Vesloxin hydrochloride pharmaceutical composition and preparation method thereof

Abstract

The invention provides a medicine composition containing vinloxacin hydrochloride. The medicine composition comprises a quick-release pellet and a sustained-release pellet. The pharmaceutical composition provided by the invention has the advantages of good stability, capability of simultaneously meeting the specific requirement on in-vitro dissolution of the viloxin hydrochloride, small variety and dosage of auxiliary materials, higher safety and suitability for preparation of a preparation. And the protective layer is sprayed on the outer surface of the sustained-release layer, so that the advantages of weakening the electrostatic interaction of the pellets and preventing the particles from caking in the aging process are further achieved. In addition, the invention also provides a preparation method of the pharmaceutical composition, and the method has the advantages of high drug application rate, less fine powder, no filter bag and spray gun head blockage phenomenon, and suitableness for industrial production and application.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a viloxazine hydrochloride pharmaceutical composition and a preparation method thereof. Background Art

[0002] Viloxazine is a morpholine derivative and a selective norepinephrine reuptake inhibitor. It was developed by Supernus Pharma and was approved by the U.S. Food and Drug Administration (FDA) in April 2021 for the treatment of attention deficit hyperactivity disorder (ADHD) in adolescents aged 6 years and above and adults. Its active ingredient is viloxazine hydrochloride, and the drug preparation is a sustained-release capsule with the trade name: Qelbree.

[0003] Qelbree is the first new non-stimulant medicine for the treatment of ADHD in children and adolescents in more than 10 years.

[0004] Viloxacin hydrochloride has the following structure:

[0005]

[0006] IN202341007187A discloses a bilayer tablet composition of viloxazine hydrochloride, including an immediate-release layer and a sustained-release layer, wherein the immediate-release layer granule preparation contains: viloxazine hydrochloride 100 mg, crospovidone 20 mg, microcrystalline cellulose 19 mg, magnesium stearate 5 mg and talc 6 mg. The sustained-release layer granule preparation includes viloxazine hydrochloride 100 mg, carbomer 25 mg, polyvinyl pyrrolidone K30 10 mg, microcrystalline cellulose 154 mg, magnesium stearate 5 mg, talc 6 mg and isopropyl alcohol. The preparation disclosed in the patent requires the use of an organic solvent, and the prepared bilayer tablet releases too quickly in the early stage, with a cumulative dissolution of more than 25% within 60 minutes, and then dissolves too slowly, with a cumulative dissolution of less than 80% within 480 minutes.

[0007] IN202011003880A discloses an amorphous dispersion of viloxazine hydrochloride and poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer, which has poor stability and is easily crystallized.

[0008] US9358204B2 discloses a sustained-release preparation of viloxazine with a high drug loading, comprising an immediate-release component and an extended-release component, wherein the immediate-release granules of viloxazine hydrochloride are first prepared, and then II White was used to coat the IR granules to gain 5% weight. E-7-19040 was coated to finally obtain a sustained-release preparation of viloxazine hydrochloride. The sustained-release preparation prepared by this method uses many kinds of auxiliary materials, has slow in vitro dissolution, and only reaches 80% in vitro release after 24 hours. In addition, the stability of the prepared sustained-release preparation of viloxazine hydrochloride needs to be improved. Summary of the invention

[0009] The present invention aims to provide a viloxazine hydrochloride sustained-release pharmaceutical composition with good stability and a dissolution curve similar to that of a reference preparation and a preparation method thereof.

[0010] First, the present invention provides a pharmaceutical composition, which comprises Q) immediate-release pellets and E) sustained-release pellets; wherein the sustained-release pellets comprise: Ea) drug-containing pellets and Eb) a sustained-release layer, wherein the sustained-release layer is coated on the outer surface of the drug-containing pellets; the immediate-release pellets comprise Qa) drug-containing pellets;

[0011] The sustained-release pellets and the immediate-release pellets have the same or substantially the same prescriptions, and both include a pellet core and a drug-containing layer, wherein the drug-containing layer is coated on the outer surface of the pellet core; wherein the pellet core is selected from at least one of sucrose, lactose, corn starch, mannitol, tartaric acid, citric acid or microcrystalline cellulose; and the drug-containing layer includes viloxazine or a pharmaceutically acceptable salt thereof;

[0012] The sustained-release layer comprises a sustained-release material and a pore-forming agent, wherein the sustained-release material is selected from one or more of ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, polyethylene glycol, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylate, and polymethacrylate; preferably, the sustained-release material comprises ethyl cellulose, cellulose acetate, or cellulose butyrate, and more preferably, the sustained-release material comprises ethyl cellulose;

[0013] The pore former is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, and sodium dodecyl sulfate; preferably, the pore former is at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, povidone, polyethylene glycol, or lactose, and more preferably, the pore former is hydroxypropyl cellulose.

[0014] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the drug-containing layer further comprises one or more of a binder and a lubricant; wherein the binder is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, povidone, sodium starch glycolate, polyvinyl alcohol, methyl cellulose and hydroxypropyl cellulose; preferably, the binder is selected from at least one of hydroxypropyl methylcellulose, polyethylene glycol, povidone and sodium starch glycolate; the lubricant is selected from one or more of magnesium stearate, silicon dioxide, micropowder silica gel, magnesium silicate, powdered polyethylene glycol, talc, glyceryl monostearate, stearic acid and sodium stearyl fumarate; preferably, the lubricant is selected from one or more of magnesium stearate, silicon dioxide, micropowder silica gel, talc stearic acid and sodium stearyl fumarate;

[0015] It is further preferred that the drug-containing layer further comprises at least one of hypromellose, polyethylene glycol or talc; more preferably, the drug-containing layer further comprises hypromellose and talc.

[0016] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the Eb) sustained-release layer comprises a sustained-release material and a pore-forming agent, wherein the sustained-release material comprises ethyl cellulose, and further preferably the ethyl cellulose is introduced by using an ethyl cellulose aqueous dispersion, wherein the main sustained-release functional component of the ethyl cellulose aqueous dispersion is ethyl cellulose, and optionally, further comprises a stabilizer such as oleic acid, hexadecanol, sodium lauryl sulfate, etc., a plasticizer such as medium-chain glycerides, etc., wherein the content of the plasticizer is generally 20-25% of the solid content of the ethyl cellulose aqueous dispersion, and the content of the stabilizer is 2-8%; the sustained-release material comprising ethyl cellulose suitable for the present invention is preferably an ethyl cellulose aqueous dispersion, and further preferably the solid content of the ethyl cellulose aqueous dispersion is 20-30% (w / w), more preferably 25% (w / w). In a preferred embodiment, the ethyl cellulose aqueous dispersion suitable for the present invention can be conveniently purchased from the market, such as the trade name provided by Colorcon Ethylcellulose aqueous dispersion type B and trade name ECD's ethylcellulose aqueous dispersion type N is suitable for the present invention. The sustained-release material containing ethylcellulose described in the present invention can also be prepared by self-production, for example, by using the direct emulsification-solvent evaporation method known in the art.

[0017] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the sustained-release material is ethylcellulose aqueous dispersion type B (trade name Or ethyl cellulose aqueous dispersion N type (trade name ECD). The trade names mentioned in the present invention are used to refer to the products or their ingredients, which include products and / or compositions that are the same or substantially the same as the products or their ingredients referred to by these trade names.

[0018] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the pore former comprises hypromellose.

[0019] In a preferred embodiment, in the pharmaceutical composition of the present invention, the weight ratio of the sustained-release material to the pore-forming agent in the sustained-release layer Eb) is (9-30):1, preferably (13-20):1, more preferably (15-20):1, for example 9:1, 10:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 30:1 and any value between any two numbers.

[0020] The weight ratio of the sustained-release material to the porogen mentioned in the context of the present invention refers to the solid content ratio of the two. For example, when the sustained-release material of the present invention is an ethyl cellulose aqueous dispersion and the porogen is HPMC, the weight ratio of the sustained-release material to the porogen refers to the weight ratio of the solid content of the ethyl cellulose aqueous dispersion to HPMC.

[0021] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the sustained-release pellets comprise Ea) drug-containing pellets and Eb) a sustained-release layer, and the amount of the Eb) sustained-release layer is 5 to 20% by weight of the Ea) drug-containing pellets, preferably 6 to 18% by weight, and further preferably 7 to 16% by weight, for example 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight or 16% by weight and any value between any two numbers.

[0022] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the sustained-release pellets comprise Ea) drug-containing pellets and Eb) sustained-release layer, and the amount of Eb) sustained-release layer is 6-10% by weight of the Ea) drug-containing pellets.

[0023] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the sustained-release pellets comprise Ea) drug-containing pellets and Eb) sustained-release layer, and the amount of Eb) sustained-release layer is 10-12% by weight of the Ea) drug-containing pellets.

[0024] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the sustained-release pellets comprise Ea) drug-containing pellets and Eb) sustained-release layer, and the amount of Eb) sustained-release layer is 12-14% by weight of the Ea) drug-containing pellets.

[0025] The amount of Eb) sustained-release layer mentioned in the context of the present invention refers to the solid content of the sustained-release layer. For example, the amount of Eb) sustained-release layer in the present invention is 5-20% by weight of the drug-containing pellets Ea), which means that the solid content of the sustained-release layer is equal to the solid content of the drug-containing pellets multiplied by 5-20%. The amount of sustained-release layer provided by the present invention is critical to achieving the specific dissolution requirements of the pharmaceutical composition, especially the viloxazine hydrochloride sustained-release pharmaceutical composition. When the amount of the sustained-release layer is too much or too little, the specific in vitro dissolution requirements of the viloxazine hydrochloride sustained-release pharmaceutical composition cannot be met.

