A sildenafil citrate orally disintegrating tablet and preparation method thereof

Abstract

The present invention provides a sildenafil citrate orodisintegrating tablet and a preparation method thereof, and belongs to the field of medical technology. Icariin, tribulus saponin and sildenafil citrate are mixed to prepare liposomes, added to a hydrogel prepared from modified maltodextrin and earthworm protein, mixed evenly, dried, ground to obtain a mixed powder, added to an auxiliary material, and tableted to obtain a sildenafil citrate orodisintegrating tablet. The sildenafil citrate orodisintegrating tablet prepared by the present invention adopts a direct tableting method, has a simple preparation method, does not require coating, has good palatability, good stability, good therapeutic effect, has a good sustained-release effect, prolongs the drug effect time, improves the patient's compliance, and has broad application prospects.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a sildenafil citrate orodisintegrating tablet and a preparation method thereof. Background Art

[0002] Sildenafil citrate is a drug for treating male erectile dysfunction. Its main function is to dilate blood vessels, improve target organ blood flow, and reduce pulmonary hypertension. It can improve male erectile dysfunction and is used for drug treatment of patients with pulmonary hypertension. It is currently the first choice for clinical treatment of various types of erectile dysfunction. The recommended dose is 50 mg and the daily dose is 25-100 mg. Sildenafil citrate has strong hygroscopicity, and its stability decreases significantly when moisture increases during long-term storage. In the prior art, the active ingredient is isolated from the air by a film coating material or a biological product is added to increase the stability of the preparation. There are disadvantages such as complex preparation process, unknown safety of excipients, and inhibition of tablet release.

[0003] Orally disintegrating tablets do not require water or only a small amount of water, and do not require chewing. The tablets are placed on the tongue and quickly disintegrate when they come into contact with saliva, and reflexively enter the body with the swallowing action. They are characterized by rapid absorption, high bioavailability, little intestinal residue, and easy to take.

[0004] Chinese patent document CN104706606A discloses a sildenafil citrate tablet and a preparation method thereof, wherein sildenafil citrate is dissolved in water, and methylcellulose, a highly water-soluble film material, is added, stirred to dissolve, and then slowly dried to coat the surface of sildenafil citrate with methylcellulose to form an isolation film. The preparation process of this method is relatively complicated, and the film material isolates sildenafil from the air, which reduces the dissolution performance of the preparation to a certain extent.

[0005] Chinese patent document CN1586483A discloses an orally disintegrating tablet of sildenafil citrate, which adopts a powder coating process, has a complicated preparation process, and does not solve the problems of bad taste, strong sandy feeling, poor patient compliance, low hardness, easy breakage, etc. of the orally disintegrating tablet. Summary of the invention

[0006] The purpose of the present invention is to provide a sildenafil citrate orodisintegrating tablet and a preparation method thereof, which adopts a direct tabletting method, has a simple preparation method, does not require coating, has good palatability, good stability, good therapeutic effect, has a good sustained-release effect, prolongs the drug effect time, improves the patient's compliance, and has broad application prospects.

[0007] The technical solution of the present invention is achieved in this way:

[0008] The invention provides a method for preparing sildenafil citrate orodisintegrating tablets. Icariin, tribulus saponin and sildenafil citrate are mixed to prepare liposomes, which are added into a hydrogel prepared from modified maltodextrin and earthworm protein, mixed evenly, dried, ground to obtain a mixed powder, added into auxiliary materials, and tableted to obtain sildenafil citrate orodisintegrating tablets.

[0009] As a further improvement of the present invention, the following steps are included:

[0010] S1. adding icariin, tribulus saponin, sildenafil citrate, glyceryl monostearate, oleic acid, and soybean lecithin to ethanol, heating and ultrasonic treatment, removing the solvent by rotary evaporation, adding a surfactant solution, hydration reaction, ultrasonic dispersion treatment, microporous membrane filtration, and freeze drying to obtain liposomes;

[0011] S2. Add maltodextrin to water, add tannic acid and a catalyst, heat and stir to react, and freeze-dry to obtain modified maltodextrin;

[0012] S3. adding modified maltodextrin and earthworm protein to water and subjecting the mixture to repeated freeze-thaw treatment to form a hydrogel;

[0013] S4. Adding the liposomes to the hydrogel, stirring and mixing, freeze-drying, grinding and sieving to obtain a mixed powder;

[0014] S5. Mix microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, sucralose, indigo aluminum lake, colloidal silicon dioxide, and flavor, grind and sieve, add mixed powder, stir and mix, add magnesium stearate, stir and mix evenly, and tablet to prepare sildenafil citrate orodisintegrating tablets.

[0015] As a further improvement of the present invention, the mass ratio of icariin, tribulus saponin, sildenafil citrate, glyceryl monostearate, oleic acid, and soybean lecithin in step S1 is 3-5:2-4:7-10:4-6:1-3:40-60, the surfactant solution is an aqueous solution containing 1-1.5wt% of Tween-80 and 0.8-1.2wt% of Span-80, the temperature of the heating ultrasonic treatment is 35-45°C, the time is 3-5min, the time of the hydration reaction is 15-25min, the power of the ultrasonic dispersion treatment is 1000-1200W, the time is 1-2min, and the pore size of the microporous filter membrane is 0.45μm.

