TPN729 tablet and preparation method thereof

Abstract

The invention provides a TPN729 tablet and a preparation method thereof. The TPN729 tablet is prepared from TPN729MA, lactose, corn starch and an auxiliary agent according to the mass ratio of the TPN729MA to the lactose to the corn starch to the auxiliary agent being (0.6 to 0.7) to (1.19 to 1.39) to (0.01 to 0.05) to (0.50 to 0.65). Aiming at the general problem that no clear and effective preparation method for TPN729 tablets exists in the prior art, the invention provides a detailed preparation process for designing and proportioning raw materials and mixing and granulating in three times. The whole preparation method is simple, efficient, easy to produce and especially suitable for large-scale industrial mass production, and conforms to the concept of green development. Besides, the TPN729 tablet produced by the process disclosed by the invention has excellent stability and dissolution rate, shows higher dissolution rate under different conditions (pH 1.0, pH 4.5, pH 6.8 and water), and is stable in quality.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a TPN729 tablet and a preparation method thereof. Background Art

[0002] TPN729 (CAS 936951-20-1) is a novel and effective selective phosphodiesterase type 5 (PDE5) inhibitor with an IC50 of 2.28nM. It is 2.5 times more selective for PDE6 than sildenafil and 500 times more selective for PDE11 than tadalafil. TPN729 selectively inhibits PDE5 and blocks the degradation of cyclic guanosine monophosphate. It has the characteristics of high activity, high selectivity, clear efficacy, low toxicity and excellent pharmacokinetic properties. It is a promising PDE5 inhibitor that can provide fewer side effects and better compliance.

[0003] However, TPN729 tablets have not yet been marketed, and there is no public information in the prior art that provides specific drug preparation methods and conditions. In view of this, the present invention is proposed. Summary of the invention

[0004] The object of the present invention is to provide a TPN729 tablet and a preparation method thereof. In view of the common problem that there is no clear and effective preparation method for TPN729 tablets in the prior art, the present invention proposes a detailed raw material design, proportioning and a preparation process of mixing and granulating in three times. The overall preparation method is simple and efficient, easy to produce, and is particularly suitable for large-scale industrial mass production, which is in line with the concept of green development. In addition, the TPN729 tablets produced by the process of the present invention have excellent stability and solubility, and show high solubility and stable quality under different conditions (PH 1.0, PH 4.5, PH 6.8 and water).

[0005] To achieve the above object, the present invention provides a TPN729 tablet, which is composed of TPN729MA, lactose, corn starch and auxiliary agents in a mass ratio of (0.6-0.7):(1.19-1.39):(0.01-0.05):(0.50-0.65).

[0006] In a preferred embodiment, the particle size of the lactose is 100-200 mesh; the particle size of the corn starch is 80-120 mesh; and the particle size of the TPN729MA is below 20 microns.

[0007] In a preferred embodiment, the auxiliary agent includes one or more of a disintegrant, a diluent, a glidant and a lubricant.

[0008] In a preferred embodiment, the disintegrant comprises one or more of corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose.

[0009] In a preferred embodiment, the diluent includes one or more of mannitol, corn starch, microcrystalline cellulose and lactose.

[0010] In a preferred embodiment, the glidant includes one or more of silicon dioxide, stearic acid, talc and magnesium stearate.

[0011] In a preferred embodiment, the lubricant includes one or more of magnesium stearate, stearic acid and polyethylene glycol.

[0012] In a preferred embodiment, the auxiliary agent is composed of a disintegrant, a diluent, a glidant and a lubricant in a mass ratio of (5-6):(5-7):(1.0-2.0):(0.1-1.5).

[0013] Another object of the present invention is to provide a method for preparing TPN729 tablets, comprising the following steps: mixing TPN729 and a diluent, and granulating them for the first time with lactose, part of a disintegrant and a binder prepared from corn starch; after drying, mixing them for the second time with a glidant and the remaining disintegrant to form whole particles; and finally mixing them for the third time with a lubricant, and then tableting and coating them to obtain the tablets.

