Duloxetine enteric-coated pellet, compound formulation and preparation method therefor

Abstract

A duloxetine enteric-coated pellet, a compound formulation and a preparation method therefor. The duloxetine enteric-coated pellet comprises a drug-containing pellet and an enteric layer, wherein the enteric layer contains hydroxypropyl methylcellulose phthalate (HPMCP), the mass ratio of HPMCP to the enteric layer is 55.6-90.9%, the enteric layer can be dissolved in a medium having a pH value of 5.5 or above, and the weight gain of the enteric layer is 12% or more. By means of optimization of the type of materials preventing ethanol-induced dose dumping and the thickness of the enteric layer, HPMCP is selected as an enteric material for preventing ethanol-induced dose dumping, so that the duloxetine enteric-coated pellet has both good preventing effect on ethanol-induced dose dumping and ideal dissolution speed.

Description

Duloxetine enteric micro-pellets and compound preparation and preparation method TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to duloxetine enteric micro-pellets and compound preparation and preparation method. BACKGROUND

[0002] Dose dumping refers to the behavior of the entire or most of the drug being released in a short time. Dose dumping can bring great risk to patients due to safety problems and / or reduced efficacy.

[0003] Duloxetine hydrochloride (Cymbalta) is an oral selective serotonin and norepinephrine reuptake inhibitor developed by Eli Lilly Company, which is widely used in the treatment of severe depression, stress incontinence and diabetic peripheral neuropathic pain, etc. Since duloxetine is unstable in gastric acid, acid hydrolysis of the ether bond thereof can produce thiophenol and 1-naphthol. 1-naphthol is toxic and can cause convulsions, abdominal pain, nausea and vomiting. Severe systemic effects include nephritis, cystitis, liver damage, convulsions and hemolysis in patients with acute intravascular red cell glucose-6-phosphate deficiency. Therefore, duloxetine is generally prepared into an enteric preparation. The general enteric material is easily soluble in ethanol, so duloxetine enteric preparation especially has dose dumping in the presence of alcohol, which is also called "alcohol dumping" (or "ethanol dumping"). It leads to premature and / or excessive release of the active pharmaceutical ingredient from the orally administered pharmaceutical composition, which can expose the patient to a high risk level of active agents, thereby possibly leading to adverse reactions and / or drug-induced toxicity. To solve the problem of alcohol dumping of duloxetine, an anti-ethanol dumping material is usually added to the enteric coating thereof. The existing anti-ethanol dumping materials include sodium alginate, cellulose acetate phthalate (CAP), etc.

[0004] The existing duloxetine marketed preparation uses hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the enteric material, and HPMCAS has no anti-ethanol dumping effect.

[0005] In actual preparation development, it is not enough to only focus on the anti-ethanol dumping effect. Some enteric preparations, due to improper selection of the type of anti-ethanol dumping material and the thickness of the enteric layer, cannot simultaneously consider the anti-ethanol dumping effect and the drug dissolution rate. Therefore, the problems of the anti-ethanol dumping effect and the drug dissolution rate of the preparation need to be comprehensively solved.

[0006] Duloxetine and gamma-aminobutyric acid (GABA) analogues, such as pregabalin, gabapentin, and mirogabalin, are existing drugs for treating neuropathic pain, including diabetic peripheral neuropathy (DSPN), however, their monotherapy effect is not very ideal, and it is of practical significance to make them into a compound preparation. Moreover, the compound preparation has a good application prospect in treating neuropathic pain, such as post-herpetic neuralgia (PHN), trigeminal neuralgia, postoperative neuropathy, sciatica, post-stroke neuralgia, and mixed pain coexisting with neuropathic pain and nociceptive pain, such as pain caused by lumbar and dorsal nerve roots, cervical nerve root disease, cancer pain, and carpal tunnel syndrome. SUMMARY

[0007] The application provides a duloxetine enteric micro-pellet and a compound preparation and a preparation method.

[0008] The application purpose of the application is achieved by the following technical solutions.

[0009] A duloxetine enteric micro-pellet contains drug-containing micro-pellets and an enteric layer.

[0010] The enteric layer contains hydroxypropyl methyl cellulose phthalate (HPMCP), wherein the mass ratio of HPMCP in the enteric layer is 55.6-90.9%.

[0011] The HPMCP can be dissolved in a medium with a pH value of 5.5.

[0012] The HPMCP dissolved in the medium with a pH value of 5.5 is preferably HP-55 or HP-55S, and the content of phthaloyl groups in the HPMCP of HP-55 and HP-55S types is 27.0-35.0%. At 20°C, the viscosity of a 10% (W / W) methanol-dichloromethane (1:1) (W / W) solution of HP-55 is 32-48 mPa·s, and the viscosity of a 10% (W / W) methanol-dichloromethane (1:1) (W / W) solution of HP-55s is 136-204 mPa·s.

[0013] Preferably, the enteric layer contains HPMCP and one or more than one auxiliary agent.

[0014] Further preferably, the enteric layer contains HPMCP, a plasticizer, and an anti-adhesion agent.

