invention are all commercially available.

[0143] The positive and progressive effects of the present invention are as follows:

[0144] (1) In the preparation process of the enteric-coated duloxetine hydrochloride preparation of the present invention, the suspension coating method of organic solvent is adopted. Therefore, duloxetine hydrochloride is insoluble in the organic solvent, the production efficiency is greatly improved, and the risk of possible crystal form transformation caused by recrystallization during the dissolution of duloxetine hydrochloride in the solvent and the evaporation of the solvent is reduced. At the same time, the problems that affect production, such as easy adhesion and granulation of the main drug layer during the coating process, are overcome, and then the integrity of the isolation layer and enteric layer is ensured, and excellent dissolution and stability are obtained. In addition, the related substances can be significantly reduced, the bioavailability is high, and the individual difference is small.

[0145] (2) In the preparation process of the enteric-coated duloxetine hydrochloride preparation of the present invention, a specific retarder is adopted, which greatly reduces the amount of the isolation layer, effectively isolates duloxetine hydrochloride from the enteric material, but does not affect the release of the drug, and greatly improves the stability of the drug.

[0146] (3) The preparation method of the enteric-coated duloxetine hydrochloride preparation of the present invention is simple. During the production process, fewer equipment can be used, the operation is simple, the process parameters are easy to master, and technicians can easily master the equipment and conditions required for the coating step. Moreover, the production efficiency is greatly improved, and it is easy to be industrialized. BRIEF DESCRIPTION OF THE DRAWINGS

[0147] Figure 1 It shows the plasma concentration-time curve of the enteric-coated duloxetine hydrochloride preparation capsule (test reagent) of Example 3 and the positive control drug (reference reagent) under fasting conditions.

[0148] Figure 2It shows the plasma concentration-time curves of the enteric-coated duloxetine hydrochloride capsules of Example 3 (test agent) and the positive control drug (reference agent) under a high-fat meal condition.

[0149] Figure 3 It shows the plasma concentration-time curves of the enteric-coated duloxetine hydrochloride capsules of Example 9 (test agent) and the positive control drug (reference agent) under a fasting condition.

[0150] Figure 4 It shows the plasma concentration-time curves of the enteric-coated duloxetine hydrochloride capsules of Example 9 (test agent) and the positive control drug (reference agent) under a high-fat meal condition. Detailed implementation manners

[0151] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0152] In the following examples, the HPMCAS is hypromellose acetate succinate; the PVP K30 is polyvinylpyrrolidone K30; the TEC is triethyl citrate; the HPMC is hydroxypropyl methylcellulose;

[0153] The trace amount is an extremely small amount and its dosage can be ignored.

[0154] Preparation of enteric-coated duloxetine hydrochloride preparation in Example 1

[0155] Table 1

[0156]

[0157] The preparation steps are as follows:

[0158] Main drug layer: 40 parts by weight of HPMC is dispersed in about 2000 parts by weight of isopropanol. After dissolution, 350 parts by weight of duloxetine hydrochloride with a d90 particle size of 38 μm is added and uniformly stirred and suspended therein to form a suspension of the medicinal liquid, wherein the solid content of duloxetine hydrochloride in isopropanol is about 17.5%; then it is coated on the surface of 500 parts by weight of sugar pills as blank pellets with a particle size of 600 - 710 μm by a granulating and coating machine in a bottom spraying manner. After the coating is completed, the product is discharged and sieved to obtain medicated pellets with a main drug layer. The process parameters of the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 35°C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying of the liquid is completed, the product is dried for 10 min.

[0159] Isolation layer: 71.2 parts by weight of HPMC was dispersed in about 1100 parts by weight of purified water. After dissolution, 17.8 parts by weight of sucrose and 35.6 parts by weight of titanium dioxide were added, and the mixture was stirred evenly to prepare a coating solution. Then, the coating solution was applied to the surface of the drug-containing pellets prepared in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with an isolation layer. The process parameters for the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product was dried for 10 min.

[0160] Enteric-coated layer: 202 parts by weight of HPMCAS was dissolved in about 3800 parts by weight of an ethanol aqueous solution, and the mixture was stirred evenly to prepare a coating solution. Then, the coating solution was applied to the surface of the drug-containing pellets with an isolation layer prepared in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with an enteric-coated layer. The process parameters for the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 38 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product was dried for 10 min.

[0161] Modifying layer: Trace amounts of talc powder were mixed with the drug-containing pellets with an enteric-coated layer prepared in the above step to obtain drug-containing pellets with a modifying layer.

[0162] The obtained drug-containing pellets with a modifying layer were filled into gelatin capsules to obtain capsules of duloxetine hydrochloride enteric-coated preparations.

[0163] Preparation of duloxetine hydrochloride enteric-coated preparation in Example 2

[0164] The specific formulation is shown in Table 2 below:

[0165] Table 2

[0166]

[0167] The duloxetine hydrochloride enteric-coated preparation of Example 2 was prepared by the same method as in Example 1.

[0168] Preparation of duloxetine hydrochloride enteric-coated preparation in Example 3

[0169] The specific formulation is shown in Table 3 below.

[0170] Table 3

[0171]

[0172]

[0173] The duloxetine hydrochloride enteric-coated preparation of Example 3 was prepared by the same method as in Example 1.

[0174] Example 4 Preparation of Duloxetine Hydrochloride Enteric-coated Preparation

[0175] The specific formula is shown in Table 4 below.

[0176] Table 4

[0177]

[0178] The preparation steps are as follows:

[0179] Main drug layer: Disperse 40 parts by weight of HPMC in approximately 2000 parts by weight of isopropyl alcohol. Once dissolved, add 350 parts by weight of duloxetine hydrochloride with a particle size of approximately 11 μm. Stir thoroughly and suspend the mixture to form a drug suspension, wherein the solids content of duloxetine hydrochloride in the isopropyl alcohol is approximately 17.5%. Then, use a granulator coater to bottom-spray coat 500 parts by weight of sugar pills with a particle size of 600-710 μm. After coating, discharge and sieve to produce drug-containing pellets with the main drug layer. The coating process parameters are: atomization pressure of 0.2 MPa, material temperature maintained at 35°C, and inlet air temperature automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 minutes.

