Bosentan micro-tablet

Abstract

A Bosentan micro-tablet, comprising: a compound I having the following structural formula or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for preparing a dispersible micro-tablet. The micro-tablet can meet the medication requirements of children for Bosentan, achieve accurate administration, and minimize the side effects of drugs.

Description

A bosentan microtablet

[0001] This application claims priority to the Chinese Patent Application No. CN202410882478.5 filed on July 2, 2024, entitled "A Bosentan Microtablet", to the Chinese Patent Application No. CN202510679857.9 filed on May 23, 2025, entitled "A Bosentan Microtablet", both of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present application belongs to the technical field of pharmaceutical preparations, and specifically relates to a bosentan microtablet. BACKGROUND

[0003] Bosentan is the first synthetic endothelin receptor A and B dual antagonist, which can reduce blood vessel pressure, prevent heart and blood vessel proliferation, reduce pulmonary fibrosis and inflammation, and is clinically used for treating pulmonary arterial hypertension patients with dyspnea symptoms at rest or during mild exercise (functional status score of grade III or IV), and for improving exercise tolerance and related symptoms.

[0004] The domestic and foreign marketed products of bosentan have two dosage forms of tablets and dispersible tablets. The tablet (specification: 62.5 mg and 125 mg) was approved for marketing in the United States FDA on November 20, 2001, and was approved for marketing in China in March 2006, and has been approved in more than 60 countries worldwide. The bosentan dispersible tablet (specification: 32 mg) was approved by the FDA in September 2017, and was approved for marketing in China in September 2019, with the trade name of Qiankeli (Tracleer).

[0005] The prevalence of pediatric pulmonary arterial hypertension (PAH) is 24 / 1,000,000-40 / 1,000,000, and the causes are congenital heart disease, idiopathic pulmonary arterial hypertension and developmental pulmonary disease. The currently marketed product for treating pediatric pulmonary arterial hypertension in China is only bosentan dispersible tablet. Patent CN101175484B discloses a prescription process of 32 mg bosentan dispersible tablet, which uses microcrystalline cellulose in combination with dicalcium phosphate filler. The advantage of the dispersible tablet is that it can optimize and individualize the dosage for pediatric patients according to body weight, and thus has better compliance.

[0006] ​However, according to the dosage and usage of the Chinese Pulmonary Hypertension Diagnosis and Treatment Guidelines (2021 version) for children with pulmonary hypertension, the preferred pediatric medication is 2 mg / kg. The bosentan dispersible tablets are dispersed and disintegrated into a suspension containing fine particles to facilitate pediatric medication, with a specification of 32 mg, and the instructions only allow half to be used (16 mg), which can achieve a minimum incremental dosing of 16 mg / 8 kg. The existing dispersible tablets can only correspond to the required dosage of the child with an 8 kg body weight increment. If the child's body weight increases in the range of 1-7 kg, the appropriate dosage cannot be administered. For example, 5-year-old and 8-year-old children, corresponding to a body weight of 18 ± 1 kg and 24 ± 1 kg, the standard dosing should be 36 mg and 48 mg, respectively. In fact, according to the instructions for bosentan dispersible tablets, the dosing for children of the above two ages is 48 mg, which is significantly higher than the theoretical dosage range for 5-year-old children, posing a certain safety risk. The product instructions clearly state that "liver transaminase elevation and hemoglobin concentration decrease are dose-dependent," therefore, long-term over-dosing may pose a risk of liver damage to the child. SUMMARY

[0007] The present application provides a bosentan microtablet, i.e., a bosentan dispersible metered microtablet, to further meet the needs of pediatric medication for bosentan and achieve precise dosing, minimizing the side effects of the drug.

[0008] In the context of the present application, any reference to Compound I can also be understood as referring to a pharmaceutically acceptable salt or solvate thereof, including hydrates, and to crystalline forms thereof, as appropriate, unless otherwise indicated. In the present application, bosentan can refer to the monohydrate of Compound I.

[0009] The microtablets of the present application are dispersible, e.g., in aqueous media, such as water. Administration of the dispersible microtablets of the present application can be dispersed, e.g., in water, which can facilitate pediatric dosing. The dispersible microtablets of the present application have a disintegration time of less than 3 minutes, preferably less than 1 minute.

[0010] According to the provisions of General Test 101 of the Chinese Pharmacopoeia 2020 Edition, Volume IV, dispersible tablets should be subjected to dissolution and dispersion uniformity tests.

Dispersion Uniformity

[0011] The Chinese import drug registration standard JX20190159 provides that the bosentan 15 min dissolution rate is not less than 80% in a pH 1.0 (0.5 wt% SDS (sodium dodecyl sulfate)) medium solution.

