Duloxetine hydrochloride enteric-coated capsule and a method for preparing the same

Abstract

The application discloses a duloxetine hydrochloride enteric-soluble capsule, which is composed of a capsule shell and content, wherein the content is a micro-pellet containing duloxetine hydrochloride, and the micro-pellet is composed of a blank pellet core, a drug-loading layer, an isolation layer, an enteric-soluble layer and a protective layer. The binder of the isolation layer of the enteric-soluble capsule micro-pellet contains both high-viscosity hypromellose and low-viscosity hypromellose. Through improvement of the composition of the isolation layer, the dissolution curve of the duloxetine hydrochloride enteric-soluble capsule meets the standard requirements, the 90-minute dissolution degree is obviously improved, and the stability is superior to that of a reference preparation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a duloxetine hydrochloride enteric capsule and a preparation method of the enteric capsule. BACKGROUND

[0002] Duloxetine is a serotonin (5-HT) and norepinephrine (NA) reuptake inhibitor (SNRI) developed by Eli Lilly Company. It was approved by FDA in 2002 for the treatment of depression. In 2004, it was also approved for the treatment of moderate to severe stress urinary incontinence in women and peripheral neuropathic pain secondary to diabetes in adults. The salt hydrochloride thereof is used in clinic.

[0003] Duloxetine has a strong inhibitory effect on the reuptake of serotonin and norepinephrine, and can increase the concentration of serotonin and norepinephrine in the brain and spinal cord. The increase of the concentration of serotonin and norepinephrine in the brain can improve the disease symptoms of depressive patients, and the increase of the concentration of serotonin and norepinephrine in the spinal cord can stimulate the nerve activity of the urethral sphincter and increase the contraction level of the sphincter, thereby preventing urine leakage.

[0004] The chemical name of duloxetine is (S)-N-methyl-3-(1-naphthoxy)-2-thiophene propylamine hydrochloride, and the molecular formula is C 18 H 19 NOS· HCL, and the structural formula is

[0005] .

[0006] Duloxetine is well absorbed by oral administration, and the t max is 4-6 hours. However, duloxetine is rapidly hydrolyzed into naphthol in an acidic medium, and naphthol has no antidepressant effect. Therefore, duloxetine is prepared into an enteric preparation so as to be dissolved and absorbed after reaching a part of the gastrointestinal tract with a pH greater than 5.5.

[0007] Chinese patent CN1759829A discloses a duloxetine enteric micro-pellet capsule and its preparation method. The enteric micro-pellet is composed of a blank pellet core and a coating layer wrapped outside the blank pellet core. The coating layer includes a main layer containing the main drug and excipients, an isolation layer wrapped outside the main drug layer, and an enteric layer wrapped outside the isolation layer. The isolation layer includes water-soluble gel material, plasticizer, defoaming agent, anti-adhesive agent, and light shielding agent. The water-soluble gel material includes hydroxypropyl methyl cellulose or polyvinyl pyrrolidone or a mixture of the two. A finishing layer is further wrapped outside the enteric layer. The dissolution rate of the enteric micro-pellet capsule reaches 100% at about 160 minutes. The type of hydroxypropyl methyl cellulose used in the isolation layer is not disclosed in the patent.

[0008] Chinese patent CN1128141A discloses that hydroxypropyl methyl cellulose can be used to improve the viscosity and adhesion of the isolation layer, but the type of hydroxypropyl methyl cellulose used is not specified.

[0009] Hydroxypropyl methyl cellulose, also known as hydroxypropyl methyl cellulose, is a non-ionic cellulose mixed ether commonly used as an excipient in oral drug formulations. According to the viscosity, hydroxypropyl methyl cellulose is divided into different specifications. In the prior art, low-viscosity hydroxypropyl methyl cellulose is used in the isolation layer of enteric capsules. In the preparation of duloxetine hydrochloride enteric capsules, it is found that when conventional low-viscosity hydroxypropyl methyl cellulose is used as a binder in the isolation layer, the obtained enteric capsule releases the drug too quickly, and its dissolution curve cannot meet the standard requirements. SUMMARY

[0010] The purpose of the present application is to provide a duloxetine hydrochloride enteric capsule, which uses low-viscosity and high-viscosity hydroxypropyl methyl cellulose in the isolation layer at the same time. The dissolution curve of the prepared duloxetine hydrochloride enteric capsule meets the standard requirements.