[0180] Seal layer: Disperse 89 parts by weight of HPMC in approximately 1400 parts by weight of purified water. Once dissolved, add 89 parts by weight of sucrose and 178 parts by weight of talc. Stir thoroughly to form a coating solution. The solution is then applied to the surface of the drug-containing pellets prepared in the above step using a granulator-coating machine via a bottom spray method to produce drug-containing pellets with a seal layer. The coating process parameters are: atomization pressure of 0.2 MPa, material temperature maintained at 43°C, and inlet air temperature automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 minutes.

[0181] Enteric layer: Dissolve 224 parts by weight of HPMCAS in approximately 3800 parts by weight of ethanol-water solution, stir evenly, add 112 parts by weight of talc and 34 parts by weight of TEC (triethyl citrate) to prepare a coating solution. This solution is then applied to the surface of the drug-containing pellets with the isolation layer prepared in the above step using a granulator-coating machine via a bottom spray method to produce drug-containing pellets with an enteric layer. The coating process parameters are: atomization pressure of 0.2 MPa, material temperature maintained at 36°C, and inlet air temperature automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 minutes.

[0182] Modified layer: 8 parts by weight of HPMC was dispersed in about 3600 parts by weight of purified water. After dissolution, 32 parts by weight of titanium dioxide was added to prepare a coating solution, and then it was coated on the surface of the drug-containing pellets with an enteric layer prepared in the above step by a bottom spraying method using a granulating and coating machine, thereby obtaining drug-containing pellets with a modified layer. The process parameters of the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 min.

[0183] The prepared drug-containing pellets with a modified layer were filled into gelatin capsules to obtain the capsules of duloxetine hydrochloride enteric preparation.

[0184] Preparation of duloxetine hydrochloride enteric preparation in Example 5

[0185] The specific formula is shown in Table 5 below.

[0186] Table 5

[0187]

[0188] The preparation steps are as follows:

[0189] Main drug layer: 40 parts by weight of HPMC was dispersed in about 2000 parts by weight of ether. After dissolution, 350 parts by weight of duloxetine hydrochloride was added and stirred evenly and suspended therein to prepare a suspension of the drug solution, wherein the solid content of duloxetine hydrochloride in ether is about 17.5%; then it was coated on the surface of 500 parts by weight of sugar pellets with a particle size of 600 - 710 μm by a bottom spraying method using a granulating and coating machine. After coating, the product was discharged and screened to obtain drug-containing pellets with a main drug layer. The process parameters of the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 35 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 min.

[0190] Isolation layer: 1 part by weight of purified water and 1 part by weight of ethanol were mixed to prepare an ethanol aqueous solution. 35 parts by weight of HPMC was dispersed in about 1400 parts by weight of the ethanol aqueous solution. After dissolution, 115 parts by weight of sucrose and 206 parts by weight of talc were added and stirred evenly to prepare a coating solution, and then it was coated on the surface of the drug-containing pellets prepared in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with an isolation layer. The process parameters of the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 36 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 min.

[0191] Enteric-coated layer: 224 parts by weight of HPMCAS was dispersed in about 3800 parts by weight of purified water, stirred evenly, and ammonia water was added to adjust the pH to 7.0. Then 67.2 parts by weight of talcum powder and 34 parts by weight of triethyl citrate (TEC) were added to prepare a coating solution, and then it was coated on the surface of the drug-containing pellets with a barrier layer prepared in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with an enteric-coated layer. The process parameters for the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 43 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0192] Modified layer: 8 parts by weight of HPMC was dispersed in about 3600 parts by weight of purified water. After dissolution, 32 parts by weight of talcum powder was added to prepare a coating solution, and then it was coated on the surface of the drug-containing pellets with an enteric-coated layer prepared in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with a modified layer; the process parameters for the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0193] The prepared drug-containing pellets with a modified layer were filled into gelatin capsules to obtain the capsules of duloxetine hydrochloride enteric-coated preparation.

[0194] Preparation of duloxetine hydrochloride enteric-coated preparation in Example 6

[0195] The specific formula is shown in Table 6 below.

[0196] Table 6

[0197]

[0198]

[0199] The duloxetine hydrochloride enteric-coated preparation of Example 6 was prepared by the same method as in Example 4.

[0200] Preparation of duloxetine hydrochloride enteric-coated preparation in Example 7

[0201] The specific formula is shown in Table 7 below.

[0202] Table 7

[0203]

[0204] The preparation steps are as follows:

[0205] Main drug layer: The main drug layer was prepared by the method of Example 4.

[0206] Isolation layer: Dissolve zein in 180 parts by weight of 80% (v / v) ethanol solution, stir evenly to prepare a coating solution, and then coat it on the surface of the drug-containing pellets obtained in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with an isolation layer. The process parameters for the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 34 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 min.

[0207] Enteric-coated layer: Prepare the enteric-coated layer according to the method of Example 4. Among them, the ethanol aqueous solution is about 3300 parts by weight.

[0208] Modification layer: Disperse 58 parts by weight of Opadry 85G68918 in about 330 parts by weight of purified water to prepare a coating solution, and then coat it on the surface of the drug-containing pellets with an enteric-coated layer obtained in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with a modification layer; the process parameters for the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 min.

[0209] Load the obtained drug-containing pellets with a modification layer into gelatin capsules to obtain the capsules of the enteric-coated duloxetine hydrochloride preparation.