[0026] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the weight ratio of the drug-containing pellets in the immediate-release pellets to the drug-containing pellets in the sustained-release pellets is (15-30): (85-70), for example 15:85, 16:84, 17:83, 19:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 30:70 and any value therebetween, preferably 20:80. The inventors found during the research that the weight ratio of the drug-containing pellets in the immediate-release pellets to the drug-containing pellets in the sustained-release pellets affects the dissolution rate of the pharmaceutical composition. When the weight ratio of the drug-containing pellets in the immediate-release pellets is too high, it will lead to too fast dissolution. When the weight ratio of the drug-containing pellets in the immediate-release pellets is too low, it will lead to too slow dissolution. The inventors determined through further research that when the weight ratio of the drug-containing pellets in the immediate-release pellets to the drug-containing pellets in the sustained-release pellets is (15-30):(85-70) and especially (15-25):(85:75), the pharmaceutical composition can satisfy a dissolution behavior similar to that of the reference preparation.

[0027] In a preferred embodiment, the pharmaceutical composition of the present invention, wherein the drug-containing pellets include a pellet core and a drug-containing layer; wherein the pellet core is selected from a sucrose pellet core; the drug-containing layer includes viloxazine or a pharmaceutically acceptable salt thereof, HPMC and talc; and the drug-containing layer is coated on the outer surface of the pellet core.

[0028] Further preferably, based on the total weight of the pellet core and the drug-containing layer, the pellet core accounts for 35-55% by weight, for example 35% by weight, 36% by weight, 37% by weight, 38% by weight, 39% by weight, 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, 50% by weight, 51% by weight, or 55% by weight and any value therebetween, preferably 40-45% by weight; and / or,

[0029] The viloxazine or a pharmaceutically acceptable salt thereof may account for 35 to 50% by weight, for example, 35% by weight, 36% by weight, 37% by weight, 38% by weight, 39% by weight, 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, or 50% by weight and any value therebetween, preferably 40 to 45% by weight; and / or,

[0030] The HPMC accounts for 1 to 10% by weight, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight and any value therebetween, preferably 5 to 10% by weight; and / or,

[0031] The talc accounts for 1 to 10% by weight, such as 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, or 10% by weight and any value therebetween, preferably 1 to 5% by weight. The pharmaceutical composition provided by the present invention is coated with a protective layer on the outer surface of the sustained-release layer of the sustained-release micropills, which is beneficial to fluidized bed granulation, reduces the electrostatic effect of the micropills, avoids the problem of unstable loading during the subsequent capsule filling process, and is beneficial to reduce the agglomeration of particles during aging. In addition, the inventors also found in the research process that compared with the sustained-release capsules without a protective layer on the outer surface of the sustained-release layer, the sustained-release capsules containing a protective layer provided by the present invention were placed for 3 months, and the dissolution results did not change significantly. Therefore, in a further preferred embodiment of the present invention, the sustained-release micropills also include an Ec) protective layer, which is coated on the outer surface of the sustained-release layer. Further preferably, the protective layer includes at least one of hydroxypropyl methylcellulose and polyethylene glycol; optionally, it also includes one or more of a plasticizer, a colorant, a lubricant, and a sweetener.

[0032] In a preferred embodiment, the pharmaceutical composition provided by the present invention, wherein the plasticizer comprises a mixture of one or more of glycerol, diacetyl monoglyceride, propylene glycol, polysorbate 80, polyethylene glycol, triethyl citrate, triacetin, acetylated monoglyceride or fumaric acid; and / or,

[0033] The colorant includes a mixture of one or more of yellow iron oxide, brown iron oxide, red iron oxide, black iron oxide, and titanium dioxide; and / or,

[0034] The lubricant comprises a mixture of one or more of talc, silicon dioxide and kaolin; and / or,

[0035] The sweetener includes a mixture of one or more of sucrose, lactose, and xylitol;

[0036] In a more preferred embodiment, the pharmaceutical composition provided by the present invention, wherein the plasticizer comprises triacetin; and / or,

[0037] The colorant comprises titanium dioxide; and / or,

[0038] The lubricant comprises talc; and / or,

[0039] The sweetener includes a mixture of one or more of sucrose and lactose.

[0040] Further preferably, the protective layer Ec) comprises HPMC, polyethylene glycol, titanium dioxide, lactose and triacetin, for example, the protective layer is a film coating premix comprising HPMC, polyethylene glycol, titanium dioxide, lactose and triacetin, and such premix suitable for the present invention can be conveniently obtained through commercial channels, such as the one provided by Colorcon Insights. The fully formulated film coating system, particularly preferably the film coating premix with model number 33G28523.

[0041] In a preferred embodiment, the pharmaceutical composition provided by the present invention, wherein the amount of the protective layer Ec) is 0.1-5% by weight, for example 0.1% by weight, 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight and any number between two values, preferably 1-3% by weight, calculated based on the total solid weight of Ea) drug-containing pellets and Eb) sustained-release layer in the sustained-release pellets.

[0042] In a preferred embodiment, the pharmaceutical composition provided by the present invention, wherein the particle size D90 of viloxazine or its pharmaceutically acceptable salt is usually no more than 30 μm, preferably D90≤20 μm, when the particle size of viloxazine or its pharmaceutically acceptable salt is no more than 30 μm, especially no more than 20 μm, it is conducive to the preparation by fluidized bed process, less fine powder in the preparation process, high drug loading rate, and continuous process. When the particle size of viloxazine or its pharmaceutically acceptable salt is too large, there is too much fine powder when the fluidized bed method is used for preparation, which will clog the filter bag and cause poor process continuity.

[0043] Therefore, in a further preferred embodiment of the present invention, the particle size D90 of the viloxazine or a pharmaceutically acceptable salt thereof is ≤30 μm, more preferably, D90 ≤20 μm.

[0044] In a preferred embodiment, the pharmaceutical composition provided by the present invention, wherein the viloxazine or a pharmaceutically acceptable salt thereof is viloxazine or viloxazine hydrochloride, and viloxazine hydrochloride is particularly preferred.

[0045] In a more specific embodiment, the present invention provides a pharmaceutical composition comprising Q) immediate-release pellets and E) sustained-release pellets,

[0046] Wherein, the sustained-release pellets comprise: Ea) drug-containing pellets and Eb) a sustained-release layer, wherein the sustained-release layer is coated on the outer surface of the drug-containing pellets; the quick-release pellets comprise Qa) drug-containing pellets;

[0047] The sustained-release pellets and the immediate-release pellets have the same or substantially the same prescriptions of the drug-containing pellets, and both include a pellet core and a drug-containing layer, wherein the drug-containing layer is coated on the outer surface of the pellet core; further, the pellet core is selected from at least one of sucrose, lactose, corn starch, mannitol, tartaric acid, citric acid or microcrystalline cellulose; the drug-containing layer includes viloxazine or viloxazine hydrochloride, HPMC and talc;

[0048] The sustained-release layer comprises a sustained-release material and a pore-forming agent, wherein the sustained-release material comprises ethyl cellulose and the pore-forming agent comprises hydroxypropyl methyl cellulose; the weight ratio of the sustained-release material to the pore-forming agent is (9-30):1, preferably (15-20):1;

[0049] The amount of the sustained-release layer Eb) is 5 to 20% by weight of the drug-containing pellets Ea), preferably 7 to 16% by weight;

[0050] Further preferably, the drug-containing pellets, wherein the pellet core accounts for 35-55% by weight, preferably 40-45% by weight, based on the total weight of the pellet core and the drug-containing layer; the viloxazine or a pharmaceutically acceptable salt thereof accounts for 35-50% by weight, preferably 40-45% by weight; the HPMC accounts for 1-10% by weight, preferably 5-10% by weight; the talc accounts for 1-10% by weight, preferably 1-5% by weight;

[0051] More preferably, the weight ratio of the drug-containing pellets in the immediate-release pellets to the drug-containing pellets in the sustained-release pellets is (15-30):(85-70), preferably 20:80.

[0052] In a preferred embodiment, the pharmaceutical composition provided by the present invention, the viloxazine or a pharmaceutically acceptable salt thereof, wherein the salt is preferably the hydrochloride of viloxazine, that is, the pharmaceutical composition of the present invention, wherein the drug-containing pellets contain viloxazine hydrochloride.

[0053] In a preferred embodiment, the pharmaceutical composition provided by the present invention is obtained by mixing a prescribed amount of rapid-release microcapsules and sustained-release microcapsules; further preferably, the pharmaceutical composition of the present invention is a capsule, which is obtained by filling a prescribed amount of rapid-release microcapsules and sustained-release microcapsules into a capsule shell.

[0054] The pharmaceutical composition provided by the present invention has the following advantages:

[0055] First of all, it has good stability and can meet the specific requirements for the in vitro dissolution of viloxazine hydrochloride. The composition provided by the present invention adopts the second method paddle method (sinking basket) of "0931 Dissolution and Release Determination Method" of "Chinese Pharmacopoeia 2020 Edition" for dissolution detection, and uses pH 6.8 phosphate buffer as the dissolution medium. It can achieve a cumulative dissolution of viloxazine hydrochloride of not less than 20% within 60 minutes and a cumulative dissolution of not less than 80% within 480 minutes.

[0056] Secondly, the pharmaceutical composition provided by the present invention has fewer types and amounts of auxiliary materials and is safer.

