Duloxetine enteric-coated pellet, compound preparation and preparation method

Abstract

The invention discloses a duloxetine enteric-coated pellet, a compound preparation and a preparation method. The duloxetine enteric-coated pellet contains a drug-containing pellet core, an enteric-coated inner layer and an enteric-coated outer layer, the enteric outer layer contains hydroxypropyl methylcellulose phthalate (HPMCP), and the mass ratio of the HPMCP to the enteric outer layer is 55.6%-90.9%; the HPMCP can be dissolved in a medium with the pH value of 5.0 or above or 5.5 or above. According to the duloxetine enteric-coated pellet and the compound preparation thereof, the duloxetine enteric-coated pellet and the compound preparation thereof have an ethanol-pouring-resistant effect and an ideal dissolution speed by optimizing the types of ethanol-pouring-resistant materials and the weight increment of the enteric-coated layer, and the content of impurities generated in a weak-acid dissolution medium with the pH value of 5.0 or below within 2 hours is relatively low.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to duloxetine enteric-coated microcapsules and compound preparations and their preparation methods. Background Technology

[0002] Dose dumping refers to the release of all or most of a drug within a short period of time. Dose dumping poses significant risks to patients due to safety concerns and / or reduced efficacy.

[0003] Duloxetine hydrochloride (trade name Cymbalta) is an oral selective serotonin and norepinephrine reuptake inhibitor developed by Eli Lilly. Clinically, it is widely used to treat severe depression, pressure urinary incontinence, and diabetic peripheral neuropathy. Because duloxetine is unstable in gastric acid, the acid hydrolysis of its ether bond produces thienol and 1-naphthol. 1-Naphthol is toxic and can cause cramps, abdominal pain, nausea, and vomiting. Serious systemic effects include nephritis, cystitis, liver damage, seizures, and hemolysis in patients with acute intravascular glucose-6-phosphate deficiency. Therefore, duloxetine is generally formulated as an enteric-coated product. Common enteric-coated materials are readily soluble in ethanol; therefore, in the presence of alcohol, enteric-coated duloxetine formulations are particularly prone to dose-induced diarrhea, a phenomenon also known as "alcohol dumping" (or "ethanol dumping"). This can lead to premature and / or excessive release of the active pharmaceutical ingredient from an orally administered drug composition, exposing patients to high-risk levels of the active agent, potentially resulting in adverse reactions and / or drug-induced toxicity. To address the issue of alcohol dumping in duloxetine, anti-ethanol dumping materials are typically added to its enteric coating. Existing anti-ethanol dumping materials include sodium alginate and cellulose acetate phthalate (CAP).

[0004] However, in actual formulation development, focusing solely on anti-ethanol dumping efficacy is insufficient. Some enteric-coated formulations suffer from a mismatch between anti-ethanol dumping efficacy and drug dissolution rate due to inappropriate selection of the type of anti-ethanol dumping material and the thickness of the enteric coating. Furthermore, some anti-ethanol dumping materials dissolve due to insufficient acid resistance, leading to the release of APIs under acidic conditions and the generation of impurities. Therefore, a comprehensive approach is needed to address the issues of anti-ethanol dumping efficacy, drug dissolution rate, and impurities in the formulation.

[0005] Duloxetine and gamma-aminobutyric acid (GABA) analogs such as pregabalin, gabapentin, and melogabalin are existing medications for treating neuropathic pain, including diabetic peripheral neuropathy (DSPN). However, their monotherapy efficacy is not yet ideal, making the formulation of these drugs into combination preparations of practical significance. Furthermore, this combination preparation shows promising application potential in treating neuropathic pain, including postherpetic neuralgia (PHN), trigeminal neuralgia, postoperative neuropathy, sciatica, and post-stroke neuralgia, as well as mixed pain, such as pain caused by lumbar nerve roots, cervical radiculopathy, cancer pain, and carpal tunnel syndrome, where neuropathic pain and nociceptive pain coexist. Summary of the Invention

[0006] The purpose of this invention is to provide a duloxetine enteric-coated microcapsules, a compound preparation, and a preparation method. By optimizing the type of material and the thickness of the enteric layer to resist ethanol dumping, the duloxetine enteric-coated microcapsules and their compound preparation achieve both anti-ethanol dumping effect and ideal dissolution rate, and the impurity content generated in a weakly acidic dissolution medium below pH 5.0 is low after 2 hours.

[0007] The objective of this invention is achieved by the following technical solution:

[0008] A duloxetine enteric-coated microcapsule comprising a drug-containing core, an inner enteric layer, and an outer enteric layer.

[0009] The enteric outer layer contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein HPMCP accounts for 55.6% to 90.9% of the mass of the enteric outer layer.

[0010] The amount of the enteric outer layer accounts for 9 to 200% of the mass of the enteric inner layer microcapsules (hereinafter also referred to as "weight gain"); the duloxetine enteric microcapsules are resistant to ethanol dumping and the dissolution rate meets the requirements.

[0011] A duloxetine enteric-coated microcapsule comprising a drug-containing core, an inner enteric layer, and an outer enteric layer.

[0012] The enteric outer layer contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein HPMCP accounts for 55.6% to 90.9% of the mass of the enteric outer layer.

[0013] The HPMCP is soluble in media with a pH value above 5.0.

[0014] The HPMCP dissolved in a medium with a pH value above 5.0 is preferably HP-50, and its phthaloyl content is 21.0% to 27.0%.

[0015] When the HPMCP is soluble in a medium with a pH value above 5.0, the amount of the enteric outer layer accounts for 9-200% of the mass of the enteric inner layer microcapsules (hereinafter also referred to as "weight gain"). Duloxetine enteric microcapsules with this weight gain can resist 20% ethanol pouring and the dissolution rate meets the requirements. Preferably, the weight gain of the enteric outer layer is 12-150%. More preferably, the weight gain of the enteric outer layer is 12-100%.

[0016] Particularly preferred is that the weight gain of the enteric outer layer is 60-200%, and the duloxetine enteric microspheres with this weight gain can resist 20-40% ethanol pouring and the dissolution rate meets the requirements.

[0017] A duloxetine enteric-coated microcapsule comprising a drug-containing core, an inner enteric layer, and an outer enteric layer.

[0018] The enteric outer layer contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein HPMCP accounts for 55.6% to 90.9% of the mass of the enteric outer layer.

[0019] The HPMCP is soluble in media with a pH value above 5.5.