[0016] As a further improvement of the present invention, the mass ratio of maltodextrin, tannic acid and catalyst in step S2 is 10:3-5:0.5-1, the catalyst is a Tris-HCl solution with a pH of 8.5-9.5, the temperature of the heating and stirring reaction is 40-50° C., and the time is 1-3 h.

[0017] As a further improvement of the present invention, the mass ratio of the modified maltodextrin and the earthworm protein in step S3 is 15-20:12-15, and the method of repeated freeze-thaw treatment is to reduce the mixed solution to -25 to -30°C for 20-40 minutes, take it out and dissolve it at room temperature for 1-2 hours, and repeat the operation 2-3 times.

[0018] As a further improvement of the present invention, the mass ratio of the liposome to the hydrogel in step S4 is 4-6:17-20, and the mesh number of the sieve is 150-200 meshes.

[0019] As a further improvement of the present invention, the mass ratio of microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, sucralose, indigo aluminum lake, colloidal silicon dioxide, flavor, mixed powder, and magnesium stearate in step S5 is 2-3:2-3:0.3-0.7:0.08-0.12:0.3-0.4:1-2:10-15:0.5-1.5, and the flavor is a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, and the mass ratio is 1-2:0.8-1.2:1-1.5.

[0020] As a further improvement of the present invention, the present invention specifically comprises the following steps:

[0021] S1. 3-5 parts by weight of icariin, 2-4 parts by weight of tribulus saponin, 7-10 parts by weight of sildenafil citrate, 4-6 parts by weight of glyceryl monostearate, 1-3 parts by weight of oleic acid, and 40-60 parts by weight of soybean lecithin are added to 500 parts by weight of ethanol, heated to 35-45° C., ultrasonically treated for 3-5 min, and the solvent is removed by rotary evaporation, and 500 parts by weight of an aqueous solution containing 1-1.5wt% of Tween-80 and 0.8-1.2wt% of Span-80 are added, hydrated for 15-25 min, ultrasonically dispersed at 1000-1200W for 1-2 min, filtered with a 0.45μm microporous membrane, and freeze-dried to obtain liposomes;

[0022] S2. Add 10 parts by weight of maltodextrin to 100 parts by weight of water, add 3-5 parts by weight of tannic acid and 0.5-1 parts by weight of a catalyst, heat to 40-50 ° C, stir the reaction for 1-3h, and freeze-dry to obtain modified maltodextrin;

[0023] The catalyst is a Tris-HCl solution with a pH of 8.5-9.5;

[0024] S3. 15-20 parts by weight of modified maltodextrin and 12-15 parts by weight of earthworm protein were added to 100 parts by weight of water, the mixture was cooled to -25 to -30 ° C for 20-40 min, removed and dissolved at room temperature for 1-2 h, and the operation was repeated 2-3 times to form a hydrogel;

[0025] S4. 4-6 parts by weight of liposomes are added to 17-20 parts by weight of hydrogel, stirred and mixed, freeze-dried, ground and sieved to obtain a mixed powder;

[0026] S5. 2-3 parts by weight of microcrystalline cellulose, 2-3 parts by weight of cross-linked sodium carboxymethyl cellulose, 0.3-0.7 parts by weight of sucralose, 0.08-0.12 parts by weight of indigo aluminum lake, 0.3-0.4 parts by weight of colloidal silicon dioxide, and 1-2 parts by weight of flavor are stirred and mixed, ground and sieved, 10-15 parts by weight of mixed powder are added, stirred and mixed, 0.5-1.5 parts by weight of magnesium stearate are added, stirred and mixed evenly, and tableted to obtain sildenafil citrate orodisintegrating tablets.

[0027] The present invention further protects a sildenafil citrate orally disintegrating tablet prepared by the above-mentioned preparation method.

[0028] The present invention further protects the use of the above-mentioned sildenafil citrate orodisintegrating tablets in the preparation of a drug for improving and treating male penile erectile dysfunction.

[0029] The present invention has the following beneficial effects:

[0030] Icariin is derived from Epimedium, which has the effects of nourishing the liver and kidney, strengthening the bones and muscles, and removing rheumatism. The mechanism of action of icariin in treating male erectile dysfunction is mainly concentrated in the nitric oxide-cyclic guanosine monophosphate-phosphodiesterase 5 pathway, which plays a protective role in vascular endothelial function, thus having a good therapeutic effect. Icariin has good water solubility and high bioavailability, but it is very hygroscopic, which reduces its stability and efficacy.

[0031] Tribulus saponins are derived from Tribulus terrestris. In addition to its function of promoting blood circulation and removing blood stasis, Tribulus terrestris also has the effect of soothing the liver and relieving depression, and has a significant effect on impotence caused by liver depression and blood stasis. Tribulus saponins are a type 5 phosphodiesterase inhibitor, which increases the level of cyclic guanosine monophosphate by improving NO concentration, and can inhibit phosphodiesterase to prevent the hydrolysis of cyclic guanosine monophosphate, thereby reducing the intracellular calcium ion concentration, relaxing blood vessels and cavernous smooth muscles, and improving erectile function. Similarly, Tribulus saponins have good water solubility, high bioavailability, and good effects, but there is also the problem of being extremely hygroscopic, which reduces its stability and efficacy.

