Paroxetine sustained release preparation as well as preparation method and application thereof

Abstract

The invention discloses a paroxetine sustained release preparation as well as a preparation method and application thereof. The paroxetine sustained release preparation comprises a core material and a wall material, the core material comprises paroxetine, a diluent, a framework material and an adhesive; the wall material comprises a film control material, a pore-foaming agent, an anti-sticking agent and a plasticizer. The core material of the paroxetine sustained-release preparation disclosed by the invention can be a multi-unit sustained-release micro-tablet and is additionally provided with a sustained-release wall material, so that compared with a tablet with a single release unit, the paroxetine sustained-release preparation has a larger surface area and is more completely absorbed, and the bioavailability can be improved; the independent release microchip system ensures the independent release behavior, the administration dosage can be reduced according to actual needs, the blood concentration fluctuation and side reaction are reduced, and the treatment effect is improved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a paroxetine sustained-release preparation, a preparation method thereof, and an application thereof. Background Art

[0002] Paroxetine hydrochloride is a phenylpiperidine compound that is a potent, highly selective central nervous system 5-HT reuptake inhibitor. It works by inhibiting the active transport of 5-HT, increasing 5-HT concentration in the synaptic cleft, and enhancing 5-HT-ergic neurotransmission. It has minimal effects on the reuptake of norepinephrine and dopamine. Its antidepressant effects are similar in intensity to those of tricyclic antidepressants (TCAs), while its side effects are significantly fewer. It is a new third-generation antidepressant. Furthermore, experimental results show that paroxetine hydrochloride has little affinity for muscarinic receptors, α-adrenergic receptors, β-adrenergic receptors, dopamine D2 receptors, histamine H1 receptors, and 5-HT2 receptors. Consequently, it has minimal adverse reactions in the central and autonomic nervous systems. Paroxetine hydrochloride was developed by GlaxoSmithKline and approved for sale by the U.S. Food and Drug Administration (FDA) in 1991. It can be used to treat various types of depression, phobia disorders with or without agoraphobia, and obsessive-compulsive disorder. It has the characteristics of rapid onset and good tolerability.

[0003] Due to the poor water solubility of paroxetine, its existing ordinary tablets have problems such as large fluctuations in blood drug concentration after administration, severe side effects, and poor therapeutic effects. Therefore, a controlled-release drug preparation is needed to overcome this defect. Summary of the Invention

[0004] The present invention aims to solve at least one of the above-mentioned technical problems in the prior art. To this end, the present invention aims to provide a paroxetine sustained-release preparation and its preparation method and application.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] The first aspect of the present invention provides a paroxetine sustained-release preparation, comprising a core material and a wall material; the core material comprises paroxetine, a diluent, a skeleton material, and an adhesive; the wall material comprises a membrane-controlling material, a pore-forming agent, an anti-adhesive agent, and a plasticizer.

[0007] In some embodiments of the present invention, the weight ratio of the core material to the wall material is (3-65):1, such as (4-50):1, (4-40):1, (1-30):1, (2-25):1, etc.

[0008] In some embodiments of the present invention, the mass proportion of the core material in the paroxetine sustained-release preparation is 55-99%, such as 75-97%, 80-96%, 90-96%, 93-96%, etc.

[0009] In some embodiments of the present invention, in the paroxetine sustained-release preparation, the mass proportion of the skeleton material is 25-50%, such as 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, and 49%.

[0010] In some embodiments of the present invention, the mass proportion of paroxetine in the core material is 3-20%, such as 4-18%, 5-17%, 6-16%, 7-15%, 8-14%, 9-11%, 9%, 10%, 11%, 12%, 13%, etc.

[0011] In some embodiments of the present invention, the paroxetine sustained-release preparation comprises, in percentage by mass: a core material and a wall material; the core material comprises 5-10% paroxetine, 25-55% diluent, 25-50% skeleton material, and 2-10% adhesive; the wall material comprises 1-8% membrane-control material, 1-5% pore-forming agent, 0.05-1.2% anti-adhesive agent, and 0.1-1% plasticizer.

