Dapoxetine tablet and preparation method thereof

Abstract

The invention discloses a dapoxetine tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The dapoxetine tablet comprises dapoxetine micelles, a filling agent, a composite disintegrating agent, a lubricant and a coating agent, dry granulation is adopted, and the stability problem caused by introduction of water is avoided. The dapoxetine hydrochloride is hermetically wrapped by the micelle (wrapped by the gastric-soluble coating), and the long-term stability of the drug is improved by matching with the antioxidant. Through the synergistic micellar effect of the composite disintegrating agent and the bicarbonate-doped coating, the prepared tablet has the technical effects of quick release and long-term stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a dapoxetine tablet and its preparation method. Background Technology

[0002] Dapoxetine is a selective serotonin reuptake inhibitor (SSRI) primarily used to treat premature ejaculation (PE) in adult men. Its mechanism of action is to prolong ejaculation latency by inhibiting the reuptake of serotonin by neurons.

[0003] The original brand-name dapoxetine drug, Priligy, has low water solubility in tablet form (belonging to BCS Class II drugs) and poor chemical stability. It is easily degraded by factors such as temperature, humidity, and light, leading to reduced efficacy or toxic side effects. Furthermore, literature indicates that dapoxetine is taken orally as needed, has a rapid onset of action, a short half-life, and reaches peak absorption within 1.5 hours. However, it needs to be taken 0.5-1 hour before sexual activity to maximize its effectiveness, indicating a slow drug release and a long waiting time for the drug to take effect, making it unsuitable for immediate treatment needs.

[0004] Existing technology CN103735525A discloses a dapoxetine tablet prepared by wet granulation. However, this method introduces water during preparation, which can easily lead to poor long-term stability of the drug. This is related to the presence of a piperidine ring and amide bond in the dapoxetine molecule, which are prone to hydrolysis or oxidation under humid and hot conditions. Existing formulations lack targeted stabilization designs, resulting in a significant decrease in drug content and excessive growth of related substances after long-term storage. Traditional wet granulation processes require the introduction of moisture and high-temperature drying, which may accelerate dapoxetine degradation. While direct compression avoids the influence of moisture, the poor flowability of the material can easily lead to large differences in tablet weight and uneven content.

[0005] Therefore, developing a dapoxetine tablet that improves both dissolution and stability through formulation optimization and process improvement is of great clinical significance. Summary of the Invention

[0006] In order to overcome the shortcomings of the existing technology, the present invention aims to provide a dapoxetine tablet and its preparation method, wherein the dapoxetine tablet has the technical effects of rapid release and long-term stability.

[0007] This invention is achieved through the following technical solution:

[0008] The present invention provides a dapoxetine tablet, which, by weight, comprises: 30 parts of dapoxetine micelles, 40-50 parts of filler, 5-10 parts of composite disintegrant, 0.3-5 parts of lubricant, and 1-6 parts of coating agent.

[0009] The dapoxetine micelles comprise 10 parts dapoxetine hydrochloride, 5-15 parts antioxidant, 1-5 parts nonionic surfactant, and 0.4-3 parts gastrointestinal coating.

[0010] Preferably, the antioxidant is α-tocopherol (vitamin E); the nonionic surfactant is vitamin E polyethylene glycol succinate (TPGS); and the gastrosoluble coating is selected from at least one of Opadry II, Opadry II HP, and Opadry AMB.

[0011] The method for preparing the dapoxetine micelles is as follows:

[0012] S1: Dissolve dapoxetine hydrochloride and antioxidant in ethanol, add nonionic surfactant, stir well to obtain solution 1.

[0013] S2: Add the above solution 1 to sterile deionized water, shear and stir at 500-2000 rpm for 1-10 min, homogenize in a high-pressure homogenizer for 2-4 cycles, freeze dry to obtain dried powder 1.

[0014] S3: Redissolve the dried powder 1 in the gastric-soluble coating solution to obtain solution 2. Use a bottom-spray fluidized bed (GlattGPCG1) and feed it into the fluidized bed inlet by a peristaltic pump, setting the atomization pressure to 0.2-0.5MPa;

[0015] Preheating: The inlet air temperature of the fluidized bed is 40-50℃ to preheat the air inside the bed. Turn on the induced draft fan to maintain the air velocity at 0.8-1.2m / s.

[0016] Drying and curing: After coating, maintain the inlet air temperature at 45-50℃, continue fluidized drying for 10-20 minutes, freeze-dry for 2-5 hours to remove residual moisture, and obtain dapoxetine micelles.