[0020] The HPMCP dissolved in a medium with a pH value above 5.5 is preferably HP-55 or HP-55S, with a phthaloyl content of 27.0% to 35.0%. At 20°C, the viscosity of a 10% (w / w) methanol-dichloromethane (1:1) solution prepared with HP-55 is 32 to 48 mPa·s, and the viscosity of a 10% (w / w) methanol-dichloromethane (1:1) solution prepared with HP-55S is 136 to 204 mPa·s.

[0021] The HPMCP is soluble in a medium with a pH value of 5.5 or higher, and the weight gain of the enteric outer layer is 9% or more. Duloxetine enteric-coated microspheres with this weight gain can resist 20% ethanol dumping. Preferably, the weight gain of the enteric outer layer is 50% or more, and duloxetine enteric-coated microspheres with this weight gain can resist 20-40% ethanol dumping.

[0022] More preferably, the weight gain of the enteric outer layer is 12-50%, and the duloxetine enteric microspheres with this weight gain can resist 20% ethanol pouring and the dissolution rate meets the requirements.

[0023] Preferably, the enteric outer layer contains HPMCP and one or more adjuvants.

[0024] More preferably, the enteric outer layer contains HPMCP, a plasticizer, and an anti-adhesion agent.

[0025] Particularly preferably, the enteric outer layer contains the following components by weight percentage:

[0026] HPMCP: 55.6%–90.9%

[0027] Plasticizer: 3.2–22.2%

[0028] Anti-adhesive: 3.7%–32.3%.

[0029] An isolation layer is provided between the drug-containing pellet core and the enteric coating. The main function of the isolation layer is to separate the drug-containing pellet core and the enteric coating to prevent unnecessary interaction between the drug and the enteric coating, thus maintaining the stability and activity of the drug.

[0030] The duloxetine enteric-coated microspheres described herein have a protective layer in addition to the enteric coating layer. The protective layer serves to reduce the static electricity of the microspheres during the capsule filling process, prevent external environmental factors (such as humidity, oxygen, light, etc.) from affecting the physical and chemical properties of the microspheres, and can also be colored to form certain appearance characteristics for identification.

[0031] The enteric inner layer contains enteric material, or may also contain one or more adjuvants; the enteric material accounts for 45.5% to 100% of the mass of the enteric inner layer.

[0032] Preferably, the enteric inner layer contains enteric material, plasticizer, and anti-adhesion agent.

[0033] The enteric material is at least one of hydroxypropyl methylcellulose acetate succinate (HPMCAS), methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, methacrylic acid copolymer type A, and polyvinyl acetate phthalate.

[0034] The amount of the enteric inner layer is 15% to 65% of the mass of the isolation layer microspheres (or containing a core), preferably 20% to 60%.

[0035] Preferably, the enteric inner layer contains the following components by weight percentage:

[0036] Enteric-coated material: 45.5%–100%

[0037] Anti-adhesive: 0–37.5%

[0038] Plasticizer: 0-37.5%.

[0039] The medicated pellet core consists of a blank pellet core and a medicated layer, and is prepared by processes such as pellet core loading; or the medicated pellet core is prepared by mixing duloxetine or its salts with adjuvants, and can be prepared by processes such as centrifugal pelleting or extrusion spheroidization.

[0040] When a core-loaded drug delivery process is used, the drug-containing core contains a blank core, duloxetine or its salt, a film-forming material, and optional adjuvants.

[0041] The blank pellet core is a sucrose pellet core, a lactose pellet core, a starch pellet core, a microcrystalline cellulose pellet core, a mannitol pellet core, a silica pellet core, or a lactose-microcrystalline cellulose pellet core.

[0042] The drug-containing layer contains duloxetine or its salts, a film-forming material, and optional adjuvants.

[0043] The weight gain of the drug-containing layer accounts for 90-130% of the weight of the blank pellet core.

[0044] Preferably, the drug-containing layer contains duloxetine or its salt, a film-forming material, and an anti-adhesion agent.

[0045] Particularly preferably, the drug-containing layer contains the following components by mass percentage:

[0046] Duloxetine or its salts: 65–80%

[0047] Film-forming material: 15~25%

[0048] Anti-adhesive: 5-10%.

[0049] When centrifugal pelleting or extrusion spheronization processes are used, the drug-containing pellet core contains duloxetine or its salt, and one or more adjuvants, preferably duloxetine or its salt, a binder, and a filler.

[0050] The isolation layer contains a film-forming material, or may also contain one or more additives, wherein the proportion of the film-forming material is 5% to 100%.

[0051] The specific composition is as follows by mass percentage:

[0052] Film-forming material: 5~100%

[0053] Pore-forming agent: 0-80%

[0054] Anti-adhesive: 0-50%.

[0055] The weight gain of the isolation layer accounts for 10-155% of the weight of the pill core.

[0056] The protective layer contains a film-forming material, or may also contain one or more additives, wherein the film-forming material accounts for 50-90%.

[0057] The specific composition is as follows by mass percentage:

[0058] Film-forming material: 50~90%

[0059] Sunscreen: 0-30%

[0060] Anti-adhesive: 10-50%.

[0061] The protective layer comprises 2-15% of the mass of the enteric outer layer of microspheres.

[0062] The method for preparing the duloxetine enteric-coated microspheres includes the following steps:

[0063] (1) Preparation of drug-containing pellet cores: Prepare a suspension of coating solution by mixing raw drug, film-forming material, adjuvant and water, use fluidized bed for bottom spray coating, and atomize the suspension of coating solution onto blank pellet cores to obtain drug-containing pellet cores; or prepare drug-containing pellet cores by centrifugal pelleting or extrusion spheroidization process.

[0064] (2) Isolation coating: The film-forming material, additives and water are prepared into an isolation coating solution, and a fluidized bed is used for bottom spray coating. The isolation coating solution is sprayed onto the drug-containing microcapsules to obtain isolation microcapsules.

[0065] (3) Enteric inner layer coating: The enteric material, additives and solvent are prepared into an enteric inner layer coating solution. The solvent is at least one of water and ethanol. The fluidized bed is used for bottom spray coating. The enteric inner layer coating solution is sprayed onto the isolation layer micro pellets to obtain enteric inner layer micro pellets.

[0066] (4) Enteric outer coating: HPMCP, additives, ethanol and water are prepared into an enteric outer coating solution, and bottom spray coating is performed using a fluidized bed. The enteric outer coating solution is sprayed onto the enteric inner microspheres to obtain enteric outer microspheres.