[0015] Particularly preferably, the enteric layer contains the following components in the following mass percentages:

[0016] HPMCP: 55.6-90.9%

[0017] Plasticizer: 3.2-22.2%

[0018] Anti-sticking agent: 3.7-32.3%.

[0019] The weight of the enteric layer compared to the weight of the inner (excluding the enteric layer) pellets (hereinafter also referred to as "weight gain") is 12% or more, and the duloxetine enteric pellets under the weight gain can resist 20% ethanol pouring; the enteric layer weight gain is preferably 65% or more, and the duloxetine enteric pellets under the weight gain can resist 20%-40% ethanol pouring.

[0020] Preferably, the weight gain of the enteric layer is 12-65%, and the duloxetine enteric pellets under the weight gain can resist 20% ethanol pouring, and the dissolution rate of the product meets the requirements.

[0021] An isolation layer can be provided between the drug-containing pellets and the enteric layer. The isolation layer does not substantially affect the dissolution of the product, but can reduce the possibility of drug reaction with the components in the enteric layer, and to some extent, reduce the impurity level of the preparation.

[0022] The duloxetine enteric pellets can be provided with a protective layer outside the enteric layer. The functions of the protective layer include reducing the static electricity of the pellets during the filling of the capsules, preventing the influence of external environmental factors (such as humidity, oxygen, light, etc.) on the physical and chemical aspects of the pellets, etc.; it can also be colored to form certain appearance characteristics for identification and differentiation, etc.

[0023] The drug-containing pellet core contains a blank pellet core and a drug-containing layer, which is prepared by a pellet core drug loading process; or a drug-containing pellet core is prepared by mixing duloxetine or its salt and adjuvants, which can be prepared by centrifugal pelletization or extrusion-spheronization process.

[0024] When the pellet core drug loading process is used, the drug-containing pellet core contains a blank pellet core, duloxetine or its salt, a film-forming material, and optionally an adjuvant.

[0025] The blank pellet core is sucrose pellet core, lactose pellet core, starch pellet core, microcrystalline cellulose pellet core, mannitol pellet core, silicon dioxide pellet core, or lactose-microcrystalline cellulose pellet core.

[0026] The drug-containing layer contains duloxetine or its salt, a film-forming material, and optionally an adjuvant.

[0027] The weight gain of the drug-containing layer accounts for 90-130% of the mass of the pellet core.

[0028] Preferably, the drug-containing layer contains duloxetine or its salt, a film-forming material, and an anti-sticking agent.

[0029] Particularly preferably, the drug-containing layer contains the following mass percentage ingredients:

[0030] Duloxetine or its salt: 65-80%

[0031] Film forming material: 5-100%

[0032] Anti-sticking agent: 0-50%.

[0033] When centrifugal pelletization or extrusion-spheronization process is used, the drug-containing pellet core contains duloxetine or its salt and one or more than one auxiliary, preferably contains duloxetine or its salt, a binder and a filler.

[0034] The isolation layer contains a film forming material, or further contains one or more than one auxiliary, and the film forming material accounts for 5-100%.

[0035] The specific composition is as follows:

[0036] Film forming material: 5-100%

[0037] Pore forming agent: 0-80%

[0038] Anti-sticking agent: 0-50%.

[0039] The isolation layer accounts for 10-155% of the weight of the drug-containing pellets.

[0040] The protective layer contains a film forming material, or further contains one or more than one auxiliary, and the film forming material accounts for 50-90%.

[0041] The specific composition is as follows:

[0042] Film forming material: 50-90%

[0043] Light shielding agent: 0-30%

[0044] Anti-sticking agent: 10-50%.

[0045] The protective layer accounts for 2-15% of the weight of the enteric pellets inside the protective layer (not including the protective layer).

[0046] The preparation method of the duloxetine enteric pellets comprises the following steps:

[0047] (1) Preparation of drug-containing pellets: the raw drug, film forming material, auxiliary and water are prepared into a suspension coating liquid, and a fluidized bed is used for bottom spraying coating, the suspension coating liquid is atomized and sprayed on the blank pellet core to obtain a drug-containing pellet core; or a centrifugal pelletization or extrusion-spheronization process is used to prepare drug-containing pellets;

[0048] (2) Isolation coating: the film forming material, auxiliary and water are prepared into an isolation layer coating liquid, and a fluidized bed is used for bottom spraying coating, the isolation layer coating liquid is sprayed on the drug-containing pellets to obtain an isolation layer pellet;

[0049] (3) enteric coating: HPMCP, auxiliary agent, ethanol and water are formulated into enteric coating liquid, and the fluidized bed is used for bottom spraying coating, the enteric coating liquid is sprayed on the isolated layer pellets, and enteric layer pellet intermediate product is obtained;

[0050] (4) protective layer coating: the film forming material, auxiliary agent and water are formulated into protective layer coating liquid, and the fluidized bed is used for bottom spraying coating, the coating liquid is sprayed on the enteric layer pellet intermediate product, and duloxetine enteric pellets are obtained.

[0051] A compound preparation containing the duloxetine enteric pellets.

[0052] The enteric layer of the duloxetine enteric pellets has a weight gain of more than 15%. 。

[0053] The compound preparation contains duloxetine enteric pellets and a gamma-aminobutyric acid analogue.