[0011] To achieve the above-mentioned purpose, the inventors provide the following technical solutions.

[0012] A duloxetine hydrochloride enteric capsule is composed of a capsule shell and a content containing duloxetine hydrochloride micro-pellets. The composition of the micro-pellets, from inside to outside, includes a blank pellet core, a drug-loaded layer, an isolation layer, an enteric layer, and a protective layer. The isolation layer contains high-viscosity hydroxypropyl methyl cellulose and low-viscosity hydroxypropyl methyl cellulose.

[0013] The isolation layer contains high-viscosity hydroxypropyl methyl cellulose, low-viscosity hydroxypropyl methyl cellulose, a pore-forming agent, an anti-adhesive agent, and a solvent.

[0014] The high-viscosity hypromellose is selected from any one or more of hypromellose E15, hypromellose E30, and hypromellose E50, and the low-viscosity hypromellose is selected from any one or more of hypromellose E3, hypromellose E4, hypromellose E5, and hypromellose E6.

[0015] The weight ratio of the high-viscosity hypromellose to the low-viscosity hypromellose is 1-5:1-5, preferably 1:1-5.

[0016] In the above duloxetine hydrochloride enteric-coated capsule, the pore-forming agent in the isolation layer is sucrose, the anti-adhesion agent is talc, and the solvent is anhydrous ethanol and purified water.

[0017] The weight ratio of the high-viscosity hypromellose, the low-viscosity hypromellose, the pore-forming agent, and the anti-adhesion agent in the isolation layer is 5-15:5-15:2-6:10-30.

[0018] In the above duloxetine hydrochloride enteric-coated capsule, the blank pellet core is a sucrose-type medicinal pellet core, the enteric-coated layer contains hydroxypropyl methyl cellulose acetate succinate, and the protective layer contains hypromellose.

[0019] In the above duloxetine hydrochloride enteric-coated capsule, the composition of the isolation layer is hypromellose E50, hypromellose E6, sucrose, talc, anhydrous ethanol, and purified water, or hypromellose E15, hypromellose E5, sucrose, talc, anhydrous ethanol, and purified water.

[0020] The application also provides a preparation method of the above duloxetine hydrochloride enteric-coated capsule, and the operation steps include:

[0021] a. Coating of the drug-loaded layer: using a fluidized bed bottom-spraying coating process, a coating liquid containing duloxetine hydrochloride is coated onto the blank pellet core to obtain drug-loaded pellets, which are sieved and reserved;

[0022] b. Coating of the isolation layer: using a fluidized bed bottom-spraying coating process, a coating liquid containing high-viscosity hypromellose and low-viscosity hypromellose is coated onto the drug-loaded pellets to obtain isolation pellets, which are sieved and reserved;

[0023] c. Enteric layer coating: using fluidized bed bottom spray coating process, coating the coating liquid containing hydroxypropyl methyl cellulose acetate succinate to the isolated pellets, to obtain enteric pellets, sieve, ready for use;

[0024] d. Protective layer coating: using fluidized bed bottom spray coating process, coating the coating liquid containing hydroxypropyl methyl cellulose to the enteric pellets, to obtain finished pellets, sieve, ready for use;

[0025] e. Capsule filling: filling the finished pellets obtained in step d into capsules, which can be used.

[0026] The preparation method of the above duloxetine hydrochloride enteric capsule, the operation steps preferably include:

[0027] a. Drug layer coating

[0028] The prescribed amount of hydroxypropyl methyl cellulose E6 is slowly added to the prescribed amount of purified water, and stirred until completely dissolved. The prescribed amount of duloxetine hydrochloride is added and stirred to disperse. Under stirring, the prescribed amount of talc is slowly added and stirred to disperse, and sieved through a 60-mesh sieve.

[0029] The coating is carried out using a fluidized bed bottom spray coating process. The height of the guide tube and the air volume are adjusted according to the amount of material to maintain good fluidization of the material. The material temperature during coating is controlled at 38-42°C; the atomization pressure is 1.5 bar; the material temperature during drying is controlled at 40-50°C, and the LOD is not more than 3%. The prepared drug-loaded pellets are sieved, and the drug-loaded pellets between 18-30 mesh are used for the next step of coating.