[0067] (5) Protective coating: The film-forming material, additives and water are prepared into a protective coating solution, and a fluidized bed is used for bottom spray coating. The coating solution is sprayed onto the enteric outer layer of microcapsules to obtain duloxetine enteric microcapsules.

[0068] A compound preparation containing the aforementioned duloxetine enteric-coated microspheres.

[0069] The compound preparation contains duloxetine enteric-coated microspheres and a γ-aminobutyric acid analogue.

[0070] The compound preparation is obtained by filling duloxetine enteric-coated microspheres and γ-aminobutyric acid analogs into capsule shells.

[0071] The γ-aminobutyric acid analogue is in an immediate-release form.

[0072] The γ-aminobutyric acid analogues mentioned are pregabalin, gabapentin, melogabalin, or cligabalin benzylsulfonate.

[0073] The immediate-release portion of the γ-aminobutyric acid analogue comprises a γ-aminobutyric acid analogue and one or more adjuvants, specifically composed of the following components by mass percentage:

[0074] γ-aminobutyric acid analogues: 7-97%

[0075] Anti-adhesive: 3-85%

[0076] Disintegrant: 0-85%

[0077] Filler: 0-90%.

[0078] The preferred γ-aminobutyric acid analogue is pregabalin.

[0079] The immediate-release fraction of pregabalin comprises pregabalin and one or more excipients, wherein pregabalin accounts for 10-97% of the immediate-release fraction, and its specific composition is as follows by mass percentage:

[0080] Pregabalin: 10-97%

[0081] Anti-adhesive: 3-85%

[0082] Disintegrant: 0-85%.

[0083] In the compound preparation, the mass ratio of pregabalin to duloxetine is (3.75–5.00):1.

[0084] The compound preparation contains 150 mg of pregabalin and 30-40 mg of duloxetine, or 75 mg of pregabalin and 15-20 mg of duloxetine.

[0085] One method of administration is to administer the above-mentioned compound preparation to the patient 1-3 times a day, preferably twice a day; in the compound preparation, the mass ratio of pregabalin to duloxetine is (3.75-5.00):1.

[0086] Preferably, the compound preparation contains 150 mg of pregabalin and 30-40 mg of duloxetine, administered twice daily.

[0087] Preferably, the compound preparation contains 75 mg of pregabalin and 15-20 mg of duloxetine, administered twice daily.

[0088] The film-forming material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl ketone, polyvinyl alcohol, gum arabic, or aminoalkyl methacrylate copolymer.

[0089] The additives are one or more of plasticizers, anti-adhesives, opacifiers, pore-forming agents, disintegrants, adhesives, or fillers.

[0090] The plasticizer is one or more of the following: triethyl citrate, tributyl citrate, polyethylene glycol, diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dibutyl sebacate, cetyl alcohol, propylene glycol, glycerin, polyethylene glycol, castor oil, diacetyl monoglyceride, olive oil, or succinic acid.

[0091] The anti-adhesion agent is an inorganic powder, preferably talc and / or silicon dioxide.

[0092] The light-blocking agent is a lake, preferably one or more of titanium dioxide, iron oxide, aluminum lake, or iron pyrophosphate.

[0093] The pore-forming agent is one or more of sucrose, lactose, mannitol, sodium chloride, potassium chloride, or polyethylene glycol.

[0094] The disintegrant is one or more of the following: croscarmellose sodium, croscarmellose, corn starch, potato starch, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl starch, or microcrystalline cellulose.

[0095] The adhesive is one or more of corn starch, potato starch, pregelatinized starch, soluble starch, water-soluble starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, or dextrin.

[0096] The filler is one or more of the following: microcrystalline cellulose, lactose monohydrate, anhydrous lactose, mannitol, anhydrous dicalcium phosphate, dicalcium phosphate dihydrate, corn starch, potato starch, sucrose, dextrin, or calcium sulfate.

[0097] This application has the following advantages and beneficial effects compared to the prior art:

[0098] 1. This application selects HPMCP as the anti-ethanol dumping enteric material (enteric outer layer) by optimizing the type of anti-ethanol dumping material and the thickness of the enteric layer. This allows duloxetine enteric microspheres to achieve both anti-ethanol dumping effect and ideal dissolution rate. Furthermore, the duloxetine enteric microspheres produce a low impurity content after 2 hours in a weakly acidic dissolution medium with a pH below 5.0.

[0099] 2. Products prepared using sodium alginate as an ethanol-resistant pour-over agent primarily utilize the principle that polysaccharides are insoluble in ethanol. With a 50% increase in the weight of the sodium alginate layer, it can resist a 40% ethanol pour-over, but not a 20% ethanol pour-over. At this weight increase, the resulting formulation lacks the ability to resist a 20% ethanol pour-over, and the dissolution rate is too slow to meet requirements. Therefore, it is unnecessary to increase the weight to make the product resistant to a 20% ethanol pour-over, as this would lead to an even slower dissolution rate.

[0100] 3. Enteric-coated pellets were prepared using cellulose acetate phthalate (CAP) to coat the enteric outer layer. Although the in vitro dissolution rate met the standard requirements after adjusting the weight gain of the enteric inner layer (with a 35% weight increase), and the formulation was resistant to 20% ethanol pour-over, in in vivo pharmacokinetic experiments in beagle dogs, C... max and AUC 0-tThe concentration was significantly lower than that of Cymbalta (the original drug, duloxetine hydrochloride enteric-coated capsules), and therefore did not meet the requirements. This is because the concentration in the beagle dog experiment was significantly lower than that in the original drug. max and AUC 0-t The levels are significantly low. Continuing to increase CAP (capacity) will only slow down the release of the formulation from the beagle's body, and will not increase C (carat weight). max and AUC 0-t Therefore, although increasing the CAP weight gain might improve its resistance to 40% ethanol dumping, the data from the beagle dog experiments clearly did not meet expectations, so there was no need to further investigate the necessity of increasing the CAP weight gain. Under the condition of a 35% increase in the enteric coating weight gain, the prepared compound formulation showed a dissolution rate of 29% at 120 minutes in the 20% ethanol dumping experiment, which is close to the limit. Therefore, there is no need to investigate lower CAP weight gain in the compound formulation. Furthermore, acetone is required as a coating solvent when using CAP coating; acetone has a certain degree of toxicity and is relatively environmentally unfriendly. The use of acetone also requires high explosion-proof conditions in the production workshop, making the formulation production environment quite demanding.