[0017] Preferably, the filler is selected from at least one of microcrystalline cellulose, anhydrous lactose, and pregelatinized starch.

[0018] Preferably, the composite disintegrant is a mixture of a polymeric disintegrant and a bicarbonate, wherein the mass ratio of the polymeric disintegrant to the bicarbonate is (5-8):(2-4); wherein the polymeric disintegrant is selected from at least one of pregelatinized starch, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch; and the bicarbonate is selected from at least one of sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate.

[0019] Preferably, the lubricant is selected from at least one of magnesium stearate, talc, and micronized silica gel.

[0020] Preferably, the coating agent is a mixture of opadry and bicarbonate, wherein the mass ratio of opadry to bicarbonate is (25-29):(1-5); the opadry is selected from at least one of opadry II, opadry II HP, and opadry AMB, and the bicarbonate is selected from at least one of sodium bicarbonate and potassium bicarbonate.

[0021] This invention provides a method for preparing dapoxetine tablets, the specific preparation steps of which include:

[0022] The filler and compound disintegrant are micronized and sieved (150-400 mesh). After mixing, dapoxetine micelles are added and mixed evenly. The mixture is then dry-granulated, sieved (50-120 mesh) to form granules, lubricant is added, and the mixture is mixed evenly. The mixture is then compressed into tablets and coated.

[0023] Beneficial effects

[0024] This invention provides a dapoxetine tablet and its preparation method, and the prepared tablet has the technical effects of rapid release and long-term stability.

[0025] The dapoxetine tablets of the present invention comprise dapoxetine micelles, fillers, composite disintegrants, lubricants, and coating agents, and are produced by dry granulation, thus avoiding stability problems caused by the introduction of moisture.

[0026] The active ingredient (dapoxetine hydrochloride) in the prepared dapoxetine tablets is encapsulated in micelles. These micelles contain antioxidants (α-tocopherol), which effectively improve the stability of the active ingredient. Furthermore, the micelles are coated with a gastrointestinal-soluble coating, which seals and preserves the active ingredient and enhances its stability. Additionally, after lyophilization, the micelles have a small particle size, and the gastrointestinal-soluble coating provides flexibility, making them suitable for dry granulation and tableting. Moreover, the active component in the micelles is dissolved into a molecular state. After tablet disintegration, the molecular state of the active component, along with the solubilizing and absorption-promoting effects of the micelles, can improve the drug's dissolution and absorption rates.

[0027] During the disintegration of tablets in the stomach, the presence of bicarbonate in the compound disintegrant allows for rapid gas production and fragmentation with gastric acid, increasing the contact area between the tablet and gastric juice. The combination of bicarbonate and polymeric disintegrants (such as low-substituted hydroxypropyl cellulose) accelerates disintegration and promotes drug dissolution. Secondly, the tablet coating is composed of bicarbonate and omeprazole. Adding an appropriate amount of bicarbonate can improve the dissolution efficiency of the coating without affecting its physical encapsulation effect. The reason bicarbonate improves the dissolution efficiency is that when the coating comes into contact with gastric juice, it dissolves and produces gas simultaneously. This gas production disrupts the integrity of the coating, thereby promoting dissolution and drug dissolution rate. The integrity of the physical encapsulation of the coating improves the stability of the tablet.

[0028] The dapoxetine tablets prepared by this invention improve the release and dissolution rate (complete disintegration within 3 minutes, cumulative dissolution rate greater than 90% within 5 minutes) and stability of the tablets through the synergistic effect of the components. Detailed Implementation

[0029] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. The described embodiments are only some preferred embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0030] Unless otherwise specified, the experimental methods used in the embodiments are conventional or common methods in the art, and the materials and reagents used are commercially available unless otherwise specified.

[0031] The raw materials used in the examples and comparative examples are described below:

[0032] Dapoxetine hydrochloride: purchased from Hubei Changao Pharmaceutical Co., Ltd.;

[0033] Vitamin E polyethylene glycol succinate (TPGS): purchased from Shanghai Yuanye Biotechnology Co., Ltd.;

[0034] α-Tocopherol (Vitamin E): Purchased from Hubei Chenxin Pharmaceutical Co., Ltd.;

[0035] Microcrystalline cellulose (PH102): purchased from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd.;

[0036] Anhydrous lactose (filler): purchased from Jiangsu Daodaoning Pharmaceutical Co., Ltd.;

[0037] Pregelatinized starch (filler, disintegrant): purchased from Qingdao Qingshan Bioengineering Co., Ltd.;

[0038] Opadry II: Purchased from Shanghai Carrefour Coating Technology Co., Ltd.;

[0039] Ethanol (anhydrous): Purchased from Hunan Jiudian Pharmaceutical Co., Ltd.