[0012] The first aspect of the present application provides a dispersible metered microtablet comprising: Compound I having the following structural formula or a pharmaceutically acceptable salt or solvate thereof,

[0013] and pharmaceutically acceptable excipients for preparing the dispersible microtablet.

[0014] In some embodiments, the dispersible metered microtablet of the present application has a diameter of 2-3 mm, a strength of 4 mg by amount of Compound I, and a tablet weight of 20-40 mg, preferably, the tablet weight can be 22-30 mg.

[0015] In some embodiments, the dispersible metered microtablet of the present application has a diameter of 3 mm, and the tablet thickness can range from 2.5-3 mm.

[0016] In some embodiments, the dispersible metered microtablet has a diameter of 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, or a range formed by any two of the above values as endpoints. In some embodiments, the strength is 4 mg by amount of Compound I, and the tablet weight of the dispersible metered microtablet can be 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, or a range formed by any two of the above values as endpoints. In some embodiments, the tablet thickness of the dispersible metered microtablet can be 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, or a range formed by any two of the above values as endpoints.

[0017] In some embodiments, the dispersible metered microtablet of the present application comprises the following pharmaceutically acceptable excipients: a co-processing of two fillers, one or more disintegrants, one or more lubricants, and one or more glidants.

[0018] In some embodiments, the dispersible metered microtablet of the present application comprises the following pharmaceutically acceptable excipients: a co-processing of two fillers, one or more disintegrants, one or more lubricants, and one or more glidants.

[0019] In some embodiments, the dispersible metered microtablet of the present application further comprises one or more flavoring agents, preferably, the flavoring agents are sweeteners and / or flavor enhancers.

[0020] The sweetener can be aspartame, sucralose, sodium saccharin or acesulfame potassium. The flavor enhancer can be fruit flavor, including but not limited to strawberry flavor, banana flavor, pear flavor, orange flavor, apple flavor, lemon flavor, cherry flavor, etc., or other flavors, including vanilla flavor, milk flavor, cream flavor, ice cream flavor, etc.

[0021] In some embodiments, the dispersible metered microtablet of the present application further comprises one or more sour agents.

[0022] In some embodiments, the dispersible metered microtablet of the present application comprises the following pharmaceutically acceptable excipients: a co-processed product of two fillers, the total weight of which accounts for 50-80% of the total weight of the microtablet, preferably, the total weight of which accounts for 60-80% of the total weight of the microtablet; one or more disintegrants, the total weight of which accounts for 1-20% of the total weight of the microtablet, preferably, the total weight of which accounts for 5-20% of the total weight of the microtablet; one or more lubricants, the total weight of which accounts for 0.5-2% of the total weight of the microtablet, preferably, the total weight of which accounts for 0.6-2% of the total weight of the microtablet; and one or more glidants, the total weight of which accounts for 0.5-2% of the total weight of the microtablet, preferably, the total weight of which accounts for 0.6-2% of the total weight of the microtablet.

[0023] In some embodiments, the total weight of the co-processed product of two fillers can account for 50%, 55%, 60%, 65%, 70%, 75%, 80% of the total weight of the microtablet, or a range formed by any two of the above numbers as endpoints. In some embodiments, the total weight of the one or more disintegrants can account for 1%, 5%, 10%, 15%, 20% of the total weight of the microtablet, or a range formed by any two of the above numbers as endpoints. In some embodiments, the total weight of the one or more lubricants can account for 0.5%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0% of the total weight of the microtablet, or a range formed by any two of the above numbers as endpoints. In some embodiments, the total weight of the one or more glidants can account for 0.5%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0% of the total weight of the microtablet, or a range formed by any two of the above numbers as endpoints.

[0024] In some embodiments, the dispersible metered microtable of the present application comprises the following pharmaceutically acceptable excipients: filler 1 and filler 2, in a total weight of 50-80% of the total weight of the microtable, preferably in a total weight of 60-80% of the total weight of the microtable; one or more disintegrants, in a total weight of 1-20% of the total weight of the microtable, preferably in a total weight of 5-20% of the total weight of the microtable; one or more binders, in a total weight of 1-8% of the total weight of the microtable, preferably in a total weight of 1-5% of the total weight of the microtable; one or more lubricants, in a total weight of 0.5-2% of the total weight of the microtable, preferably in a total weight of 0.6-2% of the total weight of the microtable; and one or more glidants, in a total weight of 0.5-2% of the total weight of the microtable, preferably in a total weight of 0.6-2% of the total weight of the microtable.