[0012] In some embodiments of the present invention, the paroxetine sustained-release preparation comprises, in parts by weight, a core material and a wall material; the core material comprises 5 to 10 parts of paroxetine, 25 to 55 parts of a diluent, 25 to 50 parts of a skeleton material, and 2 to 10 parts of an adhesive; the wall material comprises 1 to 8 parts of a membrane-controlling material, 1 to 5 parts of a pore-forming agent, 0.05 to 1.2 parts of an anti-adhesive agent, and 0.1 to 1 part of a plasticizer.

[0013] In some embodiments of the present invention, the content of paroxetine that can meet the purpose of the present invention is 5 to 10 parts by weight, such as 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, and 10 parts.

[0014] In some embodiments of the present invention, the content of the diluent that can meet the purpose of the present invention is 25 to 55 parts by weight, such as 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 60 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts, 41 parts, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 ​​parts, 49 parts, 50 parts, 51 parts, 52 parts, 53 parts, 54 parts, and 55 parts.

[0015] In some embodiments of the present invention, the content of the skeleton material that can meet the purpose of the present invention is 25 to 50 parts by weight, such as 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 60 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts, 41 parts, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 ​​parts, 49 parts, and 50 parts.

[0016] In some embodiments of the present invention, the content of the adhesive that can meet the purpose of the present invention is 2 to 10 parts by weight, such as 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, and 10 parts.

[0017] In some embodiments of the present invention, the content of the membrane control material that can meet the purpose of the present invention is 1 to 8 parts by weight, such as 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, and 8 parts.

[0018] In some embodiments of the present invention, the content of the porogen that can meet the purpose of the present invention is 1 to 5 parts by weight, such as 1 part, 2 parts, 3 parts, 4 parts, and 5 parts.

[0019] In some embodiments of the present invention, the content of the anti-sticking agent that can meet the purpose of the present invention is 0.05 to 1.2 parts by weight, such as 0.05 parts, 0.1 parts, 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1.0 parts, 1.1 parts, and 1.2 parts.

[0020] In some embodiments of the present invention, the content of the plasticizer that can meet the purpose of the present invention is 0.1 to 1 part by weight, such as 0.1 part, 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part, 0.8 part, 0.9 part, and 1.0 part.

[0021] In some embodiments of the present invention, the paroxetine sustained-release preparation comprises, in parts by weight, a core material and a wall material; the core material comprises 8 to 10 parts of paroxetine, 35 to 45 parts of a diluent, 35 to 40 parts of a skeleton material, and 4 to 7 parts of an adhesive; the wall material comprises 2 to 5 parts of a membrane-controlling material, 1 to 3 parts of a pore-forming agent, 0.2 to 0.5 parts of an anti-adhesive agent, and 0.2 to 0.6 parts of a plasticizer.

[0022] In some embodiments of the present invention, the diluent includes at least one of lactose, mannitol, microcrystalline cellulose, and starch. In the present invention, when mixed with the API, the diluent not only increases the weight (or volume) of the paroxetine formulation but also helps improve the compression moldability of the drug and increases the uniformity of the paroxetine content.

[0023] In some embodiments of the present invention, the matrix material comprises at least one of hydropropyl methylcellulose, poloxamer, methylcellulose, ethylcellulose, and carbomer. In the present invention, the matrix material swells in water to form a gel barrier that controls the release of paroxetine, or the matrix material remains virtually unchanged in water. After gastrointestinal fluid penetrates the voids of the matrix material, the drug dissolves and slowly diffuses outward through the complex, extremely fine pores within the matrix, thereby controlling the release of paroxetine.

[0024] In some embodiments of the present invention, the binder comprises at least one of copovidone, povidone, hypromellose, and hydroxypropyl cellulose. In the present invention, the binder not only acts as a binder but also acts as a surfactant, solubilizing paroxetine, thereby improving the bioavailability of paroxetine.

[0025] In some embodiments of the present invention, the membrane control material comprises at least one of ethyl cellulose, acrylic resin, cellulose acetate, and ethylene-vinyl acetate copolymer. In the present invention, the membrane control material is a water-insoluble high molecular polymer with good film-forming properties and mechanical properties.