[0040] Medium-chain triglycerides: purchased from Shaanxi Didu Pharmaceutical & Chemical Co., Ltd.

[0041] Unless otherwise specified, all components and raw materials used in the embodiments and comparative examples of this invention are commercially available, and the same type of components and raw materials are used in each parallel experiment.

[0042] Preparation of dapoxetine micelles (self-made):

[0043] S1: Dissolve dapoxetine hydrochloride and α-tocopherol (antioxidant) in ethanol (to form a saturated ethanol solution of dapoxetine hydrochloride), add a nonionic surfactant, stir until homogeneous, and obtain solution 1.

[0044] S2: Add the above solution 1 to twice the volume of sterile deionized water, shear and stir at 1500 rpm for 5 min, homogenize at 12000 psi for 3 cycles using a high-pressure homogenizer (model: M-110L), and freeze dry for 5 h to obtain dried powder 1.

[0045] S3: Redissolve the dried powder 1 in the Opadry II coating solution, and use a bottom spray fluidized bed (model Glatt GPCG 1) to feed it into the fluidized bed inlet through a peristaltic pump, setting the atomization pressure to 0.3MPa;

[0046] Preheating: The inlet air temperature of the fluidized bed is 45℃ to preheat the air inside the bed. The induced draft fan is turned on to maintain the air velocity at 1m / s.

[0047] Drying and curing: After coating, maintain the inlet air temperature at 45℃, continue fluidized drying for 15 minutes, freeze-dry for 2 hours to remove residual moisture, and obtain dapoxetine micelles.

[0048] Table 1. Raw material ratio for the preparation of dapoxetine micelles (parts by weight)

[0049]

[0050]

[0051] Determination of micelle encapsulation efficiency and particle size

[0052] The encapsulation efficiency of the micelles was determined by high performance liquid chromatography (HPLC). 100 mg of the dried powder 1 from step S2 of the preparation (self-made) of dapoxetine micelles was reconstituted in 5 mL of deionized water. The solution was centrifuged using an ultrafiltration tube with a molecular weight cutoff of 1000 Da to remove free drug. The remaining micelles were reconstituted in 5 mL of methanol, ultrasonically demulsified at 40 W for 0.5 min, diluted 4 times with methanol, and injected. The concentration was recorded as T1. Another 100 mg of the dried powder was reconstituted in 5 mL of methanol, ultrasonically demulsified at 40 W for 0.5 min, diluted 4 times with methanol, and injected. The concentration was recorded as T2. The encapsulation efficiency (%) was calculated as T1 / T2 × 100%.

[0053] The particle size was measured using a Malvern particle size analyzer (Mastersizer 3000). The particle size of the dried powder 1 from step S2 was measured (particle size 1), and the particle size of the dried dapoxetine micelles from step S3 was measured (particle size 2).

[0054] Table 2 Encapsulation efficiency (%) and particle size (nm)

[0055]

[0056] As shown in Table 2, 1) In the preparation of dapoxetine micelles, using an organic phase (α-tocopherol or medium-chain triglycerides) is beneficial for effectively improving the drug encapsulation efficiency. This is because the organic phase and the drug are dissolved together in ethanol to form an oil phase. During the emulsification process with the aqueous phase, the surfactant (TPGS) can be rapidly distributed at the interface between the oil and aqueous phases to form micelles. The drug dissolved in ethanol has reduced contact time with the aqueous phase, thus ensuring a high encapsulation efficiency of the micelles. Dapoxetine micelle 1 has a higher encapsulation efficiency than control micelle 1, possibly because the lipophilic end of the surfactant TPGS is vitamin E. Compared with the interface between medium-chain triglycerides and the aqueous phase, the lipophilic end of TPGS is more soluble in α-tocopherol (i.e., vitamin E), thus forming micelles more quickly at the interface between the oil and aqueous phases. 2) In the preparation of dapoxetine micelles, the particle size measured by the dried powder 1 is significantly different from that measured by the dapoxetine micelles after drying in step S3. This is because the coating solution is sprayed into micron-sized droplets. As can be seen from particle size 2, the prepared dapoxetine micelles have a relatively small particle size, which is beneficial for the dissolution and release of the tablets.

