A tablet of iclaprim ethanolamine and a preparation method thereof

Abstract

The application relates to the technical field of medicines, in particular to an icotinamide tablet of icotinib and a preparation method thereof; the icotinamide tablet of icotinib comprises the following components: icotinamide, an amphiphilic carrier, a microenvironment regulator and pharmaceutically acceptable adjuvants, wherein the mass ratio of the icotinamide, the amphiphilic carrier and the microenvironment regulator is 1:(1-3):(0.5-1.5), the amphiphilic carrier is Soluplus, and the microenvironment regulator is meglumine; the application discloses an icotinamide tablet of icotinib and a preparation method thereof; the three components of icotinamide, the amphiphilic carrier Soluplus and the microenvironment regulator meglumine are ground together, the solubility and the dissolution of the medicine in a high-calcium medium can be effectively improved, the postprandial bioavailability is increased, and the stability is good.

Description

Technical Field

[0001] This invention relates to the technical field of pharmaceuticals, and in particular to an eltrombopag ethanolamine tablet and its preparation method. Background Technology

[0002] Eltrombopag is a thrombopoietin (TPO) receptor agonist developed by GlaxoSmithKline (GSK) in the UK. It was launched in the US in November 2008 under the brand name Promacta and approved on November 19, 2012, for the treatment of thrombocytopenia in patients with chronic hepatitis C. This drug is also indicated for aplastic anemia (SAA), idiopathic thrombocytopenic purpura (ITP), and was the first oral treatment for immune thrombocytopenic purpura. It is classified as a BCS class II / IV, and its molecular formula is C2. 25 H 22 N4O4·2(C2H7NO), the structural formula is as follows:

[0003]

[0004] Eltrombopag ethanolamine tablets are to be taken on an empty stomach (1 hour before or 2 hours after a meal). They should be taken at least 2 hours before or 4 hours after taking antacids, dairy products, or mineral supplements containing polyvalent cations (such as aluminum, calcium, iron, magnesium, selenium, and zinc).

[0005] Studies have reported that eltrombopag can chelate with polyvalent cations such as iron, calcium, magnesium, aluminum, selenium, and zinc. A single dose of 75 mg eltrombopag ethanolamine combined with an antacid containing polyvalent cations (1524 mg aluminum hydroxide and 1425 mg magnesium carbonate) resulted in a plasma AUC of eltrombopag. 0-∞ Reduced by 70%, C max A 70% reduction. After consuming a standard high-fat breakfast (876 calories, 52g fat, 71g carbohydrates, 34g protein, and 427mg calcium), the plasma AUC... 0-INF It decreased by 59%, C max The absorption of eltrombopag ethanolamine was reduced by 65%, and the time to peak concentration was delayed by 1 hour. Furthermore, studies have shown that the calcium content in food is the main factor affecting the absorption of eltrombopag ethanolamine, and a low-calcium diet (≤50mg calcium) has no significant effect on plasma eltrombopag ethanolamine exposure. Therefore, this product should be taken at least 4 hours apart from antacids, dairy products, and other products containing polyvalent cations (such as mineral supplements) to avoid a significant reduction in the absorption of this product due to chelation.

[0006] During the research and development process, it was discovered that the solubility of eltrombopag ethanolamine is pH-dependent; it is almost insoluble in acidic media, but has a certain solubility in alkaline media and water.

[0007] In summary, eltrombopag ethanolamine is a pH-dependent, poorly soluble drug with a slow dissolution rate. When ingested, it forms chelates with polyvalent cations, further reducing dissolution and bioavailability, severely impacting the drug's efficacy.

[0008] Therefore, there is a need to develop an eltrombopag ethanolamine formulation that is not affected by polyvalent cations in food, has high solubility and dissolution, so that patients do not need to eat before or after taking the medication, thus improving patient compliance. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this invention provides eltrombopag ethanolamine tablets and their preparation method, aiming to improve the dissolution rate of eltrombopag ethanolamine, solve the problem of reduced postprandial drug absorption caused by polyvalent cations in food, and exhibit good stability, simple process, and suitability for industrial production.