[0026] In some embodiments of the present invention, the porogen includes at least one of lactose, polyethylene glycol, hypromellose, hydroxypropyl cellulose, and poloxamer. In the present invention, the porogen rapidly dissolves upon contact with gastrointestinal fluid, forming a large number of fine pores on the surface of the coating film, allowing gastrointestinal fluid to enter through the pores and subsequently contact the core material.

[0027] In some embodiments of the present invention, the anti-adhesive agent comprises at least one of talc, titanium dioxide, and monoglyceride. In the present invention, the anti-adhesive agent can prevent adhesion during the preparation process of the formulation and enable dispersion.

[0028] In some embodiments of the present invention, the plasticizer includes at least one of dibutyl sebacate, triethyl citrate, and triacetin. In the present invention, the plasticizer can increase the flexibility of the polymer material and enhance the plasticity of the membrane control material.

[0029] In some embodiments of the present invention, the core material further includes a lubricant; in parts by weight, the core material contains 0.5 to 5 parts of lubricant, such as 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1.0 parts, 1.5 parts, 2.0 parts, 2.5 parts, 3.0 parts, 3.5 parts, 4.0 parts, 4.5 parts, and 5.0 parts; the lubricant includes at least one of magnesium stearate, stearic acid, and sodium stearyl fumarate.

[0030] In some embodiments of the present invention, the core material further comprises a lubricant; and the paroxetine sustained-release preparation comprises 0.5-5% of the lubricant in terms of mass percentage.

[0031] In some embodiments of the present invention, the paroxetine sustained-release preparation is any one of paroxetine sustained-release capsules, paroxetine sustained-release tablets, and paroxetine sustained-release pellets.

[0032] In some embodiments of the present invention, the contents of the paroxetine sustained-release capsules are micropills and / or microtablets, and the micropills and / or microtablets include a core material wrapped with the wall material; in some embodiments of the present invention, the average size of the microtablets is less than 10 mm, such as 1 to 5 mm, 1 to 3 mm, etc.; the average particle size of the micropills is less than 10 mm, such as 1 to 5 mm, 1 to 3 mm, etc.; in the paroxetine sustained-release capsules, each capsule contains 2 to 40 microtablets.

[0033] In some embodiments of the present invention, the capsule includes size 1, size 0, and size 00 enteric-coated capsules.

[0034] In some embodiments of the present invention, the microtablet has a tablet weight of 15 to 200 mg, and each microtablet contains 0.5 to 10 mg of paroxetine.

[0035] In some embodiments of the present invention, the density of the microsheet is not less than 1.0 g / cm 3 , such as not less than 1.1g / cm 3 , not less than 1.2g / cm 3 An exemplary method for measuring the density of the microplatelets of the present invention is the liquid immersion method: 60 mL of liquid paraffin is accurately measured using a 100 mL graduated cylinder, approximately 10 g of microplatelets are weighed, and the mixture is slowly added to the liquid paraffin. After all the liquid paraffin is added, the total volume is read for 2 minutes, and the density of the microplatelets is calculated based on the actual volume of the microplatelets.

[0036] In some embodiments of the present invention, the friability of the microtablets is no greater than 0.8%, such as no greater than 0.5%, 0.1-0.5%, or 0.2-0.4%. An exemplary method for measuring the friability of the microtablets of the present invention is the 0923 tablet friability test method of the Chinese Pharmacopoeia 2020 edition.

[0037] In some embodiments of the present invention, the hardness of the microplate is 3 to 15 N, such as 5 to 12 N, or 5 to 8 N. Measurement of the Microplate An exemplary method for measuring the hardness of the microplate of the present invention is to use a Sotax Multitest50 high-sensitivity hardness tester.

[0038] As used herein, the microtablets of the present invention refer to dosage units obtained by compressing powders or granules and have a size of 10 mm or less.The microtablets according to the present invention can be prepared by direct compression or by any other appropriate method.

[0039] The term "capsule" refers to a dosage form comprising a plurality of solid microparticles encapsulated within a shell, which is typically made of gelatin but may also be made of other materials. The shell of the capsule disintegrates after digestion, thereby releasing the microparticle contents. Capsules include hard shell capsules and soft shell capsules such as soft gel capsules. The capsules used in the present invention refer to hard shells or one-piece, sealed soft shells, which are typically made of gelatin but may also be made of other film-forming materials.

