Dapoxetine hydrochloride tablet and preparation method thereof

Abstract

The invention relates to a dapoxetine hydrochloride tablet and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The dapoxetine hydrochloride injection comprises dapoxetine hydrochloride and auxiliary materials, wherein the auxiliary materials comprise L-aspartic acid and / or phospholipid auxiliary materials. The invention also provides a preparation method and application of the dapoxetine hydrochloride tablet.

Description

Technical Field

[0001] The present invention relates to a dapoxetine hydrochloride tablet and a preparation method thereof, belonging to the field of pharmaceutical preparations. Background Art

[0002] Dapoxetine is a short-acting selective serotonin reuptake inhibitor, initially developed as an antidepressant and later found to have significant efficacy in the treatment of male premature ejaculation (PE). In 2009, Johnson & Johnson announced that dapoxetine hydrochloride was approved for marketing in Finland and Norway under the trade name PRILIGY, becoming the first oral prescription drug approved for PE and used for on-demand treatment of PE in men aged 18 - 64 years.

[0003] In recent years, patent applications for dapoxetine tablets have mainly focused on formulation processes and compositions. Patent CN113143879A discloses a preparation method of a dapoxetine hydrochloride sustained-release tablet, which uses an insoluble skeleton material as a skeleton carrier to prepare dapoxetine sustained-release granules, then compresses the sustained-release granules into tablets, and finally coats them. The sustained-release tablets prepared by this method show stable release within 24 hours, without burst release and difficult dissolution phenomena, and the process is stable and meets the requirements.

[0004] Patent CN103735525A discloses a dapoxetine tablet and a preparation method thereof. It improves the disintegration performance and taste of the dapoxetine tablet by adding sodium dodecyl sulfate to the excipients.

[0005] Patent CN105232503A discloses a dapoxetine tablet, which prepares a solid dispersion of dapoxetine and dextrin to ensure the dissolution rate of different crystal forms of dapoxetine in this formulation and prevent the change in dissolution rate caused by different crystal forms.

[0006] In addition, patent CN106389360A discloses a direct compression tablet of dapoxetine hydrochloride and a preparation method thereof. Its excipients mainly consist of lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and magnesium stearate. Compared with the existing disclosed tablet processes, it has the advantages of simple operation, saving working hours and costs. Summary of the Invention

[0007] The first aspect of the present invention is to provide a dapoxetine hydrochloride tablet, which comprises dapoxetine hydrochloride and excipients, and the excipients include L-aspartic acid and / or phospholipid excipients.

[0008] In one embodiment, the weight ratio of the excipients to dapoxetine hydrochloride is 1 - 10:100; preferably, the weight ratio of the excipients to dapoxetine hydrochloride is 1.5 - 3:100.

[0009] In another embodiment, the excipients include L-aspartic acid and phospholipid excipients, and the weight ratio of L-aspartic acid to phospholipid excipients is 1-5:1, preferably 2:1.

[0010] In yet another embodiment, the phospholipid excipients are selected from one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol.

[0011] In yet another embodiment, the dapoxetine hydrochloride tablets further include 10 parts by weight of dapoxetine hydrochloride, 10-15 parts by weight of lactose monohydrate, 3-5 parts by weight of microcrystalline cellulose, 0.5-2 parts by weight of croscarmellose sodium, 0.5-1 part by weight of silicon dioxide, and 0.1-0.5 part by weight of magnesium stearate.

[0012] In a further embodiment, the dapoxetine hydrochloride tablets further include 10 parts by weight of dapoxetine hydrochloride, 13 parts by weight of lactose monohydrate, 4.4 parts by weight of microcrystalline cellulose, 1.2 parts by weight of croscarmellose sodium, 0.75 part by weight of silicon dioxide, and 0.36 part by weight of magnesium stearate.

[0013] In yet another embodiment, the dapoxetine hydrochloride tablets further include a coating, and the coating material is Opadry, and the coating weight gain is 4-6% (relative to the dapoxetine core tablets).

[0014] The second aspect of the present invention is to provide a method for preparing the dapoxetine hydrochloride tablets, which includes:

[0015] 1) Pass the dapoxetine hydrochloride through a 120-mesh sieve, and pass the lactose monohydrate and microcrystalline cellulose through a 60-mesh sieve;

[0016] 2) Sequentially add the weighed microcrystalline cellulose, croscarmellose sodium, silicon dioxide, dapoxetine hydrochloride, lactose monohydrate, and the excipients into a mixing hopper for mixing, then add the weighed magnesium stearate and mix again. After mixing, send it to a tableting machine and tablet at an average hardness of 5-8 kg to obtain the core tablets.