[0010] In a first aspect, this application provides a pharmaceutical composition, which adopts the following technical solution:

[0011] A pharmaceutical composition comprising the following components: eltrombopag ethanolamine, an amphiphilic carrier, and a microenvironment modifier.

[0012] Preferably, the mass ratio of eltrombopag ethanolamine, the amphiphilic carrier, and the microenvironment regulator is 1:(1-3):(0.5-1.5).

[0013] More preferably, the mass ratio of eltrombopag ethanolamine, the amphiphilic carrier, and the microenvironment regulator is 1:(1-3):1.

[0014] Preferably, the amphiphilic vector is

[0015] Preferably, the microenvironment regulator is meglumine.

[0016] In this application, eltropol ethanolamine is combined with an amphiphilic carrier. Grinding meglumine, a microenvironment modifier, and other related ingredients together can effectively improve drug solubility and dissolution in high-calcium media, increase postprandial bioavailability, and exhibit good stability. Eltrombopag ethanolamine can be combined with... By combining, the chances of the drug coming into contact with polyvalent cations are reduced, which is beneficial for drug dissolution; meglumine can provide an alkaline microenvironment for the drug, and alkaline conditions will inhibit the formation of chelates, which is beneficial for drug dissolution and makes the drug more stable. In conjunction with meglumine, it reduces the formation of chelates between polyvalent cations and eltrombopag ethanolamine, thereby improving drug solubility and dissolution rate, and increasing postprandial bioavailability. This eliminates the need for patients to eat before and after taking the medication, improving patient compliance.

[0017] The chemical name is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, composed of 13% polyethylene glycol (PEG) 6000, 57% vinylcaprolactam, and 30% vinyl acetate. The hydrophilic PEG 6000 forms the main chain, while the lipophilic vinyl acetate and vinylcaprolactam are randomly copolymerized as side chains. Therefore, It is amphiphilic, soluble in both aqueous and organic solvents. Based on this dual-function property, it can serve as a skeletal polymer for solid solutions and as a solubilizer to increase the solubility and oral bioavailability of poorly soluble drugs. When applied to solid dosage forms, it is suitable for a variety of processes, such as physical mixing, melt granulation, spray drying, and hot melt extrusion. Because of its hydrophilicity and non-ionic nature, its solubility does not change with the pH of the gastrointestinal tract. It exhibits excellent solubility, especially for Class II drugs in the Biopharmaceutics Classification System (BCS), and is widely used to improve the solubility and bioavailability of poorly soluble drugs.

[0018] N-methyl-D-glucosamine is a widely used balanced ion for improving drug solubility. It is an amino sugar derived from glucose with a PKa value of 9.6. Due to its similar permeability and ionic radius to sodium and its inability to cross cell membranes, N-methyl-D-glucosamine is increasingly being used as a sodium alternative. Compared to basic sodium salts, its high degree of dissociation in vivo significantly improves the bioavailability of the active pharmaceutical ingredient and completely avoids the toxicological effects of sodium salts.

[0019] Secondly, this application provides an eltrombopag ethanolamine tablet, which adopts the following technical solution:

[0020] An eltrombopag ethanolamine tablet comprises the above-described pharmaceutical composition and pharmaceutically acceptable excipients.

[0021] Preferred, pharmaceutically acceptable excipients include 150-300 parts by weight of filler, 20-40 parts by weight of disintegrant, and 1-10 parts by weight of lubricant.

[0022] Preferably, the filler is one or more of mannitol, lactose, microcrystalline cellulose, starch, and sorbitol.

[0023] Preferably, the disintegrant is one or more of croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and croscarmellose.

[0024] Preferably, the lubricant is one or more of stearic acid, magnesium stearate, talc, and silicon dioxide.

[0025] Thirdly, this application provides a method for preparing eltrombopag ethanolamine tablets, which adopts the following technical solution: A method for preparing eltrombopag ethanolamine tablets, the preparation steps are as follows: eltrombopag ethanolamine is ground and mixed with an amphiphilic carrier and a microenvironment regulator, and then a filler, a disintegrant, and a lubricant are added and mixed, then tableted and coated to obtain eltrombopag ethanolamine tablets.