[0030] b. Isolation layer coating

[0031] The prescribed amount of hydroxypropyl methyl cellulose E50, hydroxypropyl methyl cellulose E6, and talc is slowly added to the prescribed amount of anhydrous ethanol and stirred to disperse. The prescribed amount of sucrose is dissolved in the prescribed amount of purified water. Under stirring, the sucrose solution is slowly added to the ethanol solution and stirred to disperse, and sieved through a 60-mesh sieve.

[0032] The coating is carried out using a fluidized bed bottom spray coating process. The height of the guide tube and the air volume are adjusted according to the amount of material to maintain good fluidization of the material. The material temperature during coating is controlled at 38-42°C; the atomization pressure is 1.5 bar; the material temperature during drying is controlled at 40-50°C, and the air humidity is 8 g / m 3 The LOD is not more than 3%; the prepared isolated pellets are sieved, and the isolated pellets between 18-30 mesh are used for the next step of coating.

[0033] c. Enteric layer coating

[0034] The prescription amount of hydroxypropyl methyl cellulose acetate succinate is added into the prescription amount of purified water and stirred and dispersed. Under the stirring state, the pH is adjusted to 5.7 to 6.9 by using concentrated ammonia solution, and the stirring is continued until complete dissolution (about 1.5 h). The prescription amount of triethyl citrate is added under the stirring state and stirred and dissolved. The prescription amount of talc is slowly added, stirred and dispersed, and sieved through a 60-mesh sieve.

[0035] The height of the guide tube and the air volume are adjusted according to the material amount, so that the material is kept in a good fluidized state. The material temperature is controlled at 38-42℃ during the coating process; the atomization pressure is 1.5 bar; the material temperature is controlled at 40-50℃ during the drying process, and the LOD is not more than 3%; and the prepared enteric-coated pellets are sieved, and the pellets between 18-30 meshes are subjected to the next coating.

[0036] d. Protective layer coating

[0037] The prescription amount of hydroxypropyl methyl cellulose E6 and talc is slowly added into the prescription amount of anhydrous ethanol and stirred and dispersed. Under the stirring state, the prescription amount of purified water is slowly added, stirred and dispersed, and sieved through a 60-mesh sieve.

[0038] The height of the guide tube and the air volume are adjusted according to the material amount, so that the material is kept in a good fluidized state. The material temperature is controlled at 38-42℃ during the coating process; the atomization pressure is 1.5 bar; the material temperature is controlled at 40-50℃ during the drying process, and the LOD is not more than 3%; and the prepared enteric-coated pellets are sieved, and the pellets between 18-30 meshes are subjected to the next coating.

[0039] e. Capsule filling

[0040] The finished pellets coated with the protective layer are filled into empty capsule shells.

[0041] The diameter of the blank pellet core used in the present application is 500-710 μm, preferably 500-600 μm.

[0042] The high-viscosity hydroxypropyl methyl cellulose used in the isolation layer of the enteric-coated duloxetine hydrochloride capsule can be selected from one or multiple types, and any weight ratio can be used when multiple types are selected. The low-viscosity hydroxypropyl methyl cellulose used in the isolation layer can be selected from one or multiple types, and any weight ratio can be used when multiple types are selected.

[0043] The composition of the isolation layer can be used not only for the preparation of the enteric-coated duloxetine hydrochloride capsule, but also for the enteric-coated capsules of other drugs, such as lansoprazole enteric-coated capsules and rabeprazole enteric-coated capsules.

[0044] The enteric coated capsule of duloxetine hydrochloride of the present application is coated, and the effect of coating is measured by the weight gain of coating. The drug-loaded layer of pellets is increased by 2-3 times, preferably 2.5 times, based on the weight of the blank sucrose pellet core. The isolation layer of pellets is increased by 30%-36%, preferably 33%, based on the weight of the drug-loaded layer of pellets. The enteric layer of pellets is increased by 23%-31%, preferably 28%, based on the weight of the isolation layer of pellets.