[0025] In some embodiments, the total weight of filler 1 and filler 2 can be 50%, 55%, 60%, 65%, 70%, 75%, 80% or a range formed by any two of these values as endpoints of the total weight of the microtable. In some embodiments, the total weight of one or more disintegrants can be 1%, 5%, 10%, 15%, 20% or a range formed by any two of these values as endpoints of the total weight of the microtable. In some embodiments, the total weight of one or more binders can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% or a range formed by any two of these values as endpoints of the total weight of the microtable. In some embodiments, the total weight of one or more lubricants can be 0.5%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0% or a range formed by any two of these values as endpoints of the total weight of the microtable. In some embodiments, the total weight of one or more glidants can be 0.5%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0% or a range formed by any two of these values as endpoints of the total weight of the microtable.

[0026] In some embodiments, the total weight of flavoring agent is 0% to 5% of the total weight of the microtable. In some embodiments, the total weight of flavoring agent can be 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.7%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0% or a range formed by any two of these values as endpoints of the total weight of the microtable.

[0027] In some embodiments, the total weight of the acidulant is 0% to 2% of the total weight of the microtablet. In some embodiments, the total weight of the acidulant can be 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.7%, 1.0%, 1.5%, 2.0% or a range formed by any two of the aforementioned values as endpoints of the total weight of the microtablet.

[0028] In some embodiments, the co-processed product of the two fillers is selected from a cellulose lactose co-processed product; preferably, the cellulose lactose co-processed product is a co-processed product of 20wt%-30wt% powdered cellulose and 80wt%-70wt% lactose. The cellulose lactose co-processed product described herein can be purchased through a commercial route, or can be prepared using the method for preparing a lactose-cellulose composite excipient provided in “Preparation of Lactose-Cellulose Composite Excipient and Evaluation of Its Performance”, Hu Yan et al., pp. 6-8, Strait Pharmaceutical Journal, 2007, Vol. 19, No. 10, or using the method for preparing a pharmaceutical excipient lactose-cellulose co-processed product provided in CN114504559A.

[0029] In some embodiments, the cellulose lactose co-processed product can be a co-processed product of 20wt% powdered cellulose and 80wt% lactose, a co-processed product of 22wt% powdered cellulose and 78wt% lactose, a co-processed product of 24wt% powdered cellulose and 76wt% lactose, a co-processed product of 25wt% powdered cellulose and 75wt% lactose, a co-processed product of 26wt% powdered cellulose and 74wt% lactose, a co-processed product of 28wt% powdered cellulose and 72wt% lactose, a co-processed product of 30wt% powdered cellulose and 70wt% lactose, or a range formed by any two of the aforementioned values as endpoints.

[0030] In some embodiments, the filler 1 is selected from one or more sugar alcohol fillers; the filler 2 is selected from one or more non-sugar alcohol fillers; preferably, the sugar alcohol filler is selected from sucrose, lactose, glucose, mannitol or sorbitol; the non-sugar alcohol filler is selected from microcrystalline cellulose, anhydrous dibasic calcium phosphate or corn starch; preferably, the filler 1 is lactose; the filler 2 is microcrystalline cellulose or anhydrous dibasic calcium phosphate.

[0031] In some embodiments, the mass ratio of the filler 1 to the filler 2 is (0.8-7):1. In some embodiments, the mass ratio of the filler 1 to the filler 2 can be 0.8:1, 1.0:1, 1.5:1, 2.0:1, 2.5:1, 3.0:1, 3.5:1, 4.0:1, 4.5:1, 5.0:1, 6.0:1, 7.0:1 or a range formed by any two of the aforementioned values as endpoints.

[0032] In some embodiments, the disintegrant is selected from sodium croscarmellose, sodium carboxymethyl starch, cross-linked polyplasdone or sodium low-substituted hydroxypropyl cellulose, preferably the disintegrant is sodium croscarmellose.

[0033] In some embodiments, the binder is selected from hydroxypropyl cellulose, polyplasdone and hypromellose; preferably the binder is hydroxypropyl cellulose.

[0034] In some embodiments, the lubricant is selected from magnesium stearate, sodium stearyl fumarate or glyceryl behenate; preferably the lubricant is magnesium stearate.

[0035] In some embodiments, the glidant is selected from talc, silicon dioxide or colloidal silicon dioxide; preferably the glidant is colloidal silicon dioxide.

[0036] In some embodiments, the acidulant is selected from tartaric acid, citric acid, ascorbic acid, lactic acid or fumaric acid; preferably the acidulant is tartaric acid.

[0037] In some embodiments, the Compound I is in monohydrate form.

[0038] The dispersible microtablets of the present application can be prepared by using methods conventional or known in the art, such as conventional granulation methods, for example, direct compression of powder, wet granulation and fluidized bed granulation process, preferably using direct compression of powder or fluidized bed granulation process. Fluidized bed granulation process integrates granulation and drying in one step, which is easy to operate and the granules have good flowability and compressibility.