[0026] A method for preparing eltrombopag ethanolamine tablets, comprising the following steps:

[0027] (1) Weigh the raw materials for eltrombopag ethanolamine tablets according to the prescription amount;

[0028] (2) Grind and mix eltrombopag ethanolamine, amphiphilic carrier, and microenvironment regulator for 8-12 minutes, then pass through an 80-mesh sieve;

[0029] (3) Pass the filler, disintegrant and lubricant through a 60-mesh sieve respectively;

[0030] (4) After mixing the mixture obtained in step (2) with the filler and disintegrant for 8-12 minutes, add the lubricant and mix for 3-8 minutes to obtain intermediate particles;

[0031] (5) After compressing the intermediate particles into tablets, they are coated with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0032] In one specific feasible embodiment, a method for preparing eltrombopag ethanolamine tablets includes the following steps: reacting eltrombopag ethanolamine with an amphiphilic carrier. After grinding and mixing the microenvironment regulator meglumine, filler, disintegrant, and lubricant together, the mixture was then added, mixed evenly, compressed into tablets, and coated to obtain eltrombopag ethanolamine tablets.

[0033] In one specific feasible embodiment, a method for preparing eltrombopag ethanolamine tablets, wherein the tablets are prepared by a direct compression process from powder, and the preparation process is as follows:

[0034] (1) Weigh the raw materials for eltrombopag ethanolamine tablets according to the prescription amount;

[0035] (2) Eltrombopag ethanolamine, After grinding and mixing with meglumine for 8-12 minutes, pass through an 80-mesh sieve and set aside;

[0036] (3) Pass the filler, disintegrant and lubricant through a 60-mesh sieve and set aside;

[0037] (4) After mixing the mixture obtained in step (2) with the prescribed amount of filler and disintegrant for 8-12 minutes, add lubricant and mix for 3-8 minutes to obtain intermediate particles;

[0038] (4) The intermediate particles were compressed into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0039] (5) The eltrombopag ethanolamine tablets were coated with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0040] In this application, raw materials and excipients are ground. Mechanochemistry is an emerging interdisciplinary field that studies the changes in the physicochemical properties of materials under high-energy mechanical forces. The mechanical forces generated can be shear forces, impact forces, grinding forces during processing, or pressure and friction forces from general methods. Mechanochemistry has many advantages, such as simple preparation processes, requiring only one step to obtain the desired target product; undemanding preparation conditions, usually carried out at room temperature, avoiding the structural damage of heat-sensitive drugs caused by high temperatures and heat under thermochemical reaction conditions; minimal use of chemical reagents during preparation, saving costs and avoiding the increase in processing costs due to residual solvents; and the mechanical forces generated during preparation can promote the interaction between poorly soluble drugs and hydrophilic carriers, thereby improving the drug dissolution rate and its oral bioavailability.

[0041] In summary, this application includes at least one of the following beneficial technical effects:

[0042] 1. This application discloses an eltrombopag ethanolamine tablet and its preparation method, comprising eltrombopag ethanolamine and an amphiphilic carrier. When ground together with the microenvironment regulator meglumine, the drug's solubility and dissolution rate in high-calcium media can be effectively improved, postprandial bioavailability can be increased, and good stability can be achieved.

[0043] 2. This application discloses an eltrombopag ethanolamine tablet and its preparation method. Eltrombopag ethanolamine can be combined with... By reducing the chance of the drug coming into contact with polyvalent cations, it is beneficial to drug dissolution; meglumine can provide an alkaline microenvironment for the drug, and alkaline conditions will inhibit the formation of chelates, which is beneficial to drug dissolution and has better stability; Together with meglumine, it reduces the formation of chelates between polyvalent cations and eltrombopag ethanolamine, improving drug solubility and dissolution, increasing postprandial bioavailability, eliminating the need for patients to eat before and after taking the medication, and improving patient compliance.

[0044] 3. This application discloses an eltrombopag ethanolamine tablet and its preparation method, which has good stability, simple process, and is suitable for industrial production. Detailed Implementation

[0045] All raw materials involved in this application are commercially available products, among which,

[0046] Purchased from BASF in Germany;

[0047] Microcrystalline cellulose was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., model number SH102;

[0048] Sodium carboxymethyl starch was purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.