[0040] In some embodiments of the present invention, the release of paroxetine in the paroxetine sustained-release capsule within 120 minutes is not more than 30wt%; such as 29wt%, 28wt%, 27wt%, 26wt%, 25wt%, 24wt%, 23wt%, 22wt%, 21wt%, 20wt%, 19wt%, 18wt%. Wherein the weight percentage is based on the theoretical labeled amount of the capsule. The above-mentioned release characteristics can be measured, for example, in vitro, for example, by adopting the dissolution determination method of the slurry method of the 2020 edition 0931 of the Chinese Pharmacopoeia, or under different pH values ​​(for example, 5-10, 6-8, 6-7, 6.5-7.0, 6.8-7.0, including but not limited to 6.8, 6.9, 7.0, etc.).

[0041] The second aspect of the present invention provides a method for preparing the paroxetine sustained-release preparation, comprising the following steps:

[0042] S1: Mixing the core material components to prepare the core material;

[0043] S2: Mixing the wall material components with water to prepare a coating solution;

[0044] S3: coating the core material with the coating solution to prepare the paroxetine sustained-release preparation.

[0045] In some embodiments of the present invention, S1: mixing the core material components and pressing them into microtablets to produce the core material; in some embodiments of the present invention, in S1, the pressing method is selected from hydraulic pressing, mechanical pressing, and pneumatic pressing. In some embodiments of the present invention, the pressing equipment in S1 is a single-punch or multi-punch tablet press, for example, the Shanghai Tianfan Pharmaceutical Machinery Co., Ltd. DP-50 model, the Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd. ZPS008 model, etc.

[0046] In some embodiments of the present invention, S1: paroxetine, a skeleton material, a diluent, and a binder are mixed, a lubricant is added, and the mixture is further mixed and pressed into micro-tablets to prepare a core material.

[0047] In some embodiments of the present invention, S2: dissolving the porogen in water, and sequentially adding the plasticizer, anti-sticking agent, and film-controlling material with stirring to prepare a coating solution; the dissolution temperature is 85-100°C.

[0048] In some embodiments of the present invention, in S2, the mass concentration of the wall material in the coating solution is 20% to 30%, such as 22-28%, 20%, 21%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, and 30%.

[0049] In some embodiments of the present invention, S3: coating the core material with the coating solution, aging after drying, and filling the capsules to obtain the paroxetine sustained-release preparation; the aging temperature is 50-65°C; the aging time is 3-5 hours; the drying includes at least one of rotary evaporation, vacuum drying, freeze drying and spray drying; the drying temperature is 35-45°C; and the drying time is 10-40 minutes.

[0050] In some embodiments of the present invention, in S3, the coating temperature is 35-50°C, and the spray rate is 1.0-2.5 g / min, such as 1.0-2.0 g / min.

[0051] The third aspect of the present invention provides a use of the paroxetine sustained-release preparation in the preparation of at least one drug for treating depression, anxiety, and premature ejaculation.

[0052] The beneficial effects of the present invention are:

[0053] The core material of the paroxetine sustained-release preparation of the present invention can be a multi-unit sustained-release microtablet with an external sustained-release wall material. Compared with tablets with a single release unit, it has a larger surface area, more complete absorption, and improved bioavailability; the independently releasing microtablet system ensures its independent release behavior, can reduce the dosage according to actual needs, reduce blood concentration fluctuations and side effects, and improve the therapeutic effect.

[0054] The paroxetine sustained-release preparation of the present invention utilizes the characteristics of various pharmaceutical excipients and is used in combination to achieve a controlled-release effect consistent with that of an osmotic sustained-release preparation.

[0055] The preparation method of the paroxetine sustained-release preparation of the present invention has a simple preparation process, high equipment popularity, is suitable for large-scale production in enterprises, and has great market development prospects. DETAILED DESCRIPTION

[0056] The present invention is further described in detail below using specific examples. Unless otherwise specified, the raw materials, reagents, and apparatus used in the examples and comparative examples are available from conventional commercial sources or by conventional methods. Unless otherwise specified, all experimental or testing methods are conventional in the art.