[0014] In the present invention, the disintegrant can make the TPN729 tablets break into small particles quickly in the gastrointestinal fluid. If added at one time, it is easy to cause uneven dispersion and excessive concentration of local disintegrants in the tablets. Therefore, the disintegrant is mixed and granulated twice in the present invention. The uniformly distributed disintegrant produced in this way can make the TPN729 tablets disintegrate into small particles more quickly in the gastrointestinal fluid, thereby improving the dissolution rate and degree of the drug. At the same time, an appropriate amount of disintegrant is conducive to the stable release of TPN729 tablets in the body, so the present invention limits the aforementioned ratio.

[0015] In the present invention, a second mixing and granulation is performed by adding an appropriate amount of a glidant, the purpose of which is to further improve the fluidity of the particles after the first granulation. At the same time, the uniformly distributed glidant can reduce the static electricity problem caused by friction between particles, avoid particle agglomeration, and improve the stability of TPN729 tablets.

[0016] In the present invention, a third mixing is performed by adding an appropriate amount of lubricant, the purpose of which is to increase the lubrication effect between particles and reduce the adhesion between particles during the mixing process, and to effectively reduce the friction during the tableting process. At the same time, a reasonable amount of lubricant can reduce problems such as uneven pressure during tableting, make the internal structure of the TPN729 tablet more uniform, reduce the internal stress changes of the drug during storage, and thus improve the stability of the drug.

[0017] In summary, the present invention greatly improves the stability and solubility of TPN729 tablets by adding auxiliary agents with different functions into TPN729MA three times for mixing and granulating, and then prepares TPN729 tablets with excellent quality in a simple and efficient way.

[0018] In a preferred embodiment, the method for preparing the TPN729 tablets specifically comprises the following steps:

[0019] Ingredients: Accurately weigh TPN729MA, corn starch, lactose and additives;

[0020] Prepare a mixture: mix TPN729MA and a diluent evenly to obtain a mixture;

[0021] Preparation of adhesive: Add 1.2-1.5 times the weight of purified water to corn starch, stir evenly until the corn starch becomes a paste, add boiling water while stirring to prepare a corn starch slurry with a mass concentration of 15%, and continue stirring until the corn starch is gelatinized to obtain an adhesive;

[0022] Fluidized bed granulation: preheat the fluidized bed first, then pour 60-70% of the mass of lactose, mixture and disintegrant into the fluidized bed in turn, and start spraying the binder when the material temperature reaches 35-45°C to granulate. After spraying, dry until the weight loss is less than 2.5%;

[0023] Dry granulation: add the remaining disintegrant, glidant and fluidized bed dried material in sequence into the sieve for dry granulation;

[0024] Total mixing: Add the dry granulated materials and lubricant into the mixer for mixing;

[0025] Tableting and coating: Tablet the mixed materials and coat them with a film coating premix prepared at a coating weight gain of 3%.

[0026] Further preferably, in the fluidized bed granulation step, the fluidized bed preheating specifically includes: setting the inlet air temperature to 55-65°C, the inlet air humidity to 6.0g-10.0g / kg, the fluidizing air volume to 900-1200m 3 / h, preheat the pot to a product temperature of not less than 45°C.

[0027] Further preferably, in the dry granulation step, the mesh is a 1.5 mm round hole mesh.

[0028] Further preferably, in the total mixing step, the mixing conditions include: a mixing speed of 10-12 rpm, and a mixing time of 15-20 min.

[0029] Further preferably, in the tableting and coating steps, the tableting conditions include: selecting a φ9.0 mm shallow concave punch, an average hardness of 4-8 kg, a weight difference of ±6.5%, and a brittleness of no more than 0.8%.

[0030] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0031] In the present invention, high-quality TPN729 tablets with good stability and high solubility are prepared by formula design and process optimization using conventional raw materials that are easy to purchase. The overall process is simple and efficient, safe and environmentally friendly, has no special requirements for equipment and energy consumption, and is easy to prepare for large-scale production. DETAILED DESCRIPTION

[0032] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in detail below in conjunction with specific implementation methods, but it should be understood that the protection scope of the present invention is not limited by the specific implementation methods.