[0049] Eltrombopag ethanolamine tablets are the original formulation, manufactured by Novartis Pharma Schweiz AG, under the brand name Refulan, in a strength of 25mg, batch number 987H.

[0050] The present application will be further described in detail below with reference to embodiments and comparative examples.

[0051] Example 1

[0052] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0053] Table 1. Composition of the eltrombopag ethanolamine tablet prescription

[0054]

[0055] A method for preparing eltrombopag ethanolamine tablets, comprising the following steps:

[0056] 1) Eltrombopag ethanolamine, Grind and mix with meglumine in a 1:1:1 ratio for 10 minutes, then pass through an 80-mesh sieve for later use.

[0057] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0058] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0059] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0060] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0061] Example 2

[0062] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0063] Table 2. Composition of the eltrombopag ethanolamine tablet prescription

[0064]

[0065] A preparation process for eltrombopag ethanolamine tablets, the preparation steps are as follows:

[0066] 1) Eltrombopag ethanolamine, Grind and mix with meglumine at a ratio of 1:2:1 for 10 minutes, then pass through an 80-mesh sieve for later use;

[0067] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0068] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0069] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0070] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0071] Example 3

[0072] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0073] Table 3. Composition of the eltrombopag ethanolamine tablet prescription

[0074]

[0075] A preparation process for eltrombopag ethanolamine tablets, the preparation steps are as follows:

[0076] 1) Eltrombopag ethanolamine, Grind and mix with meglumine in a 1:3:1 ratio for 10 minutes, then pass through an 80-mesh sieve for later use;

[0077] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0078] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0079] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0080] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0081] Example 4

[0082] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0083] Table 4. Composition of the eltrombopag ethanolamine tablet prescription

[0084]

[0085] A preparation process for eltrombopag ethanolamine tablets, the preparation steps are as follows:

[0086] 1) Eltrombopag ethanolamine, Grind and mix with meglumine at a ratio of 1:2:0.5 for 10 minutes, then pass through an 80-mesh sieve for later use;

[0087] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0088] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0089] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0090] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0091] Example 5

[0092] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0093] Table 5. Composition of the Eltrombopag Ethanolamine Tablet Formula

[0094]

[0095] A preparation process for eltrombopag ethanolamine tablets, the preparation steps are as follows:

[0096] 1) Eltrombopag ethanolamine, Grind and mix with meglumine at a ratio of 1:2:1.5 for 10 minutes, then pass through an 80-mesh sieve for later use;

[0097] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0098] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0099] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0100] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0101] Comparative Example 1

[0102] In the preparation process of this comparative example, no additives were used. Specifically as follows:

[0103] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0104] Table 6. Composition of the Eltrombopag Ethanolamine Tablet Formula

[0105] raw materials Weight (g) Eltrombopag ethanolamine 31.9 meglumine 31.9 Mannitol 30 microcrystalline cellulose 210 Sodium carboxymethyl starch 27 magnesium stearate 3

[0106] A method for preparing eltrombopag ethanolamine tablets, comprising the following steps:

[0107] 1) Grind and mix eltrombopag ethanolamine and meglumine for 10 minutes, then pass through an 80-mesh sieve for later use;

[0108] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0109] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0110] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0111] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0112] Comparative Example 2

[0113] In this comparative example, eltrombopag ethanolamine, The meglumine was mixed in a ratio of 1:4:1, as follows:

[0114] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0115] Table 7. Composition of the Eltrombopag Ethanolamine Tablet Formula

[0116]

[0117] A method for preparing eltrombopag ethanolamine tablets, comprising the following steps:

[0118] 1) Eltrombopag ethanolamine, Grind and mix with meglumine at a ratio of 1:4:1 for 10 minutes, then pass through an 80-mesh sieve for later use;

[0119] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0120] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0121] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0122] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0123] Comparative Example 3

[0124] The difference between this comparative example and Example 2 is that meglumine is not added, as detailed below:

[0125] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0126] Table 8. Composition of the Eltrombopag Ethanolamine Tablet Formula

[0127]

[0128] A preparation process for eltrombopag ethanolamine tablets, the preparation steps are as follows:

[0129] 1) Eltrombopag ethanolamine and After grinding and mixing for 10 minutes, pass the mixture through an 80-mesh sieve and set aside.