[0032] Sildenafil citrate is also a water-soluble drug for treating male erectile dysfunction. Its main function is to dilate blood vessels, improve target organ blood flow, and reduce pulmonary artery hypertension. However, it is highly hygroscopic and can easily cause problems such as decreased stability and decreased efficacy. At the same time, sildenafil citrate has a short half-life of only 3-4 hours in vivo, and requires repeated administration to maintain plasma drug concentration, which is inconvenient for long-term treatment of the disease, and both oral and intravenous injections may cause some serious adverse reactions.

[0033] The present invention prepares nanoliposomes by mixing icariin, tribulus saponin and sildenafil citrate, which can not only have good embedding properties for the drugs and prevent them from contacting with water vapor to absorb moisture and reduce stability and efficacy, but also have the effects of large drug loading, high encapsulation rate, and sustained and controlled release, and is safe and has no side effects, thereby improving the sustained release and bioavailability of the drugs and reducing adverse reactions.

[0034] Earth dragon protein is extracted from earth dragon, and contains collagenase, plasmin, lumbrokinase, fibrinolytic activator protein, nucleic acid, trace elements and other ingredients. It is a short-chain small molecule substance that can help supplement nutrition, strengthen physical fitness, and also has a certain tonic effect on the kidneys. Tannic acid-modified maltodextrin introduces a hydrophilic structure into the network structure of water-soluble molecules. The hydrophilic residues combine with water molecules to connect water in the network, and the hydrophobic residues swell when exposed to water to form a three-dimensional network polymer with water as the dispersion medium. It can be repeatedly frozen and thawed with earth dragon protein through physical interaction (hydrophobic, electrostatic and hydrogen bonds), so that the movement of the main chain molecular chain of the hydrogel is restricted and crystallized at low temperature. The formed crystals constitute the physical cross-linking points in the hydrogel. The molecular chains at room temperature thaw and the crystals grow, increasing the number of freeze-thaw cycles, increasing the number of crystal nuclei, and improving the crystal structure. Physical cross-linking without chemical reagents can be achieved, thereby avoiding the addition of chemical cross-linking agents, resulting in toxic residues and improving its safety.

[0035] The prepared hydrogel and liposome are uniformly mixed, uniformly dispersed through physical interaction, freeze-dried to form a dry gel, crushed and sieved. The prepared mixed powder has a good embedding effect on the active component, greatly avoids contact with water vapor, thereby effectively avoiding moisture absorption of the active component and decreased stability, and can well cover the bitter taste of sildenafil citrate. At the same time, it also has a good sustained-release effect, prolongs the drug effect time, and improves the compliance of patients.

[0036] The sildenafil citrate orodisintegrating tablets prepared by the invention adopt a direct tabletting method, have a simple preparation method, do not need coating, have good palatability, good stability, good therapeutic effect, have a good sustained-release effect, prolong the drug effect time, improve the patient's compliance, and have broad application prospects. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] Example 1

[0039] This embodiment provides a method for preparing a sildenafil citrate orally disintegrating tablet, comprising the following steps:

[0040] S1. 3 g of icariin, 2 g of tribulus saponin, 7 g of sildenafil citrate, 4 g of glyceryl monostearate, 1 g of oleic acid, and 40 g of soybean lecithin were added to 500 g of ethanol, heated to 35 ° C, ultrasonically treated for 3 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1 wt% of Tween-80 and 0.8 wt% of Span-80 was added, hydrated for 15 min, ultrasonically dispersed at 1000 W for 1 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0041] S2. 10 g of maltodextrin was added to 100 mL of water, 3 g of tannic acid and 0.5 g of catalyst were added, heated to 40 ° C, stirred for 1 h, and freeze-dried to obtain modified maltodextrin;

[0042] The catalyst is a Tris-HCl solution with a pH of 8.5;

[0043] S3. Add 15 g of modified maltodextrin and 12 g of earthworm protein to 100 mL of water, cool the mixture to -25 °C for 20 min, take it out and dissolve it at room temperature for 1 h, repeat the operation twice to form a hydrogel;

[0044] S4. 4 g of liposomes were added to 17 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 150 mesh sieve to obtain a mixed powder;

[0045] S5. 2 g of microcrystalline cellulose, 2 g of cross-linked sodium carboxymethyl cellulose, 0.3 g of sucralose, 0.08 g of indigo aluminum lake, 0.3 g of colloidal silicon dioxide, and 1 g of flavor are stirred and mixed, ground through a 150-mesh sieve, 10 g of mixed powder are added, stirred and mixed for 20 min, 0.5 g of magnesium stearate is added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orodisintegrating tablets, wherein the flavor is a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, and the mass ratio is 1:0.8:1.

