Empagliflozin orally disintegrating tablet and preparation method thereof

Abstract

The invention discloses an empagliflozin orally disintegrating tablet and a preparation method thereof. The empagliflozin orally disintegrating tablet comprises empagliflozin, a skeleton supporting agent, an adhesive, a suspending aid, a bitterness covering agent, edible essence and a flavoring agent. Through the specific empagliflozin orally disintegrating tablet components and the preparation method thereof, the dosage form of empagliflozin is expanded, auxiliary material components are optimized by removing a wetting agent and a disintegrating agent, the disintegration speed, the dissolution rate and the taste of the empagliflozin orally disintegrating tablet are improved, and the empagliflozin orally disintegrating tablet is suitable for oral administration. And the effects of complete and full tablet shape, uniform color, good taste, rapid disintegration and uniform content are achieved.

Description

Technical Field

[0001] The present invention relates to the field of oral preparations, and in particular to an empagliflozin orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Empagliflozin is a sodium glucose co-transporter 2 (SGLT-2) inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly and Company for the treatment of type II diabetes. It can also benefit cardiovascular health and reduce the risk of cardiovascular death in patients with type 2 diabetes who suffer from heart disease. At present, the only empagliflozin dosage form available in China and abroad is tablets, with the trade name Jardiance. Empagliflozin tablets were approved for marketing through the EU centralized review in May 2014, approved for marketing by the US FDA in August 2014, and launched in China in 2017. However, empagliflozin is extremely slightly soluble in water and has a low drug solubility. The drug solubility directly affects the absorption of the drug, and the low solubility leads to low bioavailability of the existing empagliflozin tablets. Secondly, the existing empagliflozin tablets are affected by the first-pass metabolism of the liver after taking them, and their drug effects are reduced. In addition, children, the elderly, bedridden patients and severely disabled patients are prone to drug refusal, choking, and swallowing difficulties when taking empagliflozin tablets. Therefore, the existing empagliflozin tablets are not friendly to some special groups.

[0003] Patent CN110946832A discloses a tablet with empagliflozin as an active ingredient, wherein empagliflozin is an inclusion compound, the inclusion material is β-cyclodextrin, and the weight ratio of empagliflozin to the inclusion material is 1:1-1:3. However, β-cyclodextrin has low toxicity, and long-term use by diabetic patients will affect the kidneys. Patent CN106692069A discloses an empagliflozin solid dispersion granule and a preparation method thereof, including empagliflozin, a disintegrant povidone and a wetting agent. Empagliflozin and povidone are dissolved in an organic solvent, and a solid dispersion is prepared by a solvent evaporation method or a spray drying method, and then a wetting agent, a disintegrant and a sustained-release agent are added and mixed for tableting. The process flow requires evaporation or spray drying equipment that is not common in the pharmaceutical industry and is not easy to expand in batches. Organic solvents need to be used in the process, which poses a safety hazard and is not in line with environmentally friendly development.

[0004] It can be seen that in the prior art, the empagliflozin products have low dissolution, reduced efficacy, and poor safety; fillers, wetting agents, disintegrants and other excipients are often added during the preparation process, which is costly, complicated and cumbersome, not suitable for expanded production, and there are safety hazards in the production process. The prior art does not disclose an orally disintegrating tablet product of empagliflozin and its preparation method. Summary of the invention

[0005] In order to overcome the defects in the prior art, the present invention provides an empagliflozin orally disintegrating tablet and a preparation method thereof.

[0006] The first aspect of the present invention provides an empagliflozin orally disintegrating tablet, wherein the empagliflozin orally disintegrating tablet comprises:

[0007] Empagliflozin;

[0008] Adhesives;

[0009] Scaffold support agent;

[0010] Suspending agents;

[0011] Food flavors;

[0012] Bitterness masking agent;

[0013] Flavor enhancer.

[0014] Furthermore, the adhesive is selected from one or a combination of two or more of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol and chitosan. Preferably, the adhesive is pullulan.