[0054] The compound preparation is obtained by filling the duloxetine enteric pellets and the gamma-aminobutyric acid analogue into a capsule shell.

[0055] The gamma-aminobutyric acid analogue is in a rapid release form.

[0056] The gamma-aminobutyric acid analogue is pregabalin, gabapentin, methoxycarbonyl gabapentin or clorgyline.

[0057] The rapid release part of the gamma-aminobutyric acid analogue comprises the gamma-aminobutyric acid analogue and one or more auxiliary agents, and the specific components are as follows:

[0058] Gamma-aminobutyric acid analogue: 7-97%

[0059] Anti-sticking agent: 3-85%

[0060] Disintegrant: 0-85%

[0061] Filling agent: 0-90%.

[0062] The gamma-aminobutyric acid analogue is preferably pregabalin.

[0063] The rapid release part of the pregabalin comprises pregabalin and one or more auxiliary agents, wherein the pregabalin accounts for 10-97% of the rapid release part, and the specific components are as follows:

[0064] Pregabalin: 10-97%

[0065] Anti-sticking agent: 3-85%

[0066] Disintegrant: 0-85%.

[0067] The compound preparation contains pramipexole 150 mg and duloxetine 30 to 40 mg, or contains pramipexole 75 mg and duloxetine 15 to 20 mg.

[0068] The compound preparation contains pramipexole 150 mg and duloxetine 30 to 40 mg, or contains pramipexole 75 mg and duloxetine 15 to 20 mg.

[0069] The compound preparation contains pramipexole 150 mg and duloxetine 30 to 40 mg, or contains pramipexole 75 mg and duloxetine 15 to 20 mg.

[0070] The compound preparation contains pramipexole 150 mg and duloxetine 30 to 40 mg, or contains pramipexole 75 mg and duloxetine 15 to 20 mg.

[0071] The compound preparation contains pramipexole 150 mg and duloxetine 30 to 40 mg, or contains pramipexole 75 mg and duloxetine 15 to 20 mg.

[0072] The film-forming material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol, gum arabic, or aminoalkyl methacrylate copolymer.

[0073] The auxiliary agent is one or more of plasticizer, anti-adhesive, light shielding agent, pore-forming agent, disintegrant, binder, or filler.

[0074] The plasticizer is one or more of triethyl citrate, tributyl citrate, polyethylene glycol, diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dibutyl sebacate, cetyl alcohol, propylene glycol, glycerol, polyethylene glycol, castor oil, diacetyl monoglyceride, olive oil, or succinic acid.

[0075] The anti-adhesive is inorganic powder, preferably talc powder and / or silicon dioxide.

[0076] The light shielding agent is one or more of lake, preferably titanium dioxide, iron oxide, aluminum lake, or ferric pyrophosphate.

[0077] The pore-forming agent is one or more of sucrose, lactose, mannitol, sodium chloride, potassium chloride, or polyethylene glycol.

[0078] The light shielding agent is one or more of lake, preferably titanium dioxide, iron oxide, aluminum lake, or ferric pyrophosphate.

[0079] The disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, corn starch, potato starch, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl starch, or microcrystalline cellulose.

[0080] The binder is one or more of corn starch, potato starch, pre-gelatinized starch, soluble starch, water-soluble starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone or dextrin.

[0081] The filler is one or more of microcrystalline cellulose, lactose monohydrate, lactose anhydrous, mannitol, calcium hydrogen phosphate anhydrous, calcium hydrogen phosphate dihydrate, corn starch, potato starch, sucrose, dextrin, calcium sulfate.

[0082] The present application has the following advantages and beneficial effects over the prior art:

[0083] 1. By optimizing the type of anti-ethanol pouring material and the thickness of the enteric layer, HPMCP is selected as the enteric material against ethanol pouring, so that the enteric micro-pellets of duloxetine have both anti-ethanol pouring effect and ideal dissolution rate.

[0084] 2. The product prepared by using sodium alginate as the anti-ethanol pouring material can resist 40% ethanol dose pouring when the sodium alginate layer is increased by 50%, but cannot resist 20% ethanol dose pouring. At this increase, the obtained preparation does not have the ability to resist ethanol pouring, because the dissolution rate does not meet the requirements, so there is no need to increase the weight to make the product resist 20% ethanol pouring.

[0085] 3. When using cellulose acetate phthalate (CAP) as the enteric material to prepare enteric micro-pellets, at an increase of 42%, although the dissolution rate and the resistance to ethanol pouring (20% ethanol) of the sample meet the requirements, in the pharmacokinetic experiment in beagle dogs, C max and AUC 0-t are significantly lower than Cymbalta (duloxetine hydrochloride enteric capsule original research drug), which does not meet the requirements. Since C max and AUC 0-t are significantly lower in the beagle dog experiment, continuing to increase the CAP increase will only make the preparation release slower in beagle dogs, and will not improve C max and AUC 0-t , so there is no need to study the necessity of increasing the enteric layer weight. Under the condition of enteric weight increase of 42%, the prepared compound preparation in the experiment of resisting 20% ethanol dose pouring, the dissolution amount at 120 min is 32%, which exceeds the limit, so there is no need to study lower CAP increase. At the same time, when using CAP coating, acetone needs to be used as the coating solvent, which has certain toxicity and is relatively not environmentally friendly; and the use of acetone has higher requirements for workshop explosion protection, and the preparation production environment is relatively harsh.