[0101] 4. Research results from the original manufacturer of Cymbalta showed that the bioavailability of duloxetine decreased after nighttime administration. The original manufacturer attributed this to delayed gastric emptying caused by nighttime administration, which prevented the coating of the original drug from remaining intact during this extended period, leading to the degradation of duloxetine into naphthol and consequently, decreased bioavailability. The formulation of this invention incorporates an enteric coating layer, significantly increasing its acid resistance. Therefore, it is speculated that the compound formulation of this invention, after nighttime administration, will exhibit a lower degradation rate of duloxetine, resulting in improved bioavailability compared to the original product, thus enhancing efficacy and reducing adverse reactions.

[0102] 5. The inventors unexpectedly discovered that when using a double-layer enteric coating scheme (using HPMCAS and HPMCCP as the inner and outer enteric coating materials respectively) to prepare an anti-ethanol dumping formulation, the overall anti-ethanol dumping ability decreased after adding pregabalin to form a compound formulation. The inventors further optimized the thickness of the outer enteric coating layer (HPMCP) so that the release amount of duloxetine in the compound formulation of the present invention in hydrochloric acid solution containing ethanol could also meet the proposed limit.

[0103] 6. 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

[0104] 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.

[0105] Example 1

[0106] A duloxetine enteric-coated microcapsule comprises a blank core, a drug-containing layer, an isolation layer, an inner enteric layer, and an outer enteric layer. The outer enteric layer accounts for 33% of the mass of the inner enteric layer microcapsule. The composition of the inner and outer enteric layers is shown in Table 1.

[0107] Table 1. Composition of the inner and outer enteric layers of each formulation of enteric-coated microcapsules

[0108]

[0109] The batch size of the micro-pellets is 800g, and the composition of the blank pellet core, the drug-containing layer, and the isolation layer (the same for prescriptions 1-5) is shown in Table 2:

[0110] Table 2: Composition of the core, drug-containing layer, and isolation layer (mg)

[0111]

[0112] The method for preparing the duloxetine enteric-coated microspheres includes the following steps:

[0113] (1) Preparation of drug-containing pellet cores: 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 suspension of 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.

[0114] (2) Isolation Coating: Hydroxypropyl methylcellulose, sucrose, talc, and water were mixed to prepare an isolation coating solution, which was then applied via bottom spraying using a fluidized bed. Before spraying, the drug-containing 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 suspension of the coating solution was then atomized and sprayed onto the drug-containing 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 isolation layer microspheres.

[0115] (3) Enteric inner coating:

[0116] Formulas 1, 3, and 4: Prepare an enteric coating solution by mixing HPMCAS, talc (if available), triethyl citrate (if available), ethanol, and water. Perform bottom-spray coating using a fluidized bed. Before spraying, preheat the isolation layer microspheres to a target material temperature above 40°C. After preheating, set the inlet air temperature to 40–65°C, atomization pressure to 1.5 bar, and spraying speed ≤10 g / min, atomizing the coating solution onto the isolation layer microspheres. After spraying, set the inlet air temperature to 45–75°C and dry for 30 min to obtain enteric inner layer microspheres.

[0117] Formulas 2 and 5: An enteric coating solution is prepared by combining methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, and ethanol. Ethanol is used as the solvent. The solution is applied via bottom spraying in a fluidized bed. Before spraying, the isolation layer microspheres are preheated to a target material temperature above 35°C. After preheating, the inlet air temperature is set to 25–40°C, the atomization pressure to 1.7 bar, and the spraying speed to ≤10 g / min. The suspended coating solution is then atomized and sprayed onto the isolation layer microspheres. After spraying, the inlet air temperature is set to 45–75°C, and the mixture is dried for 30 min to obtain the enteric inner layer microspheres.

[0118] (4) Enteric Coating: HPMCP, plasticizer, talc, ethanol, and water were mixed to prepare an enteric coating solution, which was then applied via bottom spraying using a fluidized bed. Before spraying, the enteric inner layer microspheres were preheated to a target material temperature above 40°C. After preheating, the inlet air temperature was set to 45–65°C, the atomization pressure to 1.7 bar, and the spraying speed to ≤10 g / min. The suspended coating solution was then atomized and sprayed onto the enteric inner layer microspheres. After spraying, the inlet air temperature was set to 45–75°C, and the microspheres were dried for 30 min to obtain duloxetine enteric microspheres.

[0119] The release of duloxetine microspheres prepared according to each formulation was determined using the basket method at 100 rpm 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, to investigate the effect of ethanol on duloxetine release.

[0120] The release dose (%) of duloxetine for each formulation in a medium containing 20% ​​ethanol is shown in Table 3.

[0121] The release dose (%) of duloxetine for each formulation in a medium containing 40% ethanol is shown in Table 4.

[0122] In the embodiment, formulation 3 (30) means adjusting the weight gain of the enteric outer layer of formulation 3 to 30%; and so on.

[0123] Prescription 3-A means replacing HP-50 in the enteric outer layer of prescription 3 with HP-55, and the weight gain of the enteric outer layer remains unchanged at 33%.

[0124] Prescription 3-B means replacing HP-50 in the enteric outer layer of prescription 3 with HP-55S, while the weight gain of the enteric outer layer remains unchanged at 33%.

[0125] Prescriptions 3-A(9) and 3-B(9) indicate that the weight gain of the enteric outer layer of 3-A and 3-B is adjusted to 9% respectively; and so on.

[0126] Prescription 3' indicates the prescription obtained after removing the enteric outer layer components of prescription 3.

[0127] The comparative example is the original product Cymbalta (also referred to as the reference formulation in this invention), which uses a single-layer enteric coating with HPMCAS as the enteric material.

[0128] Prescription 3 - Sodium alginate (50) indicates that sodium alginate is used as a material to resist ethanol dumping in the formulation 3 enteric inner layer microspheres. The composition of the sodium alginate coating layer is sodium alginate and polyethylene glycol (sodium alginate: polyethylene glycol = 10:3). The weight gain of the sodium alginate coating layer is 50%.

[0129] Formula 3-CAP (35) indicates that, based on the enteric inner layer microspheres of Formula 3, CAP is used as an anti-ethanol dumping 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 35%; and so on.

[0130] When sodium alginate is used as the coating material to resist ethanol dumping, the preparation method of duloxetine microspheres is as follows:

[0131] (1) Preparation of drug-containing pellet cores: 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 suspension of 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.