[0210] Preparation of enteric-coated duloxetine hydrochloride in Example 8

[0211] The specific formula is shown in Table 8 below.

[0212] Table 8

[0213]

[0214] The preparation steps are as follows:

[0215] Main drug layer: Prepare the main drug layer according to the method of Example 1.

[0216] Isolation layer: Disperse 7.2 parts by weight of HPMC in 440 parts by weight of 80% (v / v) ethanol solution, add 36 parts by weight of cetyl alcohol after dissolution, stir evenly to prepare a coating solution, and then coat it on the surface of the drug-containing pellets obtained in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with an isolation layer. The process parameters for the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 36 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 min.

[0217] Enteric-coated layer: The same as Example 4. Among them, the ethanol aqueous solution is about 1900 parts by weight.

[0218] Modified layer: 30 parts by weight of Opadry YS-1-7027 was dispersed in about 350 parts by weight of purified water to prepare a coating solution, and then the coating solution was applied to the surface of the drug-containing pellets with an enteric coating layer prepared in the above step by a bottom spraying method using a granulation and coating machine to obtain drug-containing pellets with a modified layer; the process parameters for the coating were: the atomization pressure was 0.2 Mpa, the material temperature was controlled at 42 °C, and the inlet air temperature was automatically controlled by the equipment to maintain the material temperature. After the spraying was completed, the product was dried for 10 min.

[0219] The obtained drug-containing pellets with a modified layer were filled into gelatin capsules to obtain capsules of duloxetine hydrochloride enteric preparations.

[0220] Example 9 Preparation of multi-particle pellets tablets of duloxetine hydrochloride enteric preparations

[0221] The specific formula is shown in Table 9 below.

[0222] Table 9

[0223]

[0224]

[0225] The general preparation steps are as follows:

[0226] The conventional wet granulation process in pharmacy was adopted. Specifically, 2 - 5 parts by weight of HPMC (hydroxypropyl methylcellulose) was dissolved in purified water as a binder, and then 20 - 50 parts by weight of microcrystalline cellulose and 40 - 70 parts by weight of lactose were mixed and added to the binder, and granulated and dried to obtain blank granules.

[0227] The obtained blank granules, 2 parts by weight of cross-linked polyvinylpyrrolidone and the drug-containing pellets of the duloxetine hydrochloride enteric preparations finally prepared in Examples 1 - 8 above were mixed, and finally 3 parts by weight of magnesium stearate was added and mixed evenly, and then compressed into tablets to obtain enteric multi-particle pellets tablets. Among them, preferably 200 parts by weight of the drug-containing pellets of Example 8 were used, and finally 3 parts by weight of magnesium stearate was added and mixed evenly, and then compressed into tablets to obtain enteric multi-particle pellets tablets, and these pellets tablets were used in the following effect examples.

[0228] The specific formula refers to Table 9 above.

[0229] Example 10 Preparation of duloxetine hydrochloride enteric preparations

[0230] The specific formula is shown in Table 10 below.

[0231] Table 10

[0232]

[0233]

[0234] The preparation steps are as follows:

[0235] Main drug layer: Dissolve 9.6 parts of PVP K30 in about 140 parts of dilute ethanol aqueous solution (30% V / V). After dissolution, add 22.4 parts of duloxetine hydrochloride, 0.24 parts of sodium bisulfite, 0.96 parts of poloxamer, 1.2 parts of microcrystalline silica, and 4.8 parts of sucrose, and stir evenly to obtain a liquid medicine solution. Then, coat it on the surface of sugar pills with a particle size of 600 - 710 μm by the bottom spraying method using a granulating and coating machine. After the coating is completed, discharge the material and perform screening to obtain medicated pellets with a main drug layer. The process parameters for the coating are: atomization pressure is 0.2 Mpa, control the material temperature at 38°C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying the liquid, dry the product for 10 min.

[0236] Isolation layer: Dissolve 12 parts by weight of zein in 132 parts by weight of ethanol aqueous solution (60 - 80%, V / V), stir evenly to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with a main drug layer by the bottom spraying method using a granulating and coating machine to obtain medicated pellets with an isolation layer. The process parameters for the coating are: atomization pressure is 0.2 Mpa, control the material temperature at 34°C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying the liquid, dry the product for 10 min.

[0237] Enteric-coated layer: Dissolve 50 parts by weight of HPMCAS in 900 parts by weight of ethanol aqueous solution (80% V / V), stir evenly, add 15 parts by weight of talc powder and 5 parts by weight of TEC to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with an isolation layer by the bottom spraying method using a granulating and coating machine to obtain medicated pellets with an enteric-coated layer. The process parameters for the coating are: atomization pressure is 0.2 Mpa, control the material temperature at 36°C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying the liquid, dry the product for 10 min.

[0238] Modifying layer: Mix trace amounts of talc powder with the obtained medicated pellets with an enteric-coated layer to obtain medicated pellets with a modifying layer.

[0239] Put the obtained medicated pellets with a modifying layer into gelatin capsules to obtain duloxetine hydrochloride enteric-coated preparation capsules.