[0130] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0131] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0132] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0133] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0134] Comparative Example 4

[0135] The difference between this comparative example and Example 2 is that eltrombopag ethanolamine is not included. Co-grinding with meglumine, then directly mixing the raw materials and excipients before tableting, as detailed below:

[0136] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0137] Table 9. Composition of the Eltrombopag Ethanolamine Tablet Formula

[0138]

[0139] A preparation process for eltrombopag ethanolamine tablets, the preparation steps are as follows:

[0140] 1) Eltrombopag ethanolamine, Both the methylphenidate and meglumine were passed through an 80-mesh sieve and set aside.

[0141] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0142] 3) The prescribed amount of eltrombopag ethanolamine, After mixing meglumine, mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 minutes, magnesium stearate was added and mixed for 5 minutes to obtain intermediate particles.

[0143] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0144] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0145] Comparative Example 5

[0146] The difference between this comparative example and Example 2 is that: eltrombopag ethanolamine, Meglumine was mixed in a 1:2:2 ratio, as follows:

[0147] An eltrombopag ethanolamine tablet, each tablet containing 25mg of eltrombopag, with a conversion factor of 1.276, is equivalent to 31.9mg of eltrombopag ethanolamine; the prescription composition is as follows (a total of 1000 tablets were prepared):

[0148] Table 10. Composition of Eltrombopag Ethanolamine Tablets

[0149]

[0150] A method for preparing eltrombopag ethanolamine tablets, comprising the following steps:

[0151] 1) Eltrombopag ethanolamine, Grind and mix with meglumine in a 1:2:2 ratio for 10 minutes, then pass through an 80-mesh sieve for later use.

[0152] 2) Pass the remaining auxiliary materials through a 60-mesh sieve for later use;

[0153] 3) Mix the mixture obtained in 1) with the prescribed amounts of mannitol, microcrystalline cellulose, and sodium carboxymethyl starch for 10 min, then add magnesium stearate and mix for 5 min to obtain intermediate particles.

[0154] 4) Compress the intermediate particles obtained in 3) into tablets using a tableting machine to obtain eltrombopag ethanolamine tablets;

[0155] 5) Coat the eltrombopag ethanolamine tablets obtained in 4) with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

[0156] Test Example 1: Dissolution Curve Examination

[0157] According to reports, the peak plasma concentration of eltrombopag ethanolamine reaches 2 hours, suggesting that the main site of dissolution and absorption is the small intestine. Therefore, the FDA and Japanese drug review information selected a pH 6.8 phosphate buffer system to evaluate the dissolution behavior of the formulation. This study referenced the FDA's published dissolution method for eltrombopag ethanolamine, using 900 ml of pH 6.8 phosphate buffer containing 0.5% Tween-80 (v / v), a paddle pump at 50 rpm, and sampling at 10, 15, 20, 45, and 60 min. Dissolution was investigated for Examples 1-5, Comparative Examples 1-5, and the original formulation Refulan (25 mg). The results are shown in Table 11. Dissolution was also investigated for a simulated high-calcium meal medium (calcium chloride was added to the medium to prepare a solution containing 0.01 mol / L calcium chloride, i.e., 400 mg calcium and 0.5% Tween-80 in 900 ml of medium at pH 6.8). The results are shown in Table 12.

[0158] Table 11 Dissolution results of drug formulations in phosphate medium at pH 6.8 containing 0.5% Tween-80 (unit: %, where n = 6)

[0159] 10min 15min 20min 45min 60min Example 1 80.9 93.2 95.6 97.8 99.3 Example 2 85.3 96.8 98.2 99.2 99.5 Example 3 86.8 94.7 96.8 98.5 99.2 Example 4 75.2 91.6 95.1 99.1 99.2 Example 5 83.5 93.0 94.3 97.6 98.5 Comparative Example 1 63.5 75.3 80.4 85.9 90.6 Comparative Example 2 45.9 60.9 68.3 78.3 79.6 Comparative Example 3 68.9 77.6 81.6 87.2 91.4 Comparative Example 4 49.3 64.5 70.8 81.4 86.2 Comparative Example 5 50.3 69.7 79.1 89.2 93.2 Original reagent 82.3 92.6 95.2 98.1 98.3

