Tadalafil tablet and preparation method thereof

Abstract

The present application provides a tadalafil tablet and a preparation method thereof. The tablet is prepared by using a hot melt extrusion method with tadalafil and a carrier material in a specific ratio, polyethylene glycol 6000 as a plasticizer in a specific ratio, and fillers, disintegrants and lubricants. The tablet has a dissolution rate of more than 90% in 45 min, effectively improves the in-vivo absorption and bioavailability of the drug, and has no solvent residue in the production process, is simple to operate, and has an industrialized prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a tadalafil tablet and its preparation method. Background Technology

[0002] Tadalafil, developed by Eli Lilly, has the chemical name (6R-12aR)-6-(1,3-benzodioxano-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione. It is a phosphodiesterase type 5 (PDE-5) inhibitor, primarily used to treat erectile dysfunction (ED) and benign prostatic hyperplasia (BPH).

[0003] Tadalafil is classified as a Class IV drug (low solubility, high permeability). Due to its extremely low solubility in water and slow dissolution rate, its absorption and bioavailability after oral administration are severely limited. To achieve the effective concentration, large doses are required, increasing the likelihood of adverse reactions. Therefore, employing appropriate methods to increase the solubility and accelerate the dissolution rate of tadalafil is of great significance for improving its absorption and bioavailability in vivo.

[0004] Existing technologies often improve drug dissolution by micronizing the active pharmaceutical ingredient (API) and preparing it into a solid dispersion. Methods for preparing solid dispersions can be divided into two types: solvent drying and hot-melt extrusion. Regarding the solvent drying method, patent CN104188912A discloses dissolving tadalafil and a carrier material in anhydrous ethanol and obtaining a solid dispersion through rotary evaporation under reduced pressure at 50-90°C. However, preparing 1000 tablets of 20mg tadalafil solid dispersion requires 16L of anhydrous ethanol, indicating a large amount of organic solvent used. Patent CN105496963A also discloses a solvent-based process for preparing tadalafil solid dispersions, using a mixed solvent of ethanol and acetone. Although this reduces the amount of solvent used compared to patent CN104188912A, it still easily leads to the problem of residual organic solvent.

[0005] Patent CN105496965A discloses a process for preparing tadalafil solid dispersions using a hot-melt method. The process involves uniformly mixing tadalafil with a carrier, heating to melt, cooling, and then pulverizing to obtain the tadalafil solid dispersion. This method avoids the use of organic solvents, improving the safety of the formulation. However, the carrier used in this method is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, which is expensive and not conducive to commercial production. Furthermore, the dissolution rate of the obtained tadalafil solid dispersion does not reach the ideal value, with only 60% dissolving after 60 minutes, failing to meet the requirement for significantly improved dissolution rate of tadalafil tablets.

[0006] Therefore, developing a tadalafil tablet with a significantly improved dissolution rate compared to existing technologies, a simple preparation process, and greater suitability for commercial production is an unsolved technical problem in this field. Summary of the Invention

[0007] Based on this, the technical problem to be solved by the present invention is to improve the formulation of tadalafil tablets, and to provide a tadalafil tablet with significantly improved dissolution, which is more conducive to commercial production.

[0008] The technical solution of the present invention is as follows:

[0009] On one hand, the present invention provides a tadalafil tablet comprising the active ingredient tadalafil, the carrier copovidone, and a plasticizer, wherein the mass ratio of the active ingredient tadalafil to the carrier copovidone is 1:3 to 1:10.

[0010] Furthermore, in some embodiments, the mass ratio of the active ingredient tadalafil to the carrier copovidone is preferably 1:5 to 1:7.

[0011] In some embodiments, the plasticizer is selected from polyethylene glycol 6000 and stearic acid, preferably polyethylene glycol 6000.

[0012] In some embodiments, the amount of the carrier copovidone is 60 to 200 parts by weight, preferably 100 to 140 parts by weight, based on 20 parts by weight of tadalafil.

[0013] In some embodiments, the amount of plasticizer used is 5 to 20 parts by weight, preferably 6 to 20 parts by weight, based on 20 parts by weight of tadalafil.