[0132] (2) Isolation Coating: Hydroxypropyl methylcellulose, sucrose, talc, and water were mixed to prepare an isolation coating solution, which was then applied via bottom spraying using a fluidized bed. Before spraying, the drug-containing 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 suspension of the coating solution was then atomized and sprayed onto the drug-containing 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 isolation layer microspheres.

[0133] (3) Enteric coating: HPMCAS, talc, triethyl citrate, ethanol, and water were mixed to prepare an enteric coating solution, which was then applied via bottom spraying using a fluidized bed. Before spraying, the isolation layer microspheres were preheated to a target material temperature above 40°C. After preheating, the inlet air temperature was set to 40–65°C, the atomization pressure to 1.5 bar, and the spraying speed to ≤10 g / min. The suspended coating solution was then atomized and sprayed onto the isolation layer microspheres. After spraying, the inlet air temperature was set to 45–75°C, and the microspheres were dried for 30 min to obtain the enteric coating microspheres.

[0134] (4) Sodium alginate coating: A coating solution was prepared by mixing sodium alginate, polyethylene glycol, and water, and bottom-sprayed using a fluidized bed. After preheating, the inlet air temperature was set to 45–75°C, the atomization pressure to 1.7 bar, and the spraying speed to ≤10 g / min. The coating solution was then atomized and sprayed onto the enteric-coated microspheres. After spraying, the inlet air temperature was set to 45–75°C, and the microspheres were dried for 30 min to obtain sodium alginate-coated microspheres.

[0135] When using CAP as the enteric coating material, the preparation method of duloxetine enteric-coated microspheres is as follows:

[0136] (1) Preparation of drug-containing pellet cores: 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 suspension of 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.

[0137] (2) Isolation Coating: Hydroxypropyl methylcellulose, sucrose, talc, and water were mixed to prepare an isolation coating solution, which was then applied via bottom spraying using a fluidized bed. Before spraying, the drug-containing 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 suspension of the coating solution was then atomized and sprayed onto the drug-containing 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 isolation layer microspheres.

[0138] (3) Enteric inner layer coating: HPMCAS, talc, triethyl citrate, ethanol, and water were prepared into an enteric inner layer coating solution, which was then used for bottom spray coating in a fluidized bed. Before spraying, the isolation layer microspheres were preheated to a target material temperature of above 40℃. After preheating, the inlet air temperature was set to 40–65℃, the atomization pressure to 1.5 bar, and the spraying speed to ≤10 g / min. The suspended coating solution was then atomized and sprayed onto the isolation layer microspheres. After spraying, the inlet air temperature was set to 45–75℃, and the microspheres were dried for 30 min to obtain the enteric inner layer microspheres.

[0139] (4) Enteric coating: CAP, diethyl phthalate, and acetone were used to prepare an enteric coating solution for the outer layer, which was then applied via bottom spraying using a fluidized bed. Before spraying, the enteric inner layer microspheres were preheated to a target material temperature above 35°C. After preheating, the inlet air temperature was set to 40–60°C, the atomization pressure to 1.8 bar, and the spraying speed to ≤10 g / min. The coating solution was then atomized and sprayed onto the enteric inner layer microspheres. After spraying, the inlet air temperature was set to 45–75°C, and the microspheres were dried for 30 min to obtain the enteric outer layer microspheres (duloxetine enteric microspheres).

[0140] Table 3. Release rates (%) of each enteric-coated microcapsule formulation in a medium containing 20% ​​ethanol.

[0141] prescription 30min 45min 60min 90min 120min 1 0 0 0 0 0 2 0 0 0 0 0 3 0 0 0 0 0 4 0 0 0 0 0 5 0 0 0 0 0 3(30) 0 0 0 0 0 3(12) 0 0 0 3 9 3(9) 0 0 1 14 28 3-A 0 0 0 0 0 3-A(12) 0 0 0 2 8 3-A(9) 0 0 0 5 22 3-B 0 0 0 0 0 3-B(12) 0 0 0 2 7 3-B(9) 0 0 0 5 21 3’ 0 8 52 94 94 Comparative Example 0 7 52 93 93 3-Sodium alginate (50g) 0 1 24 52 70 3-CAP(35) 0 0 1 4 16

[0142] The 2025 edition of the Chinese Pharmacopoeia specifies that the dissolution limit of duloxetine hydrochloride enteric-coated formulations in hydrochloric acid is no more than 10% within 2 hours, but does not specify a dissolution limit for duloxetine hydrochloride in hydrochloric acid containing ethanol. In this application, the standard for compliant anti-ethanol dumping ability is a dissolution of no more than 30% within 2 hours. Under this limit, it can be considered that taking a formulation that meets this standard, even in cases involving alcohol consumption, demonstrates significantly better safety than the comparative formulation.

[0143] In comparative cases, the dissolution rate in hydrochloric acid containing 20% ​​ethanol (Table 3) and hydrochloric acid containing 40% ethanol (Table 4) both exceeded 90% after 2 hours.

[0144] Formulas 1-5 and the comparative examples showed no release (0%) within 2 hours in a 0.1 mol / L hydrochloric acid solution without ethanol.

[0145] As shown in Table 3, the formulations without the HPMCP enteric coating (comparative example and formulation 3') do not have the ability to resist 20% ethanol decantation, and the dissolution of duloxetine within 2 hours is more than 90%, which exceeds the standard of no more than 30% dissolution within 2 hours.

[0146] At a weight gain of 33%, the enteric-coated microspheres of this invention, with their double-layer enteric coating (inner layer HPMCAS + outer layer HPMCP (HP-50, HP-55, or HP-55S)) exhibited excellent resistance to 20% ethanol dumping. Therefore, the weight gain of the outer enteric coating layer was further reduced, and it was found that even at a 9% weight gain, the resistance to 20% ethanol dumping remained satisfactory.

[0147] Microparticles coated with sodium alginate did not meet the required resistance to 20% ethanol dumping at a 50% weight gain. Since the formulation using sodium alginate as the enteric coating material dissolved significantly slower than the control group at a 50% weight gain (see Table 5), it was unnecessary to increase its weight gain to improve its resistance to ethanol dumping.

[0148] Based on prescription 3, HP-50 in the enteric outer layer was replaced with CAP. With a weight gain of 35%, its effect against 20% ethanol dumping met the requirements for anti-ethanol dumping.