[0160] According to the results in Table 11, in a phosphate medium containing 0.5% Tween-80 at pH 6.8, the dissolution curves of the formulations prepared in Examples 1-5 were consistent with those of the original formulation, with a cumulative dissolution of more than 85% in 15 minutes. However, the dissolution of the formulations prepared in Comparative Examples 1-5 was slightly slower. This indicates that the eltrombopag ethanolamine tablets disclosed in this application have good dissolution performance.

[0161] Based on the results in Table 11, Examples 1-3, and Comparative Example 1, it can be seen that the dissolution rate of Examples 1-3 is better than that of Comparative Example 1, indicating that the added... Binds to eltrombopag ethanolamine, The amphiphilicity of the drug can improve its dissolution properties.

[0162] Combining the results in Table 11, Examples 1-3, and Comparative Example 2, it can be seen that the dissolution rate of Examples 1-3 is better than that of Comparative Example 2, indicating that when... When the amount of excipients increases, the excess excipients accumulating around the drug can hinder drug dissolution, thereby reducing the drug dissolution rate.

[0163] Based on the results in Table 11, Example 2, and Comparative Example 3, it can be seen that the dissolution rate of Example 2 is better than that of Comparative Example 3, indicating that the added meglumine can provide an alkaline microenvironment for the drug, which is beneficial to drug dissolution.

[0164] Combining the results in Table 11, Example 2, and Comparative Example 4, it can be seen that the dissolution rate of Example 2 is better than that of Comparative Example 4, indicating that eltrombopag ethanolamine and Meglumine was not co-ground, and eltrombopag ethanolamine and The meglumine molecules failed to bind together, thus failing to increase the drug's dissolution rate.

[0165] Based on the results in Table 11, Example 2, and Comparative Example 5, it can be seen that the dissolution rate of Example 2 is better than that of Comparative Example 5. This indicates that when the amount of meglumine increases, the excess excipients accumulating around the drug will hinder the drug's dissolution, thereby reducing the drug's dissolution rate.

[0166] Table 12 Dissolution results of pharmaceutical formulations in a phosphate medium containing 0.01 mol / L calcium chloride and 0.5% Tween-80 at pH 6.8 (unit: %, where n = 6).

[0167] 10min 15min 20min 45min 60min Example 1 78.9 90.6 93.2 96.5 97.3 Example 2 82.6 92.5 95.0 96.3 98.2 Example 3 81.5 91.9 94.5 95.9 98.9 Example 4 72.10 90.30 92.10 95.40 98.20 Example 5 80.5 90.2 91.7 95.4 96.9 Comparative Example 1 15.6 20.6 23.6 33.5 35.6 Comparative Example 2 40.6 51.3 57.3 62.8 65.9 Comparative Example 3 26.7 35.6 39.7 48.6 50.8 Comparative Example 4 17.5 23.5 25.6 31.5 32.5 Comparative Example 5 43.1 58.2 64.2 69.5 70.1 Original reagent 28.6 40.8 45.3 55.9 56.0

[0168] As shown in Tables 11 and 12, in a medium containing 0.01 mol / L calcium chloride and 0.5% Tween-80 at pH 6.8, the dissolution of the formulations in Examples 1-5 showed no significant change compared to the dissolution in a calcium-free medium, with a cumulative dissolution of more than 85% over 15 minutes. However, the dissolution curves of Comparative Examples 1-5 and the original formulations in a medium containing 0.01 mol / L calcium chloride and 0.5% Tween-80 at pH 6.8 all showed a significant decrease.