[0057] Example 1

[0058] This example prepares a paroxetine sustained-release preparation, and the specific process is as follows:

[0059] The raw material composition of paroxetine sustained-release preparation is shown in Table 1:

[0060] Table 1

[0061]

[0062] Preparation method:

[0063] S1: According to the formula, paroxetine hydrochloride, hypromellose, carbomer, lactose, and copovidone were sieved through 20-50 mesh screens respectively; the materials were then added to a mixer and mixed at 40 Hz for 10 minutes; magnesium stearate was added and mixing was continued for 5 minutes; and microtablets with a diameter of 4 mm were pressed using a Shanghai Tianfan Pharmaceutical Machinery DP-50 single-punch tablet press. Each microtablet contained 5 mg of API.

[0064] S2: Dissolve Hydroxypropyl Methylcellulose in 100℃ purified water, add lactose while stirring, add triethyl citrate after stirring for 5-20min, continue stirring for 5min, add talcum powder, stir and disperse for 5-30min, add ethyl cellulose aqueous dispersion ( E-7-7050, Colorcon, total solid content 25%, ethyl cellulose content 20%), continue stirring for more than 45 minutes, and sieve to obtain the coating solution for use.

[0065] S3: The microtablets were coated with the coating solution, and the sustained-release preparation bed temperature was set at 38°C to 45°C; the spray rate was 1.5 g / min; after coating, the tablets were dried at 42°C for 30 minutes, and then aged in a forced air drying oven at 50°C for 4 hours; the obtained microtablets were filled into capsules, and each capsule contained 4 microtablets.

[0066] Example 2

[0067] This example prepares a paroxetine sustained-release preparation, and the specific process is as follows:

[0068] The raw material composition of paroxetine sustained-release preparation is shown in Table 2:

[0069] Table 2

[0070]

[0071]

[0072] Preparation method:

[0073] S1: According to the formula, paroxetine hydrochloride, hypromellose, methylcellulose, lactose, and copovidone were sieved through 20-50 mesh screens respectively; the materials were then added to a mixer and mixed at 40 Hz for 10 minutes; magnesium stearate was added and mixing was continued for 5 minutes; and microtablets with a diameter of 3 mm were pressed using a Shanghai Tianfan Pharmaceutical Machinery DP-50 single-punch tablet press. Each microtablet contained 2 mg of API.

[0074] S2: Dissolve Hydroxypropyl Methylcellulose in 85℃ purified water, add lactose while stirring, add triethyl citrate after stirring for 5-20min, continue stirring for 5min, add talcum powder, stir and disperse for 5-30min, add ethyl cellulose aqueous dispersion ( E-7-7050, Colorcon, total solid content 25%, ethyl cellulose content 20%), continue stirring for more than 45 minutes, and sieve to obtain the coating solution for use.

[0075] S3: The microtablets were coated with the coating solution, and the sustained-release preparation bed temperature was set at 38°C to 45°C; the spray rate was 1.5 g / min; after coating, the tablets were dried at 42°C for 30 minutes and aged in a forced air drying oven at 50°C for 4 hours; the obtained microtablets were filled into capsules, and each capsule contained 10 microtablets.

[0076] Example 3

[0077] This example prepares a paroxetine sustained-release preparation, and the specific process is as follows:

[0078] The raw material composition of paroxetine sustained-release preparation is shown in Table 3:

[0079] Table 3

[0080]

[0081]

[0082] Preparation method:

[0083] S1: According to the formula, paroxetine hydrochloride, hypromellose, ethyl cellulose, lactose, and copovidone were sieved through 20-50 mesh screens respectively; the materials were then added to a mixer and mixed at 40 Hz for 10 minutes; magnesium stearate was added and mixing was continued for 5 minutes; and microtablets with a diameter of 1.5 mm were pressed using a Shanghai Tianfan Pharmaceutical Machinery DP-50 single-punch tablet press. Each microtablet contained 2 mg of API.

[0084] S2: Dissolve Hydroxypropyl Methylcellulose in 90℃ purified water, add lactose while stirring, add triethyl citrate after stirring for 5-20min, continue stirring for 5min, add talcum powder, stir and disperse for 5-30min, add ethyl cellulose aqueous dispersion ( E-7-7050, Colorcon, total solid content 25%, ethyl cellulose content 20%), continue stirring for more than 45 minutes, and sieve to obtain the coating solution for use.

