Dihydroergoline mesylate controlled release tablet and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to a dihydroergoline mesylate controlled release tablet and a preparation method thereof. The dihydroergoline mesylate controlled release tablet comprises a tablet core, an inner coating and an outer coating, wherein the tablet core is coated with the inner coating and the outer coating layer by layer; the weight ratio of the tablet core to the inner coating to the outer coating is 50: (6-8): (3-5); the dihydroergoline mesylate tablet solves the problem that the drug release rate of the existing dihydroergoline mesylate tablet is unstable, and realizes more uniform and predictable drug release characteristics. By optimizing preparation components and a preparation process, the controlled-release tablet disclosed by the invention can maintain stable drug concentration in vivo, and the treatment experience of a patient is improved.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a dihydroergotamine mesylate controlled-release tablet and a preparation method thereof. Background Art

[0002] Drug release technology is an important field in pharmaceutical engineering, which aims to improve the efficacy and safety of drugs by controlling the release rate and release pattern of drugs in the body. Traditional drug preparations often use immediate-release or sustained-release technologies, but these technologies may not meet clinical needs in some cases, especially in treatments that require precise control of drug concentrations. Dihydroergotamine mesylate is a drug used to treat sequelae of cerebrovascular disease and mild vascular dementia, with a potent vasoconstrictor effect. The pharmacological properties of dihydroergotamine mesylate make it very effective in the treatment of cerebrovascular diseases, but its drug release characteristics in the body are the key factors affecting its clinical application.

[0003] Most dihydroergotamine mesylate tablets on the market currently use traditional sustained-release technology. Although this technology can prolong the release time of the drug, in actual application, the drug release rate is affected by many factors, such as the pH value and temperature of the gastrointestinal tract, and individual differences. These factors cause the concentration of the drug in the body to fluctuate greatly, which may cause side effects or reduce the efficacy. In addition, existing sustained-release tablets usually need to be taken frequently, which increases the medication burden of patients. Summary of the invention

[0004] In view of the shortcomings of existing dihydroergotamine mesylate tablets in drug release rate, the present invention proposes a dihydroergotamine mesylate controlled-release tablet and a preparation method thereof. The controlled-release tablet is intended to solve the problem of unstable drug release rate of existing tablets, thereby achieving more uniform and predictable drug release characteristics. By optimizing the formulation ingredients and preparation process, the controlled-release tablet of the present invention can maintain a stable drug concentration in vivo and enhance the patient's treatment experience.

[0005] Based on the above purpose, the present invention provides a dihydroergotamine mesylate controlled-release tablet, characterized in that it includes a tablet core and an inner coating and an outer coating that are wrapped around the tablet core layer by layer.

[0006] Further, the weight ratio of the tablet core, the inner coating and the outer coating is 50:6-8:3-5;

[0007] Furthermore, the raw materials of the tablet core include, by weight: 400-600 parts of dihydroergotamine mesylate, 70-90 parts of sodium chloride, 16-20 parts of sodium lauryl sulfate, 25-33 parts of lactose and 7-9 parts of a binder.

[0008] Furthermore, the raw materials of the inner coating layer include, by weight: 40-60 parts of cellulose acetate, 8-12 parts of hydroxypropyl methylcellulose, 9-15 parts of emulsifier, 50-70 parts of low molecular weight PVP and 7-9 parts of plasticizer.

[0009] Furthermore, the raw materials of the outer coating include, by weight: 50-70 parts of cellulose acetate, 25-35 parts of high molecular weight PVP and 10-14 parts of plasticizer.

[0010] Furthermore, the low molecular weight PVP is PVP-400, and the high molecular weight PVP is PVP-4000.

[0011] Preferably, the adhesive is PVP-K30.

[0012] Preferably, the emulsifier is a mixture of Tween-80 and Span-40 in a weight ratio of 2:1.

[0013] Preferably, the plasticizer is phthalate or acetylated monoglyceride.