[0057] Third, the pharmaceutical composition provided by the present invention adds talcum powder to the drug-containing layer of the quick-release microcapsules and the sustained-release microcapsules, which can avoid the problem of gun clogging in the spraying process due to particle focusing during the preparation of the pharmaceutical composition by the fluidized bed method, achieve smooth spraying, improve the drug application rate, and at the same time reduce the viscosity of the drug solution, prevent pill sticking, ensure the uniformity of the microcapsule coating, and meet the requirements that the product dissolution is similar to the reference preparation, and is suitable for industrial production and application.

[0058] Furthermore, the inventors optimized the particle size of the raw material viloxazine or its pharmaceutically acceptable salt in the pharmaceutical composition, which is conducive to the preparation by fluidized bed method, with high drug loading rate, less fine powder, no clogging of filter bags and spray gun heads, and met the process continuity requirements. The pharmaceutical composition of the present invention, wherein the viscosity of the hydroxypropyl methylcellulose (HMPC) contained in the drug-containing layer is 2 to 10 mPa.s, preferably 2 to 8 mPa.s, which can meet the density requirements of the drug-containing layer.

[0059] In the pharmaceutical composition provided by the present invention, the outer surface of the pellet core is sprayed with a drug-containing layer, and the outer surface of the drug-containing layer is directly sprayed with a sustained-release layer, which can not only meet the requirement that the pharmaceutical composition has a dissolution curve similar to that of the reference preparation, but also has the advantages of good stability and suitability for preparation preparation. The outer surface of the sustained-release layer is sprayed with a protective layer, which further has the advantages of weakening the electrostatic effect of the micropills and preventing the particles from agglomerating during the aging process.

[0060] In another aspect of the present invention, a method for preparing the pharmaceutical composition is provided, wherein the method adopts a fluidized bed method.

[0061] Preferably, the method comprises the following steps:

[0062] S1) preparing drug-containing pellets;

[0063] S2) adding the sustained-release material and the pore-forming agent to a solvent and stirring to obtain a liquid preparation II, and spraying the liquid preparation II onto the surface of the prescribed amount of drug-containing pellets to obtain sustained-release pellets I; preferably, the solvent is at least one of water, ethanol, and isopropanol;

[0064] S3) adding the protective layer into water, stirring to dissolve, and then spraying it onto the surface of the sustained-release pellets I in step S2) to obtain sustained-release pellets II;

[0065] S4) putting the prescribed amount of sustained-release pellets and immediate-release pellets into capsules to obtain the product.

[0066] More preferably, step S3) further comprises aging the prepared sustained-release pellets, and the aging temperature is 50-75°C; preferably the aging temperature is 50-70°C.

[0067] In a preferred embodiment, the method, wherein step S4) further comprises aging the prepared sustained-release pellets, and the aging temperature is 50-55°C.

[0068] In a preferred embodiment, the method, wherein step S4) further comprises aging the prepared sustained-release pellets, and the aging temperature is 60-65°C.

[0069] In a preferred embodiment, the method, wherein step S4) further comprises aging the prepared sustained-release pellets, and the aging temperature is 65-70°C.

[0070] In a preferred embodiment, the method, wherein step S4) further comprises aging the prepared sustained-release pellets, and the aging temperature is 70-75°C.

[0071] In a preferred embodiment, the method, wherein step S3) does not comprise an aging step.

[0072] In a preferred embodiment, the method, wherein step S2) spraying the surface of the drug-containing pellets with the formulation II to obtain the sustained-release pellets I is carried out in a fluidized bed;

[0073] In a preferred embodiment, the method, wherein step S3) spraying the protective layer coating liquid onto the surface of the sustained-release pellets I in step S2) to obtain the sustained-release pellets is carried out in a fluidized bed;

[0074] In a preferred embodiment, in the method, during step S2) of spraying the surface of the drug-containing pellets obtained in step S1) with the preparation liquid II, the material temperature is controlled to be 30 to 50° C., preferably 35 to 45° C.;

[0075] In a preferred embodiment, in the method, during step S3) of spraying the surface of the sustained-release pellets I with the protective layer coating liquid, the material temperature is controlled to be 30-50°C, preferably 35-45°C.

[0076] In a preferred embodiment, in the method, when the sustained-release material in step S1) is an aqueous dispersion of ethylcellulose, the solvent is water, or the main component is water.

[0077] In a preferred embodiment, in the method, when the sustained-release material in step S1) is ethyl cellulose, the solvent is an organic solvent or a mixture of an organic solvent and water, wherein the organic solvent is isopropanol or ethanol.

[0078] The preparation method of the pharmaceutical composition provided by the present invention has a simple operation method and is suitable for industrial production and application. The method is applicable to the preparation of the pharmaceutical composition provided by the present invention, and the preparation process is compatible with the formulation prescription and dosage, and meets the stability and in vitro specific dissolution behavior requirements of the pharmaceutical composition; the pharmaceutical composition prepared by the method of the present invention can achieve a cumulative dissolution of not less than 20% within 60 minutes and a cumulative dissolution of not less than 80% within 480 minutes. The pharmaceutical composition prepared by the method has good stability and high safety.

[0079] Other features and beneficial effects of the present invention are further described and illustrated through the following embodiments and drawings.

[0080] Definition of terms

[0081] The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein.

[0082] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its component. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0083] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0084] The terms "include", "comprises", "has", "contains" or "involves" and other variant forms thereof in this article are inclusive or open-ended, and do not exclude other unlisted elements or method steps. That is, they include the contents specified in the present invention, but do not exclude other aspects.

[0085] The terms "selected from ...", "preferably ..." and "more preferably ..." mean that one or more elements in the groups listed later are independently selected and may include a combination of two or more elements.

[0086] The terms "optional", "optionally" or "optional" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0087] In the context of the present invention, all the numbers disclosed herein are approximate values, regardless of whether the words "about" or "approximately" are used. The value of each number may vary by less than 10% or a reasonable difference considered by those skilled in the art, such as 1%, 2%, 3%, 4% or 5%.

[0088] The "solid content" and "solid content" mentioned in the context of the present invention refer to the weight of the solid components in the composition after removing the solvent such as water.

[0089] Unless otherwise specified, the usage ratios of the components described in the present invention refer to weight ratios. The usage ratios of the sustained-release materials refer to the usage ratios of the sustained-release materials in terms of solid content.

[0090] The D90 mentioned in the context of the present invention is a parameter indicating the particle size; D90 refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%, and its physical meaning is that particles with a particle size smaller than it account for 90%.

[0091] The particle size or average particle size in the present invention can be measured by methods known to those skilled in the art, such as by a Malvern nanoparticle sizer, a Malvern laser particle sizer, a Beckman Coulter nanoparticle sizer, a ZETA potential analyzer, and the like.

[0092] The viscosity of the hydroxypropyl methylcellulose (HMPC) described in the context of the present invention is 2 to 10 mPa.s, preferably 2 to 8 mPa.s, such as 2 to 4 mPa.s, 4 to 6 mPa.s or 5 to 7 mPa.s and any value therebetween; the viscosity refers to the apparent viscosity of a 2% (w / w) HPMC aqueous solution at 20°C, in mPa.s. HPMC having a viscosity of 2 to 10 mPa.s, preferably 2 to 8 mPa.s, such as 2 to 4 mPa.s, 4 to 6 mPa.s or 5 to 7 mPa.s and any value therebetween can be purchased through commercial channels, such as HPMC E3, HPMC E5 and HPMC E6 provided by Colorcon Insights, and can also be obtained by self-production.

[0093] The "viloxazine hydrochloride" and "viloxazine hydrochloride" described in the context of the present invention can be replaced with each other, and both refer to compounds having the following structure:

[0094] The "f2 value" mentioned in the context of the present invention refers to the similarity factor. In the present invention, the dissolution curve comparison adopts the model-independent similarity factor (f2) method. The similarity of the dissolution curves of the viloxazine hydrochloride pharmaceutical composition prepared by different prescriptions and the reference preparation in the same solvent is compared by calculating the f2 value. The similarity factor (f2) varies in the range of 0 to 100. When the f2 value is ≥50, the two dissolution curves are considered to be similar. When the f2 value is <50, it is considered that there is a difference between the two. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 : A comparison of the dissolution curves of the viloxazine hydrochloride sustained-release capsules prepared by the methods of Examples 2A and 2B;

[0096] Figure 2 : A comparison of the dissolution curves of the viloxazine sustained-release pellets prepared by the methods of Examples 3A and 3B is shown;

[0097] Figure 3 : A comparison chart showing the difference in dissolution of drug-containing pellets prepared by the methods of Examples 5A and 5B;

[0098] Figure 4 : Comparison of the cumulative dissolution curves of the Viloxacin Hydrochloride Sustained-Release Capsules prepared by the method of Example 10 and the reference preparation in 0.1N HCl solution;

[0099] Figure 5 : A comparison chart showing the cumulative dissolution curves of the Viloxacin Hydrochloride Sustained Release Capsules prepared by the method of Example 10 and the reference preparation in pH 4.5 acetate buffer;

[0100] Figure 6 : Comparison of the cumulative dissolution curves of the Viloxacin Hydrochloride Sustained-Release Capsules prepared by the method of Example 10 and the reference preparation in pH 6.8 phosphate buffer. DETAILED DESCRIPTION

[0101] The technical solutions and beneficial effects of the present invention are further explained below in conjunction with specific embodiments.

[0102] First, the present invention provides a pharmaceutical composition, which comprises Q) immediate-release pellets and E) sustained-release pellets.