[0015] Furthermore, the skeleton support agent is selected from one or a combination of two or more of mannitol, glycine, serine, arginine, sorbitol, maltitol, xylitol, lactitol, erythritol, isomalt, dextran, xylose, raffinose, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, maltodextrin, sodium phosphate, sodium chloride and aluminum silicate. Preferably, the skeleton support agent is mannitol.

[0016] Furthermore, the suspending agent is selected from one or a combination of two or more of xanthan gum, gellan gum, sodium carboxymethyl cellulose, carrageenan, and guar gum. Preferably, the suspending agent is xanthan gum.

[0017] Furthermore, the edible flavor is selected from one or a combination of two or more of sweet orange flavor, pineapple flavor, and strawberry flavor. Preferably, the edible flavor is sweet orange flavor.

[0018] Furthermore, the bitterness masking agent is selected from one or a combination of two or more of TruBlock Ultra Powder, adenylic acid, cyclodextrin, and Benecoat BMI-40. Preferably, the bitterness masking agent is TruBlock Ultra Powder.

[0019] Furthermore, the flavoring agent is selected from one or a combination of two or more natural or synthetic flavoring agents such as sucralose, aspartame, saccharin sodium, neotame, acesulfame potassium, aspartame and sucrose. Preferably, the flavoring agent is sucralose and neotame.

[0020] Further, the empagliflozin orally disintegrating tablet contains 0.01-30 parts of empagliflozin by weight (e.g., 1, 2, 3, 4, 5, 6, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 30), preferably, it contains 1-30 parts of empagliflozin by weight, further preferably, it contains 5-30 parts of empagliflozin by weight, further preferably, it contains 6-28 parts of empagliflozin by weight, and particularly preferably, it contains 8-28 parts of empagliflozin by weight.

[0021] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 10 parts of empagliflozin by weight.

[0022] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 25 parts of empagliflozin by weight.

[0023] Further, the empagliflozin orally disintegrating tablet contains 0.01-20 parts of the skeleton agent by weight (such as 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.5, 8, 8.5, 9, 9 .5, 10, 10.5, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20), preferably, it contains 1-20 parts of skeleton agent by weight, further preferably, it contains 1-18 parts of skeleton agent, further preferably, it contains 2-18 parts of skeleton agent by weight, and particularly preferably, it contains 3-15 parts of skeleton agent by weight.

[0024] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 4 parts of the skeleton agent by weight.

[0025] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 10 parts of the skeleton agent by weight.

[0026] Furthermore, the empagliflozin orally disintegrating tablet contains 0.01-15 parts of a binder by weight (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3 , 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15), preferably, it contains 0.1-15 parts of adhesive by weight, further preferably, it contains 1-15 parts of adhesive by weight, further preferably, it contains 1-10 parts of adhesive by weight, and particularly preferably, it contains 2-10 parts of adhesive by weight.

[0027] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 3.2 parts of binder by weight.

[0028] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 8 parts of binder by weight.

[0029] Furthermore, the empagliflozin orally disintegrating tablet contains 0.1-10 parts of a bitter masking agent by weight (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5 , 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.5, 8, 8.5, 9, 9.5, 10), preferably, it contains 1-10 parts of bitter masking agent by weight, further preferably, it contains 1-8 parts of bitter masking agent by weight, further preferably, it contains 1-6 parts of bitter masking agent by weight, and particularly preferably, it contains 1.2-5 parts of bitter masking agent by weight.

[0030] In one embodiment of the present invention, the empagliflozin orally disintegrating tablets contain 1.6 parts of a bitter taste masking agent by weight.

[0031] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 4 parts of a bitter taste masking agent by weight.