[0033] The technical solution of the present application is described in detail below through specific embodiments:

[0034] If not otherwise specified, the technical means used in the present invention are conventional means well known to those skilled in the art, and the various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods. The reagents used in the present invention are analytically pure unless otherwise specified. In the embodiment of the present invention, the particle size of the lactose used is 100-200 mesh; the particle size of the corn starch used is 80-120 mesh; the particle size of the TPN729MA used is below 20 microns. In the embodiment of the present invention, the TPN729MA used is produced by Henan Tianfang Pharmaceutical Co., Ltd.; the coating premix used is 85G630038-CN coating agent produced by Shanghai Colorcon Coating Technology Co., Ltd.

[0035] In the present invention, parts by weight may be μg, mg, g, kg or other weight units known in the art, or multiples thereof, such as 1 / 10, 1 / 100, 10 times, 100 times or the like.

[0036] Example 1

[0037] Preparation of TPN729 tablets (specification 50 mg, hardness 5.0 kg)

[0038] 15.45 g of TPN729MA (production batch number S2307061) and 6 g of diluent (corn starch) were placed in a mixing hopper and mixed at a mixing speed of 10 rpm and a mixing time of 7 min to obtain a mixture.

[0039] Put 1g corn starch into a clean container, add 1.2 times of room temperature purified water, stir the corn starch into a paste, then add boiling purified water to prepare a starch slurry solution with a concentration of 15%, and stir quickly while adding until the corn starch is gelatinized and stirred evenly to obtain an adhesive.

[0040] Set the inlet air temperature to 60°C, the inlet air humidity to 6.0g / kg, and the fluidizing air volume to 1000m 3 / h, preheat the pot until the product temperature display value is not less than 45℃. Pour 30.68g lactose, the prepared mixture, and 3.5g disintegrant (low-substituted hydroxypropyl cellulose) into the fluidized bed in sequence, and start spraying the prepared adhesive when the material temperature reaches 35℃ for granulation. After spraying, dry until the weight loss is less than 2.5%. After drying, start discharging. Use a 1.5mm round hole screen to dry granulate 2g disintegrant (low-substituted hydroxypropyl cellulose), 1.5g flow aid (silicon dioxide) and the material dried in the fluidized bed in turn. Add the dry granulated material and 1g lubricant (magnesium stearate) into the mixer for mixing, the mixing speed is 10rpm, and the mixing time is 15min. Select a φ9.0mm shallow concave punch with an average hardness of 4kg-6kg and a weight difference of ±6.5%; the brittleness should be no more than 0.8%. The film coating premix was prepared according to a coating weight gain of 3% and the TPN729 tablets were obtained.

[0041] Example 2

[0042] Preparation of TPN729 tablets (specification 50 mg, hardness 7.0 kg)

[0043] 15.45 g of TPN729MA (production batch number S2308091) and 6 g of diluent (corn starch) were put into a mixing hopper and mixed at a mixing speed of 10 rpm and a mixing time of 7 min to obtain a mixture.

[0044] Put 1g corn starch into a clean container, add 1.2 times of room temperature purified water, stir the corn starch into a paste, then add boiling purified water to prepare a starch slurry solution with a concentration of 15%, and stir quickly while adding until the corn starch is gelatinized and stirred evenly to obtain an adhesive.