[0086] 4. The inventors unexpectedly discovered that after adding the immediate-release portion of pregabalin to the compound formulation in the embodiments of the present invention, the dissolution rate of duloxetine was increased in 20%–40% ethanol decantation experiments, indicating that the overall resistance to ethanol decantation of the formulation decreased after the addition of pregabalin. The inventors further adjusted the thickness of the enteric coating (HPMCP) to ensure that the release amount of duloxetine from the compound formulation in hydrochloric acid solution containing ethanol also met the intended limits.

[0087] 5. Cymbalta produced significantly more related substances in hydrochloric acid solution containing 20% ​​ethanol than in hydrochloric acid solution containing 40% ethanol, indicating that duloxetine is less stable in hydrochloric acid solution containing 20% ​​ethanol, and the product's resistance to 20% ethanol dumping is more important than its resistance to 40% ethanol dumping. In the compound formulation of this invention, the release of duloxetine in hydrochloric acid solution containing 20% ​​ethanol was significantly lower than that of Cymbalta. Detailed Implementation

[0088] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto.

[0089] Example 1

[0090] A duloxetine enteric-coated microcapsule comprises a core, a drug-containing layer, an isolation layer, and an enteric layer. The enteric layer accounts for 42% of the mass of the microcapsule inside the enteric layer (excluding the enteric layer itself). The composition of the enteric layer is shown in Table 1.

[0091] Table 1. Composition of the enteric coating layer of each prescription enteric-coated microsphere

[0092] The batch size of the micro-pellets is 800g, and the composition of the pellet core, drug-containing layer, and isolation layer (the same for prescriptions 1-5) is shown in Table 2:

[0093] Table 2: Composition of the core, drug-containing layer, and isolation layer (mg)

[0094] The method for preparing the duloxetine enteric-coated microspheres includes the following steps:

[0095] (1) Preparation of drug-containing microcapsules: Duloxetine hydrochloride, hydroxypropyl methylcellulose, talc, and water were mixed to form a coating solution, which was then used for bottom spray coating in a fluidized bed. Before spraying, the sucrose pellet cores were preheated to a target material temperature above 40°C. After preheating, the inlet air temperature was set to 45–75°C, the atomization pressure to 1.5 bar, and the spraying speed to ≤10 g / min. The coating solution was then atomized and sprayed onto the sucrose pellet cores. After spraying, the inlet air temperature was set to 45–75°C, and the pellets were dried for 10 min to obtain the drug-containing pellet cores.

[0096] (2) Isolation coating: the hydroxypropyl methyl cellulose, sucrose, talc and water were prepared into an isolation layer coating liquid, and a fluidized bed was used for bottom-spray coating. Before spraying, the drug-containing pellet cores were preheated, and the target material temperature was above 40°C. After preheating, the inlet air temperature was set to 45-75°C, the atomization pressure was 1.5 bar, and the spraying speed was ≤10 g / min. The suspended coating liquid was atomized and sprayed on the drug-containing pellet cores. After spraying, the inlet air temperature was set to 45-75°C, and the drying time was 10 min to obtain the isolation layer pellets;

[0097] (3) Enteric layer coating: the HPMCP, plasticizer, talc, ethanol and water were prepared into an enteric layer coating liquid, and a fluidized bed was used for bottom-spray coating. Before spraying, the isolation layer pellets were preheated, and the target material temperature was above 40°C. After preheating, the inlet air temperature was set to 45-65°C, the atomization pressure was 1.7 bar, and the spraying speed was ≤10 g / min. The suspended coating liquid was atomized and sprayed on the isolation layer pellets. After spraying, the inlet air temperature was set to 45-75°C, and the drying time was 30 min to obtain the enteric layer pellets.

[0098] The release of each prescription compound preparation in 750 mL of 0.1 mol / L hydrochloric acid solution containing 20% ethanol and 0.1 mol / L hydrochloric acid solution containing 40% ethanol was determined by the basket method at 100 rpm to investigate the effect of ethanol on the release of duloxetine.

[0099] The duloxetine release dose (%) of each prescription in the medium containing 20% ethanol is shown in Table 3.

[0100] The duloxetine release dose (%) of each prescription in the medium containing 40% ethanol is shown in Table 4.

[0101] In the following table, prescription 3(15) indicates that the enteric layer weight gain of prescription 3 is adjusted to 15%; and so on.

[0102] The comparative example is the original research product Cymbalta (also referred to as the reference preparation in the present application), which adopts a single enteric layer with HPMCAS as the enteric material.

[0103] The prescription sodium alginate (50) is based on the isolation pellets prepared by the prescription in Table 2, and first coated with HPMCAS as the enteric material, and then coated with sodium alginate as the material for resisting ethanol pouring. The components of the HPMCAS coating layer are HPMCAS, talc and triethyl citrate, and the HPMCAS coating layer has a weight gain of 30%; the components of the sodium alginate coating layer are sodium alginate and polyethylene glycol (sodium alginate: polyethylene glycol = 10:3), and the weight gain of the sodium alginate coating layer is 50%.