[0032] Furthermore, the empagliflozin orally disintegrating tablet contains 0.01-15 parts of a suspending agent by weight (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 9, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1 .8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4 , 6.5, 6.6, 6.7, 68, 6.9, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15), preferably, it contains 0.01-10 parts of suspending agents by weight, further preferably, it contains 0.01-5 parts of suspending agents by weight, even further preferably, it contains 0.05-5 parts of suspending agents by weight, and particularly preferably, it contains 0.1-3 parts of suspending agents by weight.

[0033] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 0.16 parts of a suspending agent by weight.

[0034] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 0.4 parts of a suspending agent by weight.

[0035] Furthermore, the empagliflozin orally disintegrating tablet contains 0.01-15 parts of flavoring agent by weight (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 100 parts by weight). 9, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1 .8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4 , 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15), preferably, it contains 0.01-10 parts of flavoring agents by weight, further preferably, it contains 0.01-5 parts of flavoring agents by weight, further preferably, it contains 0.01-4 parts of flavoring agents by weight, and particularly preferably, it contains 0.1-4 parts of flavoring agents by weight.

[0036] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 0.8 parts of flavoring agent by weight.

[0037] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 2 parts of flavoring agent by weight.

[0038] Furthermore, the flavoring agent is selected from: one or a combination of two or more natural or synthetic flavoring agents such as sucralose, aspartame, saccharin sodium, neotame, acesulfame potassium, aspartame and sucrose. Preferably, the flavoring agent is sucralose and neotame.

[0039] Furthermore, the empagliflozin orally disintegrating tablet contains 0.01-15 parts of sucralose by weight (0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3 .9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15), preferably, containing 0.01-10 parts of sucralose by weight, further preferably, containing 0.01-8 parts of sucralose by weight, and even more preferably, containing 0.01-4 parts of sucralose by weight.

[0040] Furthermore, the empagliflozin orally disintegrating tablet contains 0.01-15 parts of neotame by weight (0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8 , 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15), preferably, it contains 0.01-10 parts of neotame by weight, more preferably, it contains 0.01-8 parts of neotame by weight, and even more preferably, it contains 0.01-4 parts of neotame by weight.

[0041] In one embodiment of the present invention, the empagliflozin orally disintegrating tablets contain 0.4 parts of sucralose and 0.4 parts of neotame by weight.

[0042] In one embodiment of the present invention, the empagliflozin orally disintegrating tablets contain 1 part of sucralose and 1 part of neotame by weight.

[0043] Furthermore, the edible flavor is selected from: mint flavor, sweet orange flavor, pineapple flavor, strawberry flavor, or a combination of two or more thereof. Preferably, the edible flavor is sweet orange flavor.

[0044] Furthermore, the empagliflozin orally disintegrating tablet contains 0.01-10 parts (0.01, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0 .33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.45, 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10), preferably, it contains 0.01-5 parts of edible flavors by weight, and more preferably, it contains 0.01-3 parts of edible flavors by weight.

[0045] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 0.16 parts of edible flavor by weight.

[0046] In one embodiment of the present invention, the empagliflozin orally disintegrating tablet contains 0.4 parts of edible flavor by weight.

[0047] In a specific embodiment of the present invention, the empagliflozin orally disintegrating tablet comprises:

[0048] 10 portions of empagliflozin;

[0049] 3.2 parts of pullulan;

[0050] Mannitol 4 parts;

[0051] 0.16 parts of xanthan gum;

[0052] 0.16 parts of edible flavor;

[0053] 1.6 parts of bitter masking agent;

[0054] Sucralose 0.4 parts;

[0055] 0.4 portion of neotame.

[0056] In a specific embodiment of the present invention, the empagliflozin orally disintegrating tablet comprises:

[0057] Empagliflozin 25 parts;

[0058] 8 parts of pullulan;

[0059] Mannitol 10 parts;

[0060] 0.4 parts of xanthan gum;

[0061] 0.4 parts of edible flavor;

[0062] 4 parts of bitter masking agent;

[0063] 1 part sucralose;

[0064] 1 portion of neotame.