[0017] In one embodiment, the preparation method further includes a coating step, which includes: weighing 4-7% of the coating agent Opadry based on the weight of the core tablets, weighing 9 times the amount of purified water of the coating agent, pouring it into a stirring tank and stirring to obtain a coating solution, putting the uncoated core tablets into a coating machine, and coating with a weight gain of 4-6% to obtain the tablets.

[0018] The third aspect of the present invention provides the application of the dapoxetine hydrochloride tablets in the preparation of drugs for treating male premature ejaculation.

[0019] In the present invention, the dapoxetine hydrochloride is S-configuration dapoxetine hydrochloride.

[0020] According to the literature reports, the activity of dapoxetine is closely related to its configuration. The activity effect of S-configuration dapoxetine is 3.5 times that of R-configuration dapoxetine. Therefore, in the current dapoxetine hydrochloride tablets, S-configuration dapoxetine is used as the raw material ingredient for preparation.

[0021] The present invention firstly discovers that even though dapoxetine hydrochloride has high stability in component detection, its configuration changes. In the 6-month accelerated stability test, the content of R-enantiomer increases significantly, which will undoubtedly greatly reduce the efficacy of dapoxetine hydrochloride. Based on this discovery, the present invention further screens the excipient combinations for this problem and successfully obtains a dapoxetine tablet with high component stability and excellent configuration stability of dapoxetine hydrochloride. Specific Embodiments

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0023] Test Example 1 Study on the Configuration Stability Excipients of Dapoxetine Hydrochloride Tablets

[0024] 1) Preliminary Screening of Configuration-Stable Excipients

[0025] Basic Prescription: 100 g of dapoxetine hydrochloride (where the content of R-type enantiomer is less than 0.15%), 130 g of lactose monohydrate, 44 g of microcrystalline cellulose, 12 g of croscarmellose sodium, 7.5 g of silicon dioxide, 3.6 g of magnesium stearate.

[0026] To study the influence of excipients on the S-configuration stability of dapoxetine hydrochloride, the following excipients are added on the basis of the basic prescription (the addition amount is about 1% of the total amount of the basic prescription, 3 g):

[0027] Group 1: No addition

[0028] Group 2: L-Aspartic acid

[0029] Group 3: L-Tartaric acid

[0030] Group 4: Polyvinyl alcohol

[0031] Group 5: Butylated hydroxytoluene

[0032] Group 6: Phosphatidylcholine

[0033] Group 7: Mannitol

[0034] Group 8: Hydroxypropyl-β-cyclodextrin

[0035] Preparation method: Pass dapoxetine hydrochloride through a 120-mesh sieve, and pass lactose monohydrate and microcrystalline cellulose through a 60-mesh sieve; sequentially add the weighed microcrystalline cellulose, croscarmellose sodium, silicon dioxide, dapoxetine hydrochloride, lactose monohydrate and the above-mentioned groups of auxiliary materials into a mixing hopper for mixing, then add the weighed magnesium stearate and mix again. After mixing, send it to a tablet press for tableting (average hardness 5 - 8 kg) to obtain uncoated tablets.

[0036] Weigh Opadry (a film coating agent) accounting for 6.6% of the weight of the uncoated tablets, weigh purified water 9 times the amount of the film coating agent, pour it into a stirring tank and stir to obtain a film coating solution. Put the uncoated tablets into a coating machine and coat them with a weight gain of 5.5% to obtain the product.

[0037] Stability investigation: Place the tablet samples prepared in each group under the conditions of a temperature of 40 °C and a humidity of 75% for 6 months. According to the import registration standard of dapoxetine hydrochloride tablets: JX20150184, use the HPLC method to determine the main drug content of dapoxetine hydrochloride.

[0038] In addition, use an α1-acid glycoprotein-bonded silica column to detect the content of the R enantiomer of dapoxetine hydrochloride. The chromatographic conditions are as follows: Mobile phase: n-hexane - isopropanol - diethylamine (100:1:0.1); Detection wavelength: 293 nm, Flow rate: 0.5 ml / min.

[0039] The specific results are as follows:

[0040] 6 months Main drug content (%) R-type enantiomer (%) Group 1 99.78 4.39 Group 2 99.82 1.87 Group 3 98.14 2.14 Group 4 99.63 4.25 Group 5 99.85 3.94 Group 6 99.87 1.63 Group 7 99.69 4.47 Group 8 99.83 3.38

[0041] The R enantiomer (%) refers to the percentage content of the R enantiomer relative to the total amount of dapoxetine hydrochloride.