[0014] Furthermore, the present invention also provides a method for preparing dihydroergotamine mesylate controlled-release tablets, comprising the following steps:

[0015] (1) Preparation of inner coating solution: acetone and water are mixed, and then an emulsifier is added, and stirred for 10-20 minutes, and then cellulose acetate, hydroxypropyl methylcellulose, low molecular weight PVP and plasticizer are added, and stirred for 30-50 minutes to obtain an inner coating solution;

[0016] (2) Preparation of outer coating solution: acetone and water are mixed, and then cellulose acetate, high molecular weight PVP and plasticizer are added, and stirred for 20-40 minutes to obtain an outer coating solution;

[0017] (3) Preparation of adhesive solution: PVP-K30 was dissolved in 95% ethanol solution to obtain an adhesive solution;

[0018] (4) Tablet core preparation: Sodium chloride, sodium lauryl sulfate, filler and dihydroergotamine mesylate API are sieved through 80 mesh sieves respectively, and then the sieved sodium chloride, sodium lauryl sulfate, lactose and dihydroergotamine mesylate are mixed evenly, and then a binder solution is added to prepare a soft material, granulated through a 24 mesh sieve, dried at 30-40° C. for 3-5 h, sieved through a 20 mesh sieve, and tableted to obtain a tablet core;

[0019] (5) Inner coating: Place the tablet core in a coating pan, preheat at 35-40°C for 8-10 min, rotate the coating pan at 40-60 rpm, spray the coating solution at a spray gun flow rate of 4-6 mg / min, and dry at 30-40°C for 24-36 h to obtain the inner-coated tablet core;

[0020] (6) Outer coating: Place the inner coating tablet core in a coating pan, preheat at 35-40°C for 8-10 min, rotate the coating pan at 70-90 rpm, and spray the coating solution at a spray gun flow rate of 8-10 mg / min. After coating, dry at 30-40°C for 24-36 h to obtain dihydroergotamine mesylate controlled-release tablets.

[0021] Preferably, the weight ratio of acetone to water in step (1) is 19:1.

[0022] Preferably, in step (2), the weight ratio of acetone to water is 9:1.

[0023] Preferably, the concentration of PVP-K30 in the adhesive solution in step (3) is 7wt%-9wt%.

[0024] Preferably, the hardness of the core in step (4) is 10-12 kg / cm 2 , tablet weight is 500mg.

[0025] Beneficial effects of the present invention:

[0026] The invention provides a double-layer coated dihydroergotamine mesylate controlled-release tablet, wherein the inner coating contains low molecular weight PVP and cellulose acetate, and the outer coating contains high molecular weight PVP and cellulose acetate, the low molecular weight PVP and the high molecular weight PVP are used as pore formers to construct pores with different pore diameters in the inner layer and the outer layer, the larger pores in the outer layer are helpful to transfer small molecular water-soluble substances in the inner layer, and the delayed release phenomenon is reduced, and the low molecular weight PVP and the high molecular weight PVP are dissolved in water to construct a gradient osmotic pressure, so that the dihydroergotamine mesylate is released at a constant rate, so as to achieve a controlled release effect, significantly increase the compliance of patients, avoid toxic and side effects exceeding the concentration range of therapeutic drugs, and maintain the effective concentration range to achieve the maintenance of therapeutic effect.

[0027] In the preparation of the inner coating liquid, an emulsifier composed of Tween-80 and Span-40 and hydroxypropyl methylcellulose are added. The addition of Tween-80 and Span-40 helps to regulate the dispersion of water-soluble substances and water-insoluble substances in the inner coating liquid, and hydroxypropyl methylcellulose, as a sacrificial skeleton, gradually dissolves during the release process. The emulsifier and hydroxypropyl methylcellulose synergistically regulate the osmotic pressure of the inner layer, thereby ensuring the constant-rate release of dihydroergotamine mesylate.

[0028] The present invention adds sodium dodecyl sulfate into the tablet core. The sodium dodecyl sulfate promotes the dissolution of the poorly soluble dihydroergot mesylate in the release medium and regulates the release process. On the other hand, the sodium dodecyl sulfate stabilizes the dihydroergot mesylate and improves the stability of the dihydroergot mesylate controlled-release tablet under high temperature and strong light. DETAILED DESCRIPTION

[0029] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments.