[0149] Table 4. Release rates (%) of each enteric-coated microcapsule formulation in a medium containing 40% ethanol.

[0150]

[0151]

[0152] Experiments showed that the formulations of the comparative example and formulation 3', which used HPMCAS as the enteric coating material (single-layer enteric coating), exhibited dose-induced purging in 40% ethanol, with a release rate of over 90% in 2 hours.

[0153] At a weight gain of 33%, the anti-40% ethanol purging effect of the double-layer enteric coating (inner layer HPMCAS + outer layer HPMCP (HP-50, HP-55 or HP-55S)) formulation of the present invention was not ideal.

[0154] Further adjustments were made to the weight gain of the enteric coating to meet the resistance to 40% ethanol dumping. It was found that when HP-50 was used as the enteric material, the weight gain of the enteric coating needed to be at least 60%; when HP-55 or HP-55S were used as the enteric material, the weight gain of the enteric coating needed to be at least 55% and 50%, respectively.

[0155] Prescription 3 - Sodium alginate (50) can resist 40% ethanol dose dumping, and its resistance to 40% ethanol dumping is better than that of 20%, which may be due to the fact that sodium alginate is soluble in water but insoluble in ethanol.

[0156] Formula 3-CAP (35) uses CAP as the enteric coating material. With a 35% increase in the weight of the outer enteric coating, its resistance to 40% ethanol decantation is not satisfactory. However, due to this weight increase, the dissolution of the formula is already relatively slow (see Table 5 of Example 2). Further increasing the weight will inevitably slow the dissolution even more. Furthermore, relevant animal experimental data (see Table 6 of Example 3) show that in the pharmacokinetic experiment in beagle dogs, this formula C... max and AUC 0-t The results were significantly lower than those of Cymbalta (the original drug, duloxetine hydrochloride enteric-coated capsules). Therefore, there was no need to further investigate the coating weight gain against 40% ethanol purging.

[0157] Example 2

[0158] Referring to the dissolution requirements of the monograph on duloxetine hydrochloride enteric-coated capsules in Part II of the 2025 edition of the Chinese Pharmacopoeia, the release curve of duloxetine hydrochloride enteric-coated microcapsules was determined using the dissolution and release determination method (General Chapter 0931, Method 1, Enteric Coated Preparations, Chinese Pharmacopoeia 2025 Edition).

[0159] 0-2 hours: 750 mL of 0.1 mol / L hydrochloric acid solution;

[0160] After 2 hours, change the medium: Add 250 mL of 0.2 mol / L sodium phosphate solution at 37℃±0.5℃ to the above acid solution (adjust the pH to 6.8±0.05 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution if necessary), for a total volume of 1000 mL;

[0161] Rotation speed: 100 rpm.

[0162] The results are shown in Table 5.

[0163] Table 5. Dissolution rate (%) of each formulation of enteric-coated microcapsules in hydrochloric acid medium converted to pH 6.8.

[0164]

[0165] As shown in Table 5, with a 33% increase in the weight of the outer enteric coating, the formulation using HP-50 as the enteric material showed a dissolution rate well above 75% after 1 hour at pH 6.8 with hydrochloric acid, meeting the requirements (Chinese Pharmacopoeia 2025, Duloxetine Hydrochloride Enteric-Coated Capsules). Further weight increases to 200% also maintained the dissolution requirement. This indicates that a 20-65% increase in the inner enteric coating weight and a maximum 200% increase in the outer enteric coating weight are sufficient to meet the dissolution requirements.

[0166] With the same 33% increase in weight of the enteric coating, the formulation using HP-55 or HP-55S as the enteric material showed a dissolution rate of over 75% within 1 hour at pH 6.8 with hydrochloric acid, meeting the requirements. Further increasing the weight to 50% maintained the dissolution requirement. This indicates that when using HP-50 or HP-55S as the enteric coating material, dissolution at pH 6.8 with 50% or less of enteric coating weight is sufficient to meet the requirements.

[0167] The dissolution rate of prescription 3-sodium alginate (50) does not meet the requirements.

[0168] When HP-50 in the enteric outer layer of formulations 2, 3 and 5 was replaced with CAP, the dissolution rate of formulations 2-CAP (35) and 3-CAP (35) met the requirements with a 35% increase in the weight of the enteric outer layer, but the dissolution rate of 5-CAP (35) did not meet the requirements.

[0169] Example 3

[0170] Using the original product Cymbalta (60mg) as a control, five different formulations (3(150), 3-A(25), 3-B(25), 3-CAP(35), and 2-CAP(35)) of duloxetine hydrochloride enteric-coated capsules (filled using duloxetine microspheres as shown in Table 2, with the filling volume adjusted to 60mg duloxetine per capsule) were used in a beagle dog pharmacokinetic study to investigate the pharmacokinetic behavior of different formulations in beagle dogs. Blood was collected at 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 18h, 24h, and 30h, and the assay was performed by LC-MS / MS. The results are shown in Table 6.

[0171] Table 6. Pharmacokinetic parameters of each prescription enteric-coated pellet

[0172]

[0173] Enteric-coated microspheres obtained from formulations 3-CAP(35) and 2-CAP(35) showed C in beagle dogs max and AUC (0-t) The geometric mean of all three formulations was significantly lower than that of the reference formulation. For the other three formulations examined, C... max and AUC (0-t) The geometric mean values ​​were all between 90% and 110% of the reference formulation, which is quite close to the reference formulation.

[0174] Example 4

[0175] The stability of the duloxetine hydrochloride enteric-coated capsules prepared according to Formula 3 and the comparative formulation in 750 mL of 0.1 mol / L hydrochloric acid solution containing 20% ​​ethanol was determined using the basket method at 100 rpm. The observation time was 2 hours. The results of impurity detection are shown in Table 7.

[0176] Table 7. Impurity detection results of samples in 0.1 mol / L hydrochloric acid solution containing 20% ​​ethanol.

[0177]

[0178] The experimental results show that, at the same time interval, the levels of related substances detected in prescription 3 were significantly lower than those in the control group. The 20% ethanol concentration represents a cocktail, indicating that when consuming a cocktail, the levels of related substances produced when taking the homemade sample are significantly lower than those produced when taking the control group, thus improving drug safety.

[0179] The stability of the duloxetine hydrochloride enteric-coated capsules prepared according to Formula 3 and the comparative formulation in 750 mL of 0.1 mol / L hydrochloric acid solution containing 40% ethanol was determined using the basket method at 100 rpm. The results of impurity detection are shown in Table 8.