[0039] For example, when the excipients include a co-processing product of two fillers, direct compression of powder can be used, and the preparation method can specifically include: sieving and mixing Compound I (e.g., bosentan), a disintegrant and a co-processing product of two fillers, optionally adding a flavoring agent and / or an acidulant; continuing to add a glidant and mix; adding a lubricant and mix; then compressing to obtain the Compound I microtablets.

[0040] For example, when the excipients include filler 1 and filler 2, a fluid bed granulation process can be used, which can include the following steps: preparing a binder solution: dissolving the binder in water, optionally adding a flavoring agent and / or a souring agent, and stirring until completely dissolved. Compound I (e.g., bosentan), filler 1, and disintegrant are placed in a fluid bed, mixed, preheated, and the binder solution is sprayed in using the fluid bed to granulate, with the temperature controlled at 30-40°C during the granulation process. The granulation is dried, with the moisture controlled at less than 3%, and the dried granulation is sized using a 20-40 mesh screen. Filler 2, lubricant, and glidant are added, and the mixture is blended, tableted, and the resulting microtablets of Compound I are produced. The second aspect of the application provides a method of treating pulmonary arterial hypertension, comprising administering to a subject in need of such treatment the dispersible metered microtablets of the first aspect of the application.

[0041] In some embodiments of the method of treatment of the application, the subject is a child.

[0042] In some embodiments of the method of treatment of the application, it comprises administering to a child in need of such treatment the dispersible metered microtablets of the application, according to the following schedule:

[0043] i. A child of 2 ± 1 kg is administered one of the dispersible metered microtablets.

[0044] ii. A child of 4 ± 1 kg is administered two of the dispersible metered microtablets.

[0045] iii. A child of 6 ± 1 kg is administered three of the dispersible metered microtablets.

[0046] iv. A child of 8 ± 1 kg is administered four of the dispersible metered microtablets.

[0047] v. A child of 10 ± 1 kg is administered five of the dispersible metered microtablets.

[0048] vi. A child of 12 ± 1 kg is administered six of the dispersible metered microtablets.

[0049] vii. A child of 14 ± 1 kg is administered seven of the dispersible metered microtablets.

[0050] viii. A child of 16 ± 1 kg is administered eight of the dispersible metered microtablets.

[0051] ix. A child of 18 ± 1 kg is administered nine of the dispersible metered microtablets.

[0052] x. A child of 20 ± 1 kg is administered ten of the dispersible metered microtablets.

[0053] xi. A child of 22 ± 1 kg is administered eleven of the dispersible metered microtablets.

[0054] xii. 24 ± 1 kg children, 12 tablets of the dispersible metered microtablet are administered;

[0055] xiii. 26 ± 1 kg children, 13 tablets of the dispersible metered microtablet are administered;

[0056] xiv. 28 ± 1 kg children, 14 tablets of the dispersible metered microtablet are administered;

[0057] xv. 30 ± 1 kg children, 15 tablets of the dispersible metered microtablet are administered;

[0058] xvi. 32 ± 1 kg children, 16 tablets of the dispersible metered microtablet are administered.

[0059] In some embodiments of the treatment method of the present application, the administration method is to swallow the dispersible metered microtablet of the present application in whole, or to disperse the microtablet in water before taking.

[0060] The third aspect of the present application provides the use of the dispersible metered microtablet of the first aspect of the present application for the preparation of a medicament for the treatment of pulmonary arterial hypertension.

[0061] The fourth aspect of the present application provides the use of the dispersible metered microtablet of the first aspect of the present application for the preparation of a medicament for the treatment of pulmonary arterial hypertension in children.

[0062] The fifth aspect of the present application provides a capsule for the treatment of pulmonary arterial hypertension, which is filled with the dispersible metered microtablet of the first aspect of the present application, preferably, the capsule is filled with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 tablets of the microtablet.

[0063] The sixth aspect of the present application provides a pharmaceutical package for the treatment of pulmonary arterial hypertension, which comprises the dispersible metered microtablet of the first aspect of the present application, a capsule and a counter for accurately metering the number of microtablets to be administered.

[0064] The seventh aspect of the present application further provides a pharmaceutical package for the treatment of pulmonary arterial hypertension, which comprises the dispersible metered microtablet of the first aspect of the present application and a dispensing device for accurately taking out the required number of microtablets at a time. The dispenser device is a device for dispensing micro-particles (tablets), such as the dispensing device described in CN104284847A.

[0065] Advantages of the present application:

[0066] The dispersible metered microtablet provided by the present application can meet the needs of children for bosentan, achieve accurate administration, and minimize the side effects of the drug.