[0030] Embodiment 1:

[0031] (1) Preparation of inner coating solution: 950 mg of acetone and 50 mg of water were mixed, and then 8 mg of Tween-80 and 4 mg of Span-40 were added, and stirred for 15 min. Then, 50 mg of cellulose acetate, 10 mg of hydroxypropyl methylcellulose, 60 mg of PVP-400 and 8 mg of phthalate were added, and stirred for 40 min to obtain an inner coating solution;

[0032] (2) Preparation of outer coating solution: 900 mg of acetone and 100 mg of water were mixed, and then 60 mg of cellulose acetate, 30 mg of PVP-4000 and 12 mg of phthalate were added, and stirred for 30 min to obtain an outer coating solution;

[0033] (3) Preparation of adhesive solution: 8 mg of PVP-K30 was dissolved in 92 mg of 95% ethanol solution to obtain an adhesive solution;

[0034] (4) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, and then 80 mg of sodium chloride, 18 mg of sodium dodecyl sulfate, 29 mg of lactose and 500 mg of dihydroergotamine mesylate were mixed evenly, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 35°C for 4 h, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 10.9 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0035] (5) Inner coating: Place the tablet core in a coating pan, preheat at 35°C for 10 min, set the coating pan speed at 50 rpm, spray the inner coating solution at a spray gun flow rate of 5 mg / min, and dry at 35°C for 30 h to obtain an inner coating core tablet with an inner coating weight of 70 mg.

[0036] (6) Outer coating: Place the inner-coated tablet core in a coating pan and preheat at 35°C for 10 min. Set the coating pan speed to 80 rpm and the spray gun flow rate to 9 mg / min, and spray the outer coating liquid. After coating, dry at 35°C for 30 h to obtain dihydroergotamine mesylate controlled-release tablets with an outer coating weight of 40 mg.

[0037] Embodiment 2:

[0038] (1) Preparation of inner coating solution: 950 mg of acetone and 50 mg of water were mixed, and then 6 mg of Tween-80 and 3 mg of Span-40 were added, and stirred for 10 min. Then 40 mg of cellulose acetate, 8 mg of hydroxypropyl methylcellulose, 50 mg of PVP-400 and 7 mg of phthalate were added, and stirred for 30 min to obtain an inner coating solution;

[0039] (2) Preparation of outer coating solution: 900 mg of acetone and 100 mg of water were mixed, and then 50 mg of cellulose acetate, 25 mg of PVP-4000 and 10 mg of phthalate were added, and stirred for 20 min to obtain an outer coating solution;

[0040] (3) Preparation of adhesive solution: 7 mg of PVP-K30 was dissolved in 93 mg of 95% ethanol solution to obtain an adhesive solution;

[0041] (4) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, and then 70 mg of sodium chloride, 16 mg of sodium dodecyl sulfate, 25 mg of lactose and 400 mg of dihydroergotamine mesylate were evenly mixed, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 30°C for 5 h, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 10.2 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0042] (5) Inner coating: Place the tablet core in a coating pan, preheat at 35°C for 10 min, set the coating pan speed at 40 rpm, spray the inner coating solution at a spray gun flow rate of 4 mg / min, and dry at 30°C for 36 h to obtain an inner coating core tablet with an inner coating weight of 60 mg.

[0043] (6) Outer coating: Place the inner-coated tablet core in a coating pan and preheat at 35°C for 10 min. Set the coating pan speed to 70 rpm and the spray gun flow rate to 8 mg / min, and spray the outer coating liquid. After coating, dry at 30°C for 36 h to obtain dihydroergotamine mesylate controlled-release tablets with an outer coating weight of 30 mg.