[0085] S3: Coat the microtablets with the coating solution, set the sustained-release preparation bed temperature to 38°C to 45°C, spray at a rate of 1.5 g / min, dry at 42°C for 30 minutes, and age in a forced-air drying oven at 50°C for 4 hours; fill the resulting microtablets into capsules, with each capsule containing 20 microtablets.

[0086] Example 4

[0087] This example prepares a paroxetine sustained-release preparation, and the specific process is as follows:

[0088] The raw material composition of paroxetine sustained-release preparation is shown in Table 4:

[0089] Table 4

[0090]

[0091] Preparation method:

[0092] S1: According to the formula amount, paroxetine hydrochloride, hypromellose, carbomer, and lactose were sieved through 20-50 mesh respectively; the materials were then added to a mixer and mixed at 40 Hz for 10 minutes; magnesium stearate was added and mixing was continued for 5 minutes; after thorough mixing, 5% copovidone ethanol solution was added, and wet granulation was performed using a rapid mixing granulator. Micro-pellets were formed by extrusion and spheronization. The aperture of the extrusion orifice was 0.6 mm, the extrusion speed was 50 rpm, and the rotation speed of the spheronization disk was 2000 rpm. Micro-pellets were obtained by fluidized bed drying.

[0093] S2: Dissolve Hydroxypropyl Methylcellulose in 95℃ purified water, add lactose while stirring, add triethyl citrate after stirring for 5-20min, continue stirring for 5min, add talcum powder, stir and disperse for 5-30min, add ethyl cellulose aqueous dispersion ( E-7-7050, Colorcon, total solid content 25%, ethyl cellulose content 20%), continue stirring for more than 45 minutes, and sieve to obtain the coating solution for use.

[0094] S3: Coat the pellets with the coating solution, set the sustained-release preparation bed temperature at 38°C to 45°C, spray at a rate of 1.5 g / min, dry at 42°C for 30 min, and age in a forced-air drying oven at 50°C for 4 h; fill the resulting pellets into capsules, each capsule containing approximately 100 pellets.

[0095] Comparative Example 1

[0096] This comparative example prepared a paroxetine sustained-release preparation, and the specific process was as follows:

[0097] The raw material composition of paroxetine sustained-release preparation is shown in Table 5:

[0098] Table 5

[0099]

[0100] Note: ACRYL-EZE WHITE is an enteric film coating premix based on Eudragit L100-55 produced by Colorcon.

[0101] Preparation method:

[0102] S1: According to the formula, paroxetine hydrochloride, hypromellose, carbomer, lactose, and copovidone were sieved through 20-50 mesh screens respectively; the materials were then added to a mixer and mixed at 40 Hz for 10 minutes; magnesium stearate was added and mixing was continued for 5 minutes; and microtablets with a diameter of 1.5 mm were pressed using a Shanghai Tianfan Pharmaceutical Machinery DP-50 single-punch tablet press. Each microtablet contained 2 mg of API.

[0103] S2: Add ACRYL-EZE WHITE film coating premix to purified water while stirring. Continue stirring for more than 45 minutes after addition. Sieve to obtain the coating solution for later use.

[0104] S3: Coat the microtablets with the coating solution, set the sustained-release preparation bed temperature at 38°C to 45°C; spray at a rate of 1.5 g / min; dry at 42°C for 30 minutes after coating, and age in a forced air drying oven at 50°C for 4 hours; fill the obtained microtablets into capsules, each capsule containing 20 microtablets.

[0105] Test Example 1

[0106] In this test example, an in vitro dissolution experiment was conducted on the prepared paroxetine sustained-release preparation. The specific process was as follows:

[0107] Reference preparation: Paroxetine hydrochloride sustained-release tablets (25 mg), marketed in China, licensed by GLAXOSMITH KLINE INC.