[0240] Preparation of Duloxetine Hydrochloride Enteric-Coated Preparation in Example 11

[0241] The specific formula is shown in Table 11 below:

[0242] Table 11

[0243]

[0244] The preparation steps are as follows:

[0245] Main drug layer: Dissolve 7.2 parts by weight of HPMC in 550 parts by weight of purified water, add 67.2 parts by weight of duloxetine hydrochloride to make it disperse evenly, stir evenly to obtain a liquid medicine solution, and then coat it on the surface of sugar pills with a particle size of 600 - 710 μm by a bottom spray method using a granulating and coating machine. After the coating is completed, discharge the material and perform screening to obtain medicated pellets with a main drug layer. The process parameters of the coating are: the atomization pressure is 0.2 Mpa, control the material temperature at 43 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0246] Isolation layer: Disperse 2.5 parts by weight of HPMC in 125 parts by weight of 80% (v / v) ethanol solution. After dissolution, add 10 parts by weight of cetyl alcohol, stir evenly to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with a main drug layer by a bottom spray method using a granulating and coating machine to obtain medicated pellets with an isolation layer. The process parameters of the coating are: the atomization pressure is 0.2 Mpa, control the material temperature at 36 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0247] Enteric-coated layer: Dissolve 40 parts by weight of HPMCAS in 740 parts by weight of ethanol aqueous solution (80% V / V), stir evenly, add 18 parts by weight of talc powder and 5 parts by weight of TEC to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with an isolation layer by a bottom spray method using a granulating and coating machine to obtain medicated pellets with an enteric-coated layer. The process parameters of the coating are: the atomization pressure is 0.2 Mpa, control the material temperature at 36 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0248] Modification layer: Disperse 9 parts by weight of Opadry 85G68918 in 36 parts by weight of purified water to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with an enteric-coated layer by a bottom spray method using a granulating and coating machine to obtain medicated pellets with a modification layer. The process parameters of the coating are: the atomization pressure is 0.2 Mpa, control the material temperature at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0249] Load the obtained medicated pellets with a modification layer into gelatin capsules to obtain the capsules of the enteric-coated preparation of duloxetine hydrochloride.

[0250] Preparation of the enteric-coated preparation of duloxetine hydrochloride in Example 12

[0251] The specific formula is shown in Table 12 below.

[0252] Table 12

[0253]

[0254]

[0255] The preparation steps are as follows:

[0256] Main drug layer: The same as Example 11.

[0257] Isolation layer: Disperse 0.5 parts by weight of HPMC in 50 parts by weight of purified water. After dissolution, add 80 parts by weight of ethyl cellulose aqueous dispersion (solid content 25%) and stir evenly to prepare a coating solution. Then, coat it on the surface of the obtained medicated pellets with the main drug layer by the bottom spraying method using a granulating coating machine to obtain medicated pellets with an isolation layer. The process parameters for the coating are: atomization pressure is 0.2 Mpa, control the material temperature at 35°C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 min.

[0258] Enteric-coated layer: The same as Example 11.

[0259] Modifying layer: Disperse 2 parts by weight of HMPC in 90 parts by weight of purified water, then add TiO2 to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with the enteric-coated layer by the bottom spraying method using a granulating coating machine to obtain medicated pellets with a modifying layer; the process parameters for the coating are: atomization pressure is 0.2 Mpa, control the material temperature at 42°C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product is dried for 10 min.

[0260] Put the obtained medicated pellets with a modifying layer into gelatin capsules, and the capsules of duloxetine hydrochloride enteric-coated preparation are obtained.

[0261] Preparation of Duloxetine Hydrochloride Enteric-Coated Preparation in Example 13

[0262] The specific formulation is shown in Table 13 below.

[0263] Table 13

[0264]

[0265] The preparation steps are as follows:

[0266] Main drug layer: Except that HPMC is 7.8 parts by weight, the others are the same as Example 11.

[0267] Isolation layer: 16 parts by weight of HPMC was dispersed in 32 parts by weight of purified water. After dissolution, 24 parts by weight of sucrose and 40 parts by weight of talc were added, and the mixture was stirred evenly to prepare a coating solution. Then, the coating solution was coated on the surface of the obtained medicated pellets with the main drug layer by a bottom spraying method using a granulating and coating machine, thereby obtaining the medicated pellets with an isolation layer. The process parameters for the coating were: the atomization pressure was 0.2 Mpa, the material temperature was controlled at 42 °C, and the inlet air temperature was automatically controlled by the equipment to maintain the material temperature. After spraying, the product was dried for 10 min.

[0268] Enteric coating layer: 50 parts by weight of HPMCAS was dissolved in 740 parts by weight of an ethanol aqueous solution (80% V / V), stirred evenly, and 25 parts by weight of talc and 5 parts by weight of TEC were added to prepare a coating solution. Then, the coating solution was coated on the surface of the obtained medicated pellets with the isolation layer by a bottom spraying method using a granulating and coating machine, obtaining the medicated pellets with an enteric coating layer. The process parameters for the coating were: the atomization pressure was 0.2 Mpa, the material temperature was controlled at 36 °C, and the inlet air temperature was automatically controlled by the equipment to maintain the material temperature. After spraying, the product was dried for 10 min.

[0269] Modification layer: The same as Example 12.

[0270] The obtained medicated pellets with a modification layer were filled into gelatin capsules, obtaining the capsules of the enteric-coated duloxetine hydrochloride preparation.

[0271] Preparation of the enteric-coated duloxetine hydrochloride preparation in Example 14

[0272] The specific formulation is shown in Table 14 below.

[0273] Table 14

[0274]

[0275] Main drug layer: The same as Example 13.

[0276] Isolation layer: 10 parts by weight of HPMC was dispersed in 32 parts by weight of purified water. After dissolution, 15 parts by weight of sucrose and 25 parts by weight of talc (particle size d90 was about 23 μm) were added, and the mixture was stirred evenly to prepare a coating solution. Then, the coating solution was coated on the surface of the obtained medicated pellets with the main drug layer by a bottom spraying method using a granulating and coating machine, thereby obtaining the medicated pellets with an isolation layer. The process parameters for the coating were: the atomization pressure was 0.2 Mpa, the material temperature was controlled at 42 °C, and the inlet air temperature was automatically controlled by the equipment to maintain the material temperature. After spraying, the product was dried for 10 min.

[0277] Enteric coating layer: Dissolve 45 parts by weight of HPMCAS in 740 parts by weight of an aqueous ethanol solution (80% V / V), stir evenly, add 22.5 parts by weight of talc powder and 4.5 parts by weight of TEC to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with a barrier layer by a bottom spraying method using a granulating and coating machine to obtain medicated pellets with an enteric coating layer. The process parameters for the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 36 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0278] Modifying layer: The same as in Example 13.