[0042] It can be seen from the above results that for the basic formulation (Group 1), the obtained tablets have good effects in the investigation of the main drug content and good stability of the main drug. However, in the further detection of the content of the specific configuration of dapoxetine hydrochloride in the main drug, the content of the less active R enantiomer has increased from less than 0.15% in the raw material drug to 4.39%. Given that the activity of the S enantiomer of dapoxetine hydrochloride is 3.5 times that of the R enantiomer, this configuration change will undoubtedly greatly affect the efficacy of the tablets, and even this effect is greater than the effect of the stability of the main drug. This is a major technical problem existing in the existing dapoxetine hydrochloride preparations discovered by the present invention.

[0043] In order to maintain the stability of the S configuration of dapoxetine hydrochloride, the present invention has explored from various excipient perspectives. As can be seen from Group 2 and Group 3, the addition of chiral excipients L-aspartic acid and L-tartaric acid to the tablets can significantly reduce the content of the R enantiomer. However, L-tartaric acid will cause a significant decrease in the content of the main drug. Polyvinyl alcohol in Group 4 can theoretically restrict molecular movement and reduce the chance of intermolecular rearrangement or inversion, but no obvious configuration-stabilizing effect was found for dapoxetine hydrochloride. The antioxidant tert-butylhydroxytoluene in Group 5 also did not show an obvious configuration-stabilizing effect. Obvious configuration-stabilizing effect was found for phosphatidylcholine in Group 6; while mannitol in Group 7 has the effect of reducing the free activity of water in the preparation, but no obvious effect on configuration stability was found. Hydroxypropyl-β-cyclodextrin in Group 8 can theoretically fix the configuration of the main drug and shield the main drug from external interference, but no obvious effect was found for the configuration stability of dapoxetine.

[0044] 2) Investigation on the combination of excipients

[0045] According to the preliminary screening results of the above various excipients, the present invention further studied the technical effects of the combination of two excipients with better effects, L-aspartic acid and phosphatidylcholine.

[0046] Test method: the same as above

[0047] The grouping is as follows:

[0048] Weight ratio L-Aspartic acid Phosphatidylcholine Group 1 1 2 Group 2 1 1 Group 3 2 1

[0049] The addition amount of each group remains unchanged, all being 3 g

[0050] The specific results are as follows:

[0051]

[0052]

[0053] As can be seen from the above results, the combination of the two excipients can significantly improve the effect of stabilizing the S configuration of dapoxetine and has no influence on the stability of dapoxetine in the tablets. With the increase in the content of L-aspartic acid in the combined excipients, this effect becomes more obvious.

[0054] 3) Investigation on the dosage of excipients

[0055] According to the above results, the present invention further investigated the optimal addition amount of L-aspartic acid and phosphatidylcholine under the condition of a weight ratio of 2:1.

[0056] The grouping is as follows:

[0057] Dosage added Group 1 1.5g Group 2 3g Group 3 6g

[0058] The specific results are as follows:

[0059] 6 months Main drug content (%) R-type enantiomer (%) Group 1 99.87 0.55 Group 2 99.84 0.46 Group 3 99.88 0.44

[0060] As can be seen from the above results, within the current range of additive amounts investigated, no obvious effects on the stability of the dapoxetine component and its configurational stability were found. However, among the general inspection indicators of tablets, there was an obvious downward trend in the friability and dissolution of the tablets obtained in Group 3, while the tablets obtained in Group 1 and Group 2 met the relevant regulations of the imported registration standard JX20150184 of dapoxetine in all indicators. Therefore, it is suggested that the dosage of the excipient combination of L-aspartic acid and phosphatidylcholine is more appropriate between 1.5 g and 3 g.

[0061] Preparation of dapoxetine hydrochloride tablets in Example 1

[0062] Prescription: Dapoxetine hydrochloride 100 g (where the content of R-enantiomer is less than 0.15%), lactose monohydrate 130 g, microcrystalline cellulose 44 g, croscarmellose sodium 12 g, silicon dioxide 7.5 g, magnesium stearate 3.6 g, L-aspartic acid 3 g.

[0063] Preparation method: Pass dapoxetine hydrochloride through a 120-mesh sieve, and pass lactose monohydrate and microcrystalline cellulose through a 60-mesh sieve; sequentially add the weighed microcrystalline cellulose, croscarmellose sodium, silicon dioxide, dapoxetine hydrochloride, lactose monohydrate and L-aspartic acid into the mixing hopper for mixing, then add the weighed magnesium stearate and mix again. After mixing, send it to a tableting machine for tableting (average hardness 5 - 8 kg) to obtain uncoated tablets.