[0103] The sustained-release pellets comprise: Ea) drug-containing pellets and Eb) a sustained-release layer, wherein the sustained-release layer is coated on the outer surface of the drug-containing pellets, and the amount of the sustained-release layer Eb) is 5 to 20% by weight of the weight of the drug-containing pellets Ea), preferably 7 to 16% by weight, for example 7%, 8%, 9%, 10%, 11%, 12% or 16% by weight, and any value therebetween;

[0104] The Q) immediate-release pellets include Qa) drug-containing pellets;

[0105] The weight ratio of the drug-containing pellets in the immediate-release pellets to the drug-containing pellets in the sustained-release pellets is (15-30):(85-70), for example, 15:85, 16:84, 17:83, 19:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 30:70, etc. and any value therebetween, preferably (15-25):(85-75), more preferably 20:80;

[0106] More preferably, the sustained-release layer comprises a sustained-release material and a pore-forming agent, and the weight ratio of the sustained-release material to the pore-forming agent is (9-30):1, preferably (15-20):1, for example, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 30:1, etc. and any value therebetween; the sustained-release material comprises ethyl cellulose, and more preferably, the sustained-release material is an ethyl cellulose aqueous dispersion (such as a product named or ECD ethylcellulose aqueous dispersion), the pore former comprising hypromellose;

[0107] Further preferably, the drug-containing pellets comprise a pellet core and a drug-containing layer, wherein the drug-containing layer is coated on the outer surface of the pellet core, and the drug-containing layer comprises viloxazine or a pharmaceutically acceptable salt thereof, HPMC and talc; preferably, based on the total weight of the pellet core and the drug-containing layer, the pellet core accounts for 35 to 55% by weight, preferably 40 to 45% by weight, for example 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, etc. and any value therebetween; the viloxazine or a pharmaceutically acceptable salt thereof accounts for 35 to 50% by weight, preferably 40 to 45% by weight. 5 wt %, such as 40 wt %, 41 wt %, 42 wt %, 43 wt %, 44 wt %, or 45 wt % and any value therebetween; the HPMC accounts for 1 to 10 wt %, preferably 5 to 10 wt %, such as 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %, or 10 wt % and any value therebetween; the talc accounts for 1 to 10 wt %, preferably 1 to 5 wt %, such as 1 wt %, 2 wt %, 3 wt %, 4 wt %, or 5 wt % and any value therebetween;

[0108] More preferably, viloxazine or a pharmaceutically acceptable salt thereof is selected from viloxazine hydrochloride.

[0109] Further preferably, the sustained-release pellets further include Ec) a protective layer, which is coated on the outer surface of the sustained-release layer;

[0110] Further preferably, the protective layer comprises hypromellose; optionally, it further comprises one or more of a plasticizer, a colorant, a lubricant, and a sweetener;

[0111] Further preferably, the protective layer is a film coating premix comprising HPMC, polyethylene glycol, titanium dioxide, lactose and triacetin, and preferably, the protective layer has the same or substantially the same ingredients as the film coating premix of model 33G28523;

[0112] Further preferably, based on the total solid weight of Ea) the drug-containing pellets and Eb) the sustained-release layer in the sustained-release pellets, the Ec) protective layer accounts for 1 to 5 weight %, for example, 1 weight %, 2 weight %, 3 weight %, 4 weight %, or 5 weight % and any value therebetween, preferably 1 to 3 weight %.

[0113] More preferably, the particle size of the viloxazine or viloxazine hydrochloride is D90≤30 μm, and more preferably, D90≤20 μm.

[0114] In a more specific embodiment, the present invention provides a pharmaceutical composition comprising Q) immediate-release pellets and E) sustained-release pellets,

[0115] Among them, the sustained-release pellets contain:

[0116] Ea) drug-containing pellets;

[0117] Eb) sustained-release layer: the sustained-release layer comprises ethyl cellulose aqueous dispersion and hydroxypropyl methylcellulose, the weight ratio of the solid content of the ethyl cellulose aqueous dispersion to HPMC is (15-20):1; the amount of the sustained-release layer Eb) is 7-16% by weight of the drug-containing pellets Ea);

[0118] Ec) protective layer: the protective layer comprises HPMC, polyethylene glycol, titanium dioxide, lactose and triacetin; preferably, the protective layer is a film premix comprising HPMC, polyethylene glycol, titanium dioxide, lactose and triacetin; based on the total solid weight of Ea) drug-containing pellets and Eb) sustained-release layer in the sustained-release pellets, the Ec) protective layer accounts for 1 to 5 weight %;

[0119] The sustained-release layer is located between the drug-containing pellets and the protective layer and is coated on the outer surface of the drug-containing pellets, and the protective layer is coated on the outer surface of the sustained-release layer;

[0120] The immediate-release pellets include (a) drug-containing pellets; the weight ratio of the drug-containing pellets in the immediate-release pellets to the drug-containing pellets in the sustained-release pellets is (15-30):(85-70), preferably 20:80;

[0121] The drug-containing pellets contained in the sustained-release pellets and the immediate-release pellets all include a pellet core and a drug-containing layer, and the drug-containing layer is coated on the outer surface of the pellet core; the pellet core includes sucrose; the drug-containing layer includes viloxazine hydrochloride, HPMC and talcum powder; based on the total weight of the pellet core and the drug-containing layer, the pellet core accounts for 40-45% by weight; the viloxazine hydrochloride accounts for 35-50% by weight, preferably 40-45% by weight; the HPMC accounts for 5-10% by weight; and the talcum powder accounts for 1-5% by weight;

[0122] Further preferably, the pharmaceutical composition is a capsule, and the quick-release pellets and sustained-release pellets in the pharmaceutical composition are preferably filled into a capsule shell according to the prescribed amount;

[0123] More preferably, the particle size of the viloxazine hydrochloride is D90≤30 μm, and more preferably, D90≤20 μm.

[0124] In a specific embodiment, the present invention provides a method for preparing the pharmaceutical composition, the method comprising the following steps:

[0125] S1a) preparing drug-containing pellets: adding HPMC to water, stirring to dissolve, then adding viloxazine or its hydrochloride, and talcum powder, stirring to obtain preparation I; adding pellet cores (preferably sucrose pellet cores) to a fluidized bed, then spraying the preparation I on the surface of the pellet cores, then drying, and packaging to obtain drug-containing pellets; dividing the obtained drug-containing pellets into 100 portions, of which 15 to 30 portions are used as drug-containing pellets in immediate-release pellets, and the remaining portions are used as drug-containing pellets in sustained-release pellets for subsequent coating, for example, 20 portions of the drug-containing pellets are used as immediate-release pellets, and the remaining 80 portions are used as drug-containing pellets in sustained-release pellets.

[0126] S2a) adding the sustained-release material and the porogen to a solvent and stirring to obtain a liquid preparation II, spraying the liquid preparation II onto the surface of the prescribed amount of drug-containing pellets to obtain sustained-release pellets; wherein the solvent is preferably at least one of water, ethanol, and isopropanol; preferably, HPMC is added to water, and then an ethyl cellulose solution (preferably an ethyl cellulose aqueous dispersion) is added and stirred to obtain a liquid preparation II; and then the liquid preparation II is sprayed onto the surface of the drug-containing pellets obtained in step S1) to obtain sustained-release pellets I;

[0127] S3) adding a protective layer (preferably a film coating premix comprising HPMC, polyethylene glycol, titanium dioxide, lactose and triacetin) into water, stirring and dissolving to obtain a protective layer coating solution, and then spraying the protective layer coating solution on the surface of the sustained-release pellets I to obtain sustained-release pellets;

[0128] S4) putting the prescribed amount of sustained-release pellets and immediate-release pellets into capsules to obtain the product.

[0129] Optionally, step S3) further comprises the step of aging the prepared sustained-release pellets, wherein the aging temperature is 50-75°C, preferably the aging temperature is 50-55°C, or 55-60°C, or 60-65°C, or 65-70°C, or 70-75°C.

[0130] In a preferred embodiment, the method, wherein the sustained-release pellets prepared in step S3) do not comprise an aging step.

[0131] In a preferred embodiment, the method, wherein step S2) comprises adding the drug-containing pellets obtained in step S1) into a fluidized bed, and then spraying the surface of the drug-containing pellets obtained in step S1) with formulation II to obtain sustained-release pellets I.

[0132] In a preferred embodiment, the method, wherein step S3) comprises adding the sustained-release pellets I into a fluidized bed, and then spraying the surface of the sustained-release pellets I with a protective layer coating liquid to obtain sustained-release pellets.

[0133] Further preferably, in step S2), the material temperature is controlled at 30-50°C, preferably 35-45°C, during the process of spraying the surface of the drug-containing micropellets obtained in step S1) with the preparation II.

[0134] Further preferably, in step S3), during the process of spraying the protective layer coating liquid on the surface of the sustained-release pellets I, the material temperature is controlled to be 30-50°C, preferably 35-45°C.

[0135] In a more specific embodiment, the present invention provides a pharmaceutical composition comprising: Q) immediate-release pellets and E) sustained-release pellets,

[0136] Among them, the sustained-release pellets contain:

[0137] Ea) drug-containing pellets, the drug-containing pellets comprising a pellet core and a drug-containing layer, the pellet core comprising Ea1) a sucrose pellet core, the drug-containing layer comprising Ea2) viloxazine hydrochloride, Ea3) HPMC and Ea4) talcum powder; based on the total weight of Ea1), Ea2), Ea3) and Ea4), the amount of Ea1) sucrose pellet core is 35-55% by weight, preferably 40-45% by weight; the amount of Ea2) viloxazine hydrochloride is 35-50% by weight, preferably 40-45% by weight; the amount of Ea3) HPMC is 1-10% by weight, preferably 5-10% by weight; the amount of Ea4) talcum powder is 1-10% by weight, preferably 1-5% by weight;

[0138] Eb) sustained-release layer: the sustained-release layer comprises ethyl cellulose aqueous dispersion and hydroxypropyl methylcellulose, the weight ratio of the solid content of the ethyl cellulose aqueous dispersion to HPMC is (15-20):1; the amount of the sustained-release layer Eb) is 7-16% by weight of the weight of the drug-containing pellets Ea), preferably 6-10% by weight, or 10-12% by weight, or 12-14% by weight;

[0139] Wherein, the sustained-release layer is coated on the outer surface of the drug-containing micro-pellets, and the drug-containing layer is coated on the outer surface of the pellet core;

[0140] The immediate-release pellets include Qa) drug-containing pellets, preferably the immediate-release pellets only include Qa) drug-containing pellets; the weight ratio of the drug-containing pellets in the immediate-release pellets to the drug-containing pellets in the sustained-release pellets is (15-30):(85-70), preferably 20:80;

[0141] The composition of the drug-containing pellets contained in the sustained-release pellets and the immediate-release pellets is the same or substantially the same.