[0065] The second aspect of the present invention provides a method for preparing the empagliflozin orally disintegrating tablets as described in the first aspect, wherein the preparation method is selected from one of freeze-drying, tableting, melting, spray drying, solid solution technology and wet granulation followed by tableting. Preferably, the preparation method is freeze-drying.

[0066] Furthermore, the freeze-drying method comprises the following steps:

[0067] (1) Suspension agent swelling;

[0068] (2) mixing empagliflozin, a backbone agent, a bitterness masking agent, and a flavoring agent;

[0069] (3) adding a suspending agent and purified water to the mixture of step (2);

[0070] (4) using an emulsifier to shear to obtain a freeze-dried solution;

[0071] (5) Filling the freeze-dried solution into the aluminum cavity;

[0072] (6) Pre-freezing;

[0073] (7) freeze-drying the aluminum nest containing the freeze-dried solution;

[0074] (8) Sealing

[0075] The further step (1) of swelling the suspending agent comprises mixing the suspending agent with a small amount of purified water and stirring until the suspending agent is completely dissolved.

[0076] Furthermore, the mixing time described in step (2) is 1-10 min (such as 1 min, 1.5 min, 2 min, 2.5 min, 3 min, 3.5 min, 4 min, 4.5 min, 5 min, 5.5 min, 6 min, 6.5 min, 7 min, 7.5 min, 8 min, 8.5 min, 9 min, 9.5 min, 10 min). Preferably, the mixing time described in step (2) is 1-5 min.

[0077] In one embodiment of the present invention, the mixing time is 2 minutes.

[0078] Further, by weight, the purified water added in step (3) is 70% to 90% of the total amount of the raw materials (e.g., 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 85.5%, 86%, 86.5%, 87%, 87.1%, 87.15%, 87.2%, 87.25%, 87.3%). , 87.35%, 87.4%, 87.45%, 87.5%, 87.55%, 87.6%, 87.65%, 87.7%, 87.75%, 87.8%, 87.85%, 87.9%, 87.95%, 88%, 88.5%, 89%, 89.5%, 90%), preferably, in step (3), pure water is added for 80% to 90% of the total amount of raw materials.

[0079] In one embodiment of the present invention, the amount of purified water added in step (3) is 87.55% of the total amount of the raw materials.

[0080] Furthermore, the setting parameters of the emulsifier described in step (4) are as follows:

[0081] The shear speed of the emulsifier is 1000rpm-3000rpm (such as 1000rpm, 1500rpm, 2000rpm, 2100rpm, 2200rpm, 2250rpm, 2300rpm, 2350rpm, 2400rpm, 2450rpm, 2500rpm, 2550rpm, 2600rpm, 2650rpm, 2700rpm, 2750rpm, 2800rpm, 2850rpm, 2900rpm, 2950rpm, 3000rpm), preferably, the shear speed is 2000rpm-3000rpm.

[0082] The shearing time of the emulsifier is 1 min-20 min (such as 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min). Preferably, the shearing time is 5 min-15 min.

[0083] In one embodiment of the present invention, the setting parameters of the emulsifier described in step (4) are a shear speed of 2500 rpm and a shear time of 10 min.

[0084] Furthermore, the volume of the aluminum nest described in step (5) is 0.01ml-5ml (such as 0.01ml, 0.1ml, 0.2ml, 0.3ml, 0.4ml, 0.5ml, 0.6ml, 0.7ml, 0.8ml, 0.9ml, 1.0ml, 1.2ml, 1.4ml, 1.6ml, 1.8ml, 2ml, 2.5ml, 3ml, 3.5ml, 4ml, 4.5ml, 5ml), preferably, the volume of the aluminum nest described in step (5) is 0.1ml-2ml.

[0085] In one embodiment of the present invention, the volume of the aluminum socket described in step (5) is 0.2 ml.

[0086] In one embodiment of the present invention, the volume of the aluminum socket described in step (5) is 0.4 ml.