[0279] Preparation of Duloxetine Hydrochloride Enteric-coated Preparation in Example 15

[0280] The specific formula is shown in Table 15 below.

[0281] Table 15

[0282]

[0283] Main drug layer: The same as in Example 13.

[0284] Barrier layer: Disperse 6 parts by weight of HPMC in 32 parts by weight of purified water. After dissolution, add 9 parts by weight of sucrose and 15 parts by weight of talc powder (particle size d90 is about 13 μm), stir evenly to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with a main drug layer by a bottom spraying method using a granulating and coating machine to obtain medicated pellets with a barrier layer. The process parameters for the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0285] Enteric coating layer: Dissolve 42 parts by weight of HPMCAS in 740 parts by weight of an aqueous ethanol solution (80% V / V), stir evenly, add 21 parts by weight of talc powder and 4.2 parts by weight of TEC to prepare a coating solution, and then coat it on the surface of the obtained medicated pellets with a barrier layer by a bottom spraying method using a granulating and coating machine to obtain medicated pellets with an enteric coating layer. The process parameters for the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 36 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0286] Modifying layer: The same as in Example 13.

[0287] Preparation of Duloxetine Hydrochloride Enteric-coated Preparation in Example 16

[0288] The specific formula is shown in Table 16 below.

[0289] Table 16

[0290]

[0291]

[0292] The preparation steps are the same as those in Example 13. The particle size d90 of the talc powder in the isolation layer is about 10 μm.

[0293] Main drug layer: The same as in Example 13.

[0294] Isolation layer: 4 parts by weight of HPMC are dispersed in 32 parts by weight of purified water. After dissolution, 6 parts by weight of sucrose and 10 parts by weight of talc powder (particle size d90 about 10 μm) are added, and the mixture is stirred evenly to prepare a coating solution. Then, the coating solution is coated on the surface of the prepared medicated pellets with the main drug layer by a bottom spraying method using a granulating and coating machine, thereby obtaining medicated pellets with an isolation layer. The process parameters for the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0295] Enteric-coated layer: 39.6 parts by weight of HPMCAS are dissolved in 740 parts by weight of an ethanol aqueous solution (80% V / V), stirred evenly, 19.8 parts by weight of talc powder and 4 parts by weight of TEC are added to prepare a coating solution, and then the coating solution is coated on the surface of the prepared medicated pellets with the isolation layer by a bottom spraying method using a granulating and coating machine to obtain medicated pellets with an enteric-coated layer. The process parameters for the coating are: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 36 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 min.

[0296] Modification layer: The same as in Example 13.

[0297] Preparation of the enteric-coated duloxetine hydrochloride preparation in Example 17

[0298] The specific formulation is shown in Table 17 below.

[0299] Table 17

[0300]

[0301]

[0302] Main drug layer: The same as in Example 13.

[0303] Isolation layer: 2 parts by weight of HPMC was dispersed in 32 parts by weight of purified water. After dissolution, 2 parts by weight of sucrose and 4 parts by weight of talcum powder (particle size d90 is about 6.5 μm) were added, and the mixture was stirred evenly to prepare a coating solution. Then, the coating solution was applied to the surface of the obtained medicated pellets with the main drug layer by a bottom spraying method using a granulating and coating machine, thereby obtaining medicated pellets with an isolation layer. The process parameters for the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product was dried for 10 min.

[0304] Enteric-coated layer: 38 parts by weight of HPMCAS was dissolved in 740 parts by weight of an ethanol aqueous solution (80% V / V), stirred evenly, and 19 parts by weight of talcum powder and 3.8 parts by weight of TEC were added to prepare a coating solution. Then, the coating solution was applied to the surface of the obtained medicated pellets with the isolation layer by a bottom spraying method using a granulating and coating machine, obtaining medicated pellets with an enteric-coated layer. The process parameters for the coating are as follows: the atomization pressure is 0.2 Mpa, the material temperature is controlled at 36 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After spraying, the product was dried for 10 min.

[0305] Modification layer: The same as Example 13.

[0306] Preparation of Duloxetine Hydrochloride Enteric-coated Preparation in Example 18

[0307] The specific formulation is shown in Table 18 below.

[0308] Table 18

[0309]

[0310]

[0311] The preparation steps are the same as those in Example 13. The particle size d90 of the talcum powder in the isolation layer is about 10 μm. Main drug layer: The same as Example 13.

[0312] Isolation layer: The same as Example 13 except that the particle size d90 of the talcum powder is about 13 μm. Enteric-coated layer: The same as Example 13.

[0313] Modification layer: The same as Example 13.

[0314] Preparation of Duloxetine Hydrochloride Enteric-coated Preparation in Example 19

[0315] The specific formulation is shown in Table 19 below.

[0316] Table 19

[0317] <{

[0318]

[0319] The preparation steps are as follows:

[0320] Main drug layer: Dissolve 9.6 parts by weight of PVP K30 solution in about 160 parts of dilute ethanol solution. After dissolution, add 22.4 parts by weight of duloxetine hydrochloride, 0.24 parts by weight of sodium bisulfite, 0.96 parts by weight of poloxamer, 1.2 parts by weight of microcrystalline silica, and 4.8 parts by weight of sucrose, and stir evenly to obtain a solution of the drug solution. Then, coat it on the surface of 200 parts by weight of sugar pills with a particle size of 600 - 710 μm by a bottom spraying method using a granulating and coating machine. After the coating is completed, discharge the product and perform screening to obtain drug-containing pellets with a main drug layer. The process parameters of the coating are as follows: the atomization pressure is 0.2 Mpa, control the material temperature at 38 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 minutes.