[0169] Referring to Tables 11 and 12, it can be seen that the formulations prepared in Examples 1-5 have similar dissolution curves to the original formulation in a calcium-free medium; however, in a calcium-containing medium, the dissolution rate of Examples 1-5 is superior to that of Comparative Examples 1-5 and the original formulation, indicating that the eltrombopag ethanolamine tablets disclosed in this application, with eltrombopag ethanolamine and added... The combined action of meglumine and eltrombopag ethanolamine reduces the formation of chelates between polyvalent cations and eltrombopag ethanolamine, thus ensuring that the prepared formulation still exhibits good dissolution performance in calcium-containing media.

[0170] Based on the results in Table 12, Examples 1-3, and Comparative Example 1, it can be seen that the dissolution rate of Examples 1-3 is better than that of Comparative Example 1, indicating that the added... By binding with eltrombopag ethanolamine, the chance of the drug coming into contact with polyvalent cations is reduced, and the formation of chelates between the drug and polyvalent cations is avoided, so that the prepared formulation still has good dissolution performance in calcium-containing media.

[0171] Combining the results in Table 12, Examples 1-3, and Comparative Example 2, it can be seen that the dissolution rate of Examples 1-3 is better than that of Comparative Example 2, indicating that when... When the amount of excipients increases, the excess excipients accumulating around the drug can hinder drug dissolution, thereby reducing the drug dissolution rate.

[0172] Based on the results in Table 12, Example 2, and Comparative Example 3, it can be seen that the dissolution rate of Example 2 is better than that of Comparative Example 3, indicating that the added meglumine can provide an alkaline microenvironment for the drug. Alkaline conditions will hinder the formation of chelates and facilitate drug dissolution.

[0173] Combining the results in Table 12, Example 2, and Comparative Example 4, it can be seen that the dissolution rate of Example 2 is better than that of Comparative Example 4, indicating that eltrombopag ethanolamine and Meglumine was not co-ground, and eltrombopag ethanolamine and The meglumine failed to bind with the other components, thus failing to improve the drug's dissolution rate; in this application, eltrapoethanolamine is combined with an amphiphilic carrier. Grinding the microenvironment regulator meglumine together with these three ingredients can effectively improve the solubility and dissolution of drugs in high-calcium media.

[0174] Based on the results of Example 2 and Comparative Example 5, it can be seen that the dissolution rate of Example 2 is better than that of Comparative Example 5. This indicates that when the amount of meglumine increases, the excess excipients accumulating around the drug will hinder the drug's dissolution, thereby reducing the drug's dissolution rate.

[0175] Test Example 2: Stability Assessment

[0176] Samples prepared from the original reagent Refulan, Examples 1-5 and Comparative Examples 1-5 were placed continuously for 6 months under accelerated conditions of 40℃±2℃ and 75%RH±5%RH, and the relevant substances were detected at 0 days, 3 months and 6 months.

[0177] Table 13. Substances related to acceleration conditions (unit: %)

[0178] 0 days March June Example 1 0.05 0.09 0.18 Example 2 0.06 0.11 0.20 Example 3 0.06 0.13 0.23 Example 4 0.04 0.08 0.21 Example 5 0.07 0.09 0.16 Comparative Example 1 0.07 0.12 0.22 Comparative Example 2 0.09 0.10 0.21 Comparative Example 3 0.06 0.23 0.52 Comparative Example 4 0.08 0.18 0.31 Comparative Example 5 0.06 0.12 0.23 Original reagent 0.05 0.16 0.38

[0179] According to the relevant substance results in Table 13, the relevant substance content in Examples 1-5 after 6 months of accelerated storage was less than 0.5%, indicating better stability than the original formulation. This demonstrates that the eltrombopag ethanolamine tablets disclosed in this application incorporate eltrombopag ethanolamine and an amphiphilic carrier. When these three agents are ground and mixed together, the resulting formulation exhibits better stability.

[0180] Based on Examples 2 and 3, it can be seen that the related substances in Comparative Example 3, which did not contain meglumine, increased more rapidly, indicating that meglumine can provide an alkaline microenvironment for the drug. The addition of meglumine increases the alkalinity of the formulation, which makes eltrombopag ethanolamine more stable.

[0181] Test Example 3: In vivo pharmacokinetic study in beagle dogs

[0182] Thirty-three healthy beagle dogs were randomly divided into 11 groups of three dogs each, and were given tablets prepared in Examples 1-5, Comparative Examples 1-5, and the original formulation, respectively.