[0014] In some embodiments, the tadalafil tablets also include pharmaceutically acceptable excipients, such as fillers, lubricants, and disintegrants.

[0015] Furthermore, in some embodiments, the filler is selected from one or more combinations of lactose, mannitol, microcrystalline cellulose, and corn starch, including but not limited to lactose, mannitol, microcrystalline cellulose, and corn starch.

[0016] Furthermore, in some embodiments, the lubricant is selected from one or more combinations of magnesium stearate, sodium fumarate stearate, colloidal silica, and talc, including but not limited to magnesium stearate, sodium fumarate stearate, colloidal silica, and talc.

[0017] Furthermore, in some embodiments, the disintegrant is selected from one or more combinations of sodium carboxymethyl starch, croscarmellose sodium, and low-substituted hydroxypropyl cellulose.

[0018] In some embodiments, the tadalafil tablet comprises the following components in parts by weight:

[0019] Tadalafil 20 parts by weight

[0020] Copolyvinylpyrrolidone 60-200 parts by weight,

[0021] Polyethylene glycol 6000: 5-20 parts by weight

[0022] 75-250 parts by weight of filler

[0023] Disintegrant 15-45 parts by weight

[0024] Lubricant 1 to 5 parts by weight.

[0025] Furthermore, in some embodiments, the tadalafil tablet comprises the following components in parts by weight:

[0026] Tadalafil 20 parts by weight

[0027] Copolyvinylpyrrolidone 60-200 parts by weight,

[0028] Polyethylene glycol 6000: 6-20 parts by weight

[0029] Lactose 25-120 parts by weight

[0030] 50-150 parts by weight of microcrystalline cellulose

[0031] 15-45 parts by weight of croscarmellose sodium cellulose

[0032] 1-5 parts by weight of magnesium stearate.

[0033] On the other hand, the present invention provides a method for preparing tadalafil tablets, comprising the following steps:

[0034] (1) Weighing ingredients: Weigh the prescribed amounts of tadalafil, carrier, and plasticizer;

[0035] (2) Premix 1: Premix tadalafil, carrier and plasticizer;

[0036] (3) Hot melt extrusion: Set the hot melt parameters and conduct hot melt extrusion tests;

[0037] (4) Crushing: Crushing the solid dispersion collected by hot melt extrusion;

[0038] (5) Mixing: Calculate the amount of added materials based on the yield, and weigh the filler, lubricant and disintegrant; after mixing evenly, compress into tablets;

[0039] (6) Tableting: Adjust the tablet weight and hardness, and then compress the tablets.

[0040] In some embodiments, in step (3), the hot melt extrusion temperature is set to 140-200℃ and the twin screw speed is 200-500rpm.

[0041] In another aspect, the present invention provides the use of tadalafil tablets in the preparation of drugs for treating erectile dysfunction and benign prostatic hyperplasia.

[0042] Compared with the prior art, the advantages of this invention are as follows: By limiting the ratio of tadalafil and covitamin to 1:3 to 1:10 and adding a specific proportion of polyethylene glycol 6000 as a plasticizer, this invention significantly improves the dissolution rate of tadalafil tablets, reaching over 90% within 45 minutes, thus greatly improving the bioavailability and in vivo absorption of tadalafil tablets. At the same time, this invention adopts a hot melt extrusion process, avoiding the solvent residue problem in the traditional solvent drying method, and the cost of formulation excipients (such as covitamin) is lower, the process operation is simpler, and it is more conducive to commercial production. Detailed Implementation

[0043] The technical solution of the present invention will be further described below with reference to the embodiments. However, the scope of protection of the present invention includes, but is not limited to, these embodiments. Any changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention. Specific techniques or conditions not specified in the examples shall be performed in accordance with the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products in the field obtained through commercial purchase.

[0044] The sources of some of the materials used in the following embodiments are shown in Table 1 below.

[0045] Table 1. Material Sources

[0046]

[0047] Example 1

[0048] One type of tadalafil tablet has the following specific ingredients, as shown in Table 2.