[0067] Of course, practicing either product or method of the present application does not necessarily achieve all of the above stated advantages. DETAILED DESCRIPTION

[0068] The technical solutions in the present application will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. All other embodiments obtained by those skilled in the art based on the present application shall fall within the scope of the present application.

[0069] The bosentan used in the embodiments and comparative examples of the present application refers to the monohydrate of compound I, which is purchased from Megafine Company in India.

[0070] The cellulose lactose co-processed substance used in the embodiment 1 of the present application is purchased from Meghajel Company in Germany, with the product model of Cellactose 80; the microcrystalline cellulose and anhydrous calcium hydrogen phosphate co-processed substance used in the comparative example 6 is purchased from Dongchen Pharmaceutical Company, with the product model of The lactose pre-gelatinized starch co-processed substance used in the comparative example 7 is purchased from Meghajel Company in Germany, with the product model of Starlac.

[0071] The embodiments 1 and the comparative examples 1, 3-7 of the present application all use the powder direct compression process to prepare the dispersible metered micro-tablets, including the steps of:

[0072] 1) Equally add the bosentan, the co-processed substance of the two fillers (or all the fillers), the disintegrating agent through a 60-mesh sieve and optionally add the flavoring agent and / or the acidifying agent through a 60-mesh sieve, mix in the mixer for 2 min;

[0073] 2) Further add the flow agent through a 60-mesh sieve, mix in the mixer for 5 min;

[0074] 3) Add the lubricant through a 60-mesh sieve, mix in the mixer for 3 min;

[0075] 4) Tabletting: use 3mm round punches to tablet, to obtain the dispersible metered micro-tablets.

[0076] The embodiments 2-8, the comparative examples 2, 8-9 of the present application all use the fluidized bed granulation process to prepare the dispersible metered micro-tablets, including the steps of:

[0077] 1) Prepare the binder solution with water; optionally, add the flavoring agent and / or the acidifying agent and dissolve;

[0078] 2) Granulation: mix the filler 1, the bosentan and the disintegrating agent with the fluidized bed and preheat; spray the binder solution to granulate, and control the material temperature to be 30-40℃ during the granulation process;

[0079] 3) Drying: The granules prepared are dried in a fluid bed to control moisture content to less than 3%;

[0080] 4) Sizing: The dried granules are sized through 20-40 mesh screen;

[0081] 5) Additional mixing: The filler 2 (if any), glidant and lubricant are mixed uniformly;

[0082] 6) Compression: The tablets are compressed using 3 mm round punches to obtain dispersible metered micro-tablets.

[0083] Example 1

[0084] The amounts of the components added in this example are shown in Table 1 below.

[0085] Table 1 Note: The proportion of lactose in the cellulose lactose co-processed product is 75 wt%, and the proportion of powdered cellulose is 25 wt%. In Example 1, the proportion of lactose is 53.92 wt%, and the proportion of powdered cellulose is 17.98 wt%.

[0086] Example 2

[0087] The amounts of the components added in this example are shown in Table 2 below.

[0088] Table 2

[0089] Example 3

[0090] The amounts of the components added in this example are shown in Table 3 below.

[0091] Table 3

[0092] Example 4

[0093] The amounts of the components added in this example are shown in Table 4 below.

[0094] Table 4

[0095] Example 5

[0096] The amounts of the components added in this example are shown in Table 5 below.

[0097] Table 5

[0098] Example 6

[0099] The amounts of the components added in this example are shown in Table 6 below.

[0100] Table 6

[0101] Example 7

[0102] The amounts of the components added in this example are shown in Table 7 below.

[0103] Table 7

[0104] Example 8

[0105] The amounts of the components added in this example are shown in Table 8 below.

[0106] Table 8

[0107] Comparative Example 1

[0108] The amounts of the components added in this comparative example are shown in Table 9 below.

[0109] Table 9

[0110] Comparative Example 2

[0111] The amounts of the components added in this comparative example are shown in Table 10 below.

[0112] Table 10

[0113] Comparative Example 3

[0114] The amounts of the components added in this comparative example are shown in Table 11 below.

[0115] Table 11

[0116] Comparative Example 4

[0117] The amounts of the components added in this comparative example are shown in Table 12 below.

[0118] Table 12

[0119] Comparative Example 5

[0120] The amounts of the components added in this comparative example are shown in Table 13 below.

[0121] Table 13

[0122] Comparative Example 6

[0123] The amounts of the components added in this comparative example are shown in Table 14 below.

[0124] Table 14 Note: The proportion of microcrystalline cellulose in the microcrystalline cellulose and anhydrous calcium hydrogen phosphate co-processed product is 70 wt%, and the proportion of anhydrous calcium hydrogen phosphate is 30 wt%.

[0125] Comparative Example 7

[0126] The amounts of the components added in the present comparative example are shown in Table 15 below.