[0044] Embodiment 3:

[0045] (1) Preparation of inner coating solution: 950 mg of acetone and 50 mg of water were mixed, and then 10 mg of Tween-80 and 5 mg of Span-40 were added, and stirred for 20 min. Then, 60 mg of cellulose acetate, 12 mg of hydroxypropyl methylcellulose, 70 mg of PVP-400 and 9 mg of phthalate were added, and stirred for 50 min to obtain an inner coating solution;

[0046] (2) Preparation of outer coating solution: 900 mg of acetone and 100 mg of water were mixed, and then 70 mg of cellulose acetate, 35 mg of PVP-4000 and 14 mg of phthalate were added, and stirred for 40 min to obtain an outer coating solution;

[0047] (3) Preparation of adhesive solution: 9 mg of PVP-K30 was dissolved in 91 mg of 95% ethanol solution to obtain an adhesive solution;

[0048] (4) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, and then 90 mg of sodium chloride, 20 mg of sodium dodecyl sulfate, 33 mg of lactose and 600 mg of dihydroergotamine mesylate were mixed evenly, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 340°C for 3 hours, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 11.8 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0049] (5) Inner coating: Place the tablet core in a coating pan, preheat at 40°C for 8 min, set the coating pan speed at 60 rpm, spray the inner coating solution at a spray gun flow rate of 6 mg / min, and dry at 40°C for 24 h to obtain an inner coating core tablet with an inner coating weight of 80 mg.

[0050] (6) Outer coating: Place the inner-coated tablet core in a coating pan and preheat at 40°C for 8 min. Set the coating pan speed to 90 rpm and the spray gun flow rate to 10 mg / min, and spray the outer coating liquid. After coating, dry at 40°C for 24 h to obtain dihydroergotamine mesylate controlled-release tablets with an outer coating weight of 50 mg.

[0051] Comparative Example 1:

[0052] The difference between Comparative Example 1 and Example 1 is that only the inner coating liquid is coated, and the specific steps are as follows:

[0053] (1) Preparation of inner coating solution: 950 mg of acetone and 50 mg of water were mixed, and then 8 mg of Tween-80 and 4 mg of Span-40 were added, and stirred for 15 min. Then, 50 mg of cellulose acetate, 10 mg of hydroxypropyl methylcellulose, 60 mg of PVP-400 and 8 mg of phthalate were added, and stirred for 40 min to obtain an inner coating solution;

[0054] (2) Preparation of adhesive solution: 8 mg of PVP-K30 was dissolved in 92 mg of 95% ethanol solution to obtain an adhesive solution;

[0055] (3) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, and then 80 mg of sodium chloride, 18 mg of sodium dodecyl sulfate, 29 mg of lactose and 500 mg of dihydroergotamine mesylate were evenly mixed, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 35°C for 4 hours, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 10.9 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0056] (4) Inner coating: Place the tablet core in a coating pan, preheat at 35°C for 10 min, set the coating pan speed at 50 rpm, spray the inner coating solution at a spray gun flow rate of 5 mg / min, and dry at 35°C for 30 h to obtain tablets with an inner coating weight of 110 mg.

[0057] Comparative Example 2:

[0058] The difference between Comparative Example 2 and Example 1 is that only the outer coating liquid is coated, and the specific steps are as follows:

[0059] (1) Preparation of outer coating solution: 900 mg of acetone and 100 mg of water were mixed, and then 60 mg of cellulose acetate, 30 mg of PVP-4000 and 12 mg of phthalate were added, and stirred for 30 min to obtain an outer coating solution;

[0060] (2) Preparation of adhesive solution: 8 mg of PVP-K30 was dissolved in 92 mg of 95% ethanol solution to obtain an adhesive solution;

[0061] (3) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, and then 80 mg of sodium chloride, 18 mg of sodium dodecyl sulfate, 29 mg of lactose and 500 mg of dihydroergotamine mesylate were evenly mixed, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 35°C for 4 hours, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 10.9 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0062] (4) Outer coating: Place the tablet cores in a coating pan and preheat at 35°C for 10 min. Set the coating pan speed to 80 rpm and the spray gun flow rate to 9 mg / min. Spray the outer coating liquid. After coating, dry at 35°C for 30 h to obtain tablets with an outer coating weight of 110 mg.