[0046] Example 2

[0047] This embodiment provides a method for preparing a sildenafil citrate orally disintegrating tablet, comprising the following steps:

[0048] S1. 5 g of icariin, 4 g of tribulus saponin, 10 g of sildenafil citrate, 6 g of glyceryl monostearate, 3 g of oleic acid, and 60 g of soybean lecithin were added to 500 g of ethanol, heated to 45 ° C, ultrasonically treated for 5 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1.5 wt% of Tween-80 and 1.2 wt% of Span-80 was added, hydrated for 25 min, ultrasonically dispersed at 1200 W for 2 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0049] S2. Add 10 g of maltodextrin to 100 mL of water, add 5 g of tannic acid and 1 g of catalyst, heat to 50 ° C, stir and react for 3 h, and freeze-dry to obtain modified maltodextrin;

[0050] The catalyst is a Tris-HCl solution with a pH of 9.5;

[0051] S3. Add 20 g of modified maltodextrin and 15 g of earthworm protein to 100 mL of water, cool the mixture to -30 ° C for 40 min, take it out and dissolve it at room temperature for 2 h, repeat the operation 3 times to form a hydrogel;

[0052] S4. 6 g of liposomes were added to 20 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0053] S5. Mix 3 g of microcrystalline cellulose, 3 g of cross-linked sodium carboxymethyl cellulose, 0.7 g of sucralose, 0.12 g of indigo aluminum lake, 0.4 g of colloidal silicon dioxide, and 2 g of flavor, grind through a 200-mesh sieve, add 15 g of mixed powder, stir and mix for 20 min, add 1.5 g of magnesium stearate, stir and mix for 20 min, and tablet to obtain sildenafil citrate orodisintegrating tablets; the flavor is a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 2:1.2:1.5.

[0054] Example 3

[0055] This embodiment provides a method for preparing a sildenafil citrate orally disintegrating tablet, comprising the following steps:

[0056] S1. 4 g of icariin, 3 g of tribulus saponin, 8.5 g of sildenafil citrate, 5 g of glyceryl monostearate, 2 g of oleic acid, and 50 g of soybean lecithin were added to 500 g of ethanol, heated to 40 ° C, ultrasonically treated for 4 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1.2 wt% of Tween-80 and 1 wt% of Span-80 was added, hydrated for 20 min, ultrasonically dispersed at 1100 W for 1.5 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0057] S2. 10 g of maltodextrin was added to 100 mL of water, 4 g of tannic acid and 0.7 g of catalyst were added, heated to 45 ° C, stirred for 2 h, and freeze-dried to obtain modified maltodextrin;

[0058] The catalyst is a Tris-HCl solution with a pH of 9;

[0059] S3. Add 17 g of modified maltodextrin and 13.5 g of earthworm protein to 100 mL of water, cool the mixture to -27 ° C for 30 min, take it out and dissolve it at room temperature for 1.5 h, repeat the operation 3 times to form a hydrogel;

[0060] S4. 5 g of liposomes were added to 18.5 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0061] S5. 2.5 g of microcrystalline cellulose, 2.5 g of cross-linked sodium carboxymethyl cellulose, 0.5 g of sucralose, 0.1 g of indigo aluminum lake, 0.35 g of colloidal silicon dioxide, and 1.5 g of flavor are stirred and mixed, ground through a 200-mesh sieve, 12 g of mixed powder is added, stirred and mixed for 20 min, 1 g of magnesium stearate is added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orally disintegrating tablets, wherein the flavor is a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, and the mass ratio is 1.5:1:1.2.

[0062] Comparative Example 1

[0063] Compared with Example 3, the difference is that icariin is not added in step S1.

[0064] The details are as follows:

[0065] S1. 7 g of Tribulus terrestris saponin, 8.5 g of sildenafil citrate, 5 g of glyceryl monostearate, 2 g of oleic acid, and 50 g of soy lecithin were added to 500 g of ethanol, heated to 40 ° C, ultrasonically treated for 4 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1.2 wt% of Tween-80 and 1 wt% of Span-80 was added, hydrated for 20 min, ultrasonically dispersed at 1100 W for 1.5 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0066] S2. 10 g of maltodextrin was added to 100 mL of water, 4 g of tannic acid and 0.7 g of catalyst were added, heated to 45 ° C, stirred for 2 h, and freeze-dried to obtain modified maltodextrin;

[0067] The catalyst is a Tris-HCl solution with a pH of 9;

[0068] S3. Add 17 g of modified maltodextrin and 13.5 g of earthworm protein to 100 mL of water, cool the mixture to -27 ° C for 30 min, take it out and dissolve it at room temperature for 1.5 h, repeat the operation 3 times to form a hydrogel;

[0069] S4. 5 g of liposomes were added to 18.5 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0070] S5. 2.5 g of microcrystalline cellulose, 2.5 g of cross-linked sodium carboxymethyl cellulose, 0.5 g of sucralose, 0.1 g of indigo aluminum lake, 0.35 g of colloidal silicon dioxide, and 1.5 g of flavor were stirred and mixed, ground through a 200-mesh sieve, 12 g of mixed powder was added, stirred and mixed for 20 min, 1 g of magnesium stearate was added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orally disintegrating tablets, wherein the flavor was a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 1.5:1:1.2. .

[0071] Comparative Example 2

[0072] Compared with Example 3, the difference is that no Tribulus terrestris saponin is added in step S1.