[0045] In the enteric coated capsule of duloxetine hydrochloride provided by the present application, the hypromellose used in the drug-loaded layer is low-viscosity hypromellose; and the hypromellose used in the protective layer is also low-viscosity hypromellose. The protective layer protects the enteric layer on the one hand, avoiding the exposure of the enteric coating film to the outside, which is abraded in subsequent operations and affects the product quality; on the other hand, the addition of talc in the prescription of the protective layer can significantly reduce the static electricity between the pellets, which is beneficial to the operation of the subsequent capsule filling process.

[0046] The content of the enteric coated capsule of duloxetine hydrochloride of the present application is a multi-layer coated pellet. The type, model and ratio of the materials selected for each layer of coating, and the coating process and other factors all have a synergistic effect on the dissolution of the product. The isolation layer, as an indispensable part of the enteric coated capsule of duloxetine hydrochloride, plays an important role in the dissolution of the drug.

[0047] The enteric material used in the enteric layer of the enteric coated pellet of the present application is hypromellose acetate succinate, which is acidic. Duloxetine hydrochloride is unstable under acidic conditions and is prone to decomposition. Therefore, the isolation layer is arranged between the drug-loaded layer containing duloxetine hydrochloride and the enteric layer containing hypromellose acetate succinate to prevent the decomposition of duloxetine hydrochloride due to contact with the acidic enteric material.

[0048] The inventors found during the development of the enteric coated capsule of duloxetine hydrochloride that when low-viscosity hypromellose is used as the binder to prepare the isolation layer, the enteric coated capsule of duloxetine hydrochloride prepared has a faster dissolution than the reference preparation, and the similarity factor f2 is less than 50, which does not meet the standard requirements. Analysis shows that the reason for the faster dissolution is that in the pH 6.8 phosphate medium, the enteric layer is rapidly broken and dissolved, exposing the isolation layer coating film, and the isolation layer coating film prepared using low-viscosity hypromellose is also rapidly broken and dissolved, ultimately leading to the premature dissolution of the drug in the drug-loaded layer. Based on this consideration, the inventors chose high-viscosity hypromellose to prepare the isolation layer, because its high viscosity slows down the speed of breaking and dissolving of the isolation layer coating film, thereby slowing down the speed of dissolution of the drug in the drug-loaded layer.

[0049] The dissolution curve of the duloxetine hydrochloride enteric-coated capsule of the present application is compared with the reference preparation by dissolution experiment, and the similarity factor f2 is greater than 50, which achieves the consistency with the standard. Meanwhile, the dissolution rate of the duloxetine hydrochloride enteric-coated capsule of the present application at 90 minutes is obviously higher than that of the reference preparation, which can further improve the bioavailability of duloxetine hydrochloride and improve the curative effect.

[0050] The stability of the duloxetine hydrochloride enteric-coated capsule of the present application is obviously better than that of the reference preparation by 6-month accelerated stability study. BRIEF DESCRIPTION OF DRAWINGS

[0051] Figure 1 The dissolution curve in the stability experiment of the duloxetine hydrochloride enteric-coated capsule of the present application in Example 5.

[0052] Figure 2 The dissolution curve in the stability experiment of the reference preparation in Example 5. DETAILED DESCRIPTION

[0053] The content of the present application is further described in detail below in combination with specific examples.

[0054] Example 1 Preparation of duloxetine hydrochloride enteric-coated capsule

[0055] Prescription:

[0056] Blank pellet core: sucrose type medicinal pellet core, diameter 500-600 mm, 122 g

[0057] Drug-loaded layer: duloxetine hydrochloride 135 g (active ingredient), hydroxypropyl methyl cellulose E6 13 g (adhesive), talc 33 g (anti-adhesive), purified water 1056 g (solvent)

[0058] Isolation layer: hydroxypropyl methyl cellulose E50 11 g (adhesive), hydroxypropyl methyl cellulose E6 33 g (adhesive), sucrose 9 g (pore-forming agent), talc 44 g (anti-adhesive), anhydrous ethanol 1097 g, purified water 731 g (solvent)

[0059] Enteric layer: hydroxypropyl methyl cellulose acetate succinate 68 g (enteric material), triethyl citrate 14 g (plasticizer), talc 21 g (anti-adhesive), concentrated ammonia solution (pH adjuster) 6 g, purified water 1270 g (solvent)

[0060] Protective layer: hydroxypropyl methyl cellulose E6 10 g (adhesive), talc 20 g (anti-adhesive), anhydrous ethanol 270 g (solvent), purified water 128 g (solvent)

[0061] Preparation method:

[0062] a. Drug-loaded layer coating

[0063] The amount of hydroxypropyl methylcellulose E6 is slowly added to the amount of purified water, and stirred until completely dissolved. The amount of duloxetine hydrochloride is added, and stirred to disperse. The amount of talc is slowly added while stirring, and stirred to disperse and pass through a 60 mesh sieve.