[0087] Further, the pre-freezing in step (6) includes: the pre-freezing temperature is -5°C to -80°C (such as -5°C, -10°C, -15°C, -20°C, -25°C, -30°C, -35°C, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, -80°C), preferably, the pre-freezing temperature is -20°C to -80°C, more preferably, the pre-freezing temperature is -40°C to -70°C. The pre-freezing time is 10-20min (such as 10min, 11min, 12min, 13min, 14min, 15min, 16min, 17min, 18min, 19min, 20min).

[0088] In one embodiment of the present invention, the pre-freezing temperature is -60°C and the pre-freezing time is 15 minutes.

[0089] Further, the freeze-drying of the aluminum nest containing the freeze-dried solution in step (7) includes an inlet temperature of -25°C to -40°C (such as -25°C, -26°C, -27°C, -28°C, -29°C, -30°C, -31°C, -32°C, -33°C, -34°C, -35°C, -36°C, -37°C, -38°C, -39°C, -40°C);

[0090] Raise the temperature to -12°C to -20°C (e.g., -12°C, -13°C, -14°C, -15°C, -16°C, -17°C, -18°C, -19°C, -20°C), take 10 min to 20 min (e.g., 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min), maintain for 20 min to 40 min (e.g., 20 min, 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, 35 min, 36 min, 37 min, 38 min, 39 min, 40 min);

[0091] Raise the temperature to 0°C to -10°C (e.g., 0°C, -1°C, -2°C, -3°C, -4°C, -5°C, -6°C, -7°C, -8°C, -9°C, -10°C), take 5min-20min (e.g., 5min, 6min, 7min, 8min, 9min, 10min, 11min, 12min, 13min, 14min, 15min, 16min, 17min, 18min, 19min, 20min), maintain for 60min-120min (e.g., 60min, 65min, 70min, 75min, 80min, 85min, 90min, 95min, 100min, 105min, 110min, 115min, 120min);

[0092] Heat to 5°C ~ 40°C (e.g. 5°C, 10°C, 15°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 40°C), time 5min-40min (e.g. 5min, 10min, 15min, 20min, 21min, 22min, 23min, 24min, 25min, 26min, 27min, 28min The time of treatment should be 20-30 minutes (such as 80min, 85min, 90min, 95min, 100min, 105min, 110min, 115min, 120min, 125min, 130min, 135min, 140min, 145min, 150min).

[0093] In one embodiment of the present invention, freeze-drying the aluminum nest containing the freeze-dried solution comprises:

[0094] -30℃ inlet temperature;

[0095] Raise the temperature from -30℃ to -15℃ in 15min and maintain for 30min;

[0096] Raise the temperature from -15°C to -5°C in 10 minutes and maintain for 90 minutes;

[0097] The temperature was raised from -5°C to 25°C in 30 min and maintained for 120 min.

[0098] Furthermore, the sealing temperature in step (8) is 170°C to 180°C.

[0099] The present invention provides an empagliflozin orally disintegrating tablet and a preparation method thereof through a large number of experimental explorations. Compared with the prior art, the present invention has the following advantages:

[0100] 1. The empagliflozin orally disintegrating tablets of the present invention disintegrate rapidly and can be absorbed by the oral mucosa. The disintegrated small particles are easily absorbed by the stomach and intestines, thereby improving the drug solubility and bioavailability.

[0101] 2. The orally disintegrating tablet of the present invention does not require the addition of a wetting agent and a disintegrant, thereby simplifying the preparation process and production cost, reducing potential safety hazards, and facilitating expansion of production.

[0102] 3. The orally disintegrating tablet of the present invention has good taste and moderate hardness and softness, which solves the problem of single dosage form of empagliflozin, is friendly to special groups of people, improves patients' compliance with medication, and expands the audience range. BRIEF DESCRIPTION OF THE DRAWINGS

[0103] Figure 1 Schematic diagram of the empagliflozin orally disintegrating tablets prepared according to Example 1.

[0104] Figure 2 Schematic diagram of the empagliflozin orally disintegrating tablets prepared according to Example 2.