[0180] Table 8. Impurity detection results of samples in 0.1 mol / L hydrochloric acid solution containing 40% ethanol.

[0181]

[0182]

[0183] The experimental results show that, under the same time conditions, the levels of related substances detected in prescription 3 were significantly lower than those in the control sample. The 40% ethanol concentration represents baijiu (Chinese white liquor), indicating that when taking medication while consuming baijiu, the levels of related substances produced in the self-made sample will be significantly lower than in the control sample, thus improving product safety.

[0184] Formula 3 is more resistant to 20% ethanol than to 40% ethanol. Therefore, the related substances detected in Formula 3 in a 0.1 mol / L hydrochloric acid solution containing 20% ​​ethanol are lower than those detected in a 0.1 mol / L hydrochloric acid solution containing 40% ethanol.

[0185] The comparative sample showed poor resistance to both 20% and 40% ethanol. The pH of a 0.1 mol / L hydrochloric acid solution containing 20% ​​ethanol was lower than that containing 40% ethanol. Therefore, over the same time period, the comparative sample showed higher levels of related substances detected in the 0.1 mol / L hydrochloric acid solution containing 20% ​​ethanol compared to the 0.1 mol / L solution containing 40% ethanol. This indicates that duloxetine is more unstable in hydrochloric acid solutions containing 20% ​​ethanol, and the product's resistance to 20% ethanol dumping is more important than its resistance to 40% ethanol dumping.

[0186] Example 5

[0187] Formula 3 (External HP-50) is based on Formula 3, but with the inner enteric coating removed, leaving only the outer enteric coating.

[0188] Duloxetine enteric-coated microspheres obtained from formulations 3, 3 (external HP-50), 3-A, and 3-B were placed in a medium with a pH of 5.0, and the impurity content was examined. The impurity analysis method is as follows:

[0189] Take one capsule, use the basket dissolution apparatus at 100 rpm, place it in 500 mL of sodium phosphate (pH 5.0) buffer solution at 37 °C, and conduct the experiment. Take samples at 2 h and 6 h to detect relevant substances.

[0190] Octylsilane-bonded silica gel (Zorbax SB C8, 4.6 mm × 150 mm, 3.5 μm) was used as the packing material. Gradient elution was performed using phosphate buffer (3.4 g of potassium dihydrogen phosphate and 15 mL of triethylamine were dissolved in 1000 mL of water, and the pH was adjusted to 5.5 ± 0.05 with phosphoric acid)-methanol (60:40) as mobile phase A and methanol as mobile phase B. The flow rate was 1.5 mL per minute; the column temperature was 45 °C; the detection wavelength was 230 nm; and the injection volume was 80 μL.

[0191] The results are shown in the table below:

[0192] Table 9. Impurity content of enteric-coated microcapsules for each prescription.

[0193]

[0194] As shown in Table 9, under the double-layer enteric coating scheme (inner layer HPMCAS + outer layer HPMCP) of the present invention (Formulas 3, 3-A and 3-B), the content of duloxetine-related substances is very low, with total impurities less than 0.05% at 2 hours and 0.05% to 0.07% at 6 hours.

[0195] In contrast, the formulation using HP-50 as a single enteric coating (Formulation 3 (external HP-50)) produced significant impurities at both 2 and 6 hours. This is because HP-50 dissolves at pH 5.0, leading to drug release. Duloxetine hydrochloride is relatively unstable at pH 5.0 and degrades, producing impurities. Including an inner enteric coating can prevent premature drug release at pH 5.0, thereby reducing impurity formation and lowering the risk of toxic side effects in vivo. This highlights the necessity of using a two-layer enteric coating formulation when using HP-50 as the enteric material.

[0196] Example 6

[0197] A compound preparation containing duloxetine enteric-coated microspheres and an immediate-release portion of a γ-aminobutyric acid analogue;

[0198] The composition of the immediate-release fraction of γ-aminobutyric acid analogues is shown in Table 10:

[0199] Table 10 Composition of the immediate-release fraction of γ-aminobutyric acid analogues

[0200]

[0201]

[0202] Preparation process of prescriptions P1 to P4: Add γ-aminobutyric acid analogue, talc, corn starch, mannitol (if any) and microcrystalline cellulose (if any) to a laboratory hopper mixer and mix for 25 minutes at a mixing speed of 15 rpm. The mixing batch is 500g. The product is obtained after mixing.

[0203] Compound capsule formulations were obtained by filling gelatin hard shells with the immediate-release fraction of pregabalin prepared according to formulation P1 and duloxetine enteric-coated microspheres of different formulations, wherein the filling weight of duloxetine enteric-coated microspheres was reduced (the number of microspheres used remained the same), and each capsule contained 75 mg of pregabalin and 17.5 mg of duloxetine. Compound capsule formulations were also obtained by filling gelatin hard shells with the immediate-release fraction of gabapentin prepared according to formulation P3 and duloxetine enteric-coated microspheres, wherein the filling weight of duloxetine enteric-coated microspheres was reduced (the number of microspheres used remained the same), and each capsule contained 225 mg of gabapentin and 17.5 mg of duloxetine. Finally, compound capsule formulations were obtained by filling gelatin hard shells with the immediate-release fraction of merogabalin prepared according to formulation P4 and duloxetine enteric-coated microspheres, wherein the filling weight of duloxetine enteric-coated microspheres was reduced (the number of microspheres used remained the same), and each capsule contained 5 mg of merogabalin and 17.5 mg of duloxetine. As shown in the table below:

[0204] Table 11. Formulation of Compound Preparations

[0205]

[0206] The filling weight of duloxetine enteric-coated microspheres was adjusted so that the duloxetine enteric-coated microsphere fraction contained 30-40 mg of duloxetine. Then, the immediate-release fraction of pregabalin prepared according to formulation P2 and duloxetine enteric-coated microspheres of different formulations were filled into gelatin hard capsule shells to obtain a compound capsule formulation. Each capsule contained 150 mg of pregabalin and 30-40 mg of duloxetine, as shown in the table below:

[0207] Table 12. Formulation of Compound Preparations

[0208]

[0209] The dissolution curves of duloxetine in the compound capsules prepared according to formulations 6 and 8-14 (detected according to the method in Example 2) were similar to the dissolution behavior exhibited by the corresponding duloxetine enteric-coated microspheres in Example 2. This indicates that the addition of the immediate-release portion of the γ-aminobutyric acid analogue, and the adjustment of the ratio of γ-aminobutyric acid analogue to duloxetine, had no significant effect on the dissolution behavior of the duloxetine enteric-coated microspheres.