[0057] Example 1

[0058] A method for preparing dapoxetine tablets, the specific preparation steps of which include:

[0059] The filler and compound disintegrant are micronized and sieved (200 mesh). After mixing, dapoxetine micelles (homemade) are added and mixed evenly. The mixture is then dry-granulated, sieved (80 mesh), and granulated to obtain tablet granules. Lubricant is added to the tablet granules, mixed evenly, and then tableted and coated.

[0060] Examples 2-4 and Comparative Examples 1-4

[0061] Examples 2-4 and Comparative Examples 1-4 were prepared using the same methods as Example 1, except that the materials or the amount of materials were adjusted.

[0062] Table 3. Material proportions (parts by weight) for Examples 1-4 and Comparative Examples 1-4

[0063]

[0064]

[0065] 1. Disintegration time test

[0066] This experiment was conducted according to the requirements of the disintegration time test method in the 2020 edition of the Chinese Pharmacopoeia. The time required for complete disintegration of a tablet in 0.1 mol / L hydrochloric acid solution was determined using the rotating basket method to simulate the gastric fluid environment. Disintegration was defined as the tablet completely passing through a sieve or leaving only softened granules without a hard core.

[0067] Table 4. Complete Disintegration Time Record (S)

[0068]

[0069] According to the data in Table 4: 1) The dapoxetine tablets prepared in Examples 1-4 can all achieve complete disintegration within 176 seconds, which is extremely fast (less than 3 minutes). This rapid disintegration characteristic meets the needs of immediate treatment with this drug. 2) Compared with Comparative Example 1, the complete disintegration time of the dapoxetine tablets prepared in Example 1 is comparable. This is because the composite disintegrant and coating agent used in Example 1 and Comparative Example 1 are the same. 3) Compared with Comparative Example 2, the disintegrants in the dapoxetine tablets prepared in Example 1 are different. Example 1 uses a composite disintegrant composed of sodium bicarbonate and low-substituted hydroxypropyl cellulose, while Comparative Example 2 only uses low-substituted hydroxypropyl cellulose as a disintegrant. Obviously, the composite disintegrant after adding sodium bicarbonate can significantly improve the disintegration efficiency, shorten the complete disintegration time, accelerate drug release, and thus promote rapid drug absorption. 4) Comparing Example 1 with Comparative Examples 3 and 4, it can be seen that the coating agent composed of sodium bicarbonate and Opadry can more quickly promote the dissolution of the dapoxetine tablet coating, thereby accelerating drug release.

[0070] 1. Dissolution and release test

[0071] This experiment was conducted according to the requirements of the 2020 edition of the Chinese Pharmacopoeia for the determination of dissolution and release rates. A paddle method was used, with a paddle diameter of 50 mm ± 1 mm, made of stainless steel (316L). The rotation speed was adjusted to 50 rpm, and the medium temperature was stably controlled at 37.0℃ ± 0.5℃. The dissolution vessel had a capacity of 1000 mL. The release medium was 0.1 mol / L hydrochloric acid solution (simulating the gastric juice environment). High-performance liquid chromatography (HPLC) was used to determine the dissolution rate (%).

[0072] Table 5 Cumulative Dissolution Rate (%)

[0073]

[0074]

[0075] According to the data in Table 5, 1) the cumulative dissolution rate of the dapoxetine tablets prepared in Examples 1-4 was higher than 90.5% within 5 minutes, indicating that the prepared dapoxetine tablets have the characteristic of efficient release in a short time. 2) The cumulative dissolution rate of the dapoxetine tablets prepared in Example 1 and Comparative Example 1 was comparable within the same time period. The dapoxetine tablets prepared in Comparative Example 2 required 13 minutes to achieve complete dissolution because the efficiency of simple microcrystalline cellulose as a disintegrant is slower than that of a composite disintegrant. The slower dissolution in Comparative Example 3 was due to the slower dissolution rate of the oophored coating compared to the oophored coating doped with sodium bicarbonate.

[0076] 2. Stability test

[0077] The dapoxetine tablets prepared in the examples and comparative examples were packaged in aluminum-plastic packaging for stability testing. Long-term stability test conditions were set as follows: temperature 30±1℃, RH 65±5%. Accelerated stability test conditions were set as follows: temperature 40±1℃, RH 75±5%. Related substances were investigated using high-performance liquid chromatography (HPLC), and the total amount (%) of related substances was recorded. The total amount of related substances was used as an indicator to evaluate the stability of the dapoxetine tablets. The appearance of the tablets was also recorded during the long-term stability test.