[0321] Isolation layer: Disperse 9.6 parts by weight of HPMC in about 110 parts by weight of purified water. After dissolution, add 2.4 parts by weight of titanium dioxide, and stir evenly to prepare a coating solution. Then, coat it on the surface of the drug-containing pellets obtained in the above step by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with an isolation layer. The process parameters of the coating are as follows: the atomization pressure is 0.2 Mpa, control the material temperature at 42 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 minutes.

[0322] Enteric coating layer: Add 167 parts by weight of Eudragit L30D-55 to about 70 parts by weight of purified water and stir evenly; disperse 5 parts by weight of triethyl citrate and 10 parts by weight of talc powder in about 70 parts by weight of purified water; slowly pour the latter into the former and stir evenly to prepare a coating solution. Then, coat it on the surface of the drug-containing pellets with an isolation layer by a bottom spraying method using a granulating and coating machine to obtain drug-containing pellets with an enteric coating layer. The process parameters of the coating are as follows: the atomization pressure is 0.2 Mpa, control the material temperature at 32 °C, and the inlet air temperature is automatically controlled by the equipment to maintain the material temperature. After the spraying is completed, the product is dried for 10 minutes.

[0323] Load the obtained drug-containing pellets with an enteric coating layer into gelatin capsules to obtain duloxetine hydrochloride enteric preparation capsules.

[0324] Preparation of Duloxetine Hydrochloride Enteric Preparation in Example 20

[0325] The specific formula is shown in Table 20 below.

[0326] Table 20

[0327]

[0328] The preparation steps are as follows:

[0329] Main drug layer: Dissolve 36 parts by weight of HPMC in 1200 parts by weight of purified water, add 180 parts by weight of duloxetine hydrochloride, and evenly disperse. Stir to prepare a drug solution. The solution is then applied to the surface of sugar pills with a particle size of 600-710 μm using a granulator-coating machine using a bottom spray method. After coating, the pellets are discharged and sieved to produce drug-containing pellets with a main drug layer. The coating process parameters are: atomization pressure of 0.2 MPa, a controlled material temperature of 43°C, and an automatically controlled inlet air temperature. After spraying, the product is dried for 10 minutes.

[0330] Seal layer: 33.36 parts by weight of HPMC was dispersed in 1100 parts by weight of purified water and stirred to form a coating solution. The solution was then applied to the surface of the drug-containing pellets with the main drug layer using a granulator-coating machine via bottom spraying to produce drug-containing pellets with a seal layer. The coating process parameters were: atomization pressure of 0.2 MPa, a controlled material temperature of 42°C, and an inlet air temperature automatically controlled by the equipment to maintain the material temperature. After spraying, the product was dried for 10 minutes.

[0331] Enteric layer: 118 parts by weight of Eudragit L30D-55 was added to 70 parts by weight of purified water and stirred to obtain solution (1); 3.5 parts by weight of TEC and 7 parts by weight of talc were dispersed in 70 parts by weight of purified water to obtain solution (2); solution (2) was slowly poured into solution (1) and stirred to obtain a coating solution, which was then coated on the surface of the obtained drug-containing pellets with an isolation layer by a granulating coating machine in a bottom spraying manner to obtain drug-containing pellets with an enteric layer. The coating process parameters were as follows: atomization pressure of 0.2 MPa, material temperature of 32°C, and air inlet temperature automatically controlled by the equipment to maintain the material temperature. After the spraying was completed, the product was dried for 10 minutes.

[0332] The prepared drug-containing pellets with an enteric layer are loaded into gelatin capsules to obtain duloxetine hydrochloride enteric-coated preparation capsules.

[0333] Summary of production data of Example 1

[0334] The drug application rate, adhesion rate and production time of the main drug layer coating production of Examples 1-4, 6 and 19 were statistically analyzed, and the results are shown in Table 21 below:

[0335] Table 21

[0336] Example Feeding amount of blank pellets Drug loading rate Adhesion rate Production time 1 500g 70％ 1.33％ 5.5 hours 2 500g 79％ 0.52％ 4.5 hours 3 500g 83％ 0.79％ 4.5 hours 4 500g 95％ 0.17％ 3.5 hours 6 500g 89％ 2.91％ 4 hours 19 500g 68％ 5.84％ 12 hours

[0337] As shown in the table above, the production time is shortened from 12 hours in Example 19 to 3.5 to 5.5 hours after the organic solvent coating, which greatly improves the efficiency. The drug application rate is not less than that of Example 19, and the drug application rate of Example 4 is higher than 95%.

[0338] Drug coating rate: It refers to the mass percentage (w / w) of the actual weight of the active ingredient layer coated on the blank pellets during the production process of the examples to the theoretical weight.

[0339] Adhesion rate: It refers to the mass percentage (w / w) of the adhered pellets to all the collected pellets after coating in the examples.

[0340] Production time: It refers to the time from the start of liquid spraying and coating to the end of drying by the granulation and coating machine in the examples.

[0341] Effect Example 2 In vitro release test

[0342] The in vitro release curves of the examples were determined according to USP 40 and compared with the positive control drug (Cymbalta of Eli Lilly and Company). The results are shown in Table 22:

[0343] Table 22

[0344]

[0345]

[0346] As can be seen from Table 22 above and the in vitro release curves, the f2 similarity factors of the in vitro release of Examples 1-4, 8-9, 11, 13-18 and the positive control drug (Cymbalta of Eli Lilly and Company) are all greater than 50, while the f2 similarity factors of the in vitro release of Examples 19-20 as controls are 37.4 and 35.0 respectively, both less than 50.