[0104] The prescription CAP (42) is based on the isolated pellets prepared by the prescription in Table 2, using CAP as the enteric material for coating, the components of the CAP coating layer are CAP and diethyl phthalate (CAP: diethyl phthalate = 3: 1), and the weight gain of the CAP coating layer is 42%.

[0105] When sodium alginate is used as the coating material for resisting ethanol pouring, the preparation method of duloxetine pellets is as follows:

[0106] (1) Preparation of drug-containing pellets: prepare a suspension coating liquid by mixing hydroxypropyl methyl cellulose, talc and water, and use a fluidized bed to perform bottom spraying coating. Before spraying, preheat the sucrose pellet cores, and the target material temperature is above 40°C. After preheating, set the inlet air temperature to 45-75°C, the atomization pressure to 1.5 bar, and the spraying speed to ≤10 g / min, and atomize and spray the suspension coating liquid on the sucrose pellet cores. After spraying, set the inlet air temperature to 45-75°C and dry for 10 min to obtain drug-containing pellets;

[0107] (2) Isolation coating: prepare an isolation layer coating liquid by mixing hydroxypropyl methyl cellulose, sucrose, talc and water, and use a fluidized bed to perform bottom spraying coating. Before spraying, preheat the drug-containing pellets, and the target material temperature is above 40°C. After preheating, set the inlet air temperature to 45-75°C, the atomization pressure to 1.5 bar, and the spraying speed to ≤10 g / min, and atomize and spray the suspension coating liquid on the drug-containing pellets. After spraying, set the inlet air temperature to 45-75°C and dry for 10 min to obtain isolation layer pellets;

[0108] (3) Enteric layer coating: prepare an enteric inner layer coating liquid by mixing HPMCAS, talc, triethyl citrate, ethanol and water, and use a fluidized bed to perform bottom spraying coating. Before spraying, preheat the isolation layer pellets, and the target material temperature is above 40°C. After preheating, set the inlet air temperature to 40-65°C, the atomization pressure to 1.5 bar, and the spraying speed to ≤10 g / min, and atomize and spray the suspension coating liquid on the isolation layer pellets. After spraying, set the inlet air temperature to 45-75°C and dry for 30 min to obtain enteric layer pellets;

[0109] (4) Sodium alginate coating: prepare a coating liquid by mixing sodium alginate, polyethylene glycol and water, and use a fluidized bed to perform bottom spraying coating. After preheating, set the inlet air temperature to 45-75°C, the atomization pressure to 1.7 bar, and the spraying speed to ≤10 g / min, and atomize and spray the coating liquid on the enteric layer pellets. After spraying, set the inlet air temperature to 45-75°C and dry for 30 min to obtain sodium alginate-coated pellets.

[0110] When CAP is used as the enteric layer coating material, the preparation method of duloxetine enteric pellets is as follows:

[0111] (1) Drug-containing pellet preparation: The hydrochloric acid duloxetine, hydroxypropyl methyl cellulose, talc and water are prepared into a suspension coating liquid, and a fluidized bed is used for bottom-spray coating. Before spraying, the sucrose pellet cores are preheated, and the target material temperature is above 40°C. After preheating, the inlet air temperature is set to 45-75°C, the atomization pressure is 1.5 bar, and the spraying speed is ≤10 g / min. The suspension coating liquid is atomized and sprayed on the sucrose pellet cores. After spraying, the inlet air temperature is set to 45-75°C, and the drying time is 10 min to obtain the drug-containing pellets;

[0112] (2) Isolation coating: The hydroxypropyl methyl cellulose, sucrose, talc and water are prepared into an isolation layer coating liquid, and a fluidized bed is used for bottom-spray coating. Before spraying, the drug-containing pellets are preheated, and the target material temperature is above 40°C. After preheating, the inlet air temperature is set to 45-75°C, the atomization pressure is 1.5 bar, and the spraying speed is ≤10 g / min. The suspension coating liquid is atomized and sprayed on the drug-containing pellets. After spraying, the inlet air temperature is set to 45-75°C, and the drying time is 10 min to obtain the isolation layer pellets;

[0113] (3) Enteric layer coating: The CAP, diethyl phthalate and acetone are prepared into an enteric outer layer coating liquid, and a fluidized bed is used for bottom-spray coating. Before spraying, the isolation layer pellets are preheated, and the target material temperature is above 35°C. After preheating, the inlet air temperature is set to 40-60°C, the atomization pressure is 1.8 bar, and the spraying speed is ≤10 g / min. The coating liquid is atomized and sprayed on the isolation layer pellets. After spraying, the inlet air temperature is set to 45-75°C, and the drying time is 30 min to obtain the enteric layer pellets.