[0064] The fluidized bed bottom spray coating process is used, and the height of the guide tube and the air volume are adjusted according to the amount of material, so that the material is kept in a good fluidized state. The material temperature during coating is controlled at 38-42°C; the atomization pressure is 1.5 bar; the material temperature during drying is controlled at 40-50°C, and the LOD is not more than 3%. The prepared drug-loaded pellets are sieved, and the drug-loaded pellets between 18-30 mesh sieves are subjected to the next step of coating.

[0065] Isolation layer coating

[0066] The amount of hydroxypropyl methylcellulose E50, hydroxypropyl methylcellulose E6, and talc is slowly added to the amount of anhydrous ethanol, and stirred to disperse. The amount of sucrose is dissolved in the amount of purified water. The sucrose solution is slowly added to the ethanol solution while stirring, and stirred to disperse and pass through a 60 mesh sieve.

[0067] The fluidized bed bottom spray coating process is used, and the height of the guide tube and the air volume are adjusted according to the amount of material, so that the material is kept in a good fluidized state. The material temperature during coating is controlled at 38-42°C; the atomization pressure is 1.5 bar; the material temperature during drying is controlled at 40-50°C, and the air humidity is 8 g / m 3 The LOD is not more than 3%; the prepared isolation pellets are sieved, and the isolation pellets between 18-30 mesh sieves are subjected to the next step of coating.

[0068] Enteric layer coating

[0069] The amount of hydroxypropyl methylcellulose acetate succinate is added to the amount of purified water, and stirred to disperse. The pH is adjusted to 5.7 to 6.9 with concentrated ammonia solution while stirring, and stirring is continued until completely dissolved (about 1.5 h). The amount of triethyl citrate is added while stirring, and stirred to dissolve. The amount of talc is slowly added while stirring, and stirred to disperse and pass through a 60 mesh sieve.

[0070] The fluidized bed bottom spray coating process is used, and the height of the guide tube and the air volume are adjusted according to the amount of material, so that the material is kept in a good fluidized state. The material temperature during coating is controlled at 38-42°C; the atomization pressure is 1.5 bar; the material temperature during drying is controlled at 40-50°C, and the LOD is not more than 3%; the prepared enteric pellets are sieved, and the pellets between 18-30 mesh sieves are subjected to the next step of coating.

[0071] Protective layer coating

[0072] The amount of hydroxypropyl methylcellulose E6 and talc is slowly added to the amount of anhydrous ethanol, and stirred and dispersed. Under stirring, the amount of purified water is slowly added, stirred and dispersed, and passed through a 60-mesh sieve.

[0073] The fluidized bed bottom-spray coating process is used, the height of the guide tube and the air volume are adjusted according to the amount of the material, so that the material is in a good fluidized state. The material temperature is controlled at 38-42°C during the coating process; the atomization pressure is 1.5 bar; the material temperature is controlled at 40-50°C during the drying process, and the LOD is not more than 3%; the obtained pellets are sieved, and the pellets between 18-30 meshes are the finished pellets, which are used to fill the capsules.

[0074] Capsule filling

[0075] The finished pellets coated with the protective layer are filled into empty capsule shells.

[0076] Example 2 Preparation of enteric-coated duloxetine hydrochloride capsules

[0077] Prescription:

[0078] Blank pellet core: diameter 600-710 mm

[0079] Isolation layer: hydroxypropyl methylcellulose E15 22 g (binder), hydroxypropyl methylcellulose E5 22 g (binder), sucrose 13 g (porogen), talc 33 g (anti-adhesive), anhydrous ethanol 1097 g, purified water 731 g (solvent)

[0080] The others are the same as in Example 1.