[0078] Table 6. Results of stability test (total amount of relevant substances %)

[0079]

[0080] Table 6 shows that: 1) The dapoxetine tablets prepared in Examples 1-4 exhibited excellent stability in both long-term and accelerated stability tests, with minimal increase in the total amount of related substances. 2) Compared to Example 1, Comparative Examples 1 and 2 showed decreased stability. In Comparative Example 1, the organic phase in the micelles was replaced by medium-chain triglycerides instead of α-tocopherol, while Comparative Example 2 contained no organic phase. This indicates that the organic phase is beneficial to the stability of dapoxetine hydrochloride, and α-tocopherol is more beneficial to its stability. 3) Compared to Example 1, the dapoxetine tablets prepared in Comparative Example 3 showed comparable stability, and the tablets all had normal appearance. This indicates that the coating agent formed by sodium bicarbonate and omeprazole in Example 1 had a similar physical encapsulation effect on the tablets as the pure omeprazole coating agent, effectively preventing the influence of air and moisture on tablet stability. Compared to Example 1, the dapoxetine tablets prepared in Comparative Example 4 showed decreased stability and cracked appearance. This may be because excessive sodium bicarbonate damaged the integrity of the coating, leading to moisture penetration and cracking.

[0081] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A dapoxetine tablet, comprising, by weight: [unclear text - possibly a typo, should be removed] 30 parts of poxetine micelles, 40-50 parts of filler, 5-10 parts of composite disintegrant, 0.3-5 parts of lubricant, and 1-6 parts of coating agent; The dapoxetine micelles comprise 10 parts dapoxetine hydrochloride, 5-15 parts antioxidant, 1-5 parts nonionic surfactant, and 0.4-3 parts gastrointestinal coating.

2. The dapoxetine tablets according to claim 1, characterized in that, The antioxidant is α-tocopherol; the nonionic surfactant is vitamin E polyethylene glycol succinate (TPGS); and the gastrosoluble coating is selected from at least one of Opadry II, Opadry II HP, and Opadry AMB.

3. The dapoxetine tablets according to claim 1, characterized in that, The method for preparing the dapoxetine micelles is as follows: S1: Dissolve dapoxetine hydrochloride and antioxidant in ethanol, add nonionic surfactant, stir well to obtain solution 1; S2: Add the above solution 1 to sterile deionized water, shear and stir at 500-2000 rpm for 1-10 min, homogenize in a high-pressure homogenizer for 2-4 cycles, freeze dry to obtain dried powder 1; S3: The dried powder 1 is reconstituted in the gastrointestinal coating solution to obtain solution 2. The solution is then atomized, fluidized, and freeze-dried using a bottom-spray fluidized bed to obtain dapoxetine micelles.

4. The dapoxetine tablets according to claim 1, characterized in that, The filler is selected from at least one of microcrystalline cellulose, anhydrous lactose, and pregelatinized starch.

5. The dapoxetine tablets according to claim 1, characterized in that, The composite disintegrant is a mixture of a polymeric disintegrant and a bicarbonate.

6. The dapoxetine tablets according to claim 5, characterized in that, The polymer disintegrant is selected from at least one of pregelatinized starch, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch; the bicarbonate is selected from at least one of sodium bicarbonate and potassium bicarbonate.

7. The dapoxetine tablets according to claim 1, characterized in that, The lubricant is selected from at least one of magnesium stearate, talc, and micronized silica gel.

8. The dapoxetine tablets according to claim 1, characterized in that, The coating agent is a mixture of omega-3 and bicarbonate, with a mass ratio of omega-3 to bicarbonate of (25-29):(1-5).

9. The dapoxetine tablets according to claim 8, characterized in that, The Opadry salt is selected from at least one of Opadry II, Opadry II HP, and Opadry AMB, and the bicarbonate is selected from at least one of sodium bicarbonate and potassium bicarbonate.

10. The method for preparing dapoxetine tablets according to any one of claims 1-9, characterized in that, The preparation steps include: The filler and compound disintegrant are micronized, sieved, mixed, and then dapoxetine micelles are added and mixed evenly. The mixture is then dry-granulated, sieved and granulated, lubricant is added, mixed evenly, tableted, and coated.

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