[0105] Figure 3 This is a schematic diagram of the empagliflozin orally disintegrating tablets after sealing prepared according to Example 1.

[0106] Figure 4 This is a schematic diagram of the empagliflozin orally disintegrating tablets after sealing prepared according to Example 2. DETAILED DESCRIPTION

[0107] In order to more clearly understand the technical content of the present invention, the following embodiments are specifically described in detail, the purpose of which is only to better understand the content of the present invention but not to limit the protection scope of the present invention.

[0108] Example 1 Preparation of 10 mg empagliflozin orally disintegrating tablets

[0109] Table 2 Content of each component in the examples and comparative examples

[0110] name effect Example 1 Example 2 Comparative Example 1 Empagliflozin Active ingredients 10mg 25mg 10mg Mannitol Scaffold support agent 4mg 10mg 4mg Pullulan Adhesives 3.2mg 8mg 3.2mg TruBlock Ultra Powder Bitterness masking agent 1.6mg 4mg 1.6mg Sucralose Flavoring agents 0.4mg 1mg 0.4mg Neotame Flavoring agents 0.4mg 1mg 0.4mg Xanthan gum Suspending Agents 0.16mg 0.4mg 0.16mg Sweet orange flavor Food flavors 0.16mg 0.4mg - Mint flavor Food flavors - - 0.16mg Polysorbate 80 Wetting Agents - - Purified water Solvents 140.1mg 350.2mg Total weight / 160.02mg 400mg

[0111] After weighing the components according to Table 2, empagliflozin orally disintegrating tablets were prepared by freeze-drying method, and the steps were as follows:

[0112] (1) Suspending agent swelling: Mix xanthan gum with a small amount of purified water and stir until completely dissolved;

[0113] (2) Mix empagliflozin, backbone agent, bitterness masking agent and flavoring agent by manual mixing for 2 minutes and adding a small amount of purified water to dissolve into a paste;

[0114] (3) Adding a suspending agent and purified water to the mixture in step (2): Add the xanthan gum solution to the paste solution in step (2), continue to add purified water to the amount of the component, and stir until there are no large lumps;

[0115] (4) using an emulsifier for shearing to obtain a freeze-dried solution: the speed is 2500 rpm, and the time is 10 min;

[0116] (5) Fill the lyophilized solution into an aluminum cup: fill into a 0.2 ml aluminum cup;

[0117] (6) Prefreezing: Prefreeze in -60℃ refrigerator for 15 minutes.

[0118] (7) The aluminum nest containing the freeze-dried solution is freeze-dried to form a freeze-drying curve:

[0119] -30℃ inlet temperature;

[0120] Raise the temperature to -15°C for 15 minutes and maintain for 30 minutes;

[0121] Raise the temperature to -5°C in 10 minutes and maintain for 90 minutes;

[0122] Raise the temperature to 25°C in 30 minutes and maintain for 120 minutes.

[0123] (8) Sealing: Sealed at 170℃~180℃.

[0124] Example 2 Preparation of 25 mg empagliflozin orally disintegrating tablets

[0125] After weighing the weight of each component of Example 2 according to Table 2, empagliflozin orally disintegrating tablets were prepared by freeze-drying method, and the steps were as follows:

[0126] (1) Suspending agent swelling: Mix xanthan gum with a small amount of purified water and stir until completely dissolved;

[0127] (2) Mix empagliflozin, backbone agent, bitterness masking agent and flavoring agent by manual mixing for 2 minutes and adding a small amount of purified water to dissolve into a paste;

[0128] (3) Adding a suspending agent and purified water to the mixture in step (2): Add the xanthan gum solution to the paste solution in step (2), continue to add purified water to the amount of the component, and stir until there are no large lumps;

[0129] (4) using an emulsifier for shearing to obtain a freeze-dried solution: the speed is 2500 rpm, and the time is 10 min;

[0130] (5) Fill the lyophilized solution into an aluminum cup: fill into a 0.4 ml aluminum cup;

[0131] (6) Prefreezing: Prefreeze in -60℃ refrigerator for 15 minutes.