[0081] Preparation method:

[0082] The same as in Example 1.

[0083] Example 3 Preparation of enteric-coated duloxetine hydrochloride capsules

[0084] Prescription:

[0085] Hydroxypropyl methylcellulose E50 4.4 g (binder), hydroxypropyl methylcellulose E15 4.4 g (binder), hydroxypropyl methylcellulose E6 35.8 g (binder), sucrose 9 g (porogen), talc 44 g (anti-adhesive), anhydrous ethanol 1097 g, purified water 731 g (solvent)

[0086] The others are the same as in Example 1.

[0087] Preparation method:

[0088] The same as in Example 1.

[0089] Comparative Example 1

[0090] Prescription:

[0091] Isolation layer: Hypromellose E6 44 g (binder), sucrose 9 g (pore-forming agent), talc 44 g (anti-adhesive agent), anhydrous ethanol 1097 g, purified water 731 g (solvent)

[0092] The other is the same as Example 1.

[0093] Preparation method:

[0094] The same as Example 1.

[0095] Example 4 Comparison of dissolution curves

[0096] In order to investigate the dissolution of the duloxetine hydrochloride enteric-coated capsules provided by the application, the inventors determined the dissolution curves of the duloxetine hydrochloride enteric-coated capsules prepared in Examples 1-3 and Comparative Example 1, and the reference preparation, and evaluated the consistency of the dissolution curves, according to the relevant provisions of the dissolution of enteric-coated capsules in the Chinese Pharmacopoeia 2020 edition, as follows:

[0097] I. Dissolution conditions

[0098] (I) Acid stage

[0099]

[0100] (II) Buffer salt stage

[0101]

[0102] II. Chromatographic conditions

[0103]

[0104] III. Reference preparation

[0105] The reference preparation selected for this experiment is duloxetine hydrochloride enteric-coated capsules, with the trade name Cymbalta, and the license holder is Eli Lilly and Company, which is a U.S. listed reference preparation. Specifications: 60 mg, batch number C810517A.

[0106] IV. Preparation of detection solution

[0107] ① Blank solution: diluent (buffer stage release medium).

[0108] ② Control stock solution: prepare a 0.28 mg / ml duloxetine hydrochloride control or working control solution equivalent to 0.25 mg / ml duloxetine using the buffer stage medium. Dissolve the duloxetine hydrochloride with no more than 2% of the final volume of methanol.

[0109] Take about 28 mg of duloxetine hydrochloride reference substance or working reference substance into a 100 ml flask, add 2.0 ml of methanol to dissolve, dilute to the mark with buffer stage medium, mix well.

[0110] ③ Acid stage reference solution: dilute the reference stock solution with buffer stage medium to get 0.0023 mg / ml of duloxetine hydrochloride reference substance or working reference substance solution, which is equivalent to 0.002 mg / ml of duloxetine.

[0111] Take 2.0 ml of the reference stock solution into a 250 ml flask, dilute to the mark with buffer stage medium, mix well.

[0112] ④ Buffer stage reference solution: dilute the reference stock solution with buffer stage medium to get 0.023 mg / ml of duloxetine hydrochloride reference substance or working reference substance solution, which is equivalent to 0.02 mg / ml of duloxetine.

[0113] Take 2.0 ml of the reference stock solution into a 25 ml flask, dilute to the mark with buffer stage medium, mix well.

[0114] ⑤ Test solution:

[0115] Acid stage test solution: sample at 2 hours of acid stage dissolution, filter with 0.45 mm nylon filter membrane.

[0116] Buffer stage test solution: sample at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, respectively, filter with 0.45 mm nylon filter membrane.

[0117] Five, sample detection

[0118] ① After the system is stable, sample one needle of blank solution.

[0119] ② Sample six needles of acid stage reference solution continuously.

[0120] ③ Sample one needle of acid stage test solution.

[0121] ④ Sample twelve needles of test solution or sample one needle of acid stage reference solution at the end of sequence.

[0122] ⑤ Sample six needles of buffer stage reference solution continuously.

[0123] ⑥ Sample one needle of buffer stage test solution.

[0124] ⑦ Sample twelve needles of test solution or sample one needle of acid stage reference solution at the end of sequence.