[0114] Table 3 Release rate (%) of each prescription enteric micro-pellet in a medium containing 20% ethanol

[0115] Note: In the 2025 edition of the Chinese Pharmacopoeia, the dissolution of duloxetine hydrochloride in hydrochloric acid is limited to not more than 10% in 2 hours, and there is no dissolution limit of duloxetine hydrochloride in hydrochloric acid containing ethanol. In the comparative example, the dissolution in 2 hours in hydrochloric acid containing 20% ethanol (Table 3) and hydrochloric acid containing 40% ethanol (Table 4) is more than 90%. In this application, the standard for anti-ethanol pouring capacity is that the dissolution in 2 hours is not more than 30%. Within this limit, it can be considered that the preparation meeting the standard has obvious safety advantages over the comparative example in hydrochloric acid solution containing ethanol.

[0116] The preparations of prescriptions 1-5 and the comparative example have no release in 0.1 mol / L hydrochloric acid solution without ethanol in 2 hours.

[0117] As can be seen from Table 3, the prescription without HPMCP enteric layer (comparative example) does not have the ability to resist 20% ethanol pouring, and the duloxetine dissolution in 2 hours is 93%, which exceeds the standard of not more than 30% in 2 hours.

[0118] The anti-20% ethanol pour-out effect of the single-layer enteric coating layer (HP-55 or HP-55S) of the present application is very ideal at a weight gain of 42% (Formulations 1-5). Therefore, the weight gain of the outer enteric coating layer can also be reduced, and it is found that the anti-20% ethanol pour-out effect is still up to standard at a weight gain of 12%.

[0119] The anti-20% ethanol pour-out effect of sodium alginate as an anti-ethanol pour-out material is not up to standard at a weight gain of 50%. Since the dissolution of the formulation using sodium alginate as an anti-ethanol pour-out material is slow at a weight gain of 50% (see Table 5), it is unnecessary to increase the weight gain to improve the anti-ethanol pour-out capacity.

[0120] The anti-20% ethanol pour-out effect of CAP as an anti-ethanol pour-out material is up to the standard at a weight gain of 42%.

[0121] Table 4 Release rate (%) of each formulation of enteric-coated pellets in a medium containing 40% ethanol

[0122] It is found in the experiment that the dosage pour-out in 40% ethanol exists for the comparative example using HPMCAS as the enteric coating material, and the release amount is more than 90% at 2 h.

[0123] The anti-40% ethanol pour-out effect of the duloxetine enteric-coated pellets prepared using HPMCP as the enteric coating material (type HP-55 and HP-55S) is not ideal at a weight gain of 42%. Further adjustment of the weight gain of the enteric coating layer shows that the duloxetine enteric-coated pellets prepared using HP-55 as the enteric coating material can resist the dosage pour-out in 40% ethanol when the weight gain of the enteric coating layer is 70%, and the duloxetine enteric-coated pellets prepared using HP-55S as the enteric coating material can resist the dosage pour-out in 40% ethanol when the weight gain of the enteric coating layer is 65%.

[0124] The formulation of sodium alginate (50) can resist the dosage pour-out in 40% ethanol, and the anti-40% ethanol pour-out effect is better than that in 20%, which is probably caused by the fact that sodium alginate is soluble in water but not in ethanol.

[0125] The anti-40% ethanol pour-out effect of the duloxetine enteric-coated pellets prepared using CAP as the enteric coating material is not ideal at a weight gain of 42%. Further adjustment of the weight gain of the enteric coating layer shows that the duloxetine enteric-coated pellets can resist the dosage pour-out in 40% ethanol when the weight gain of the enteric coating layer is 85%.

[0126] Example 2

[0127] The release curve of the duloxetine enteric-coated pellets is determined by using the dissolution and release determination method (Dissolution and Release Determination Method, Chinese Pharmacopoeia 2025 Edition, General Rule 0931, Method 1 for Enteric Coating Preparations) according to the dissolution requirement of the duloxetine hydrochloride enteric-coated capsule in the Chinese Pharmacopoeia 2025 Edition, Part II.

[0128] 0-2 hours: 0.1 mol / L hydrochloric acid solution, 750 mL;

[0129] 2 hours after changing the medium: add 0.2 mol / L sodium phosphate solution at 37°C ± 0.5°C to the above acid solution (adjust the pH value to 6.8 ± 0.05 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution as necessary), the total volume is 1000 mL;

[0130] Rotation speed: 100 rpm.

[0131] Table 5 Dissolution rate (%) of each prescription enteric-coated pellet in hydrochloric acid pH 6.8 medium

[0132] As can be seen from Table 5, when the weight gain of the enteric-coated layer is 42%, the dissolution amount of the prescription using HP-55 and HP-55S as the enteric-coated material in hydrochloric acid pH 6.8 is higher than 75% after 1 hour, which meets the requirements (Chinese Pharmacopoeia 2025 edition). When the weight gain of HP-55 and HP-55S as the enteric-coated material is further increased to 65%, the dissolution still meets the requirements.

[0133] The dissolution rate of the prescription sodium alginate (50) does not meet the requirements.

[0134] The dissolution rate of the prescription CAP (42) meets the requirements.