[0142] Further preferably, the rapid-release pellets and sustained-release pellets in the pharmaceutical composition are filled into the capsule shell according to the prescribed amount.

[0143] More preferably, the particle size of the viloxazine hydrochloride is D90≤30 μm, and more preferably, D90≤20 μm.

[0144] In a specific embodiment, the present invention provides a method for preparing the pharmaceutical composition, the method comprising the following steps:

[0145] S1b) preparing drug-containing pellets: adding Ea3) HPMC to water, stirring to dissolve, then adding viloxazine hydrochloride and talcum powder, stirring to obtain liquid preparation I; adding sucrose pellet cores to a fluidized bed, controlling the material temperature to 30-50° C., preferably 35-45° C., then spraying the surface of the sucrose pellet cores with liquid preparation I, then drying, and packaging to obtain drug-containing pellets; dividing the obtained drug-containing pellets into 100 portions, of which 15-30 portions are used as drug-containing pellets in quick-release pellets, and the remaining portions are used as drug-containing pellets in sustained-release pellets for subsequent coating;

[0146] S2b) preparing sustained-release pellets: adding a prescribed amount of HPMC for the sustained-release layer to water, then adding an ethyl cellulose aqueous solution (preferably ethyl cellulose aqueous dispersion type B) and stirring to obtain a preparation II; adding a prescribed amount of drug-containing pellets prepared in step S1) to a fluidized bed, controlling the material temperature to 30-50° C., preferably 35-45° C., and then spraying the surface of the drug-containing pellets with the preparation II to obtain sustained-release pellets;

[0147] Optionally, S3b) adding the obtained sustained-release pellets to a fluidized bed or an oven for aging, preferably the aging temperature is 50-75° C., for example, 50-55° C., 55-60° C., 60-65° C., 65-70° C., or 70-75° C.;

[0148] S4b) The prescribed amount of sustained-release pellets and immediate-release pellets are loaded into capsules to obtain the product.

[0149] Example

[0150] The following is a more detailed description of the technical scheme and beneficial effects of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. The raw materials and reagents used in the following examples are all commercially available unless otherwise specified. The excipients used, such as HPMC, ethyl cellulose, talcum powder, sucrose, etc., are all standard pharmaceutical excipients.

[0151] The viloxazine hydrochloride used in the following examples was homemade (purity not less than 99.7%), HPMC (model: E3, E5 or E6) was purchased from Colorcon, and ethylcellulose aqueous dispersion (trade name: Model: Type B, solid content 25%) purchased from Colorcon, the film coating premix used for the protective layer (trade name: II, model: 33G28523-CN (containing lactose)) was purchased from Colorcon. The reference preparation was viloxazine hydrochloride sustained-release capsules (trade name: QELBREE, purchased from SUPERNUS PHARMS, specification: 200 mg).

[0152] The solid content of the ethyl cellulose aqueous dispersion (type B) used in the following examples is 25%. Unless otherwise specified, the content values ​​of the ethyl cellulose aqueous dispersion (type B) listed in the table refer to the weight of the aqueous dispersion, wherein the water is removed during the coating process. The solid content of the ethyl cellulose aqueous dispersion (type B) is obtained by multiplying the values ​​in the table by 25%.

[0153] Dissolution test method I: The dissolution test was carried out using the second paddle method (sinking basket) of "0931 Dissolution and Release Determination Method" of the "Chinese Pharmacopoeia 2020 Edition". The rotation speed was 50 rpm, the dissolution medium was pH 6.8 phosphate buffer, and the medium volume was 900 ml. 5 mL was automatically sampled at 10 min, 30 min, 60 min, 120 min, 240 min, 300 min, 360 min, 480 min, 600 min and 720 min, respectively. The sample was filtered and tested by HPLC. The solubility was calculated and the cumulative dissolution release curve was drawn.

[0154] Preparation Example I: Preparation of drug-containing pellets:

[0155] The prescribed amount of HPMC for the drug-containing layer was added to purified water, stirred until completely dissolved, and then the prescribed amount of viloxazine hydrochloride and talc were added, and stirring was continued for about 0.5 h to obtain solution I.

[0156] Add the sucrose pellet core into the fluidized bed, control the material temperature at 40±5°C, and spray all the liquid I. After the spraying is completed, dry it in the fluidized bed and pass it through 0.5mm and 1.0mm sieves to obtain drug-containing pellets.

[0157] Preparation Example II: Preparation of sustained-release pellets

[0158] 1) Add the prescribed amount of HPMC in the sustained-release layer to the prescribed amount of purified water, stir until completely dissolved, add ethyl cellulose aqueous dispersion (type B), continue stirring for about 0.5h, and obtain liquid II; take the prescribed amount of drug-containing pellets and add them to the fluidized bed, control the material temperature at 40±5°C, spray the sustained-release layer liquid II, and obtain sustained-release pellets I;

[0159] 2) Add the prescribed amount of protective layer film coating premix (33G28523-CN) into purified water and stir until completely dissolved to obtain a protective layer coating solution, then add the sustained-release pellets I into the fluidized bed, control the material temperature at 40-45°C, spray the protective layer coating solution to obtain sustained-release pellets II;

[0160] 3) Optionally, the obtained sustained-release pellets II are added to an oven at 50-70° C. for aging, and then passed through 0.5 mm and 1.0 mm sieves to obtain sustained-release pellets.

[0161] Preparation Example III: Preparation of Pharmaceutical Composition

[0162] The drug-containing pellets prepared in Preparation Example I in the prescribed amount were taken as quick-release pellets and the sustained-release pellets prepared in Preparation Example II were filled into capsules to obtain viloxazine hydrochloride sustained-release capsules containing quick-release pellets and sustained-release pellets.

[0163] Example 1: Viroxaquin Hydrochloride Pharmaceutical Composition (Sustained Release Capsules)

[0164] Table 1.1: Composition of drug-containing pellets

[0165]

[0166] Note [1]: Purified water is removed during the coating process.

[0167] (1) Preparation method of drug-containing pellets:

[0168] Add the prescribed amount of HPMC (E5, viscosity 4-6 mPa.s) in Table 1.1 to the prescribed amount of purified water, stir until completely dissolved, then add the prescribed amount of viloxazine hydrochloride and talc, and continue stirring for about 0.5 h to prepare solution I.

[0169] Add the sucrose pellets to the fluidized bed, control the material temperature at 40±5°C, and spray all the liquid I. After the spraying is completed, dry it in the fluidized bed and pass it through 0.5mm and 1.0mm sieves to obtain drug-containing pellets. Weigh the weight and divide it into 20% by weight of drug-containing pellets as quick-release pellets and 80% by weight of drug-containing pellets for the preparation of sustained-release pellets.

[0170] Take 80% of the weight of the drug-containing pellets and continue to coat the sustained-release layer and the protective layer to prepare sustained-release pellets. The specific preparation method of the sustained-release pellets is as follows:

[0171] Table 1.2 Prescription of sustained-release pellets

[0172]

[0173] Note [2]: The drug-containing pellets are prepared as described in (1);

[0174] Note [3]: The solid content of ethyl cellulose aqueous dispersion is 25%, and the water is removed during the coating process;

[0175] Note [4]: ​​Purified water is removed during the coating process.

[0176] (2) Preparation method of sustained-release micropellets:

[0177] Add the prescribed amount of HPMC (E5, viscosity 4-6 mPa.s) in Table 1.2 to the prescribed amount of purified water, stir until completely dissolved, add the prescribed amount of ethyl cellulose aqueous dispersion (type B), continue stirring for about 0.5 h, and obtain liquid II; take 80% by weight of the drug-containing pellets (432 mg) prepared in step (1) and add them to the fluidized bed, control the material temperature at 40±5°C, and spray the sustained-release layer liquid II; obtain sustained-release pellets I;

[0178] Add the protective layer film coating premix (containing lactose, 33G28523-CN) in the prescription amount of Table 1.2 to the prescription amount of purified water, stir until completely dissolved to obtain a protective layer coating solution, then add the sustained-release pellets I into the fluidized bed, control the material temperature at 40-45°C, spray the protective layer coating solution to obtain sustained-release pellets II;

[0179] The obtained sustained-release micropellets II were placed in an oven at 50-75°C for aging, then passed through 0.5 mm and 1.0 mm sieves and weighed.

[0180] (3) Preparation of Viloxacin Hydrochloride Sustained Release Capsules

[0181] 20% by weight of the drug-containing pellets (108 mg) prepared in (1) were taken as quick-release pellets and encapsulated with the sustained-release pellets prepared in (2) to obtain sustained-release capsules of viloxazine hydrochloride containing quick-release pellets and sustained-release pellets.