[0125] Six, result calculation

[0126] 1. Calculate the concentration of duloxetine in the acid phase (C1):

[0127] Result = (r U / r S ) x C S x (M r1 / M r2 )

[0128] r U = peak area of duloxetine in the acid phase of the test solution

[0129] r S = average peak area of duloxetine in the acid phase of the reference solution

[0130] C S = concentration of hydrochloride duloxetine in the acid phase of the reference solution (mg / ml)

[0131] M r1 = molecular weight of duloxetine, 297.42

[0132] M r2 = molecular weight of hydrochloride duloxetine, 333.88

[0133] 2. Calculate the concentration of alpha-naphthol equivalent to duloxetine in the acid phase (C2):

[0134] Result = (r U / r S ) x C S x (M r1 / M r2 ) x (M r1 / M r3 )

[0135] r U = peak area of alpha-naphthol in the acid phase of the test solution

[0136] r S = average peak area of duloxetine in the acid phase of the reference solution

[0137] C S = concentration of hydrochloride duloxetine in the acid phase of the reference solution (mg / ml)

[0138] M r1 = molecular weight of duloxetine, 297.42

[0139] M r2 = molecular weight of hydrochloride duloxetine, 333.88

[0140] M r3 = molecular weight of α-naphthol, 144.17

[0141] iii. Calculate the percentage of the labeled amount of duloxetine equivalent in the acid stage (Q A ):

[0142] Result = (C1 + C2) x V x (1 / L) x 100

[0143] C1 = concentration of duloxetine in the acid stage (mg / ml)

[0144] C2 = concentration of α-naphthol equivalent in duloxetine in the acid stage (mg / ml)

[0145] V = volume of medium, 1000 ml

[0146] L = labeled amount of duloxetine

[0147] iv. Calculate the percentage of the labeled amount of duloxetine equivalent in the buffer stage:

[0148] Result = [(r U / r S ) x (C S / L) x V x (M r1 / M r2 ) x 100] + Q A

[0149] r U = peak area of duloxetine in the test sample in the buffer stage

[0150] r S = average peak area of duloxetine in the reference solution in the buffer stage

[0151] C S = concentration of duloxetine hydrochloride in the reference solution in the buffer stage (mg / ml)

[0152] L = labeled amount

[0153] V = volume of medium, 1000 ml

[0154] M r1 = molecular weight of duloxetine, 297.42

[0155] M r2 = molecular weight of duloxetine hydrochloride, 333.88

[0156] Q A = percentage of the labeled amount of duloxetine equivalent in the acid stage

[0157] Seven, Standard Requirements

[0158] Dissolution in acid (2 hours): not more than 10% of the labeled amount.

[0159] Dissolution in buffer (1 hour): not less than 75% of the labeled amount.

[0160] Eight, Results

[0161] Table 4 shows the results of the dissolution test.

[0162]

[0163] As can be seen from the results in Table 4, the similarity factor f2 of the present application examples 1-3 is greater than 50 compared with the reference preparation, indicating that the dissolution curve of the present application duloxetine hydrochloride enteric-coated capsule is consistent with the reference preparation. The similarity factor of Comparative Example 1 is less than 50, and its dissolution curve does not meet the requirements of the standard. At the same time, the dissolution of the duloxetine hydrochloride enteric-coated capsules of the present application examples 1-3 at 90 minutes is significantly higher than that of the reference preparation, which can further improve the bioavailability of duloxetine hydrochloride and thus improve its efficacy.

[0164] Example 5 Stability Investigation

[0165] The inventors conducted stability experiments on the duloxetine hydrochloride enteric-coated capsules of the present application and the reference preparation under the same conditions, as follows:

[0166] The samples prepared according to the method of Example 1 and the reference preparation were subjected to stability study at 40℃ / 75% RH, and the sampling time points were 0 days, 1 month, 2 months, 3 months, and 6 months. The dissolution curves in 0.1N HCl to pH 6.8 phosphate buffer were detected, and the results were compared.

[0167] Table 5 shows the dissolution test results of the samples of Example 1.

[0168]

[0169] Table 6 shows the dissolution test results of the reference preparation.