[0108] Dissolution method: Pulp method according to Chinese Pharmacopoeia 2020 edition 0931. Dissolution medium: Weigh 40.8 g of potassium dihydrogen phosphate, dissolve in water, and dilute to 5000 mL. Adjust the pH to 6.9 ± 0.1 with 3 mol / L potassium hydroxide. Medium volume: 900 mL; Rotation speed: 50 rpm; Temperature: 37 ± 0.5°C.

[0109] Dissolution sample analysis: The solution obtained in the dissolution test was filtered through a 0.45 μm filter membrane and the filtrate was collected and measured by UV spectrophotometry at a wavelength of 305 nm using a Shimadzu UV-2550 instrument.

[0110] The results are shown in Table 6:

[0111] Table 6 Dissolution behavior of different preparations in pH 6.8 medium

[0112]

[0113] As shown in Table 6, when the sustained-release matrix material in Examples 1 and 2 was 39% and 37% respectively, the paroxetine sustained-release capsules were prepared using the micro-tablet process, and each sustained-release tablet had a good sustained-release effect. When the sustained-release matrix material in Example 3 was 24%, the paroxetine sustained-release capsules were prepared using the micro-tablet process, and 50% was released in the first 2 hours. When the sustained-release matrix material in Example 4 was 39%, the paroxetine sustained-release capsules were prepared using the micro-pellet process, and 45% was released in the first 2 hours. Comparative Example 1 was coated with an enteric material, and 55% was released in the first 2 hours, with a burst release phenomenon, and a good sustained-release effect was not achieved.

[0114] In summary, the sustained-release capsules prepared using the microtablet process of the present invention can achieve good sustained-release effects without a burst-release effect when the microtablet core is a sustained-release skeleton material and the sustained-release coating material is used for coating.

[0115] Test Example 2

[0116] This test example conducts a pharmacokinetic test on the prepared paroxetine sustained-release preparation. The specific process is as follows:

[0117] Test Method: Eight Beagle dogs, half male and half female, were randomly divided into two groups of four based on body weight. A two-cycle crossover dosing study was conducted using a self-made (20 mg) and a commercially available (25 mg) formulation. Based on the drug's blood concentration data, the pharmacokinetic parameter AUC was calculated using the WinNonlin 5.2 non-compartmental model. 0→t , AUC 0→∞ , MRT 0→∞ 、C max 、T max and t 1 / 2 The main pharmacokinetic parameters of 8 Beagle dogs after oral administration of the paroxetine sustained-release preparation of Example 1 and the reference preparation on an empty stomach are shown in Table 7:

[0118] Table 7

[0119] parameter Example 1 Reference ratio <![CDATA[C max (ng.ml -1 )]]> 5.53±3.79 5.82±6.71 <![CDATA[AUC 0→t (ng.h.ml -1 )]]> 35.34±29.97 38.48±38.55 <![CDATA[AUC 0→∞ (ng.h.ml -1 )]]> 43.89±36.58 48.12±45.56 <![CDATA[T max (h)]]> 5.46±3.24 6.84±6.95 <![CDATA[t 1 / 2 (h)]]> 3.68±2.21 3.83±2.65 <![CDATA[MRT 0→∞ (h)]]> 6.59±2.95 7.36±3.44

[0120] As shown in Table 7, the main pharmacokinetic parameters of the paroxetine sustained-release preparation of Example 1 and the reference preparation are similar, indicating that there is no statistical difference in the main pharmacokinetic parameters between the two.

[0121] Therefore, the in vitro release of the paroxetine sustained-release preparation of Example 1 was basically consistent with that of the reference preparation, and there was no statistical difference in the main pharmacokinetic parameters in Beagle dogs.

[0122] In summary, the present invention adopts a skeleton sustained-release tablet core with an external membrane pore coating to prepare paroxetine sustained-release preparations with different release rates, thereby solving the shortcomings of ordinary sustained-release preparations, such as large fluctuations in blood drug concentration, large side effects, and poor therapeutic effects; and the paroxetine sustained-release preparations prepared according to Examples 1 and 2 can be considered to have consistent in vitro release behavior compared with the reference preparations, and have the possibility of clinical substitution. The present invention adopts a preparation process of making a multi-unit sustained-release microtablet with a sustained-release material and then adding a sustained-release coating film. Compared with the tablets with a single release unit, the present invention has a larger surface area and more complete absorption, and the obtained preparation can improve bioavailability; the capsule of the paroxetine sustained-release preparation contains multiple independently released microtablet systems, and the dosage can be adjusted by adjusting the number of microtablets in the capsule. The paroxetine sustained-release preparation of the present invention reduces the number of microtablets in the capsule without changing the release behavior, thereby solving the problem that the reference preparation (osmotic pump tablet) cannot be broken apart and the dosage cannot be adjusted according to individual differences.