[0210] Referring to the method in Example 1, the release of duloxetine enteric-coated microspheres from compound prescriptions 6-9 and 12-18 in hydrochloric acid solutions containing 20% ​​ethanol and 40% ethanol was detected, and the dose-discharge of the duloxetine enteric-coated microspheres used in the above compound prescriptions was compared with that of the monotherapy, to investigate the effect of pregabalin on the dose-discharge experiment of duloxetine enteric-coated microspheres.

[0211] Table 13. Release rate (%) of duloxetine from the formulation in a medium containing 20% ​​ethanol.

[0212]

[0213]

[0214] Table 14. Release rate (%) of duloxetine from the formulation in a medium containing 40% ethanol.

[0215]

[0216]

[0217] As can be seen from Tables 13 and 14, the addition of the immediate-release portion of pregabalin reduces the ability to resist ethanol dumping.

[0218] In 20% ethanol medium, the two-hour anti-ethanol dumping ability of the compound preparations (formulas 6-9, 12-15, and 17) all met the standard. Formulation 16 (corresponding to a 9% increase in enteric coating weight) had a lower enteric coating weight gain; although its corresponding single-component formulation met the two-hour anti-ethanol dumping ability standard, the overall anti-ethanol dumping ability of the product deteriorated after the addition of the pregabalin immediate-release component, and therefore the anti-ethanol dumping ability of its compound preparation did not meet the standard. After adjusting the enteric coating weight gain, the anti-ethanol dumping ability of the compound preparation of formulation 15 (corresponding to a 12% increase in enteric coating weight gain) also met the standard. The compound preparation of Formula 17 showed a two-hour release of 29% duloxetine in 20% ethanol medium, which is close to the limit. This indicates that when CAP is used as the enteric coating, the compound preparation can meet the standard for resistance to 20% ethanol dumping when the weight gain of the enteric coating is less than 35%. However, if the weight gain of the enteric coating is further reduced, the two-hour release of duloxetine is very likely to exceed 30% (which does not meet the acceptable standard). Formula 18, since it does not contain an enteric coating, has virtually no resistance to ethanol dumping. Its two-hour release of both monotherapy and compound preparations is 94%.

[0219] In a 40% ethanol medium, compound formulation 7 (corresponding to a 60% increase in the weight of the enteric coating) also meets the ethanol dumping resistance standard. This indicates that the compound formulation with the dual enteric coating scheme of the present invention exhibits good ethanol dumping resistance at lower ethanol concentrations (20%), while at higher ethanol concentrations (40%), the weight gain of the enteric coating (HPMCP) needs to be optimized to achieve the desired ethanol dumping resistance.

[0220] The reason why the addition of pregabalin affects the anti-dose dumping effect of duloxetine microspheres is speculated to be that the increased ion concentration of the medium after pregabalin dissolves in hydrochloric acid containing ethanol leads to a faster dissolution rate of the enteric material. Gabapentin, melogabalin, and pregabalin have partially similar compound structures; therefore, it is speculated that gabapentin or melogabalin may also affect the anti-ethanol dumping ability of duloxetine enteric microspheres.

[0221] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A duloxetine enteric-coated microsphere, characterized in that... It contains a drug-coated core, an inner enteric coating, and an outer enteric coating. The enteric outer layer contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein HPMCP accounts for 55.6% to 90.9% of the mass of the enteric outer layer; The weight gain of the enteric outer layer is 9-200%.

2. The duloxetine enteric-coated microspheres according to claim 1, characterized in that: The HPMCP is soluble in media with a pH value above 5.

0.

3. The duloxetine enteric-coated microspheres according to claim 2, characterized in that: The HPMCP that dissolves in a medium with a pH value above 5.0 is model HP-50.

4. A duloxetine enteric-coated microsphere, characterized in that... It contains a drug-coated core, an inner enteric coating, and an outer enteric coating. The enteric outer layer contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein HPMCP accounts for 55.6% to 90.9% of the mass of the enteric outer layer; The HPMCP is soluble in media with a pH value above 5.5; The weight gain of the enteric outer layer is more than 9%.

5. The duloxetine enteric-coated microspheres according to claim 4, characterized in that: The HPMCP dissolved in a medium with a pH value above 5.5 is of model HP-55 or HP-55S.

6. The duloxetine enteric-coated microspheres according to any one of claims 1-5, characterized in that: The enteric inner layer contains enteric material, or may also contain one or more adjuvants; the enteric material accounts for 45.5% to 100% of the mass of the enteric inner layer; The enteric material is at least one of hydroxypropyl methylcellulose acetate succinate (HPMCAS), methacrylate-ethyl acrylate copolymer and its aqueous dispersion, methacrylate copolymer type A, or polyvinyl acetate phthalate. The weight gain of the enteric inner lining is 15-65%.

7. The duloxetine enteric-coated microspheres according to any one of claims 1-5, characterized in that: An isolation layer is provided between the drug-containing pill core and the enteric inner layer.

8. The duloxetine enteric-coated microcapsules according to any one of claims 1-5, characterized in that: The duloxetine enteric-coated microspheres have a protective layer outside the enteric coating layer.

9. A compound preparation, characterized in that: Contains duloxetine enteric-coated microspheres as described in any one of claims 1-8.

10. The compound preparation according to claim 9, characterized in that: The enteric outer layer of the duloxetine enteric microspheres has a weight gain of 12-200%.

11. The compound preparation according to claim 10, characterized in that: It contains duloxetine enteric-coated microspheres and a gamma-aminobutyric acid analogue.

12. The compound preparation according to claim 11, characterized in that: The γ-aminobutyric acid analogue is in an immediate-release form.

13. The compound preparation according to claim 11 or 12, characterized in that: The γ-aminobutyric acid analogues mentioned are pregabalin, gabapentin, melogabalin, or cligabalin benzylsulfonate.

14. The compound preparation according to claim 13, characterized in that: The mass ratio of pregabalin to duloxetine is (3.75–5.00):

1.

15. The compound preparation according to claim 14, characterized in that: The compound preparation contains 150 mg of pregabalin and 30-40 mg of duloxetine, or 75 mg of pregabalin and 15-20 mg of duloxetine.

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