[0170]

[0171] As can be seen from the results in Table 5 and Table 6, the sample of Example 1 of the present application has no obvious change in dissolution during the 6-month acceleration process, and the similarity factor f2 is greater than 50 when compared with the dissolution curve at 0 day. The reference preparation has a downward trend in dissolution during the 6-month acceleration process, and the similarity factor f2 is less than 50 when compared with the dissolution curve at 0 day at 3 months and 6 months, and the dissolution curve is inconsistent with that at 0 day. Thus, the stability of the duloxetine hydrochloride enteric-coated capsules of the present application is better than that of the reference preparation.

[0172] In addition, it is found during the detection process that the pellets in the reference preparation capsules have a gelatinous film at 3 months and 6 months, and cannot be dispersed and dissolved. The pellets in the enteric-coated capsules of the present application have no change in appearance.

Claims

1. A duloxetine hydrochloride enteric-coated capsule, comprising a capsule shell and contents, wherein the contents are microspheres containing duloxetine hydrochloride, and the microspheres are composed, from the inside out, of a blank core, a drug-loaded layer, an isolation layer, an enteric coating layer, and a protective layer, characterized in that, The isolation layer comprises high-viscosity hypromellose and low-viscosity hypromellose, the high-viscosity hypromellose is selected from any one or more of hypromellose E15, hypromellose E30, hypromellose E50, the low-viscosity hypromellose is selected from any one or more of hypromellose E3, hypromellose E4, hypromellose E5, hypromellose E6, and the weight ratio of the high-viscosity hypromellose to the low-viscosity hypromellose is 1-5:1-5.

2. The duloxetine hydrochloride enteric-coated capsule according to claim 1, wherein The isolation layer comprises high-viscosity hypromellose, low-viscosity hypromellose, a pore-forming agent, an anti-adhesion agent and a solvent.

3. The duloxetine hydrochloride enteric-coated capsule according to claim 2, wherein The pore-forming agent is sucrose, the anti-adhesion agent is talc, and the solvent is anhydrous ethanol and purified water.

4. The duloxetine hydrochloride enteric-coated capsule according to claim 2, wherein The weight ratio of the high-viscosity hypromellose, the low-viscosity hypromellose, the pore-forming agent and the anti-adhesion agent is 5-15:5-15:2-6:10-30.

5. The duloxetine hydrochloride enteric-coated capsule according to claim 1, wherein The blank pellet core is a sucrose-type medicinal pellet core, the enteric layer comprises hydroxypropyl methyl cellulose acetate succinate, and the protective layer comprises hypromellose.

6. The duloxetine hydrochloride enteric-coated capsule according to claim 1, wherein The composition of the isolation layer is hypromellose E50, hypromellose E6, sucrose, talc, anhydrous ethanol and purified water, or hypromellose E15, hypromellose E5, sucrose, talc, anhydrous ethanol and purified water.

7. The duloxetine hydrochloride enteric-coated capsule according to claim 6, wherein In terms of weight parts, the weight ratio of hypromellose E50, hypromellose E6, sucrose and talc in the composition of the isolation layer is 5:15:4:20, or the weight ratio of hypromellose E15, hypromellose E5, sucrose and talc is 5:5:2:

10.

8. The process for preparing duloxetine hydrochloride enteric-coated capsule according to claim 1, wherein The operation steps comprise: a. Drug-loaded layer coating: using a fluidized bed bottom-spraying coating process, a coating liquid containing duloxetine hydrochloride is coated onto the blank pellet core to obtain drug-loaded pellets, which are sieved and reserved; b. Isolation layer coating: using a fluidized bed bottom-spraying coating process, a coating liquid containing high-viscosity hypromellose and low-viscosity hypromellose is coated onto the drug-loaded pellets to obtain isolation pellets, which are sieved and reserved; c. Enteric layer coating: using a fluidized bed bottom-spraying coating process, a coating liquid containing hydroxypropyl methyl cellulose acetate succinate is coated onto the isolation pellets to obtain enteric pellets, which are sieved and reserved; d. Protective layer coating: using a fluidized bed bottom-spraying coating process, a coating liquid containing hypromellose is coated onto the enteric pellets to obtain finished pellets, which are sieved and reserved; e. Capsule filling: the finished pellets obtained in step d are filled into capsules, and the process is completed.

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