[0073] The details are as follows:

[0074] S1. 7 g of icariin, 8.5 g of sildenafil citrate, 5 g of glyceryl monostearate, 2 g of oleic acid, and 50 g of soy lecithin were added to 500 g of ethanol, heated to 40 ° C, ultrasonically treated for 4 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1.2 wt% of Tween-80 and 1 wt% of Span-80 was added, hydrated for 20 min, ultrasonically dispersed at 1100 W for 1.5 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0075] S2. 10 g of maltodextrin was added to 100 mL of water, 4 g of tannic acid and 0.7 g of catalyst were added, heated to 45 ° C, stirred for 2 h, and freeze-dried to obtain modified maltodextrin;

[0076] The catalyst is a Tris-HCl solution with a pH of 9;

[0077] S3. Add 17 g of modified maltodextrin and 13.5 g of earthworm protein to 100 mL of water, cool the mixture to -27 ° C for 30 min, take it out and dissolve it at room temperature for 1.5 h, repeat the operation 3 times to form a hydrogel;

[0078] S4. 5 g of liposomes were added to 18.5 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0079] S5. 2.5 g of microcrystalline cellulose, 2.5 g of cross-linked sodium carboxymethyl cellulose, 0.5 g of sucralose, 0.1 g of indigo aluminum lake, 0.35 g of colloidal silicon dioxide, and 1.5 g of flavor were stirred and mixed, ground through a 200-mesh sieve, 12 g of mixed powder was added, stirred and mixed for 20 min, 1 g of magnesium stearate was added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orally disintegrating tablets, wherein the flavor was a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 1.5:1:1.2. .

[0080] Comparative Example 3

[0081] Compared with Example 3, the difference is that icariin and tribulus saponin are not added in step S1.

[0082] The details are as follows:

[0083] S1. 15.5 g of sildenafil citrate, 5 g of glyceryl monostearate, 2 g of oleic acid, and 50 g of soybean lecithin were added to 500 g of ethanol, heated to 40 ° C, ultrasonically treated for 4 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1.2 wt% of Tween-80 and 1 wt% of Span-80 was added, hydrated for 20 min, ultrasonically dispersed at 1100 W for 1.5 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0084] S2. 10 g of maltodextrin was added to 100 mL of water, 4 g of tannic acid and 0.7 g of catalyst were added, heated to 45 ° C, stirred for 2 h, and freeze-dried to obtain modified maltodextrin;

[0085] The catalyst is a Tris-HCl solution with a pH of 9;

[0086] S3. Add 17 g of modified maltodextrin and 13.5 g of earthworm protein to 100 mL of water, cool the mixture to -27 ° C for 30 min, take it out and dissolve it at room temperature for 1.5 h, repeat the operation 3 times to form a hydrogel;

[0087] S4. 5 g of liposomes were added to 18.5 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0088] S5. 2.5 g of microcrystalline cellulose, 2.5 g of cross-linked sodium carboxymethyl cellulose, 0.5 g of sucralose, 0.1 g of indigo aluminum lake, 0.35 g of colloidal silicon dioxide, and 1.5 g of flavor were stirred and mixed, ground through a 200-mesh sieve, 12 g of mixed powder was added, stirred and mixed for 20 min, 1 g of magnesium stearate was added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orally disintegrating tablets, wherein the flavor was a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 1.5:1:1.2. .

[0089] Comparative Example 4

[0090] Compared with Example 3, the difference is that in step S1, liposome embedding is not performed, and simple mixing is used.

[0091] The details are as follows:

[0092] S1. 4 g of icariin, 3 g of tribulus saponin, and 8.5 g of sildenafil citrate were mixed to obtain a material;

[0093] S2. 10 g of maltodextrin was added to 100 mL of water, 4 g of tannic acid and 0.7 g of catalyst were added, heated to 45 ° C, stirred for 2 h, and freeze-dried to obtain modified maltodextrin;

[0094] The catalyst is a Tris-HCl solution with a pH of 9;

[0095] S3. Add 17 g of modified maltodextrin and 13.5 g of earthworm protein to 100 mL of water, cool the mixture to -27 ° C for 30 min, take it out and dissolve it at room temperature for 1.5 h, repeat the operation 3 times to form a hydrogel;

[0096] S4. 5 g of the material was added to 18.5 g of the hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0097] S5. 2.5 g of microcrystalline cellulose, 2.5 g of cross-linked sodium carboxymethyl cellulose, 0.5 g of sucralose, 0.1 g of indigo aluminum lake, 0.35 g of colloidal silicon dioxide, and 1.5 g of flavor were stirred and mixed, ground through a 200-mesh sieve, 12 g of mixed powder was added, stirred and mixed for 20 min, 1 g of magnesium stearate was added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orally disintegrating tablets, wherein the flavor was a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 1.5:1:1.2. .

[0098] Comparative Example 5

[0099] Compared with Example 3, the difference is that step S2 is not performed.

[0100] The details are as follows:

[0101] S1. 4 g of icariin, 3 g of tribulus saponin, 8.5 g of sildenafil citrate, 5 g of glyceryl monostearate, 2 g of oleic acid, and 50 g of soybean lecithin were added to 500 g of ethanol, heated to 40 ° C, ultrasonically treated for 4 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1.2 wt% of Tween-80 and 1 wt% of Span-80 was added, hydrated for 20 min, ultrasonically dispersed at 1100 W for 1.5 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0102] S2. Add 17 g of maltodextrin and 13.5 g of earthworm protein to 100 mL of water, cool the mixture to -27 °C for 30 min, take it out and dissolve it at room temperature for 1.5 h, repeat the operation 3 times to form a hydrogel;

[0103] S4. 5 g of liposomes were added to 18.5 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0104] S4. 2.5 g of microcrystalline cellulose, 2.5 g of cross-linked sodium carboxymethyl cellulose, 0.5 g of sucralose, 0.1 g of indigo aluminum lake, 0.35 g of colloidal silicon dioxide, and 1.5 g of flavor were stirred and mixed, ground through a 200-mesh sieve, 12 g of mixed powder was added, stirred and mixed for 20 min, 1 g of magnesium stearate was added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orally disintegrating tablets, wherein the flavor was a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 1.5:1:1.2. .