[0064] Weigh Opadry, a coating agent, accounting for 6.6% of the weight of the tablets, and weigh 9 times the amount of purified water of the coating agent. Pour them into a stirring tank and stir to obtain a coating solution. Put the uncoated tablets into a coating machine and coat them with a weight gain of 5.5% to obtain the tablets.

[0065] Preparation of dapoxetine hydrochloride tablets in Example 2

[0066] Prescription: Dapoxetine hydrochloride 100 g (where the content of R-enantiomer is less than 0.15%), lactose monohydrate 130 g, microcrystalline cellulose 44 g, croscarmellose sodium 12 g, silicon dioxide 7.5 g, magnesium stearate 3.6 g, phosphatidylcholine 3 g.

[0067] Preparation method: Pass dapoxetine hydrochloride through a 120-mesh sieve, and pass lactose monohydrate and microcrystalline cellulose through a 60-mesh sieve; sequentially add the weighed microcrystalline cellulose, croscarmellose sodium, silicon dioxide, dapoxetine hydrochloride, lactose monohydrate and phosphatidylcholine into the mixing hopper for mixing, then add the weighed magnesium stearate and mix again. After mixing, send it to a tableting machine for tableting (average hardness 5 - 8 kg) to obtain uncoated tablets.

[0068] Weigh Opadry, a coating agent, accounting for 6.6% of the weight of the plain tablets, and weigh purified water nine times the amount of the coating agent. Pour them into a stirring tank and stir to obtain the coating solution. Put the uncoated plain tablets into a coating machine and perform coating with a weight gain of 5.5% to obtain the product.

[0069] Preparation of dapoxetine hydrochloride tablets in Example 3

[0070] Prescription: Dapoxetine Hydrochloride 100 g (where the content of R-enantiomer is less than 0.15%), Lactose Monohydrate 130 g, Microcrystalline Cellulose 44 g, Croscarmellose Sodium 12 g, Silicon Dioxide 7.5 g, Magnesium Stearate 3.6 g, L-Aspartic Acid 1 g, Phosphatidylcholine 0.5 g.

[0071] Preparation method: Pass Dapoxetine Hydrochloride through a 120-mesh sieve, and pass Lactose Monohydrate and Microcrystalline Cellulose through a 60-mesh sieve; sequentially add the weighed Microcrystalline Cellulose, Croscarmellose Sodium, Silicon Dioxide, Dapoxetine Hydrochloride, Lactose Monohydrate, L-Aspartic Acid, and Phosphatidylcholine into a mixing hopper for mixing, then add the weighed Magnesium Stearate and mix again. After mixing, send it to a tableting machine for tableting (average hardness 5 - 8 kg) to obtain uncoated plain tablets.

[0072] Weigh Opadry, a coating agent, accounting for 6.6% of the weight of the plain tablets, and weigh purified water nine times the amount of the coating agent. Pour them into a stirring tank and stir to obtain the coating solution. Put the uncoated plain tablets into a coating machine and perform coating with a weight gain of 5.5% to obtain the product.

[0073] Preparation of Dapoxetine Hydrochloride Tablets in Example 4

[0074] Prescription: Dapoxetine Hydrochloride 100 g (where the content of R-enantiomer is less than 0.15%), Lactose Monohydrate 130 g, Microcrystalline Cellulose 44 g, Croscarmellose Sodium 12 g, Silicon Dioxide 7.5 g, Magnesium Stearate 3.6 g, L-Aspartic Acid 2 g, Phosphatidylcholine 1 g.

[0075] Preparation method: Pass Dapoxetine Hydrochloride through a 120-mesh sieve, and pass Lactose Monohydrate and Microcrystalline Cellulose through a 60-mesh sieve; sequentially add the weighed Microcrystalline Cellulose, Croscarmellose Sodium, Silicon Dioxide, Dapoxetine Hydrochloride, Lactose Monohydrate, L-Aspartic Acid, and Phosphatidylcholine into a mixing hopper for mixing, then add the weighed Magnesium Stearate and mix again. After mixing, send it to a tableting machine for tableting (average hardness 5 - 8 kg) to obtain uncoated plain tablets.

[0076] Weigh Opadry, a coating agent, accounting for 6.6% of the weight of the plain tablets, and weigh purified water nine times the amount of the coating agent. Pour them into a stirring tank and stir to obtain the coating solution. Put the uncoated plain tablets into a coating machine and perform coating with a weight gain of 5.5% to obtain the product.