[0127] Table 15 Note: The proportion of lactose in the lactose and pre-gelatinized starch co-processed product is 85 wt%, and the proportion of pre-gelatinized starch is 15 wt%.

[0128] Comparative Example 8

[0129] The amounts of the components added in the present comparative example are shown in Table 16 below.

[0130] Table 16

[0131] Comparative Example 9

[0132] The amounts of the components added in the present comparative example are shown in Table 17 below.

[0133] Table 17

[0134] The performance of the dispersible metered micro-tablets prepared in the examples and comparative examples of the present application is illustrated below through effect tests.

[0135] 1. Results of the properties of each preparation

[0136] Reference preparation information: Bosentan dispersible tablets, trade name: Tracleer; manufacturer: Actelion Pharmaceuticals Ltd.

[0137] (1) Comparison of the basic properties of each preparation

[0138] 0921 Disintegration time test: The basket is suspended on the support through the upper end of the stainless steel shaft by the inspection method, immersed in a 1000 mL beaker, the screen hole diameter of the stainless steel mesh is 710 μm, and the water temperature is 15-25°C; 6 pieces of test sample should be completely disintegrated and pass through the screen within 3 minutes, if a small amount cannot pass through the screen but has been softened into light and has no hard core, it meets the requirements.

[0139] Content: The assay was performed as follows: 5 tablets were taken into a 250 mL volumetric flask, 50 mL of water was added, and the mixture was mechanically shaken for 10 minutes, ultrasonic treatment was performed in a 40°C water bath for 15 minutes, and then the mixture was taken out and placed at room temperature. 50 mL of acetonitrile was added, the mixture was shaken, 1100 mL of diluent was added, and the mixture was magnetically stirred for at least 1 hour. The mixture was diluted to the mark with the diluent, shaken, and 15 mL of the mixture was accurately taken into a 25 mL volumetric flask, diluted to the mark with the diluent, and shaken. The mixture was filtered, and the filtrate was used as the test sample solution. About 40 mg of the bosentan reference substance was accurately weighed into a 100 mL volumetric flask, dissolved in 1 mL of acetonitrile, diluted to the mark with the diluent, and shaken to obtain a reference sample solution. 25 μL of the reference sample solution and the test sample solution were accurately taken and injected into a liquid chromatograph, respectively, and a chromatogram was recorded. The peak area was calculated by the external standard method, and the content was obtained.

[0140] The specific results are shown in Table 18 below.

[0141] Conclusion: From the above results, it can be seen that Examples 1-8 meet the requirements in all aspects. The prescription composition of Comparative Example 1 is basically consistent with the original research prescription in patent CN101175484B, but cracking, sticking, and abnormal tablet weight occur during the tabletting process, indicating that the microtablets have high requirements for the compressibility, flowability, and uniformity of the materials. The prescription of the original research preparation has difficulties and problems in the tabletting process for preparing microtablets. Comparative Example 2 is abnormal during the tabletting process, and the tablet weight is unstable. Therefore, although the single filler lactose can meet the requirements of granulation, it has deficiencies in tabletting performance, affecting the molding and quality of the tablets. Comparative Example 1 and Comparative Example 2 are abnormal during the tabletting process, and the content does not meet the requirements.

[0142] Comparative Examples 4-7 all have certain problems during the tabletting process, and Comparative Examples 4, 5, and 6 have unqualified friability, indicating that the microtablets have high requirements for the compressibility of the fillers. Except for microcrystalline cellulose (Comparative Example 3), the remaining excipients (Comparative Examples 2, 4, and 5) in the original research patent cannot meet the requirements of microtablet tabletting as a single filler. The microtablet prescription requires excipients with good compressibility, such as microcrystalline cellulose, or a combination of microcrystalline cellulose and other excipients.

[0143] (2) Dissolution results

[0144] According to the dissolution curve detection method of the import registration standard JX20190159, the dissolution was determined by the paddle method with pH 1.0 hydrochloric acid (containing 0.5 wt% SDS) as the 900 mL dissolution medium, the rotation speed was 75 rpm per minute, 8 tablets of the microtablets and 1 tablet of the reference preparation were placed, samples were taken at 5 min, 10 min, 15 min, 20 min, and 30 min, the peak area was determined by high performance liquid chromatography, the dissolution was calculated, and the 15 min limit was 80% of the labeled amount.

[0145] The dissolution results of the examples and the comparative examples are shown in Table 19 below.