[0347] Effect Example 3

[0348] In Examples 13-18, talc powder with different particle sizes was selected as the retardant for coating the barrier layer, and its particle size and the weight gain of the barrier layer were statistically analyzed. The results are shown in Table 23

[0349] Table 23

[0350]

[0351] As can be seen from Table 22 and Table 23, the smaller the particle size of the talc powder, the better its retardant effect, and the weight gain of the barrier layer gradually decreases, which will greatly reduce the production time and improve the production efficiency. At the same time, when the particle size of the talc powder is reduced to less than 10 μm, maintaining a relatively high weight gain of the barrier layer has little effect on the in vitro release curve, but a larger weight gain will cause a slightly lower release at the end point.

[0352] Effect Example 4 Investigation of related substances

[0353] The related substances of the following embodiments were examined according to USP40 and compared with the positive control drug (Cymbalta of Eli Lilly). The results are shown in Table 24.

[0354] Table 24

[0355] Impurity H 1 - naphthol Other single impurities Total related substances Example 1 Not detected 0.07％ Not detected 0.07％ Example 2 Not detected Not detected 0.08％ 0.08％ Example 3 0.06 Not detected 0.07％ 0.13％ Example 4 Not detected Not detected Not detected Not detected Example 8 0.06 Not detected Not detected 0.06％ Example 9 Not detected Not detected 0.05％ 0.05％ Example 13 0.03 Not detected 0.02％ 0.05％ Example 14 Not detected Not detected 0.06％ 0.06％ Example 15 Not detected Not detected Not detected Not detected Example 16 0.06％ Not detected Not detected 0.06％ Example 17 Not detected Not detected Not detected Not detected Example 18 Not detected 0.09％ Not detected 0.09％ Example 19 0.12％ 0.15％ 0.18％ 0.45％ Example 20 0.21％ 0.11％ 0.24％ 0.56％ Cymbalta C641626A Not detected 0.05 Not detected 0.05％

[0356] As can be seen from Table 24, the related substances of Examples 1-4, 8-9, 13-18 are close to those of the positive control drug, and all meet the USP requirements for single impurity ≤ 0.2% and total related substances ≤ 0.4%. In Example 19 as a control, although the single impurity ≤ 0.2%, the total impurity is 0.45%, greater than 0.4%. Similarly, the total impurity in Example 20 as a control is also relatively high and does not meet the requirements.

[0357] Effect Example 5 Stability Study

[0358] The stability of Examples 3, 4, 8-9, 19 above was examined according to the requirements of the Chinese Pharmacopoeia, and the results are shown in Table 25.

[0359] Table 25

[0360]

[0361]

[0362] From the results obtained in the above table, it can be seen that since a specific organic solvent is used in the preparation process of the main drug layer suspension of the present invention, the problems affecting production such as easy adhesion and granulation during the coating process of the main drug layer are overcome. At the same time, a specific retarder is used in the preparation of the isolation layer, and the product has good stability. Specifically, in Examples 3, 4, 8, 9, there is no significant difference compared with day 0 after 6 months of accelerated or 6 months of long-term storage. In Example 19 as a control, the release rate decreased significantly during the stability study, and was lower than 80% after 6 months of acceleration, and the related substances were also significantly higher.

[0363] At the same time, the content uniformity of the product of the present invention is also better than that of Example 19 as a control, and the within-batch difference is small.

[0364] Effect Example 6 Pharmacokinetic Concentration-Time Curve

[0365] Under fasting and high-fat meal conditions, the capsules of the duloxetine hydrochloride enteric-coated preparations (test preparations) prepared in Examples 3 and 9 were orally administered once, together with Cymbalta (reference preparation) as the positive control drug, and the pharmacokinetics and bioequivalence between the two preparations in healthy volunteers were obtained, and the average concentration-time curve as shown Figure 1 - Figure 4 was obtained.

[0366] Among them, Figure 1It represents the pharmacokinetic concentration-time curve of the enteric-coated duloxetine hydrochloride preparation capsule (test reagent) of Example 3 and the positive control drug (reference reagent) under fasting conditions. Figure 2 It represents the pharmacokinetic concentration-time curve of the enteric-coated duloxetine hydrochloride preparation capsule (test reagent) of Example 3 and the positive control drug (reference reagent) under high-fat meal conditions. Figure 3 It represents the pharmacokinetic concentration-time curve of the enteric-coated duloxetine hydrochloride preparation capsule (test reagent) of Example 9 and the positive control drug (reference reagent) under fasting conditions. Figure 4 It represents the pharmacokinetic concentration-time curve of the enteric-coated duloxetine hydrochloride preparation capsule (test reagent) of Example 9 and the positive control drug (reference reagent) under high-fat meal conditions. The results show that the enteric-coated duloxetine hydrochloride preparation prepared by the present invention has a similar in vivo bioavailability to existing drugs.

[0367] As described above, it is only a preferred embodiment of the present invention and does not impose any formal or substantial limitations on the present invention. It should be noted that for those of ordinary skill in the art, without departing from the method of the present invention, several improvements and supplements can still be made, and these improvements and supplements should also be regarded as the protection scope of the present invention.

Claims

1. An enteric-coated preparation of duloxetine hydrochloride, characterized in that: It includes: Blank pellet core: 500 parts by weight of microcrystalline cellulose pellets; the particle size of the microcrystalline cellulose pellets is 500-700 μm; Main drug layer: 350 parts by weight of duloxetine hydrochloride, accounting for 89.6% of the main drug layer, the particle size d90 of the duloxetine hydrochloride is 24 μm; 40 parts by weight of hydroxypropyl methylcellulose, accounting for 10.3% of the main drug layer; 0.5 parts by weight of micropowder silica gel, accounting for 0.1% of the main drug layer; Isolation layer: 40 parts by weight of hydroxypropyl methylcellulose, accounting for 30.8% of the isolation layer; 5 parts by weight of lactose, accounting for 3.8% of the isolation layer; 5 parts by weight of micropowdered silica gel, accounting for 3.8% of the isolation layer; 80 parts by weight of titanium dioxide, accounting for 61.6% of the isolation layer; Enteric layer: 214 parts by weight of hydroxypropyl methylcellulose acetate succinate, accounting for 67.3% of the enteric layer mass fraction; 64 parts by weight of talc, accounting for 20.1% of the enteric layer mass fraction; 40 parts by weight of triethyl citrate, accounting for 12.6% of the enteric layer mass fraction.