[0077] Preparation of Dapoxetine Hydrochloride Tablets in Example 5

[0078] Prescription: Dapoxetine Hydrochloride 100 g (content of R - enantiomer is less than 0.15%), Lactose Monohydrate 130 g, Microcrystalline Cellulose 44 g, Croscarmellose Sodium 12 g, Silicon Dioxide 7.5 g, Magnesium Stearate 3.6 g, L - Aspartic Acid 2 g, Phosphatidylcholine 1 g.

[0079] Preparation method: Pass Dapoxetine Hydrochloride through a 120 - mesh sieve, and pass Lactose Monohydrate and Microcrystalline Cellulose through a 60 - mesh sieve; sequentially add the weighed Microcrystalline Cellulose, Croscarmellose Sodium, Silicon Dioxide, Dapoxetine Hydrochloride, Lactose Monohydrate, L - Aspartic Acid, and Phosphatidylcholine into a mixing hopper for mixing, then add the weighed Magnesium Stearate and mix again. After mixing, send it to a tableting machine for tableting (average hardness 5 - 8 kg) to obtain the tablets.

[0080] The Dapoxetine Hydrochloride tablets obtained in Examples 1 - 5 were all detected to meet the relevant regulations of the import standard JX20150184. And after 6 months of accelerated stability test, the main drug content was not less than 99.80%, and the content of R - enantiomer did not exceed 0.6%. In particular, the uncoated tablets obtained in Example 5 also achieved similar effects, which indicates that in the future, coating treatment of dapoxetine may not be necessary under the excipient formulation of the present invention.

Claims

1. A dapoxetine hydrochloride tablet, comprising dapoxetine hydrochloride and excipients, wherein the excipients comprise L-aspartic acid and / or phospholipid excipients.

2. The dapoxetine hydrochloride tablet according to claim 1, characterized in that: The weight ratio of the auxiliary material to dapoxetine hydrochloride is 1-10:

100.

3. The dapoxetine hydrochloride tablet according to claim 2, characterized in that: The weight ratio of the auxiliary material to dapoxetine hydrochloride is 1.5-3:

100.

4. The dapoxetine hydrochloride tablet according to claim 1, characterized in that: The auxiliary materials include L-aspartic acid and phospholipid auxiliary materials, and the weight ratio of L-aspartic acid to phospholipid auxiliary materials is 1-5:

1.

5. The dapoxetine hydrochloride tablet according to claim 1, characterized in that: The phospholipid auxiliary material is selected from: one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine or phosphatidylinositol.

6. The dapoxetine hydrochloride tablet according to claim 1, characterized in that: The dapoxetine hydrochloride tablet further comprises 10 parts by weight of dapoxetine hydrochloride, 10-15 parts by weight of lactose monohydrate, 3-5 parts by weight of microcrystalline cellulose, 0.5-2 parts by weight of cross-linked sodium carboxymethyl cellulose, 0.5-1 parts by weight of silicon dioxide and 0.1-0.5 parts by weight of magnesium stearate.

7. The dapoxetine hydrochloride tablet according to claim 1, characterized in that: The dapoxetine hydrochloride tablets further include a coating, the coating material is Opadry, and the coating weight gain is 4-6% (relative to the dapoxetine plain tablets).

8. A method for preparing the dapoxetine hydrochloride tablet according to any one of claims 1 to 7, comprising: 1) Pass dapoxetine hydrochloride through a 120-mesh sieve, and pass lactose monohydrate and microcrystalline cellulose through a 60-mesh sieve; 2) The weighed microcrystalline cellulose, croscarmellose sodium, silicon dioxide, dapoxetine hydrochloride, lactose monohydrate and the excipients are sequentially added to a mixing hopper and mixed, and then the weighed magnesium stearate is added and mixed again. After mixing, the mixture is sent to a tablet press and tableted at an average hardness of 5-8 kg to obtain a plain tablet.

9. The method for preparing dapoxetine hydrochloride tablets according to claim 8, further comprising a coating step, comprising: Weigh 4-7% of the weight of the plain tablets as the coating agent Opadry, weigh 9 times the amount of purified water as the coating agent, pour into a mixing tank and stir to obtain a coating solution, put the uncoated plain tablets into a coating machine, and coat them at a weight gain of 4-6%.

10. Use of the dapoxetine hydrochloride tablet according to any one of claims 1 to 7 in the preparation of a drug for treating male premature ejaculation.

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