[0105] Comparative Example 6

[0106] Compared with Example 3, the difference is that in step S3, no repeated freeze-thaw treatment is performed, and direct mixing is used.

[0107] The details are as follows:

[0108] S1. 4 g of icariin, 3 g of tribulus saponin, 8.5 g of sildenafil citrate, 5 g of glyceryl monostearate, 2 g of oleic acid, and 50 g of soybean lecithin were added to 500 g of ethanol, heated to 40 ° C, ultrasonically treated for 4 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1.2 wt% of Tween-80 and 1 wt% of Span-80 was added, hydrated for 20 min, ultrasonically dispersed at 1100 W for 1.5 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0109] S2. 10 g of maltodextrin was added to 100 mL of water, 4 g of tannic acid and 0.7 g of catalyst were added, heated to 45 ° C, stirred for 2 h, and freeze-dried to obtain modified maltodextrin;

[0110] The catalyst is a Tris-HCl solution with a pH of 9;

[0111] S3. Add 17 g of modified maltodextrin and 13.5 g of earthworm protein to 100 mL of water, cool the mixture to -27 ° C for 30 min, take it out and dissolve it at room temperature for 1.5 h, repeat the operation 3 times to form a hydrogel;

[0112] S4. 5 g of liposomes were added to 18.5 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0113] S5. 2.5 g of microcrystalline cellulose, 2.5 g of cross-linked sodium carboxymethyl cellulose, 0.5 g of sucralose, 0.1 g of indigo aluminum lake, 0.35 g of colloidal silicon dioxide, and 1.5 g of flavor were stirred and mixed, ground through a 200-mesh sieve, 12 g of mixed powder was added, stirred and mixed for 20 min, 1 g of magnesium stearate was added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orally disintegrating tablets, wherein the flavor was a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 1.5:1:1.2. .

[0114] Comparative Example 7

[0115] Compared with Example 3, the difference is that no earthworm protein is added in step S3.

[0116] The details are as follows:

[0117] S1. 4 g of icariin, 3 g of tribulus saponin, 8.5 g of sildenafil citrate, 5 g of glyceryl monostearate, 2 g of oleic acid, and 50 g of soybean lecithin were added to 500 g of ethanol, heated to 40 ° C, ultrasonically treated for 4 min, and the solvent was removed by rotary evaporation. 500 g of an aqueous solution containing 1.2 wt% of Tween-80 and 1 wt% of Span-80 was added, hydrated for 20 min, ultrasonically dispersed at 1100 W for 1.5 min, filtered using a 0.45 μm microporous membrane, and freeze-dried to obtain liposomes;

[0118] S2. 10 g of maltodextrin was added to 100 mL of water, 4 g of tannic acid and 0.7 g of catalyst were added, heated to 45 ° C, stirred for 2 h, and freeze-dried to obtain modified maltodextrin;

[0119] The catalyst is a Tris-HCl solution with a pH of 9;

[0120] S3. Add 30.5 g of modified maltodextrin to 100 mL of water, cool the mixture to -27 °C for 30 min, take it out and dissolve it at room temperature for 1.5 h, repeat the operation 3 times to form a hydrogel;

[0121] S4. 5 g of liposomes were added to 18.5 g of hydrogel, stirred and mixed for 20 min, freeze-dried, and ground through a 200 mesh sieve to obtain a mixed powder;

[0122] S5. 2.5 g of microcrystalline cellulose, 2.5 g of cross-linked sodium carboxymethyl cellulose, 0.5 g of sucralose, 0.1 g of indigo aluminum lake, 0.35 g of colloidal silicon dioxide, and 1.5 g of flavor were stirred and mixed, ground through a 200-mesh sieve, 12 g of mixed powder was added, stirred and mixed for 20 min, 1 g of magnesium stearate was added, stirred and mixed for 20 min, and tableted to obtain sildenafil citrate orally disintegrating tablets, wherein the flavor was a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 1.5:1:1.2. .

[0123] Test Example 1 In vitro release test

[0124] The sildenafil citrate orodisintegrating tablets prepared in Examples 1-3 and Comparative Examples 1-7 and commercially available sildenafil citrate orodisintegrating tablets were crushed and added into water to prepare a 1 mg / mL suspension.

[0125] The in vitro release test was carried out by dynamic membrane dialysis. 1 mL of the suspension was accurately measured and transferred into a pretreated dialysis bag (retention relative molecular mass: 8000-14000D). The two ends of the dialysis bag were clamped with dialysis clamps and placed in a beaker containing 200 mL of release medium. The container mouth was sealed and placed in a constant temperature air bath oscillator. 1 mL of dialysis medium was taken from the release medium at 0.5, 1, 4, 8, 24, and 48 h, and the same volume of release medium was replenished in time; the content of sildenafil citrate was determined by HPLC after the release medium was filtered through a 0.45 μm filter membrane, and the cumulative release amount of the drug at different sampling time points (Q n The results are shown in Table 1.

[0126]

[0127] In the formula, C n is the measured concentration of SC at time t, C i is the SC concentration measured before time t, V0 is the volume of solution added to the receiving pool, V is the sampling volume, and Q0 is the total amount of drug in the dosing pool at the beginning.