[0045] Set the inlet air temperature to 60°C, the inlet air humidity to 6.0g / kg, and the fluidizing air volume to 900m 3 / h, preheat the pot until the product temperature display value is not less than 45℃. Pour 30.68g lactose, the prepared mixture, and 3.5g disintegrant (low-substituted hydroxypropyl cellulose) into the fluidized bed in sequence, and start spraying the prepared adhesive when the material temperature reaches 35℃ for granulation. After spraying, dry until the weight loss is less than 2.5%. After drying, start discharging. Use a 1.5mm round hole screen to dry granulate 2g disintegrant (low-substituted hydroxypropyl cellulose), 1.5g flow aid (silicon dioxide) and the material dried in the fluidized bed in turn. Add the dry granulated material and 1g lubricant (magnesium stearate) into the mixer for mixing, the mixing speed is 10rpm, and the mixing time is 15min. Select a φ9.0mm shallow concave punch with an average hardness of 4kg-6kg and a weight difference of ±6.5%; the brittleness should be no more than 0.8%. The film coating premix was prepared according to a coating weight gain of 3% and the TPN729 tablets were obtained.

[0046] Example 3

[0047] Preparation of TPN729 tablets (specification 50 mg, hardness 6.0 kg)

[0048] 15.45 g of TPN729MA (production batch number S2310101) and 6 g of diluent (corn starch) were charged into a mixing hopper and mixed at a mixing speed of 10 rpm and a mixing time of 7 min to obtain a mixture.

[0049] Put 0.5g corn starch into a clean container, add 1.2 times of room temperature purified water, stir the corn starch into a paste, then add boiling purified water to prepare a starch slurry solution with a concentration of 15%, and stir quickly while adding until the corn starch is gelatinized and stirred evenly to obtain an adhesive.

[0050] Set the inlet air temperature to 60°C, the inlet air humidity to 6.0g / kg, and the fluidizing air volume to 1000m 3 / h, preheat the pot until the product temperature display value is not less than 45℃. Pour 30.68g lactose, the prepared mixture, and 3.5g disintegrant (low-substituted hydroxypropyl cellulose) into the fluidized bed in sequence, and start spraying the prepared adhesive when the material temperature reaches 35℃ for granulation. After spraying, dry until the weight loss is less than 2.5%. After drying, start discharging. Use a 1.5mm round hole screen to dry granulate 2g disintegrant (low-substituted hydroxypropyl cellulose), 1.3g flow aid (silicon dioxide) and the material dried in the fluidized bed in turn. Add the dry granulated material and 0.5g lubricant (magnesium stearate) into the mixer for mixing, the mixing speed is 10rpm, and the mixing time is 15min. Select a φ9.0mm shallow concave punch with an average hardness of 4kg-6kg and a weight difference of ±6.5%; the brittleness should be no more than 0.8%. The film coating premix was prepared according to a coating weight gain of 3% and the TPN729 tablets were obtained.

[0051] Application Examples

[0052] The TPN729 tablets prepared in Examples 1-3 of the present invention were subjected to in vitro release tests and in vivo bioavailability tests, and the results were as follows:

[0053] 1. Medium

[0054] pH 1.0 hydrochloric acid solution: Take 9 ml of hydrochloric acid, dilute it to 1000 ml with water, shake well, and degas.

[0055] pH 4.5 phosphate buffer: Take 6.8g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 1000ml, shake well, and degas.

[0056] pH 6.8 phosphate buffer: Take 250 ml of 0.2 mol / L potassium dihydrogen phosphate (take 27.22 g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 1000 ml) and mix it with 112.0 ml of 0.2 mol / L sodium hydroxide solution (take 8.00 g of sodium hydroxide, dissolve it in water and dilute it to 1000 ml), dilute it with water to 1000 ml, shake well, degas, and obtain.

[0057] Water: Take purified water and degas it.

[0058] 2. Dissolution Method

[0059] Medium volume: 900ml; Rotation speed: 100rpm; Temperature: 37±0.5℃; Sampling volume: 7ml; Rehydration volume: 7ml; Sampling time points: 5min, 10min, 15min, 20min, 30min

[0060] 3. Determination method

[0061] Test solution: Take 6 or 12 tablets of this product and put them into 6 or 12 dry rotating baskets respectively. Lower the rotating baskets into the dissolution cup. Operate according to the law. Take 7 ml of solution (add 7 ml of dissolution medium) at each time point, filter with a 0.45 μm filter membrane, and take the filtrate as the test solution.