[0063] Comparative Example 3:

[0064] The difference between Comparative Example 3 and Example 1 is that the inner coating liquid is coated on the outer layer of the tablet core, and the outer coating liquid is coated on the inner layer of the tablet core. The specific steps are as follows:

[0065] (1) Preparation of inner coating solution: 950 mg of acetone and 50 mg of water were mixed, and then 8 mg of Tween-80 and 4 mg of Span-40 were added, and stirred for 15 min. Then, 50 mg of cellulose acetate, 10 mg of hydroxypropyl methylcellulose, 60 mg of PVP-400 and 8 mg of phthalate were added, and stirred for 40 min to obtain an inner coating solution;

[0066] (2) Preparation of outer coating solution: 900 mg of acetone and 100 mg of water were mixed, and then 60 mg of cellulose acetate, 30 mg of PVP-4000 and 12 mg of phthalate were added, and stirred for 30 min to obtain an outer coating solution;

[0067] (3) Preparation of adhesive solution: 8 mg of PVP-K30 was dissolved in 92 mg of 95% ethanol solution to obtain an adhesive solution;

[0068] (4) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, and then 80 mg of sodium chloride, 18 mg of sodium dodecyl sulfate, 29 mg of lactose and 500 mg of dihydroergotamine mesylate were mixed evenly, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 35°C for 4 h, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 10.9 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0069] (5) Inner coating: Place the tablet core in a coating pan, preheat at 35°C for 10 min, set the coating pan speed at 50 rpm, spray the outer coating solution at a spray gun flow rate of 5 mg / min, and dry at 35°C for 30 h to obtain an inner coating core tablet with an inner coating weight of 70 mg.

[0070] (6) Outer coating: Place the inner-coated tablet core in a coating pan and preheat at 35°C for 10 min. Set the coating pan speed to 80 rpm and the spray gun flow rate to 9 mg / min. Spray the inner-coating solution. After coating, dry at 35°C for 30 h to obtain tablets with an outer-coating weight of 40 mg.

[0071] Comparative Example 4:

[0072] The difference between Comparative Example 4 and Example 1 is that Tween-80 and Span-40 are not added to the inner coating liquid, and the specific steps are as follows:

[0073] (1) Preparation of inner coating solution: Mix 950 mg of acetone and 50 mg of water, add 50 mg of cellulose acetate, 10 mg of hydroxypropyl methylcellulose, 60 mg of PVP-400 and 8 mg of phthalate, and stir for 40 min to obtain an inner coating solution;

[0074] (2) Preparation of outer coating solution: 900 mg of acetone and 100 mg of water were mixed, and then 60 mg of cellulose acetate, 30 mg of PVP-4000 and 12 mg of phthalate were added, and stirred for 30 min to obtain an outer coating solution;

[0075] (3) Preparation of adhesive solution: 8 mg of PVP-K30 was dissolved in 92 mg of 95% ethanol solution to obtain an adhesive solution;

[0076] (4) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, and then 80 mg of sodium chloride, 18 mg of sodium dodecyl sulfate, 29 mg of lactose and 500 mg of dihydroergotamine mesylate were mixed evenly, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 35°C for 4 h, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 10.9 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0077] (5) Inner coating: Place the tablet core in a coating pan, preheat at 35°C for 10 min, set the coating pan speed at 50 rpm, spray the coating solution at a spray gun flow rate of 5 mg / min, and dry at 35°C for 30 h to obtain an inner-layer coated tablet core with an inner-layer coating weight of 70 mg.

[0078] (6) Outer coating: Place the inner-coated tablet core in a coating pan and preheat at 35°C for 10 min. Set the coating pan speed to 80 rpm and the spray gun flow rate to 9 mg / min. Spray the coating solution. After coating, dry at 35°C for 30 h to obtain tablets with an outer coating weight of 40 mg.

[0079] Comparative Example 5:

[0080] The difference between Comparative Example 5 and Example 1 is that hydroxypropyl methylcellulose is not added to the inner coating liquid, and the specific steps are as follows:

[0081] (1) Preparation of inner coating solution: 950 mg of acetone and 50 mg of water were mixed, and then 8 mg of Tween-80 and 4 mg of Span-40 were added, and stirred for 15 min. Then, 60 mg of cellulose acetate, 60 mg of PVP-400 and 8 mg of phthalate were added, and stirred for 40 min to obtain an inner coating solution;

[0082] (2) Preparation of outer coating solution: 900 mg of acetone and 100 mg of water were mixed, and then 60 mg of cellulose acetate, 30 mg of PVP-4000 and 12 mg of phthalate were added, and stirred for 30 min to obtain an outer coating solution;