[0182] The sustained-release capsules of viloxazine hydrochloride prepared in Example 1 and the reference preparation QELBREE were taken for in vitro dissolution test, and the dissolution similarity of the two was compared. Specifically, the second paddle method (sinking basket) of "0931 Dissolution and Release Determination Method" of "Chinese Pharmacopoeia 2020 Edition" was used for dissolution test. The rotation speed was 50 rpm, and the dissolution medium was 0.1 N hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and the medium volume was 900 ml. 5 mL was automatically sampled at 10 min, 30 min, 60 min, 120 min, 240 min, 360 min, 480 min, 600 min and 720 min, respectively, filtered, and tested by HPLC. The solubility was calculated, and the cumulative dissolution release curve was drawn.

[0183] The test results show that in pH 4.5 acetate buffer and pH 6.8 phosphate buffer, the sustained-release capsules of viloxazine hydrochloride prepared by the method of the present invention and the reference preparation have a cumulative dissolution of viloxazine hydrochloride greater than 20% within 60 minutes and a cumulative dissolution greater than 80% within 480 minutes, which can meet the specific dissolution requirements. In addition, in the three media, the dissolution similarity factor (f2) of the sustained-release capsules of viloxazine hydrochloride prepared by the method of the present invention and the reference preparation is much greater than 50, indicating that the dissolution behaviors of the two are similar.

[0184] Example 2: Effect of isolation layer on stability and dissolution of sustained-release capsules

[0185] The following examples study the effects of adding a separation layer between the drug-containing pellets and the sustained-release layer, and not adding a separation layer between the drug-containing pellets and the sustained-release layer on the stability and dissolution release of the prepared pharmaceutical composition.

[0186] The isolation layer used in the following examples has the same composition as the protective layer described in the present invention.

[0187] Table 2.1 Prescriptions for Examples 2A to 2B

[0188]

[0189]

[0190] Note [1]: The solid content of ethyl cellulose aqueous dispersion is 25%, and the water is removed during the coating process;

[0191] Preparation method:

[0192] The drug-containing pellets of Examples 2A and 2B were prepared according to the method of Preparation Example I; the prepared drug-containing pellets were divided into 20% by weight and 80% by weight, wherein 20% by weight of the drug-containing pellets were used as immediate-release pellets, and 80% by weight of the drug-containing pellets were used as sustained-release pellets for subsequent coating.

[0193] Example 2A: The film coating premix (33G28523-CN) in the prescription amount of Table 2.1 was added to the prescription amount of purified water, stirred until completely dissolved, to obtain an isolation layer coating solution, and then 80% by weight of the drug-containing pellets were added to the fluidized bed, the material temperature was controlled at 40-45°C, and the isolation layer coating solution was sprayed to obtain sustained-release pellets 2A1;

[0194] Add the HPMC (E5, viscosity 4-6 mPa.s) in the sustained-release layer of Example 2A in Table 2.1 into purified water, stir until completely dissolved, add ethyl cellulose aqueous dispersion (type B), continue stirring for about 0.5 h, and obtain liquid II; add sustained-release pellets 2A1 into the fluidized bed, control the material temperature at 40±5°C, and spray the sustained-release layer liquid II; obtain sustained-release pellets 2A2;

[0195] The sustained-release pellets 2A2 were added to an oven for aging, and then passed through 0.5 mm and 1.0 mm sieves and weighed to obtain the sustained-release pellets 2A of Example 2A.

[0196] Example 2B: Add the prescribed amount of HPMC (E5, viscosity 4-6 mPa.s) of the sustained-release layer of Example 2B in Table 2.1 to the prescribed amount of purified water, stir until completely dissolved, add the prescribed amount of ethyl cellulose aqueous dispersion (type B), continue stirring for about 0.5h, and obtain liquid II; then add 80% by weight of the prepared drug-containing micropellets into the fluidized bed, control the material temperature at 40±5°C, and spray the sustained-release layer liquid II; obtain sustained-release micropellets I;

[0197] The obtained sustained-release pellets I were added to an oven for aging, and then passed through 0.5 mm and 1.0 mm sieves and weighed to obtain sustained-release pellets 2B of Example 2A.

[0198] The prepared sustained-release pellets 2A and 2B were mixed with 20% by weight of drug-containing pellets, respectively, and filled into capsules to obtain viloxazine hydrochloride sustained-release capsules 2A and 2B, respectively.

[0199] The prepared viloxazine hydrochloride sustained-release capsules 2A and 2B were subjected to in vitro dissolution tests, and the test results were as follows: Figure 1 As shown, from Figure 1 It can be seen that compared with the sustained-release capsule 2B without the isolation layer, after the isolation layer was added between the drug-containing pellets and the sustained-release layer, the obtained sustained-release capsule 2A dissolved too quickly.

[0200] Example 3: Effect of protective layer on dissolution of sustained-release capsules

[0201] The following Examples 3A and 3B study the effect of the protective layer on the outer surface of sustained-release pellets on dissolution results and stability.

[0202] Table 3.1 Prescriptions for Examples 3A-3B

[0203]

[0204] Preparation method:

[0205] The drug-containing pellets of Examples 3A and 3B were prepared according to the method of Preparation Example I; the prepared drug-containing pellets were divided into 20% by weight and 80% by weight, of which 20% by weight were used as immediate-release pellets and 80% by weight were used as drug-containing pellets in sustained-release pellets for subsequent coating.

[0206] According to the method of Preparation Example II, the sustained-release pellets of the prescription described in Example 3A were prepared and recorded as sustained-release pellets 3A;

[0207] The sustained-release pellets of the formulation described in Example 3B were prepared in a similar manner to that of Preparation Example II, except that the sustained-release pellets prepared in Example 3B did not contain a protective layer, and were recorded as sustained-release pellets 3B;

[0208] The obtained sustained-release pellets 3A and 3B were respectively loaded into capsules with 20% by weight of drug-containing pellets, and then the dissolution and stability were tested. Figure 2 As shown, the dissolution curves of the pharmaceutical compositions prepared in Example 3A and Example 3B are substantially similar.

[0209] In addition, it was observed during the preparation process that, compared with the formulation of Example 3B, after the protective layer was wrapped around the outer surface of the sustained-release layer in Example 3A, the electrostatic effect of the microcapsules was weakened, and the problem of unstable filling volume could be avoided during the subsequent capsule filling process. At the same time, the agglomeration phenomenon during the aging process was also significantly reduced.

[0210] Example 4: Pharmaceutical composition and preparation thereof

[0211] Table 4.1 Prescription of pharmaceutical composition

[0212]

[0213] Preparation method:

[0214] (1) Preparation of drug-containing pellets: The prescribed amount of HPMC (E5, viscosity 4-6 mPa.s) of the drug-containing layer of Examples 4A-4F was added to purified water, stirred until completely dissolved, and then the prescribed amount of viloxazine hydrochloride and talc were added, and stirring was continued for about 0.5 h to prepare solution I.

[0215] Add the sucrose pellets to the fluidized bed, control the material temperature at 40±5°C, and spray all the liquid I. After the spraying is completed, dry in the fluidized bed and pass through 0.5mm and 1.0mm sieves to obtain drug-containing pellets. The prepared drug-containing pellets are divided into 20% weight parts and 80% weight parts, of which 20% weight parts are used as immediate-release pellets and 80% weight parts are used as drug-containing pellets in sustained-release pellets for subsequent coating.

[0216] (2) Preparation of sustained-release pellets:

[0217] Add the prescribed amount of HPMC (E5, viscosity 4-6 mPa.s) of the sustained-release layer of Examples 4A-4F to the prescribed amount of purified water, stir until completely dissolved, add the prescribed amount of ethyl cellulose aqueous dispersion (type B), continue stirring for about 0.5 h, and obtain liquid II; take 80% by weight of the drug-containing pellets prepared in step (1) and add them to the fluidized bed, control the material temperature at 40±5°C, and spray the sustained-release layer liquid II; obtain sustained-release pellets I;

[0218] The sustained-release pellets I prepared in Examples 4A, 4B and 4C were respectively placed in an oven at 50-70° C. for aging, and then passed through 0.5 mm and 1.0 mm sieves and weighed to obtain sustained-release pellets 4A, 4B and 4C, respectively;

[0219] The sustained-release pellets I prepared in Examples 4D, 4E and 4F were directly passed through 0.5 mm and 1.0 mm sieves without aging and weighed to obtain sustained-release pellets 4D, sustained-release pellets 4E and sustained-release pellets 4F;

[0220] (3) Preparation of pharmaceutical compositions

[0221] 20% by weight of the drug-containing pellets (108 mg) prepared in Examples 4A to 4F were respectively taken as quick-release pellets and sustained-release pellets 4A to 4E to be capsuled, and then the viloxazine hydrochloride sustained-release capsules prepared in Examples 4A to 4F and the reference preparation were respectively taken for dissolution test to compare the similarity of the dissolution curves of the viloxazine hydrochloride sustained-release capsules prepared in Examples 4A to 4F and the reference preparation.

[0222] The detection method adopts dissolution detection method I. The detection results are shown in Table 4.1. The viloxazine hydrochloride sustained-release capsules prepared in Examples 4A to 4F have similar dissolution behaviors as the reference preparation, indicating that the pharmaceutical composition provided by the present invention has a bioavailability similar to that of the reference preparation and has good effectiveness.

[0223] Stability test: The viloxazine hydrochloride sustained-release capsules prepared in Examples 4A to 4F were placed in an accelerated stability test chamber (40°C ± 2°C, 75% RH ± 5%) and sealed for storage. Samples were taken at 0 day, 1 month, 2 months, 3 months, and 6 months to detect related substances. The test results showed that compared with 0 day, there was no change in the maximum unknown single impurities and total impurities in each group at 1 month, 2 months, 3 months, and 6 months, all of which were below 0.06%.