[0132] (7) The aluminum nest containing the freeze-dried solution is freeze-dried to form a freeze-drying curve:

[0133] -30℃ inlet temperature;

[0134] Raise the temperature to -15°C for 15 minutes and maintain for 30 minutes;

[0135] Raise the temperature to -5°C in 10 minutes and maintain for 90 minutes;

[0136] Raise the temperature to 25°C in 30 minutes and maintain for 120 minutes.

[0137] (8) Sealing: Sealed at 170℃~180℃.

[0138] Comparative Example 1

[0139] The components of Comparative Example 1 in Table 2 were weighed and empagliflozin orally disintegrating tablets were prepared by freeze-drying. The steps were the same as those in Example 1, except that polysorbate 80 was added as a wetting agent in step (2), and the sweet orange flavor in Example 1 was replaced by mint flavor.

[0140] Experimental Results

[0141] 1. The scores of various indicators of the 10 mg empagliflozin orally disintegrating tablets prepared in Example 1 are as follows:

[0142] The scoring standard is: 5 points are the full score, and 3 points and above are considered a pass.

[0143] Table 3 Ratings of 10 mg empagliflozin orally disintegrating tablets

[0144]

[0145]

[0146] It can be seen that the empagliflozin orally disintegrating tablets of Example 1 have good tablet shape, and the tablet shape, disintegration time and content uniformity all meet the requirements.

[0147] 2. Content uniformity test of empagliflozin orally disintegrating tablets prepared in Example 1 and Example 2

[0148] Table 4 Disintegration time of 10 mg and 25 mg orally disintegrating tablets

[0149]

[0150] Table 5 Content uniformity test results of 10 mg and 25 mg orally disintegrating tablets

[0151]

[0152]

[0153] Table 6 Scoring of various indicators for 10mg and 25mg specifications

[0154]

[0155]

[0156] It can be seen that the empagliflozin orally disintegrating tablets prepared in Example 1 and Example 2 both have stable quality.

[0157] In the uniformity test results of Example 1 and Example 2, there were samples with lower content values ​​(about 94%) and abnormal deviations (about 104%) in the 10 mg (230510-1-2 batch) and 25 mg (230510-1-1 batch) samples. After conversion by tablet weight, it was found that the errors were caused by manual filling, which could be controlled and were low-risk. The A+2.2S of the two batches of samples were 6.1 and 5.3 respectively, which met the requirements.

[0158] 3. In Comparative Example 1, the intermediate drug solution of the orally disintegrating tablets to which a wetting agent and mint flavor were added was a white suspension, and the tablets were round freeze-dried tablets, but the tablet shape was not full and had cracks. It has been verified that the incomplete tablet shape and the cracks were caused by the mint flavor reducing the surface tension of the drug solution. It can be seen that sweet orange flavor is more conducive to improving the texture quality of empagliflozin orally disintegrating tablets than mint flavor. The embodiments described above are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, other embodiments obtained by technicians in this field without creative labor belong to the scope of protection of the present invention.

Claims

1. An empagliflozin orally disintegrating tablet, characterized in that: The orally disintegrating tablet comprises empagliflozin, a binder, a skeleton support agent, a suspending agent, an edible flavor, a bitterness masking agent and a flavor corrective, and no wetting agent and disintegrant are added to the orally disintegrating tablet.

2. The empagliflozin orally disintegrating tablet according to claim 1, characterized in that The components of the orally disintegrating tablet include, by weight, 8-28 parts of empagliflozin, 2-10 parts of a binder, 3-15 parts of a skeleton support agent, 0.1-3 parts of a suspending agent, 0.1-3 parts of an edible flavor, 1-5 parts of a bitterness masking agent, and 0.1-4 parts of a flavor corrector.