[0083] (3) Preparation of adhesive solution: 8 mg of PVP-K30 was dissolved in 92 mg of 95% ethanol solution to obtain an adhesive solution;

[0084] (4) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, and then 80 mg of sodium chloride, 18 mg of sodium dodecyl sulfate, 29 mg of lactose and 500 mg of dihydroergotamine mesylate were mixed evenly, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 35°C for 4 h, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 10.9 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0085] (5) Inner coating: Place the tablet core in a coating pan, preheat at 35°C for 10 min, set the coating pan speed at 50 rpm, spray the coating solution at a spray gun flow rate of 5 mg / min, and dry at 35°C for 30 h to obtain an inner-layer coated tablet core with an inner-layer coating weight of 70 mg.

[0086] (6) Outer coating: Place the inner-coated tablet core in a coating pan and preheat at 35°C for 10 min. Set the coating pan speed to 80 rpm and the spray gun flow rate to 9 mg / min. Spray the coating solution. After coating, dry at 35°C for 30 h to obtain tablets with an outer coating weight of 40 mg.

[0087] Comparative Example 6:

[0088] The difference between Comparative Example 6 and Example 1 is that sodium lauryl sulfate is not added to the tablet core, and the specific steps are as follows:

[0089] (1) Preparation of inner coating solution: 950 mg of acetone and 50 mg of water were mixed, and then 8 mg of Tween-80 and 4 mg of Span-40 were added, and stirred for 15 min. Then, 50 mg of cellulose acetate, 10 mg of hydroxypropyl methylcellulose, 60 mg of PVP-400 and 8 mg of phthalate were added, and stirred for 40 min to obtain an inner coating solution;

[0090] (2) Preparation of outer coating solution: 900 mg of acetone and 100 mg of water were mixed, and then 60 mg of cellulose acetate, 30 mg of PVP-4000 and 12 mg of phthalate were added, and stirred for 30 min to obtain an outer coating solution;

[0091] (3) Preparation of adhesive solution: 8 mg of PVP-K30 was dissolved in 92 mg of 95% ethanol solution to obtain an adhesive solution;

[0092] (4) Tablet core preparation: Sodium chloride, sodium dodecyl sulfate, filler and dihydroergotamine mesylate API were sieved through 80 mesh sieves respectively, 80 mg of the sieved sodium chloride, 29 mg of lactose and 500 mg of dihydroergotamine mesylate were mixed evenly, and then 100 mg of binder solution was added to make a soft material, granulated with a 24 mesh sieve, dried in an oven at 35°C for 4 h, sieved with a 20 mesh sieve, and pressed into tablets to obtain a hardness of 10.9 kg / cm 2 , a core tablet having a tablet weight of 500 mg;

[0093] (5) Inner coating: Place the tablet core in a coating pan, preheat at 35°C for 10 min, set the coating pan speed at 50 rpm, spray the coating solution at a spray gun flow rate of 5 mg / min, and dry at 35°C for 30 h to obtain an inner-layer coated tablet core with an inner-layer coating weight of 70 mg.

[0094] (6) Outer coating: Place the inner-coated tablet core in a coating pan and preheat at 35°C for 10 min. Set the coating pan speed to 80 rpm and the spray gun flow rate to 9 mg / min. Spray the coating solution. After coating, dry at 35°C for 30 h to obtain tablets with an outer coating weight of 40 mg.

[0095] In vitro release test: The release characteristic test was carried out by using the release determination method (Appendix XD of Part II of the Chinese Pharmacopoeia 2010 Edition) and the dissolution determination method (Appendix XC of Part II of the Chinese Pharmacopoeia 2010 Edition) device. The release medium was a phosphate buffer solution with a pH of 6.8. The cumulative release of the dihydroergotamine mesylate controlled-release tablets prepared in the embodiments and comparative examples was calculated at 2 h, 4 h, 8 h, and 16 h, and the zero-order equation was used to fit the in vitro release data. The results are shown in Table 1.