[0135] Example 3

[0136] The 60 mg specification (use the duloxetine pellets in Table 2 to fill, and adjust the amount of pellets filled to contain duloxetine 60 mg per capsule) of hydrochloric acid duloxetine enteric-coated capsules obtained from 5 prescriptions, i.e. 1 (15), 3, 4 (65), 5 (65), CAP (42), etc., were used as controls to conduct beagle dog PK tests to investigate the pharmacokinetics of different prescriptions in beagle dogs. The blood sampling time points were 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 18 h, 24 h and 30 h, and the determination method was LC-MS / MS. The results are shown in Table 6:

[0137] Table 6 Pharmacokinetic parameters of enteric-coated pellets of each prescription

[0138] The geometric mean of C max and AUC (0-t) of the enteric-coated pellets obtained from the prescription CAP (42) in beagle dogs were significantly lower than those of the reference preparation. The geometric mean of C max and AUC (0-t)The geometric mean of each sample was between 90% and 110% of the reference formulation, which was relatively close to the reference formulation.

[0139] Example 4

[0140] The stability of the duloxetine hydrochloride enteric-coated capsule single preparation prepared according to prescription 3 and prescription 4 and the comparative example in 750 mL of 0.1 mol / L hydrochloric acid solution containing 20% ethanol was determined by using a basket method at 100 rpm, and the detection results of impurities were shown in Table 7.

[0141] Table 7 Detection results of impurities of samples in 0.1 mol / L hydrochloric acid solution containing 20% ethanol

[0142] From the experimental results, the detected related substance levels of prescription 3 and prescription 4 were significantly lower than those of the comparative example at the same time. The 20% ethanol concentration represented a cocktail, which indicated that the related substances produced by taking the samples prepared according to prescription 3 and prescription 4 would be significantly lower than those produced by taking the comparative example in the case of drinking a cocktail, and the safety of the product could be improved.

[0143] The stability of the duloxetine hydrochloride enteric-coated capsule single preparation prepared according to prescription 3 and prescription 4 and the comparative example in 750 mL of 0.1 mol / L hydrochloric acid solution containing 40% ethanol was determined by using a basket method at 100 rpm, and the detection results of impurities were shown in Table 8.

[0144] Table 8 Detection results of impurities of samples in 0.1 mol / L hydrochloric acid solution containing 40% ethanol

[0145] From the experimental results, the detected related substance levels of prescription 3 and prescription 4 were significantly lower than those of the comparative example at the same time. The 40% ethanol concentration represented a liquor, which indicated that the related substances produced by taking the samples prepared according to prescription 3 and prescription 4 would be significantly lower than those produced by taking the comparative example in the case of drinking a liquor, and the safety of the product could be improved.

[0146] The ability of prescription 3 and prescription 4 to resist 20% ethanol was stronger than the ability to resist 40% ethanol, so the detected related substances of prescription 3 and prescription 4 in 0.1 mol / L hydrochloric acid solution containing 20% ethanol were lower than those in 0.1 mol / L hydrochloric acid solution containing 40% ethanol.

[0147] The comparative example was poor in resistance to 20% ethanol and 40% ethanol, and the pH value of the 0.1 mol / L hydrochloric acid solution containing 20% ethanol was lower than that of the 0.1 mol / L hydrochloric acid solution containing 40% ethanol, so the related substances detected in the 0.1 mol / L hydrochloric acid solution containing 20% ethanol were higher than those detected in the 0.1 mol / L hydrochloric acid solution containing 40% ethanol in the same time. It is indicated that duloxetine is more unstable in the hydrochloric acid solution containing 20% ethanol, and the resistance of the product to 20% ethanol is more important than the resistance to 40% ethanol.

[0148] Example 5

[0149] A compound preparation containing duloxetine enteric micro-pellets and a GABA analogue immediate-release part;

[0150] The composition of the GABA analogue immediate-release part is shown in Table 9:

[0151] Table 9 Composition of the GABA analogue immediate-release part

[0152] The preparation process of the prescriptions P1-P4: the GABA analogue, talc, corn starch, mannitol (if any) and microcrystalline cellulose (if any) are mixed in the laboratory hopper mixer, mixed for 25 min, the mixing speed is 15 rpm, the mixing batch is 500 g, and the mixing is finished.

[0153] The duloxetine enteric micro-pellets of different prescriptions prepared by the prescription P1 are filled into gelatin hard capsule shells to obtain compound capsule preparations, wherein the filling weight of the duloxetine enteric micro-pellets is adjusted downward (the micro-pellets used are unchanged, so the proportion of the excipients in the duloxetine enteric micro-pellets is unchanged), and each capsule contains pregabalin 75 mg and duloxetine 17.5 mg. The gabapentin immediate-release part prepared by the prescription P3 is filled into gelatin hard capsule shells with duloxetine enteric micro-pellets to obtain compound capsule preparations, wherein the filling weight of the duloxetine enteric micro-pellets is adjusted downward (the micro-pellets used are unchanged), and each capsule contains gabapentin 225 mg and duloxetine 17.5 mg. The meloxicam immediate-release part prepared by the prescription P4 is filled into gelatin hard capsule shells with duloxetine enteric micro-pellets to obtain compound capsule preparations, wherein the filling weight of the duloxetine enteric micro-pellets is adjusted downward (the micro-pellets used are unchanged), and each capsule contains meloxicam 5 mg and duloxetine 17.5 mg. The following table:

[0154] Table 10 Prescription composition of the compound preparation

[0155] The fill weight of the enteric duloxetine pellets was adjusted so that the portion of the enteric duloxetine pellets contained 30-40 mg of duloxetine. Then the P2 formulation of immediate-release portion of pregabalin was filled into the gelatin hard capsule shells with the different formulations of enteric duloxetine pellets to obtain the compound capsule formulations, each of which contained 150 mg of pregabalin and 30-40 mg of duloxetine. The formulations are shown in the following table:

[0156] Table 11 Formulation composition of the compound formulations

[0157] The dissolution curves of duloxetine in the compound capsules prepared according to Formulations 6-18 were detected (according to the method in Reference Example 2), and the dissolution behavior of the corresponding enteric duloxetine pellets in Example 2 was similar. This shows that the addition of the immediate-release portion of the gamma-aminobutyric acid analog and the adjustment of the ratio of the gamma-aminobutyric acid analog and duloxetine have no obvious effect on the dissolution behavior of the enteric duloxetine pellets.

[0158] The release of Formulations 6-10 and 13-18 in a hydrochloric acid solution containing 20% ethanol was detected according to the method in Reference Example 1, and the release of Formulations 6-10 and 13-15 in a hydrochloric acid solution containing 40% ethanol was detected to investigate the effect of pregabalin on the dose dumping experiment of the enteric duloxetine pellets.

[0159] Table 12 Release rate of duloxetine in the formulations in a medium containing 20% ethanol (%)

[0160] Table 13 Release rate of duloxetine in the formulations in a medium containing 40% ethanol (%)

[0161] After the addition of pregabalin to prepare the compound formulations, the release rate of some batches in the hydrochloric acid medium containing ethanol was accelerated, indicating that the addition of the immediate-release portion of pregabalin can reduce the anti-ethanol dumping capacity of the product. However, overall, the effect of the addition of pregabalin on the anti-ethanol dumping effect is limited, and the anti-ethanol dumping capacity of the compound capsules containing HPMCP is still significantly better than that of the original duloxetine product Cymbalta.

[0162] The anti-ethanol pouring abilities of the compound preparations of prescription 6-10 and 13-16 in 20% ethanol medium meet the standard; the anti-ethanol pouring ability of the compound preparation of prescription 17 (corresponding to the enteric layer with 12% weight gain) does not meet the standard, although the corresponding single preparation can meet the two-hour anti-ethanol pouring ability standard, because the overall anti-ethanol pouring ability of the product is poor after the addition of the immediate-release component of pregabalin. After adjusting the weight gain of the enteric layer, the anti-ethanol pouring ability of the compound preparation of prescription 16 (corresponding to the enteric layer with 15% weight gain) also meets the standard. The two-hour release amount of duloxetine of the compound preparation prepared by prescription 18 in 20% ethanol medium is 32%, which exceeds the limit, indicating that when CAP is used as the enteric material for coating, the anti-20% ethanol pouring ability of the compound preparation prepared when the weight gain of the enteric layer is less than 42% does not meet the standard.

[0163] The above embodiments are preferred embodiments of the present application, but the embodiments of the present application are not limited to the above embodiments, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application should be equivalent replacement methods, and are all included in the protection scope of the present application.

Claims

1. A dloxetine enteric-coated pellet, characterized by The enteric layer contains hydroxypropyl methyl cellulose phthalate (HPMCP), wherein the mass ratio of HPMCP to the enteric layer is 55.6-90.9%; The HPMCP can be dissolved in a medium with pH value above 5.

5. The enteric layer has a weight gain of 12% or more. The enteric layer has a weight gain of 12%-65%.

2. The dloxetme enteric micro-pellets according to claim 1, characterized by: The HPMCP dissolved in a medium with pH value above 5.5 is type HP-55 or HP-55S.

3. The dloxetme enteric micro-pellets according to claim 1, characterized by: The drug-containing pellets contain pellet cores and drug-containing layers, or are prepared from duloxetine and excipients.

4. The dloxetme enteric micro-pellets according to claim 1, characterized by: The drug-containing pellets and the enteric layer are separated by a separating layer.

5. The dloxetme enteric micro-pellets according to claim 1, wherein: The duloxetine enteric pellets have a protective layer outside the enteric layer.

6. The dloxetme enteric micro-pellets according to claim 1, wherein: The enteric pellets contain duloxetine enteric pellets, and the enteric layer of the enteric pellets has a weight gain of 15% or more.

7. A compound preparation, characterized in that: The duloxetine enteric pellets and a gamma-aminobutyric acid analogue.

8. The complex preparation according to claim 7, characterized in that: The gamma-aminobutyric acid analogue is in a rapid-release form. The gamma-aminobutyric acid analogue is pregabalin, gabapentin, mirogabalin or cloragelael. The mass ratio of pregabalin to duloxetine is (3.75-5.00):

1.

9. The complex preparation according to claim 8, characterized in that: The compound preparation contains pregabalin 150 mg and duloxetine 30-40 mg, or pregabalin 75 mg and duloxetine 15-20 mg.

10. The complex preparation according to claim 9, characterized in that: ​

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