[0062] IV. Results

[0063] 1. PH1.0 dissolution results, as shown in Table 1

[0064] Table 1: pH 1.0 dissolution results

[0065]

[0066]

[0067] 2. PH4.5 dissolution results, as shown in Table 2

[0068] Table 2: pH 4.5 dissolution results

[0069]

[0070] 3. PH6.8 dissolution results, as shown in Table 3

[0071] Table 3: pH 6.8 dissolution results

[0072]

[0073] 4. The dissolution results in water are shown in Table 4.

[0074] Table 4: Dissolution results in water

[0075]

[0076] V. Conclusion

[0077] It can be seen from the experimental results that the TPN729 tablets prepared in Examples 1-3 showed high solubility under different conditions (PH 1.0, PH 4.5, PH 6.8 and water), and the product quality was excellent, the stability was reliable, and the difference between batches was small, indicating that the TPN729 tablets prepared by the method of the present invention have excellent drug dissolution performance.

[0078] The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims

1. A TPN729 tablet, characterized in that: The TPN729 tablets are composed of TPN729MA, lactose, corn starch and adjuvants in a mass ratio of (0.6-0.7):(1.19-1.39):(0.01-0.05):(0.50-0.65).

2. The TPN729 tablet according to claim 1, characterized in that: The particle size of the lactose is 100-200 mesh; the particle size of the corn starch is 80-120 mesh; and the particle size of the TPN729MA is below 20 microns.

3. The TPN729 tablet according to claim 1, characterized in that: The auxiliary agent includes one or more of a disintegrant, a diluent, a glidant and a lubricant.

4. The TPN729 tablet according to claim 3, characterized in that: The disintegrant comprises one or more of corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose.

5. The TPN729 tablet according to claim 3, characterized in that: The diluent includes one or more of mannitol, corn starch, microcrystalline cellulose and lactose.

6. The TPN729 tablet according to claim 3, characterized in that: The glidant includes one or more of silicon dioxide, stearic acid, talc and magnesium stearate.

7. The TPN729 tablet according to claim 3, characterized in that: The lubricant includes one or more of magnesium stearate, stearic acid and polyethylene glycol.

8. The TPN729 tablet according to claim 3, characterized in that: The auxiliary agent is composed of a disintegrant, a diluent, a glidant and a lubricant in a mass ratio of (5-6): (5-7): (1.0-2.0): (0.1-1.5).

9. The method for preparing TPN729 tablets according to claim 3, characterized in that: The following steps are involved: TPN729 and the diluent are mixed, and the mixture is granulated for the first time with lactose, part of the disintegrant and a binder prepared from corn starch; after drying, the mixture is mixed with the glidant and the remaining disintegrant for the second time to form whole granules; finally, the mixture is mixed with the lubricant for the third time, and then tablets are pressed and coated.

10. The method for preparing TPN729 tablets according to claim 9, characterized in that: The specific steps include: Ingredients: Accurately weigh TPN729MA, corn starch, lactose and additives; Prepare a mixture: mix TPN729MA and a diluent evenly to obtain a mixture; Preparation of adhesive: Add 1.2-1.5 times the weight of purified water to corn starch, stir evenly until the corn starch becomes a paste, add boiling water while stirring to prepare a corn starch slurry with a mass concentration of 15%, and continue stirring until the corn starch is gelatinized to obtain an adhesive; Fluidized bed granulation: preheat the fluidized bed first, then pour 60-70% of the mass of lactose, mixture and disintegrant into the fluidized bed in turn, and start spraying the binder when the material temperature reaches 35-45°C to granulate. After spraying, dry until the weight loss is less than 2.5%; Dry granulation: add the remaining disintegrant, glidant and fluidized bed dried material in sequence into the sieve for dry granulation; Total mixing: Add the dry granulated materials and lubricant into the mixer for mixing; Tableting and coating: Tablet the mixed materials and coat them with a film coating premix prepared at a coating weight gain of 3%.

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