[0146] Conclusion: From the above results, it can be seen that Examples 1-8 meet the requirements of dissolution. The dissolution results of Comparative Examples 1, 2, 8 and 9 at 15 min are all <80%, which do not meet the limit requirements. The dissolution results of Comparative Examples 1 and 2 are lower than the limit; Comparative Examples 8 and 9 do not contain sugar alcohol fillers in the prescription, and the dissolution performance is poor, so the dissolution results do not meet the limit requirements. The dissolution of Comparative Examples 4-7 meets the requirements, and the dissolution result of Comparative Example 3 at 15 min is <80%, which does not meet the limit requirements, indicating that although microcrystalline cellulose exhibits excellent tabletting performance, since microcrystalline cellulose is insoluble in water, the dissolution performance is poor, and bosentan is a poorly soluble drug, which needs to be combined with a good dissolving aid. The filler of Example 1 is a microcrystalline cellulose-lactose co-processed material, which can prepare micro-tablets that meet the requirements.

[0147] In summary, the combination of two fillers or the use of cellulose-lactose co-processed material can meet the requirements of granulation and micro-tablet compression in the process, and the dissolution results are good, and the prepared micro-tablets meet the expected requirements.

[0148] (3) Stability results

[0149] The comparison results of the accelerated test of the reference preparation and Example 3 are shown in Table 20.

[0150] Table 20

[0151] From the comparison results, it can be seen that the quality indicators of the preparation of Example 3 of the present application are not lower than those of the reference preparation, and the stability data show that the process has good dissolution stability.

[0152] 2. Animal pharmacokinetic experiment

[0153] The single-dose pharmacokinetic characteristics of bosentan dispersible tablets (specification: 32 mg, code: Compound-B1) and bosentan metered micro-tablets (Example 3, specification: 4 mg, code: Compound-B2; Example 4, specification: 4 mg, code: Compound-B3; Example 5, specification: 4 mg, code: Compound-B4) in Beagle dogs were compared.

[0154] Methods: Four male beagle dogs were used in the experiment, and four cycles of cross-dosing were performed, with one animal in each group per cycle. Four kinds of tablets were orally administered to the four animals in four cycles. The dosing amount was 16 mg per animal, and Compound-B1 was administered as 1 / 2 tablet, and Compound-B2, B3, and B4 were administered as four tablets of the Compound-B1. Blood samples were collected before dosing (0 h) and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h, 36 h, and 48 h after dosing in each cycle, and plasma samples were obtained for determination of the bosentan content in the plasma by LC-MS / MS. The cross-dosing design table is shown in Table 21.

[0155] Table 21 Cross-dosing test design

[0156] After oral administration of Compound B1, Compound B2, Compound B3, and Compound B4 tablets (16 mg per animal) to male beagle dogs, the main pharmacokinetic parameters of the four cycles are shown in Table 22.

[0157] Table 22 Main pharmacokinetic parameters of Compound-B1, B2, B3, and B4 in four cycles

[0158] From the above results, it can be seen that the bosentan metered microtablets provided in Examples 3-5 have good pharmacokinetic properties.

[0159] The above description is merely preferred embodiments of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of protection of the present application.

Claims

1. A dispersible metered microtable comprising: Compound I having the following structural formula: ###00001### or a pharmaceutically acceptable salt or solvate thereof, ​ and pharmaceutically acceptable excipients for the preparation of dispersible microtablets.

2. The dispersible metered microflake according to claim 1, wherein, The dispersible metering microtablets have a diameter of 2-3 mm, a strength of 4 mg in terms of the amount of Compound I, a tablet weight of 20-40 mg, preferably 22-30 mg.

3. The dispersible metering microtablets according to claim 2, comprising the following pharmaceutically acceptable excipients: a co-processed mixture of two fillers, one or more disintegrants, one or more lubricants and one or more glidants; or, comprising the following pharmaceutically acceptable excipients: filler 1 and filler 2, one or more disintegrants, one or more binders, one or more lubricants and one or more glidants; Optionally, the dispersible metering microtablets further comprise one or more flavourings, preferably the flavourings are sweeteners and / or flavour enhancers; optionally, the dispersible metering microtablets further comprise one or more acidulants.

4. The dispersible metering microtablets according to claim 3, comprising the following pharmaceutically acceptable excipients: a co-processed mixture of two fillers, which together represent 50-80% of the total weight of the microtablets, preferably 60-80% of the total weight of the microtablets; one or more disintegrants, which together represent 1-20% of the total weight of the microtablets, preferably 5-20% of the total weight of the microtablets; one or more lubricants, which together represent 0.5-2% of the total weight of the microtablets, preferably 0.6-2% of the total weight of the microtablets; and one or more glidants, which together represent 0.5-2% of the total weight of the microtablets, preferably 0.6-2% of the total weight of the microtablets; or, comprising the following pharmaceutically acceptable excipients: filler 1 and filler 2, which together represent 50-80% of the total weight of the microtablets, preferably 60-80% of the total weight of the microtablets; one or more disintegrants, which together represent 1-20% of the total weight of the microtablets, preferably 5-20% of the total weight of the microtablets; one or more binders, which together represent 1-8% of the total weight of the microtablets, preferably 1-5% of the total weight of the microtablets; one or more lubricants, which together represent 0.5-2% of the total weight of the microtablets, preferably 0.6-2% of the total weight of the microtablets; and one or more glidants, which together represent 0.5-2% of the total weight of the microtablets, preferably 0.6-2% of the total weight of the microtablets.