3. The empagliflozin orally disintegrating tablet according to claim 1, characterized in that The adhesive is selected from one or a combination of two or more of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol and chitosan; preferably, the adhesive is pullulan; and / or, The skeleton support agent is selected from one or a combination of two or more of mannitol, glycine, serine, arginine, sorbitol, maltitol, xylitol, lactitol, erythritol, isomalt, dextran, xylose, raffinose, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, maltodextrin, sodium phosphate, sodium chloride and aluminum silicate; preferably, the skeleton support agent is mannitol; and / or, The suspending agent is selected from one or a combination of two or more of xanthan gum, gellan gum, sodium carboxymethyl cellulose, carrageenan, and guar gum; preferably, the suspending agent is xanthan gum; and / or, The edible flavor is selected from one or a combination of two or more of sweet orange flavor, pineapple flavor and strawberry flavor; preferably, the edible flavor is sweet orange flavor; and / or, The bitterness masking agent is selected from one or a combination of two or more of TruBlock Ultra Powder, adenylic acid, cyclodextrin, and Benecoat BMI-40; preferably, the bitterness masking agent is TruBlock Ultra Powder; and / or, The flavoring agent is selected from one or a combination of two or more natural or synthetic flavoring agents such as sucralose, aspartame, saccharin sodium, neotame, acesulfame potassium, aspartame and sucrose; preferably, the flavoring agent is sucralose and neotame.

4. A method for preparing the empagliflozin orally disintegrating tablet according to claim 1, characterized in that: The preparation method is freeze-drying.

5. The preparation method according to claim 4, characterized in that: The freeze-drying method comprises the following steps: (1) Swelling the suspending agent for standby use; (2) mixing empagliflozin, a skeleton agent, a binder, an edible flavor, a bitterness masking agent, and a flavor corrector; (3) adding the swollen suspending agent and purified water to the mixture of step (2); (4) using an emulsifier to shear to obtain a freeze-dried solution; (5) Filling the freeze-dried solution into the aluminum cavity; (6) Pre-freezing; (7) freeze-drying the aluminum nest containing the freeze-dried solution; (8) Sealing.

6. The preparation method according to claim 5, characterized in that: Step (1) comprises mixing the suspending agent with a small amount of purified water and stirring until completely dissolved; and / or, The mixing time in step (2) is 1-10 min; preferably, the mixing time is 1-5 min; and / or, By weight, the amount of purified water added in step (3) is 70% to 90% of the total amount of the raw materials. Preferably, the amount of purified water added in step (3) is 80% to 90% of the total amount of the raw materials; and / or, In step (4), the speed of shearing by the emulsifier is 1000rpm-3000rpm, and the shearing time is 1-20min; preferably, the speed of shearing by the emulsifier is 2000rpm-3000rpm, and the shearing time is 5-15min; and / or, The volume of the aluminum socket described in step (5) is 0.01-5 mL; preferably, the volume of the aluminum socket described in step (5) is 0.1-2 mL.

7. The preparation method according to claim 5, characterized in that: The pre-freezing conditions described in step (6) include: a pre-freezing time of 10-20 minutes, a pre-freezing temperature of -20°C to -80°C; preferably, the pre-freezing temperature is -40°C to -70°C.

8. The preparation method according to claim 5, characterized in that: The freeze-drying molding described in step (7) comprises the following steps: Step (7-1) -25℃~-40℃ entering the box; Step (7-2) is to raise the temperature from -25°C to -40°C to -12°C to -20°C for 10 min to 20 min and maintain for 20 min to 40 min; Step (7-3) is to raise the temperature from -12°C to -20°C to 0°C to -10°C for 5 min to 20 min and maintain for 60 min to 120 min; Step (7-4) is to raise the temperature from 0°C to -10°C to 5°C to 40°C for 5 min to 40 min and maintain for 80 min to 150 min.

9. The preparation method according to claim 5, characterized in that: The sealing temperature in step (8) is 170°C to 180°C.

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