[0096] Table 1 In vitro release test results

[0097] 2h 4h 6h 8h 10h 12h 14h 16h Example 1 9.2 22.1 35.2 48.0 61.1 73.8 86.9 99.8 Example 2 12.1 27.7 43.5 58.9 74.5 90.3 99.9 99.9 Example 3 7.8 18.6 29.5 40.1 51.1 61.9 72.8 83.9 Comparative Example 1 30.2 57.4 78.3 91.3 99.7 99.9 99.9 99.9 Comparative Example 2 15.2 30.1 55.4 70.1 84.5 90.2 94.3 96.1 Comparative Example 3 13.4 22.5 30.8 38.9 43.5 46.2 47.3 47.9 Comparative Example 4 3.1 9.1 19.6 39.3 54.2 67.9 77.2 84.7 Comparative Example 5 2.5 7.6 16.2 35.4 53.9 67.5 72.3 79.6 Comparative Example 6 8.6 18.2 29.3 38.2 48.3 57.6 64.9 69.2

[0098] Data Analysis:

[0099] It can be seen from the data of Examples 1-3 that the dihydroergotamine mesylate controlled-release tablets prepared by the present invention have a shorter delayed release phenomenon in the early stage, and release the drug at a constant rate after the delayed release until the drug is completely released, which can significantly increase the patient's compliance, and the drug can be slowly released into the body, and the peak-to-valley fluctuation of the blood drug concentration is small, which can avoid the toxic and side effects exceeding the therapeutic drug concentration range, and can be maintained within the effective concentration range to achieve the maintenance of therapeutic effect.

[0100] From the data of Example 1 and Comparative Example 1, it can be seen that the tablets prepared by coating the inner layer alone exhibited a burst release phenomenon in the early stage.

[0101] It can be seen from the data of Example 1 and Comparative Example 2 that the tablets prepared by coating the outer layer alone have a fast release rate in the early stage and a slow release rate in the later stage.

[0102] From the data of Example 1 and Comparative Example 3, it can be seen that the tablets obtained by coating the inner coating liquid on the outer layer of the tablet core and the outer coating liquid on the inner layer of the tablet core have a slow release rate in the later stage and are almost difficult to release after 12 hours. This may be because the internal large-molecule PVP blocks the pores produced by the external small-molecule PVP.

[0103] From the data of Example 1 and Comparative Examples 4-5, it can be seen that the tablets prepared by the inner coating without Tween-80, Span-40 and hydroxypropyl methylcellulose have a significant delayed release phenomenon and are difficult to release completely, which is mainly due to the low internal osmotic pressure.

[0104] It can be seen from the data of Example 1 and Comparative Example 6 that it is difficult to achieve complete release for tablets without sodium lauryl sulfate, which is mainly due to the solubilizing effect of sodium lauryl sulfate.

[0105] Stability test: The tablets prepared in Examples 1-3 and Comparative Examples 1-6 and the Examples were tested for the content of related substances in accordance with the drug stability test in Appendix XC of the Chinese Pharmacopoeia 2010 Edition under high temperature, high humidity and strong light for 10 days. The results are shown in Table 2.

[0106]

[0107]

[0108] Data Analysis:

[0109] It can be seen from the data of Examples 1-3 that the dihydroergotamine mesylate controlled-release tablets prepared by the present invention have high stability under high temperature, high humidity and strong light.

[0110] It can be seen from the data of Example 1 and Comparative Examples 1-3 that the inner coating has poor stability under high temperature, high humidity and strong light, which will lead to an increase in related substances in the internal dihydroergotamine mesylate original drug, especially under high humidity conditions, the related substances of the tablets wrapped with the inner coating alone increased by 128%. This may be because the inner coating skeleton is prone to collapse in a high humidity environment, and the outer coating helps prevent the inner coating skeleton from collapsing in a high humidity environment.

[0111] It can be seen from Example 1 and Comparative Example 4 that Tween-80 and Span-40 help to improve the stability of dihydroergotamine mesylate controlled-release tablets.

[0112] It can be seen from Example 1 and Comparative Example 6 that sodium dodecyl sulfate can significantly improve the stability of dihydroergotamine mesylate controlled-release tablets under high temperature and strong light, which is mainly due to the interaction between sodium dodecyl sulfate and dihydroergotamine mesylate.