[0128] Table 1

[0129]

[0130] It can be seen from the above table that the sildenafil citrate orodisintegrating tablets prepared in Examples 1-3 of the present invention have a good sustained-release effect.

[0131] Test Example 2

[0132] After one week of adaptive feeding of SPF rats, a vascular erectile dysfunction (ED) rat model was established by bilateral internal iliac artery ligation. The rats that had completed bilateral internal iliac artery ligation were fed in cages, 1 in each cage, to facilitate wound healing. In the sham operation group, the rats were fixed on the operating table, a midline incision was made in the lower abdomen, and after opening the abdominal cavity, the bilateral internal iliac arteries were found and exposed without ligation, and then the abdominal tissue and viscera were reset and sutured in sequence. A total of 120 vascular ED model rats were selected and divided into 12 groups on average: model group, positive control group, Example 1-3 group, and Comparative Example 1-7 group, with 10 rats in each group. The rats in the positive control group were given tadalafil solution by gavage at a dose of 0.8 mg / kg per day, the rats in the Example 1-3 group and the Comparative Example 1-7 group were given sildenafil citrate orodisintegrating tablets prepared by gavage at a dose of 40 mg / kg per day, and the rats in the model group and the sham operation group (10 rats) were not given drug intervention, but only given an equal amount of normal saline by gavage every day. After 30 days of continuous gavage, the rat corpus cavernosum specimens were taken and stored in cryopreservation tubes at -80°C.

[0133] Maximum intracavernous pressure (ICP) of rat penis max ) Measurement: 4 weeks after membrane formation, the pressure transducer was connected to the RM-6240E multi-channel physiological signal acquisition and processing system, and 20 mL of heparinized saline was injected into the pressure transducer pump head. The syringe needle on the pressure transducer pump head was inserted into the left corpus cavernosum of the rat, and the intracavernosal pressure (ICP) of the penis was observed through the RM-6240E multi-channel physiological signal acquisition and processing system. After gradually stabilizing, the cavernous nerve was electrically stimulated to observe the ICP after stimulation max The same method was used to stimulate the cavernous nerve of the penis twice, with an interval of 10 minutes between the two times. The ICP after the second stimulation was recorded. max As the rat's penile ICP max value.

[0134] Masson staining of rat corpus cavernosum tissue: Part of rat corpus cavernosum tissue was taken, dehydrated, trimmed, embedded, sliced, stained, sealed, and observed under a microscope. Masson staining was used to determine the fibrosis of rat corpus cavernosum tissue. Each slice was first observed under a 4x microscope for all tissues, and then 3 areas were selected according to the size and expression of the tissue and magnified 40 times to collect images. Image-ProPlus6.0 software was used to analyze the integrated optical density (IOD) of the collected images.

[0135] The results are shown in Table 2.

[0136] Table 2

[0137] Group ICPmax(mmHg) IOD Sham operation group 62.10±2.44 50.82±2.14 Model Group 20.17±1.12* 62.21±3.42* Tadalafil group 39.28±2.18# 54.57±1.39# Example 1 57.82±2.09# 51.38±2.37# Example 2 58.16±2.13# 51.19±1.58# Example 3 58.44±1.37# 51.07±2.04# Comparative Example 1 52.11±3.25 57.68±3.11 Comparative Example 2 51.48±3.17 56.98±2.97 Comparative Example 3 48.92±3.75 59.45±3.42 Comparative Example 4 53.14±3.21 58.10±3.10 Comparative Example 5 50.93±2.86 59.03±3.14 Comparative Example 6 50.18±3.05 58.57±3.05 Comparative Example 7 47.69±3.42 60.22±3.57

[0138] Note: * compared with the sham operation group, P < 0.05; # compared with the model group, P < 0.05.

[0139] As can be seen from the above table, the sildenafil citrate orally disintegrating tablets prepared in Examples 1-3 of the present invention can significantly improve ICP max value, reduce the IOD value.

[0140] Test Example 3

[0141] The sildenafil citrate orally disintegrating tablets prepared in Examples 1-3 of the present invention and Comparative Examples 1-7 were tested.

[0142] The taste was tested by volunteers; the sample tablets (with the inner packaging of the sample opened) were tested for hygroscopicity according to the 2021 Chinese Pharmacopoeia Part IV 9103 Drug Hygroscopicity Test Guidelines, with a temperature of 23°C ± 2°C and a humidity of 80% ± 5%. The results are shown in Table 3.

[0143] Table 3

[0144]

[0145]

[0146] It can be seen from the above table that the sildenafil citrate orodisintegrating tablets prepared in Examples 1-3 of the present invention have good taste and low moisture absorption rate.