[0224] Example 5: Effect of particle size of viloxazine hydrochloride on process and dissolution

[0225] Drug-containing pellets were prepared according to the prescription and preparation method of Reference Example 1(1), and the effects of different particle sizes of viloxazine hydrochloride (API) on the dissolution results and preparation process were investigated.

[0226] Table 5.1: Phenomena and experimental results observed in the formulation and fluidized bed process of drug-containing pellets

[0227]

[0228]

[0229] Note[1]:

[0230] Note[2]:

[0231] The dissolution difference of drug-containing pellets prepared from batches 5A and 5B was investigated. The dissolution test method used the paddle method (sinking basket), the rotation speed was 50 rpm, the dissolution medium was pH 6.8 phosphate buffer, the dissolution volume was 900 ml, and HPLC was used for detection;

[0232] The dissolution test results are as follows Figure 3 As shown, there is no significant difference in the dissolution of samples prepared with two particle sizes, and both samples reach more than 85% of the total dissolution within 15 min.

[0233] As shown in Table 5.1, when the particle size D90 of viloxazine hydrochloride (API) is ≤30 μm, the drug application rate of the prescription is high and the continuity of the preparation process is good.

[0234] Example 6: Drug-containing layer formulation study

[0235] The drug-containing pellets of the prescriptions described in Examples 6A and 6B were prepared according to the method of Preparation Example I, and the experimental phenomena were observed.

[0236] Table 6.1: Prescription and process phenomena of drug-containing pellets in Examples 6A and 6B

[0237]

[0238] Example 7 Stability Study

[0239] The stability of the viloxazine hydrochloride sustained-release capsules prepared by the method of Example 2B was studied.

[0240] Stability test method: Take the viloxazine hydrochloride sustained-release capsules prepared in Example 2B and place them in an accelerated (40°C ± 2°C, 75% RH ± 5%) stability test box, seal them and store them. Samples are taken at 0 day, 1 month, 2 months, 3 months and 6 months to detect related substances. The test results are shown in Table 7.1 below.

[0241] Table 7.1 Stability test results of the Viloxacin Hydrochloride Sustained Release Capsules provided by the present invention

[0242]

[0243] ND means below the detection limit (0.02%), not detected.

[0244] From the above experimental results, it can be seen that after the isolation layer is omitted in the present invention, the maximum unknown single impurity and total impurity contents do not change significantly after being placed in a high temperature and high humidity environment for 6 months, and the invention has very good stability.

[0245] Example 8 Light Stability Study:

[0246] Sample 8A: Viloxacin hydrochloride API;

[0247] Sample 8B: Take viloxazine hydrochloride and film coating premix (33G28523-CN) and mix them evenly in a weight ratio of 2:1 to obtain;

[0248] Sample 8C: Take viloxazine hydrochloride and hypromellose (E5) and mix them evenly in a weight ratio of 1:1 to obtain;

[0249] Sample 8D: Take viloxazine hydrochloride and ethyl cellulose aqueous dispersion (evaporate to remove water and retain solid) and mix them evenly in a weight ratio of 3:1 to obtain;

[0250] Sample 8E: sustained-release pellets prepared by the method of Example 4A;

[0251] Sample 8F: sustained-release pellets prepared by the method of Example 4D;

[0252] The above samples 8A~8F were taken separately and placed under lighting conditions (illuminance: 4500±500lx) and sealed for storage. Samples 8A~8D were tested for related substances by HPLC on the 0th day, the 10th day, the 20th day and the 30th day respectively; samples 8E~8F were tested for related substances by HPLC on the 0th day, the 10th day and the 15th day respectively, among which the contents of viloxazine hydrochloride, the maximum unknown impurity and the total impurities were calculated as percentages of the HPLC peak area. The test results are shown in Table 8.1 below.

[0253] Table 8.1: Stability test results under light conditions

[0254]

[0255]

[0256] Note: The HPLC detection limit of related substances is 0.02%. ND means below the detection limit and not detected.

[0257] It can be seen from the experimental results in Table 8.1 that viloxazine hydrochloride is unstable under light conditions when in direct contact with the film coating premix (33G28523). The sustained-release pellets prepared by the present invention have good light stability when in direct contact with the sustained-release layer materials (solid components of ethyl cellulose aqueous dispersion and HPMC). The maximum single impurity and total impurity contents of the sustained-release pellets prepared from Examples 4A and 4D of the present invention were basically unchanged on the 0th day and the 15th day, indicating that the sustained-release pellets prepared by the present invention have good light stability.

[0258] Example 9: Viloxacin hydrochloride pharmaceutical composition and preparation method thereof

[0259] Table 9.1: Pharmaceutical composition prescription

[0260]

[0261] Preparation method: (1) Add the prescribed amount of HPMC (E5, viscosity 4-6 mPa.s) in Table 9.1 to the prescribed amount of purified water, stir until completely dissolved, then add the prescribed amount of viloxazine hydrochloride and talc, and continue stirring for about 0.5 h to prepare solution I.

[0262] Add the sucrose pellets to the fluidized bed, control the material temperature at 40±5°C, and spray all the liquid I. After the spraying is completed, dry it in the fluidized bed and pass it through 0.5mm and 1.0mm sieves to obtain drug-containing pellets. Weigh the weight and divide it into 20% by weight of drug-containing pellets as quick-release pellets and 80% by weight of drug-containing pellets for the preparation of sustained-release pellets.

[0263] (2) Adding the prescribed amount of HPMC (E5, viscosity 4-6 mPa.s) of the sustained-release layer to the prescribed amount of purified water, stirring until completely dissolved, adding the prescribed amount of ethyl cellulose aqueous dispersion (type B), and continuing to stir for about 0.5 h to obtain liquid II; taking 80% by weight of the drug-containing micropellets prepared in step (1) and adding them to the fluidized bed, controlling the material temperature at 40±5°C, and spraying the sustained-release layer liquid II; obtaining sustained-release micropellets I;

[0264] Add the prescribed amount of protective layer film coating premix (33G28523-CN) to the prescribed amount of purified water, stir until completely dissolved, and obtain the protective layer coating solution. Then add the sustained-release micropellets I to the fluidized bed, control the material temperature at 40-45°C, spray the protective layer coating solution, and obtain sustained-release micropellets II; pass the obtained sustained-release micropellets through 0.5 mm and 1.0 mm sieves to obtain sustained-release micropellets.

[0265] 20% by weight of the drug-containing pellets prepared in (1) are taken as quick-release pellets and encapsulated with the sustained-release pellets prepared in (2) to obtain sustained-release capsules of viloxazine hydrochloride containing quick-release pellets and sustained-release pellets.

[0266] The prepared sustained-release capsules of viloxazine hydrochloride and the reference preparation QELBREE were subjected to in vitro dissolution test to compare the dissolution similarity of the two, and the test method was the same as the dissolution test method I. The test results showed that in a phosphate buffer of pH 6.8, the dissolution similarity factor (f2) of the sustained-release capsules of viloxazine hydrochloride prepared by the method of the present invention and the reference preparation was greater than 50, indicating that the dissolution behaviors of the two were similar.

[0267] Example 10: Viloxacin hydrochloride pharmaceutical composition and preparation method thereof

[0268] Table 10.1 Prescription of drug-containing pellets

[0269]

[0270] Table 10.2 Prescription of sustained-release pellets

[0271]

[0272]

[0273] The drug-containing pellets and sustained-release pellets were prepared according to the method of Example 1. The drug-containing pellets prepared according to the prescription in Table 10.1 were divided into 100 parts, 20 of which were used as immediate-release pellets. The prescribed amount of immediate-release pellets and sustained-release pellets were then filled into capsule shells to obtain 400,000 viloxazine hydrochloride sustained-release capsules.

[0274] The prepared viloxazine hydrochloride sustained-release capsules and the reference preparation QELBREE were subjected to in vitro dissolution test to compare the dissolution similarity of the two. The detection method adopted the second paddle method (sinking basket) of "0931 Dissolution and Release Determination Method" of "Chinese Pharmacopoeia 2020 Edition" for dissolution detection. The rotation speed was 50 rpm, and the dissolution media were 0.1 N hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. The medium volume was 900 ml. 5 mL was automatically sampled at 0 min, 10 min, 30 min, 60 min, 120 min, 240 min, 300 min, 720 min, 840 min, 960 min, 1200 min and 1440 min, respectively, filtered, and tested by HPLC. The solubility was calculated and the cumulative dissolution release curve was drawn.

[0275] Test results such as Figures 4 to 6 As shown, in the three media, the dissolution similarity factors (f2) of the sustained-release capsules of viloxazine hydrochloride prepared by the method of the present invention and the reference preparation are much larger than 50, and the pharmaceutical composition provided by the present invention has good safety and efficacy.

[0276] The prepared viloxazine hydrochloride sustained-release capsules were placed in an accelerated (40°C ± 2°C, 75% RH ± 5%) stability test chamber, sealed and stored, and samples were taken at 0 day, 1 month, 2 months, 3 months, and 6 months to detect related substances and in vitro dissolution (the detection method was the same as dissolution detection method I). The test results showed that the detection results of related substances in the first to sixth months were unchanged compared with those on the 0th day, and the dissolution similarity factor f2 values ​​of the first to sixth months and the 0th day were both between 50 and 80, which was the same as the dissolution release change trend of the reference preparation, indicating that the pharmaceutical composition provided by the present invention has stable physicochemical properties and good safety.