[0123] The paroxetine sustained-release preparation of the present invention has a simple production process, universal production equipment, low cost, is easy for patients to carry and swallow, and is convenient for doctors to adjust the dosage individually. It also has the same therapeutic effect as existing dosage forms.

[0124] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A paroxetine sustained-release preparation, characterized in that: It comprises a core material and a wall material; the core material comprises paroxetine, a diluent, a skeleton material and an adhesive; the wall material comprises a membrane control material, a pore-forming agent, an anti-sticking agent and a plasticizer.

2. The paroxetine sustained-release preparation according to claim 1, wherein: The weight ratio of the core material to the wall material is (3-65):1; and / or, in the paroxetine sustained-release preparation, the mass proportion of the skeleton material is 25-50%.

3. The paroxetine sustained-release preparation according to claim 1, wherein: Calculated by mass percentage, the paroxetine sustained-release preparation includes a core material and a wall material; the core material includes 5-10% paroxetine, 25-55% diluent, 25-50% skeleton material, and 2-10% adhesive; the wall material includes 1-8% membrane control material, 1-5% pore-forming agent, 0.05-1.2% anti-adhesive agent, and 0.1-1% plasticizer.

4. The paroxetine sustained-release preparation according to claim 1, characterized in that: The core material meets at least one of the following conditions: (I) the diluent comprises at least one of lactose, mannitol, microcrystalline cellulose, and starch; (II) the matrix material comprises at least one of hypromellose, poloxamer, methylcellulose, ethylcellulose, and carbomer; (III) The binder comprises at least one of copovidone, povidone, hypromellose, and hydroxypropyl cellulose.

5. The paroxetine sustained-release preparation according to claim 1, characterized in that: The wall material meets at least one of the following conditions: (I) the membrane control material comprises at least one of ethyl cellulose, acrylic resin, cellulose acetate, and ethylene-vinyl acetate copolymer; (II) the porogen comprises at least one of lactose, polyethylene glycol, hypromellose, hydroxypropyl cellulose, and poloxamer; (III) the anti-adhesive agent comprises at least one of talc, titanium dioxide, and monoglyceride; (IV) The plasticizer includes at least one of dibutyl sebacate, triethyl citrate, and triacetin.

6. The paroxetine sustained-release preparation according to claim 1, characterized in that: The paroxetine sustained-release preparation is any one of paroxetine sustained-release capsules, paroxetine sustained-release tablets, and paroxetine sustained-release pellets.

7. The paroxetine sustained-release preparation according to claim 6, characterized in that: The paroxetine sustained-release capsules contain micropellets and / or microtablets; preferably, the micropellets and / or microtablets comprise a core material wrapped by the wall material.

8. The paroxetine sustained-release preparation according to claim 7, characterized in that: The paroxetine sustained-release capsules meet at least one of the following conditions: (I) the average size of the microchips is less than 10 mm; (II) The paroxetine sustained-release capsules, each capsule containing 2 to 40 microtablets; (III) the microtablet has a tablet weight of 15 to 200 mg, and each microtablet contains 0.5 to 10 mg of paroxetine; (IV) The release of paroxetine in the paroxetine sustained-release capsule within 120 minutes is no more than 30 wt%.

9. A method for preparing the paroxetine sustained-release preparation according to any one of claims 1 to 8, comprising the following steps: S1: Mixing the core material components to prepare the core material; S2: Mixing the wall material components with water to prepare a coating solution; S3: coating the core material with the coating solution to prepare the paroxetine sustained-release preparation.

10. Use of the paroxetine sustained-release preparation according to any one of claims 1 to 8 in the preparation of at least one medicament for treating depression, anxiety, and premature ejaculation.

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