5. The dispersible metered microflake according to claim 3 or 4, wherein, the co-processed mixture of two fillers is selected from a cellulose lactose co-processed mixture; preferably, the cellulose lactose co-processed mixture is a co-processed mixture of 20-30 wt% powdered cellulose and 80-70 wt% lactose; The filler 1 is selected from one or more sugar alcohol fillers; the filler 2 is selected from one or more non-sugar alcohol fillers; preferably, the sugar alcohol fillers are selected from sucrose, lactose, glucose, mannitol or sorbitol; the non-sugar alcohol fillers are selected from microcrystalline cellulose, anhydrous calcium hydrogen phosphate or corn starch; preferably, the filler 1 is lactose; the filler 2 is microcrystalline cellulose or anhydrous calcium hydrogen phosphate.

6. The dispersible metered microflake according to claim 3 or 4, wherein, The disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone or low-substituted hydroxypropyl cellulose sodium, preferably, the disintegrant is croscarmellose sodium; optionally, the binder is selected from hydroxypropyl cellulose, povidone or hypromellose; preferably, the binder is hydroxypropyl cellulose; optionally, the lubricant is selected from magnesium stearate, sodium stearyl fumarate or glyceryl behenate; preferably, the lubricant is magnesium stearate; optionally, the glidant is selected from talc, silicon dioxide or colloidal silicon dioxide; preferably, the glidant is colloidal silicon dioxide; optionally, the acidifier is selected from tartaric acid, citric acid, ascorbic acid, lactic acid or fumaric acid; preferably, the acidifier is tartaric acid.

7. The dispersible metered microflake according to any one of claims 1-6, wherein, The compound I is in a monohydrate form.

8. A method of treating pulmonary arterial hypertension, comprising administering to a subject in need of such treatment the dispersible metered microtablets of any one of claims 1-7; preferably, the subject is a child.

9. The method of treatment of claim 8, comprising administering to a child in need of such treatment the dispersible metered microtablets of any one of claims 1-7, by the following method: i. a child of 2 ± 1 kg is given one tablet of the dispersible metered microtablets; ii. a child of 4 ± 1 kg is given two tablets of the dispersible metered microtablets; iii. a child of 6 ± 1 kg is given three tablets of the dispersible metered microtablets; iv. a child of 8 ± 1 kg is given four tablets of the dispersible metered microtablets; v. a child of 10 ± 1 kg is given five tablets of the dispersible metered microtablets; vi. a child of 12 ± 1 kg is given six tablets of the dispersible metered microtablets; vii. a child of 14 ± 1 kg is given seven tablets of the dispersible metered microtablets; viii. a child of 16 ± 1 kg is given eight tablets of the dispersible metered microtablets; ix. a child of 18 ± 1 kg is given nine tablets of the dispersible metered microtablets; x. a child of 20 ± 1 kg is given ten tablets of the dispersible metered microtablets; xi. a child of 22 ± 1 kg is given eleven tablets of the dispersible metered microtablets; xii. a child of 24 ± 1 kg is given twelve tablets of the dispersible metered microtablets; xiii. a child of 26 ± 1 kg is given thirteen tablets of the dispersible metered microtablets; xiv. a child of 28 ± 1 kg is given fourteen tablets of the dispersible metered microtablets; xv. a child of 30 ± 1 kg is given fifteen tablets of the dispersible metered microtablets; xvi. a child of 32 ± 1 kg is given sixteen tablets of the dispersible metered microtablets.

10. The method of treatment according to claim 8 or 9, wherein, The method of administration is to swallow the microtablets whole, or to disperse the microtablets in water for consumption.

11. A capsule for use in the treatment of pulmonary arterial hypertension, wherein, The capsule is filled with the dispersible metered microtablets according to any one of claims 1 to 7, preferably the capsule is filled with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 of the microtablets.

12. A pharmaceutical package for the treatment of pulmonary arterial hypertension comprising the dispersible metered microtablets according to any one of claims 1 to 7, a capsule and a counter for the accurate metering of the number of microtablets to be administered.

13. A pharmaceutical package for the treatment of pulmonary arterial hypertension comprising the dispersible metered microtablets according to any one of claims 1 to 7 and a dispenser device for the accurate removal of the required number of microtablets at one time.

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