2. An enteric-coated preparation of duloxetine hydrochloride, characterized in that: It includes: Blank pill core: 500 parts by weight of sugar pills; the particle size of the sugar pills is 600-710 μm; Main drug layer: 350 parts by weight of duloxetine hydrochloride, accounting for 89.7% of the main drug layer, the particle size d90 of the duloxetine hydrochloride is 11 μm; 40 parts by weight of hydroxypropyl methylcellulose, accounting for 10.3% of the main drug layer; Isolation layer: 89 parts by weight of hydroxypropyl methylcellulose, accounting for 25% of the isolation layer; 89 parts by weight of sucrose, accounting for 25% of the isolation layer; 178 parts by weight of talc, accounting for 50% of the isolation layer; Enteric layer: 224 parts by weight of hydroxypropyl methylcellulose acetate succinate, accounting for 60.5% of the enteric layer mass fraction; 112 parts by weight of talc, accounting for 30.3% of the enteric layer mass fraction; 34 parts by weight of triethyl citrate, accounting for 9.2% of the enteric layer mass fraction; Modifying layer: 8 parts by weight of hydroxypropyl methylcellulose, accounting for 20% of the mass fraction of the modifying layer; 32 parts by weight of titanium dioxide, accounting for 80% of the mass fraction of the modifying layer.

3. An enteric-coated preparation of duloxetine hydrochloride, characterized in that: It includes: Blank pill core: 500 parts by weight of sugar pills; the particle size of the sugar pills is 250-300 μm; Main drug layer: 200 parts by weight of duloxetine hydrochloride, accounting for 90.9% of the main drug layer, the particle size d90 of the duloxetine hydrochloride is 25 μm; 20 parts by weight of povidone K30, accounting for 9.1% of the main drug layer; Isolation layer: 36 parts by weight of hexadecanol, accounting for 83.3% of the isolation layer mass fraction; 7.2 parts by weight of hydroxypropyl methylcellulose, accounting for 16.7% of the isolation layer mass fraction; Enteric layer: 138 parts by weight of hydroxypropyl methylcellulose acetate succinate, accounting for 66.7% of the enteric layer mass fraction; 52 parts by weight of talc, accounting for 25.1% of the enteric layer mass fraction; 17 parts by weight of triethyl citrate, accounting for 8.2% of the enteric layer mass fraction; Modifying layer: 30 parts by weight of Opadry YS-1-7027.

4. The enteric-coated duloxetine hydrochloride preparation according to any one of claims 1 to 3, wherein The main drug layer is obtained by drying the main drug layer suspension; the main drug layer suspension is prepared by the following steps: suspending the components of the main drug layer in an organic solvent; The organic solvent is isopropyl alcohol.

5. The enteric-coated duloxetine hydrochloride preparation according to claim 4, wherein The main drug layer suspension is coated onto blank micropellets, and after drying, drug-containing pellets with the main drug layer are obtained.

6. The enteric-coated duloxetine hydrochloride preparation according to any one of claims 1 to 3, wherein The isolation layer can be prepared by drying the isolation layer coating liquid.

7. The enteric-coated duloxetine hydrochloride preparation according to claim 6, wherein The isolation layer coating liquid is coated on the drug-containing pellets with the main drug layer, and the drug-containing pellets with the isolation layer are prepared after drying.

8. The enteric-coated duloxetine hydrochloride preparation according to any one of claims 1 to 3, wherein The enteric layer is obtained by drying the enteric layer coating liquid.

9. The enteric-coated duloxetine hydrochloride preparation according to any one of claims 1 to 3, wherein The duloxetine hydrochloride enteric-coated preparation is a capsule or a multi-granule micropill tablet.

10. A method for preparing an enteric-coated preparation of duloxetine hydrochloride, characterized in that: The preparation method of the duloxetine hydrochloride enteric-coated preparation is as follows: (1) preparing a main drug layer suspension of a duloxetine hydrochloride enteric-coated preparation according to the method for preparing a main drug layer suspension of a duloxetine hydrochloride enteric-coated preparation as described in claim 4, and coating the obtained main drug layer suspension on blank pill cores to obtain drug-containing pellets having a main drug layer; (2) applying the isolation layer coating solution as claimed in claim 6 or 7 onto the surface of the drug-containing pellets having the main drug layer obtained in step (1) to obtain drug-containing pellets having the isolation layer; (3) applying the enteric layer coating solution as claimed in claim 8 onto the surface of the drug-containing pellets with the isolation layer obtained in step (2) to obtain drug-containing pellets with the enteric layer.

11. The method for preparing the enteric-coated duloxetine hydrochloride preparation according to claim 10, wherein: After step (3) is completed, the process further includes wrapping the drug-containing pellets with the enteric layer with a modification layer; the modification layer is hydroxypropyl methylcellulose and titanium dioxide or Opadry YS-1-7027.

12. The method for preparing the enteric-coated duloxetine hydrochloride preparation according to claim 10 or 11, wherein: In step (1), the blank pill core is selected from sugar pills and / or microcrystalline cellulose pills.

13. A duloxetine hydrochloride enteric-coated preparation prepared by the method for preparing the duloxetine hydrochloride enteric-coated preparation according to any one of claims 10 to 12.

14. The enteric-coated preparation of duloxetine hydrochloride according to claim 13, wherein The duloxetine hydrochloride enteric-coated preparation is prepared into capsules or multi-granule micropill tablets.

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