[0049] Table 2: Prescription for Tadalafil Tablets

[0050]

[0051] The preparation process includes the following steps:

[0052] (1) Weighing the ingredients: Weigh the prescribed amounts of tadalafil, copovidone, and polyethylene glycol 6000;

[0053] (2) Premix 1: Tadalafil, copovidone, and polyethylene glycol 6000 are premixed;

[0054] (3) Hot melt extrusion: Set the hot melt temperature to 140-200℃ and the twin screw speed to 200-500rpm, and conduct hot melt extrusion tests;

[0055] (4) Crushing: Crushing the solid dispersion collected by hot melt extrusion;

[0056] (5) Mixing: Calculate the amount of added materials based on the yield, and weigh lactose, microcrystalline cellulose, sodium croscarmellose and magnesium stearate; after mixing evenly, compress into tablets;

[0057] (6) Tableting: Adjust the tablet weight and hardness, and then compress the tablets.

[0058] Examples 2-6

[0059] Based on Example 1, Examples 2-6 investigated the effect of changing the mass ratio of tadalafil to copovidone on the dissolution of tadalafil tablets, as shown in Table 3, and tadalafil tablets were prepared according to the method of Example 1.

[0060] Table 3: Prescriptions for Tadalafil Tablets

[0061]

[0062] Comparative Example 1

[0063] Based on Example 1, the effect of not using plasticizers on the dissolution of tadalafil tablets was investigated, as shown in Table 4.

[0064] Table 4: Prescription for Tadalafil Tablets

[0065]

[0066] The preparation process of Comparative Example 1 includes the following steps:

[0067] (1) Weighing ingredients: Weigh the prescribed amounts of tadalafil and copovidone;

[0068] (2) Premix 1: Tadalafil and copovidone are premixed;

[0069] (3) Hot melt extrusion: Set the hot melt temperature to 140-200℃ and the twin screw speed to 200-500rpm, and conduct hot melt extrusion tests;

[0070] (4) Crushing: Crushing the solid dispersion collected by hot melt extrusion;

[0071] (5) Mixing: Calculate the amount of added materials based on the yield, and weigh lactose, microcrystalline cellulose, sodium croscarmellose and magnesium stearate. Mix them evenly and then compress them into tablets.

[0072] (6) Tableting: Adjust the tablet weight and hardness, and then compress the tablets.

[0073] Comparative Example 2

[0074] Based on Example 1, the effect of changing the type of plasticizer on the dissolution of tadalafil tablets was investigated, as shown in Table 5.

[0075] Table 5. Prescriptions for Tadalafil Tablets

[0076]

[0077] The preparation process of Comparative Example 2 includes the following steps:

[0078] (1) Weighing ingredients: Weigh the prescribed amounts of tadalafil, copovidone, and stearic acid;

[0079] (2) Premix 1: Tadalafil, copovidone, and stearic acid are premixed;

[0080] (3) Hot melt extrusion: Set the hot melt temperature to 140-200℃ and the twin screw speed to 200-500rpm, and conduct hot melt extrusion tests;

[0081] (4) Crushing: Crushing the solid dispersion collected by hot melt extrusion;

[0082] (5) Mixing: Calculate the amount of added materials based on the yield, weigh lactose, microcrystalline cellulose, sodium croscarmellose and magnesium stearate, mix them evenly, and then compress them into tablets.

[0083] (6) Tableting: Adjust the tablet weight and hardness, and then compress the tablets.

[0084] Test case

[0085] Dissolution of tadalafil tablets in Examples 1-6 and Comparative Examples 1-2 was determined. The dissolution was performed according to the second method (paddle method; 50 rpm) of General Chapter 0931 in Part IV of the Chinese Pharmacopoeia 2025. The dissolution medium was 900 mL of phosphate buffer solution with a pH of 6.8. Samples were taken at 0, 5, 10, 15, 20, 30 and 45 min. The dissolution results are shown in Table 6.