[0113] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention is limited to these examples. Under the concept of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

Claims

1. A dihydroergotamine mesylate controlled-release tablet, characterized in that: It comprises a tablet core and an inner coating and an outer coating which are wrapped around the tablet core layer by layer; the weight ratio of the tablet core, the inner coating and the outer coating is 50:6-8:3-5; The raw materials of the tablet core include, by weight: 400-600 parts of dihydroergotamine mesylate, 70-90 parts of sodium chloride, 16-20 parts of sodium lauryl sulfate, 25-33 parts of lactose and 7-9 parts of a binder; The raw materials of the inner coating layer include, by weight: 40-60 parts of cellulose acetate, 8-12 parts of hydroxypropyl methylcellulose, 9-15 parts of emulsifier, 50-70 parts of low molecular weight PVP and 7-9 parts of plasticizer; The raw materials of the outer coating include, by weight: 50-70 parts of cellulose acetate, 25-35 parts of high molecular weight PVP and 10-14 parts of plasticizer; The low molecular weight PVP is PVP-400, and the high molecular weight PVP is PVP-4000.

2. The dihydroergotamine mesylate controlled-release tablet according to claim 1, characterized in that The adhesive is PVP-K30.

3. The dihydroergotamine mesylate controlled-release tablet according to claim 1, characterized in that: The emulsifier is a mixture of Tween-80 and Span-40 in a weight ratio of 2:

1.

4. The dihydroergotamine mesylate controlled-release tablet according to claim 1, characterized in that: The plasticizer is phthalate or acetylated monoglyceride.

5. A method for preparing the dihydroergotamine mesylate controlled-release tablets according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) Preparation of inner coating solution: acetone and water are mixed, and then an emulsifier is added, and stirred for 10-20 minutes, and then cellulose acetate, hydroxypropyl methylcellulose, low molecular weight PVP and plasticizer are added, and stirred for 30-50 minutes to obtain an inner coating solution; (2) Preparation of outer coating solution: acetone and water are mixed, and then cellulose acetate, high molecular weight PVP and plasticizer are added, and stirred for 20-40 minutes to obtain an outer coating solution; (3) Preparation of adhesive solution: PVP-K30 was dissolved in 95% ethanol solution to obtain an adhesive solution; (4) Tablet core preparation: Sodium chloride, sodium lauryl sulfate, filler and dihydroergotamine mesylate API are sieved through 80 mesh sieves respectively, and then the sieved sodium chloride, sodium lauryl sulfate, lactose and dihydroergotamine mesylate are mixed evenly, and then a binder solution is added to prepare a soft material, granulated through a 24 mesh sieve, dried at 30-40° C. for 3-5 h, sieved through a 20 mesh sieve, and tableted to obtain a tablet core; (5) Inner coating: Place the tablet core in a coating pan, preheat at 35-40°C for 8-10 min, rotate the coating pan at 40-60 rpm, spray the coating solution at a spray gun flow rate of 4-6 mg / min, and dry at 30-40°C for 24-36 h to obtain the inner-coated tablet core; (6) Outer coating: Place the inner coating tablet core in a coating pan, preheat at 35-40°C for 8-10 min, rotate the coating pan at 70-90 rpm, and spray the coating solution at a spray gun flow rate of 8-10 mg / min. After coating, dry at 30-40°C for 24-36 h to obtain dihydroergotamine mesylate controlled-release tablets.

6. The dihydroergotamine mesylate controlled-release tablet according to claim 1, characterized in that: The weight ratio of acetone to water in the step (1) is 19:

1.

7. The dihydroergotamine mesylate controlled-release tablet according to claim 1, characterized in that: The weight ratio of acetone to water in step (2) is 9:

1.

8. The dihydroergotamine mesylate controlled-release tablet according to claim 1, characterized in that: The concentration of PVP-K30 in the adhesive solution in step (3) is 7wt%-9wt%.

9. The dihydroergotamine mesylate controlled-release tablet according to claim 1, characterized in that: The hardness of the tablet core in step (4) is 10-12 kg / cm 2 , tablet weight is 500mg.

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