[0183] Fasting test: Beagle dogs were given the drug after fasting for 12 hours. Blood samples were collected at specified time points to determine blood drug concentration and calculate AUC. 0-t and C max The average value.

[0184] Postprandial test: After the fasting test, beagle dogs that had completed the fasting period were fasted for 12 hours, then given a high-fat meal. The drug was administered immediately after the meal, and blood samples were collected at the specified time to determine the blood drug concentration and calculate the AUC. 0-t and C max The average value.

[0185] The dosing regimen is shown in Table 14 below, and the pharmacokinetic results of the beagle dogs are shown in Table 15.

[0186] Table 14 Dosing Regimen

[0187] Grouping fasting After the meal 1 Example 1 Example 1 2 Example 2 Example 2 3 Example 3 Example 3 4 Example 4 Example 4 5 Example 5 Example 5 6 Comparative Example 1 Comparative Example 1 7 Comparative Example 2 Comparative Example 2 8 Comparative Example 3 Comparative Example 3 9 Comparative Example 4 Comparative Example 4 10 Comparative Example 5 Comparative Example 5 11 Original reagent Original reagent

[0188] Table 15 Pharmacokinetic Results of Beagles

[0189]

[0190] According to the pharmacokinetic results of beagle dogs in Table 15, the AUC of the formulations in Examples 1-5 were obtained after meals and on an empty stomach. 0-t C max The ratio is much greater than that of Comparative Examples 1-5 and the original formulation, indicating that the eltrombopag ethanolamine tablets disclosed in this application, with eltrombopag ethanolamine and added... The combined action of meglumine and eltrombopag ethanolamine reduces the formation of chelates between polyvalent cations and eltrombopag ethanolamine, allowing the prepared formulation to significantly avoid the influence of food on the absorption of eltrombopag ethanolamine, and significantly improve postprandial bioavailability.

[0191] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. An ethanamine tablet of ixekizumab, characterized by: This includes pharmaceutical compositions and pharmaceutically acceptable excipients; The pharmaceutical composition comprises the following components: eltrombopag ethanolamine, an amphiphilic carrier, and a microenvironment modifier; The mass ratio of eltrombopag ethanolamine, the amphiphilic carrier, and the microenvironment regulator was 1:(1-3):(0.5-1.5). The amphiphilic carrier is Soluplus®; the microenvironment regulator is meglumine. The pharmaceutically acceptable excipients include 150-300 parts by weight of filler, 20-40 parts by weight of disintegrant, and 1-10 parts by weight of lubricant; The preparation method of the eltrombopag ethanolamine tablets includes the following steps: eltrombopag ethanolamine is ground and mixed with an amphiphilic carrier and a microenvironment regulator, and then a filler, disintegrant, and lubricant are added and mixed. The mixture is then compressed into tablets and coated to obtain eltrombopag ethanolamine tablets.

2. The elacridar ethanolamine tablet according to claim 1, wherein: The filler is one or more of mannitol, lactose, microcrystalline cellulose, starch, and sorbitol.

3. The elacridar ethanolamine tablet according to claim 1, wherein: The disintegrant is one or more of croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and croscarmellose.

4. The elacridar ethanolamine tablet of claim 1, wherein: The lubricant is one or more of stearic acid, magnesium stearate, talc, and silicon dioxide.

5. The elacridar ethanolamine tablet of claim 1, wherein, The preparation method of the eltrombopag ethanolamine tablets includes the following steps: (1) Weigh the raw materials for eltrombopag ethanolamine tablets according to the prescription amount; (2) Grind and mix eltrombopag ethanolamine, amphiphilic carrier, and microenvironment regulator for 8-12 minutes, then pass through an 80-mesh sieve; (3) Pass the filler, disintegrant and lubricant through a 60-mesh sieve respectively; (4) After mixing the mixture obtained in step (2) with the filler and disintegrant for 8-12 minutes, add the lubricant and mix for 3-8 minutes to obtain intermediate particles; (5) After the intermediate particles are compressed into tablets, they are coated with Opadry coating powder to obtain eltrombopag ethanolamine tablets.

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