[0086] Table 6. Dissolution test results

[0087]

[0088] The " / " indicates that the hot melt material does not form a solid shape because the matrix ratio is too small.

[0089] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, are covered within the scope of protection of the present invention.

Claims

1. A tadalafil tablet, characterized in that, The tadalafil tablets comprise the active ingredient tadalafil, the carrier copovidone, and a plasticizer, wherein the mass ratio of tadalafil to copovidone is 1:3 to 1:

10.

2. The tadalafil tablet according to claim 1, characterized in that, The mass ratio of tadalafil to copovidone is 1:5 to 1:

7.

3. The tadalafil tablet according to claim 1, characterized in that, The plasticizer is selected from either polyethylene glycol 6000 or stearic acid, preferably polyethylene glycol 6000.

4. The tadalafil tablet according to any one of claims 1 or 2, characterized in that, Based on 20 parts by weight of tadalafil, the amount of copovidone used is 60 to 200 parts by weight, preferably 100 to 140 parts by weight.

5. The tadalafil tablet according to any one of claims 1 or 3, characterized in that, Based on 20 parts by weight of tadalafil, the amount of plasticizer used is 5 to 20 parts by weight, preferably 6 to 20 parts by weight.

6. The tadalafil tablet according to claim 1, characterized in that, The tadalafil tablets also include pharmaceutically acceptable excipients, which are one or more of fillers, disintegrants, and lubricants.

7. The tadalafil tablet according to claim 6, characterized in that, The filler is selected from one or more combinations of lactose, mannitol, microcrystalline cellulose, and corn starch, including but not limited to lactose, mannitol, microcrystalline cellulose, and corn starch; the lubricant is selected from one or more combinations of magnesium stearate, sodium fumarate stearate, colloidal silica, and talc, including but not limited to magnesium stearate, sodium fumarate stearate, colloidal silica, and talc; the disintegrant is selected from one or more combinations of sodium carboxymethyl starch, sodium croscarmellose, and low-substituted hydroxypropyl cellulose, including but not limited to sodium carboxymethyl starch, sodium croscarmellose, and low-substituted hydroxypropyl cellulose.

8. The tadalafil tablet according to claim 1, characterized in that, The tadalafil tablets comprise the following components in parts by weight: Tadalafil 20 parts by weight 60-200 parts by weight of copolyvinylpyrrolidone Polyethylene glycol 6000: 5-20 parts by weight 75-250 parts by weight of filler Disintegrant 15-45 parts by weight Lubricant 1 to 5 parts by weight.

9. The tadalafil tablet according to claim 8, characterized in that, It is made from the following components in parts by weight: Tadalafil 20 parts by weight 60-200 parts by weight of copolyvinylpyrrolidone Polyethylene glycol 6000: 6-20 parts by weight Lactose 25-120 parts by weight 50-150 parts by weight of microcrystalline cellulose 15-45 parts by weight of croscarmellose sodium cellulose 1 to 5 parts by weight of magnesium stearate.

10. A method for preparing tadalafil tablets as described in any one of claims 1 to 9, characterized in that, Includes the following steps: (1) Weighing the ingredients: Weigh tadalafil, carrier copovidone and plasticizer according to the prescription amount; (2) Premixing: Mix the weighed tadalafil, copovidone, and plasticizer evenly to obtain the premixed material; (3) Hot melt extrusion: The premixed material is hot melt extruded to prepare a solid dispersion; (4) Crushing: The solid dispersion obtained by hot melt extrusion is crushed; (5) Overall mixing: Based on the yield of solid dispersion, calculate and weigh the filler, disintegrant, and lubricant, and mix them evenly with the pulverized solid dispersion; (6) Tableting: Adjust the tablet weight and hardness, and compress the tablet to obtain the tadalafil tablet.

11. The preparation method according to claim 10, characterized in that, In step (3), the hot melt extrusion temperature is 140-200℃ and the twin screw speed is 200-500rpm.

12. The use of the tadalafil tablet according to any one of claims 1 to 9 in the preparation of a medicament for treating erectile dysfunction and / or benign prostatic hyperplasia in men.

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