[0147] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a sildenafil citrate orodisintegrating tablet, characterized in that: Icariin, tribulus saponin and sildenafil citrate are mixed to prepare liposomes, added to the hydrogel prepared from modified maltodextrin and earthworm protein, mixed evenly, dried, ground to obtain mixed powder, added to the auxiliary materials, and tableted to obtain sildenafil citrate orodisintegrating tablets. The following steps are involved: S1. Add icariin, tribulus saponin, sildenafil citrate, glyceryl monostearate, oleic acid, and soybean lecithin to ethanol, heat and ultrasonically treat, remove the solvent by rotary evaporation, add a surfactant solution, hydrate, ultrasonically disperse, filter with a microporous membrane, and freeze-dry to prepare liposomes; the mass ratio of icariin, tribulus saponin, sildenafil citrate, glyceryl monostearate, oleic acid, and soybean lecithin is 3-5:2-4:7-10:4-6:1-3:40-60; the surfactant solution is an aqueous solution containing 1-1.5wt% of Tween-80 and 0.8-1.2wt% of Span-80; S2. Add maltodextrin to water, add tannic acid and a catalyst, heat and stir to react, and freeze-dry to obtain modified maltodextrin; the mass ratio of the maltodextrin, tannic acid and catalyst is 10:3-5:0.5-1; the catalyst is a Tris-HCl solution with a pH of 8.5-9.5; S3. The modified maltodextrin and earthworm protein were added to water and repeatedly frozen and thawed to form a hydrogel; the mass ratio of the modified maltodextrin and earthworm protein was 15-20:12-15; S4. The liposomes were added to the hydrogel, stirred and mixed, freeze-dried, ground and sieved to obtain a mixed powder; the mass ratio of the liposomes to the hydrogel was 4-6:17-20; S5. Mix microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, sucralose, indigo aluminum lake, colloidal silicon dioxide, and flavor, grind and sieve, add mixed powder, mix, add magnesium stearate, mix evenly, and tablet to prepare sildenafil citrate orally disintegrating tablets; the mass ratio of microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, sucralose, indigo aluminum lake, colloidal silicon dioxide, flavor, mixed powder, and magnesium stearate is 2-3:2-3:0.3-0.7:0.08-0.12:0.3-0.4:1-2:10-15:0.5-1.

5.

2. The preparation method according to claim 1, characterized in that: The temperature of the heating ultrasonic treatment in step S1 is 35-45°C, the time is 3-5 minutes, the time of the hydration reaction is 15-25 minutes, the power of the ultrasonic dispersion treatment is 1000-1200W, the time is 1-2 minutes, and the pore size of the microporous filter membrane is 0.45 μm.

3. The preparation method according to claim 1, characterized in that: The temperature of the heating and stirring reaction in step S2 is 40-50° C. and the time is 1-3 h.

4. The preparation method according to claim 1, characterized in that: The method of repeated freeze-thaw treatment in step S3 is to cool the mixed solution to -25 to -30°C for 20-40 minutes, take it out and dissolve it at room temperature for 1-2 hours, and repeat the operation 2-3 times.

5. The preparation method according to claim 1, characterized in that: The mesh size of the sieve used in step S4 is 150-200 meshes.

6. The preparation method according to claim 1, characterized in that: The flavor in step S5 is a mixture of orange powder flavor, sour orange powder flavor, and lemon powder flavor, with a mass ratio of 1-2:0.8-1.2:1-1.

5.

7. The preparation method according to claim 1, characterized in that: The specific steps include: S1. 3-5 parts by weight of icariin, 2-4 parts by weight of tribulus saponin, 7-10 parts by weight of sildenafil citrate, 4-6 parts by weight of glyceryl monostearate, 1-3 parts by weight of oleic acid, and 40-60 parts by weight of soybean lecithin are added to 500 parts by weight of ethanol, heated to 35-45° C., ultrasonically treated for 3-5 min, and the solvent is removed by rotary evaporation, and 500 parts by weight of an aqueous solution containing 1-1.5wt% of Tween-80 and 0.8-1.2wt% of Span-80 are added, hydrated for 15-25 min, ultrasonically dispersed at 1000-1200W for 1-2 min, filtered with a 0.45μm microporous membrane, and freeze-dried to obtain liposomes; S2. Add 10 parts by weight of maltodextrin to 100 parts by weight of water, add 3-5 parts by weight of tannic acid and 0.5-1 parts by weight of a catalyst, heat to 40-50 ° C, stir the reaction for 1-3h, and freeze-dry to obtain modified maltodextrin; The catalyst is a Tris-HCl solution with a pH of 8.5-9.5; S3. 15-20 parts by weight of modified maltodextrin and 12-15 parts by weight of earthworm protein were added to 100 parts by weight of water, the mixture was cooled to -25 to -30 ° C for 20-40 min, removed and dissolved at room temperature for 1-2 h, and the operation was repeated 2-3 times to form a hydrogel; S4. 4-6 parts by weight of liposomes are added to 17-20 parts by weight of hydrogel, stirred and mixed, freeze-dried, ground and sieved to obtain a mixed powder; S5. 2-3 parts by weight of microcrystalline cellulose, 2-3 parts by weight of cross-linked sodium carboxymethyl cellulose, 0.3-0.7 parts by weight of sucralose, 0.08-0.12 parts by weight of indigo aluminum lake, 0.3-0.4 parts by weight of colloidal silicon dioxide, and 1-2 parts by weight of flavor are stirred and mixed, ground and sieved, 10-15 parts by weight of mixed powder are added, stirred and mixed, 0.5-1.5 parts by weight of magnesium stearate are added, stirred and mixed evenly, and tableted to obtain sildenafil citrate orodisintegrating tablets.

8. A sildenafil citrate orally disintegrating tablet prepared by the preparation method according to any one of claims 1 to 7.

9. Use of the sildenafil citrate orodisintegrating tablets as claimed in claim 8 in the preparation of a medicament for improving and treating male penile erectile dysfunction.

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