[0277] The above examples show that the viloxazine hydrochloride sustained-release capsules prepared by the method of the present invention have similar dissolution behaviors to the reference preparation, and the prepared pharmaceutical composition has good light stability and chemical stability. In addition, the present invention optimizes the prescription of the drug-containing layer and the composition and structure of the sustained-release pellets, so that the obtained pharmaceutical composition is more suitable for preparation by the fluidized bed process, avoids clogging of the spray gun and spray drying, has good process continuity, high drug application rate, and is conducive to industrial application. In addition, the preparation method provided by the present invention has the advantages of simple process and being suitable for large-scale production application in workshops.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises Q) immediate-release pellets and E) sustained-release pellets, Wherein, the sustained-release pellets comprise: Ea) drug-containing pellets and Eb) a sustained-release layer, wherein the sustained-release layer is coated on the outer surface of the drug-containing pellets; The rapid-release pellets include (a) drug-containing pellets; The sustained-release pellets and the immediate-release pellets have the same or substantially the same drug-containing pellets formulations, and the drug-containing pellets include a pellet core and a drug-containing layer, wherein the drug-containing layer is coated on the outer surface of the pellet core; wherein the pellet core includes at least one of sucrose, lactose, corn starch, mannitol, tartaric acid, citric acid or microcrystalline cellulose; and the drug-containing layer includes viloxazine or a pharmaceutically acceptable salt thereof; The sustained-release layer comprises a sustained-release material and a pore-forming agent, wherein the sustained-release material is selected from one or more of ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, polyethylene glycol, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylate, and polymethacrylate; preferably, the sustained-release material comprises at least one of ethyl cellulose, cellulose acetate, or cellulose butyrate, and more preferably, the sustained-release material comprises ethyl cellulose; The pore-forming agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, povidone, lactose, polyethylene glycol, polyvinyl alcohol or sodium lauryl sulfate; preferably, the pore-forming agent is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, povidone or lactose, and more preferably, the pore-forming agent comprises hydroxypropyl methylcellulose.

2. The pharmaceutical composition according to claim 1, characterized in that The drug-containing layer further comprises one or more of an adhesive and a lubricant; wherein the adhesive is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, povidone, sodium starch glycolate, polyvinyl alcohol, methylcellulose and hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, silicon dioxide, micropowdered silica gel, magnesium silicate, powdered polyethylene glycol, talc, glyceryl monostearate, stearic acid and sodium stearyl fumarate; Preferably, the drug-containing layer further comprises at least one of hypromellose, polyethylene glycol or talc; more preferably, the drug-containing layer further comprises hypromellose and talc.

3. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that The sustained-release material comprises ethylcellulose, and the pore-forming agent comprises hypromellose.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The sustained-release pellets comprise Ea) drug-containing pellets and Eb) a sustained-release layer, wherein the amount of Eb) the sustained-release layer is 5-20% by weight, preferably 7-16% by weight, of the drug-containing pellets Ea).

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The weight ratio of the sustained-release material to the pore-forming agent in the sustained-release layer Eb) is (9-30):1, preferably (13-20):1 or (15-20):

1.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The weight ratio of the drug-containing pellets in the quick-release pellets to the drug-containing pellets in the sustained-release pellets is (15-30):(85-70), preferably 20:

80.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The drug-containing pellets include a pellet core and a drug-containing layer; wherein the pellet core includes sucrose; the drug-containing layer includes viloxazine or a pharmaceutically acceptable salt thereof, HPMC and talcum powder; and the drug-containing layer is coated on the outer surface of the pellet core; More preferably, based on the total weight of the pellet core and the drug-containing layer, the pellet core accounts for 35-55% by weight, preferably 40-45% by weight; and / or Viloxacin or a pharmaceutically acceptable salt thereof accounts for 35 to 50% by weight, preferably 40 to 45% by weight; and / or, HPMC accounts for 1 to 10% by weight, preferably 5 to 10% by weight; and / or, The talc accounts for 1 to 10% by weight, preferably 1 to 5% by weight.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that The sustained-release pellets further include a protective layer Ec), which is coated on the outer surface of the sustained-release layer; Further preferably, the protective layer comprises at least one of hydroxypropyl methylcellulose or polyethylene glycol; and optionally further comprises one or more of a plasticizer, a colorant, a lubricant or a sweetener.

9. The pharmaceutical composition according to claim 8, characterized in that: The plasticizer comprises a mixture of one or more of glycerol, diacetyl monoglyceride, propylene glycol, polysorbate 80, polyethylene glycol, triethyl citrate, triacetin, acetylated monoglyceride or fumaric acid; and / or, The colorant includes a mixture of one or more of yellow iron oxide, brown iron oxide, red iron oxide, black iron oxide, and titanium dioxide; and / or, The lubricant comprises a mixture of one or more of talc, silicon dioxide and kaolin; and / or, The sweetener includes a mixture of one or more of sucrose, lactose, and xylitol; Preferably, the plasticizer comprises triacetin; and / or, The colorant comprises titanium dioxide; and / or, The lubricant comprises talc; and / or, The sweetener includes a mixture of one or more of sucrose and lactose.

10. The pharmaceutical composition according to any one of claims 8 to 9, characterized in that The protective layer Ec) comprises at least one of hypromellose, polyethylene glycol, triacetin, titanium dioxide and lactose; Further preferably, the Ec) protective layer comprises HPMC, polyethylene glycol, titanium dioxide, lactose and triacetin; Further preferably, the Ec) protective layer is a film coating premix comprising HPMC, polyethylene glycol, titanium dioxide, lactose and triacetin; More preferably, the protective layer Ec) accounts for 1 to 5 weight % based on the total solid weight of Ea) the drug-containing pellets and Eb) the sustained-release layer in the sustained-release pellets.

11. The pharmaceutical composition according to any one of claims 1 to 10, characterized in that The particle size of viloxazine or a pharmaceutically acceptable salt thereof is D90≤30 μm, more preferably, D90≤20 μm.

12. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises Q) immediate-release pellets and E) sustained-release pellets, Wherein, the sustained-release pellets comprise: Ea) drug-containing pellets and Eb) sustained-release layer; the quick-release pellets comprise Qa) drug-containing pellets; The prescription of the drug-containing pellets contained in the sustained-release pellets and the immediate-release pellets is the same or substantially the same, and both include a pellet core and a drug-containing layer, wherein the drug-containing layer is coated on the outer surface of the pellet core; wherein the pellet core includes at least one of sucrose, lactose, corn starch, mannitol, tartaric acid, citric acid or microcrystalline cellulose; and the drug-containing layer includes viloxazine or viloxazine hydrochloride, HPMC and talc; The sustained-release layer comprises a sustained-release material and a pore-forming agent, wherein the sustained-release material comprises ethyl cellulose and the pore-forming agent comprises hydroxypropyl methyl cellulose; the weight ratio of the sustained-release material to the pore-forming agent is (9-30):1, preferably (13-20):1 or (15-20):1; The amount of the sustained-release layer Eb) is 5 to 20% by weight of the drug-containing pellets Ea), preferably 7 to 16% by weight; Further preferably, based on the total weight of the pellet core and the drug-containing layer, the pellet core accounts for 35-55% by weight, preferably 40-45% by weight; the viloxazine or viloxazine hydrochloride accounts for 35-50% by weight, preferably 40-45% by weight; the HPMC accounts for 1-10% by weight, preferably 5-10% by weight; the talc accounts for 1-10% by weight, preferably 1-5% by weight; More preferably, the weight ratio of the drug-containing pellets in the immediate-release pellets to the drug-containing pellets in the sustained-release pellets is (15-30):(85-70), preferably 20:

80.

13. The pharmaceutical composition according to claim 12, characterized in that The sustained-release pellets comprise Ea) drug-containing pellets and Eb) a sustained-release layer, wherein the amount of the Eb) sustained-release layer is 6 to 10% by weight of the Ea) drug-containing pellets; Alternatively, the amount of the sustained-release layer Eb) is 10-12% by weight of the drug-containing pellets Ea); Alternatively, the amount of the sustained-release layer Eb) is 12-14% by weight of the drug-containing pellets Ea).

14. The method for preparing the pharmaceutical composition according to any one of claims 1 to 13, characterized in that: The method comprises the following steps: S1) preparing drug-containing pellets; S2) adding the sustained-release material and the pore-forming agent into a solvent and stirring to obtain a liquid preparation II, and then spraying the liquid preparation II onto the surface of the prescribed amount of drug-containing pellets to obtain sustained-release pellets I; S3) adding the protective layer into water and stirring to obtain a protective layer coating solution, and then spraying the protective layer coating solution onto the surface of the sustained-release pellets I described in step S2) to obtain sustained-release pellets; S4) putting the prescribed amount of sustained-release pellets and immediate-release pellets into capsules to obtain; Further preferably, the solvent in step S2) is at least one of water, ethanol or isopropanol; Further preferably, the step S2) of spraying the surface of the drug-containing pellets with the preparation II to obtain the sustained-release pellets I is carried out in a fluidized bed; Further preferably, the step S3) of spraying the protective layer coating liquid onto the surface of the sustained-release pellets I in step S2) to obtain the sustained-release pellets is carried out in a fluidized bed; Further preferably, in the process of spraying the surface of the drug-containing pellets with the preparation II in step S2), the material temperature is controlled to be 30-50°C, preferably 35-45°C; Further preferably, in step S3), during the process of spraying the surface of the sustained-release pellets I with the protective layer coating liquid, the material temperature is controlled to be 30-50° C., preferably 35-45° C.; Optionally, step S3) further comprises the step of aging the prepared sustained-release pellets, wherein the aging temperature is 50-75°C, preferably 50-55°C, or 55-60°C, or 60-65°C, or 65-70°C or 70-75°C.

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