PHARMACEUTICAL COMPOSITION BASED ON A SULFONYLUREA DERIVATIVE

Abstract

The present disclosure provides a pharmaceutical composition of a sulfonylurea derivative. Specifically, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stabilizer, and a buffering agent. The composition has excellent stability. =

Description

A pharmaceutical composition of sulfonylurea derivatives

[0001] This application claims the benefit of Chinese patent application No. 2023113828300, filed October 24, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to the field of pharmaceutical preparations, and in particular to a pharmaceutical composition of a sulfonylurea derivative and a preparation method thereof. Background Art

[0003] Cerebral stroke, also known as "stroke" or "cerebral vascular accident" (CVA), is an acute cerebrovascular disease. It is a group of diseases caused by the sudden rupture of a cerebral blood vessel or the inability of blood to flow to the brain due to blood vessel blockage, resulting in brain tissue damage. It includes ischemic and hemorrhagic strokes. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, accounting for 60% to 70% of all strokes. Occlusion and stenosis of the internal carotid artery and vertebral artery can cause ischemic stroke. It mostly affects people over 40 years old and is more common in men than women. Severe cases can cause death. Hemorrhagic stroke has a higher mortality rate. Surveys show that stroke has become the leading cause of death in my country in both urban and rural areas combined and is the leading cause of disability among Chinese adults. Stroke is characterized by high morbidity, mortality, and disability rates.

[0004] The most common cause of stroke is a small embolus on the inner wall of a blood vessel supplying the brain, which can break off and cause arterial embolism, an ischemic stroke. It can also be caused by bleeding into a cerebral vessel or thrombosis, a hemorrhagic stroke. Patients with coronary artery disease and atrial fibrillation are prone to mural thrombosis of the heart valves. If this embolus breaks off, it can block cerebral blood vessels and cause an ischemic stroke. Other contributing factors include hypertension, diabetes, and hyperlipidemia.

[0005] In 2018, the biopharmaceutical company Biogen evaluated BIIB093 (intravenous glibenclamide) for the prevention and treatment of severe cerebral edema in patients with massive cerebral infarction (LHI) in a Phase III clinical study. BIIB093 is a high-affinity inhibitor of the SUR1-TRPM4 (sulfonylurea receptor 1-transient receptor potential ion channel protein 4) channel, which is upregulated after ischemia and trauma. The opening of these channels can lead to cerebral edema, midline shift, increased intracranial pressure and brain herniation, leading to permanent disability or death. BIIB093 is an experimental drug that is currently being developed for the prevention and treatment of severe cerebral edema caused by LHI. CN101932308B discloses a lyophilized formulation comprising glibenclamide, which may contain a small amount of buffer (<5mM) or no buffer, and the prepared formulation has a suitable pH for injection.

[0006] WO2022012666 relates to a series of new sulfonylurea derivatives, among which the compound represented by formula (I) has good activity and its structure is shown below:

[0007] Summary of the Invention

[0008] The present disclosure aims to provide a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the composition has good formulation stability.

[0009] The present disclosure provides a pharmaceutical composition comprising an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stabilizer, and a phosphate buffer.

[0010] In some embodiments, examples of phosphate buffers include, but are not limited to, disodium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate-potassium dihydrogen phosphate, sodium dihydrogen phosphate-sodium hydroxide, sodium phosphate-phosphoric acid, disodium hydrogen phosphate-citric acid, and the like.

[0011] In some embodiments, the stabilizer is selected from one or more of mannitol, sucrose, trehalose, maltose, dextrose and lactose. In some embodiments, the stabilizer is mannitol and trehalose.

[0012] In some embodiments, the concentration of the buffer in the pharmaceutical composition is 5-200 mM, including but not limited to 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, The ratio of the active ingredient compound represented by formula (I) or its pharmaceutically acceptable salt to the buffer agent is suitable, which is conducive to the stability of the pH of the composition.

[0013] In some embodiments, the concentration of the stabilizer is 1 mg / mL to 150 mg / mL, non-limiting examples include 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL and any range therebetween. In some embodiments, the concentration of the stabilizer is 10 mg / mL to 80 mg / mL.

[0014] In some embodiments, the pH of the pharmaceutical composition is 7-12, non-limiting examples include: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, or any value therebetween. In some embodiments, the pharmaceutical composition has a pH of 8-12.

[0015] In some embodiments, the pharmaceutical composition may further comprise a pH adjuster, which may be sodium hydroxide, hydrochloric acid, etc., for example, sodium hydroxide. The pH adjuster can assist in adjusting the pH of the pharmaceutical composition to a desired range after the addition of a buffer.

[0016] In some embodiments, the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.01 mg / mL to 50 mg / mL, or 0.1 mg / mL to 20 mg / mL, or 0.3 mg / mL to 10 mg / mL, non-limiting examples include 0.02 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3.0 mg / mL, 4.0 mg / mL, 5.0 mg / mL, 6.0 mg / mL, 7.0 mg / mL, 8.0 mg / mL, 9.0 mg / mL, 10.0 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL or any value in between.

[0017] The present disclosure also provides a pharmaceutical composition comprising:

[0018] 0.1 mg / mL to 20 mg / mL of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

[0019] 10 mg / mL to 80 mg / mL mannitol or trehalose stabilizer;

[0020] 10-50 mM phosphate buffer;

[0021] and optionally a pH adjuster,

[0022] The pH of the composition is 8-12.

[0023] The pharmaceutical composition of the present disclosure may further comprise other pharmaceutical excipients, such as cosolvents, isotonicity regulators, adsorbents, complexing agents, and the like.

[0024] The pharmaceutical compositions provided herein may be solid or liquid, wherein the solid form of the pharmaceutical composition is often obtained by freeze-drying a liquid form composition or by reconstitution or reconstitution to obtain a liquid form composition. The liquid form of the pharmaceutical composition may be in the form of a solution or a suspension, preferably a solution. In some embodiments, the liquid composition is obtained by reconstitution or reconstitution of a freeze-dried composition or is a liquid composition before freeze-drying. In some embodiments, the solid composition is reconstituted or reconstituted to obtain the aforementioned pharmaceutical composition.

[0025] In some embodiments, any of the aforementioned pharmaceutical compositions is a liquid formulation. The liquid formulation or the reconstituted formulation disclosed herein has good stability.

[0026] In some embodiments, after storage of the pharmaceutical composition of the present disclosure at 25°C / 60%RH for 30 days, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is ≥96%, for example ≥97% or ≥98%.

[0027] The present disclosure also provides a lyophilized preparation, wherein the preparation can form the aforementioned pharmaceutical composition after reconstitution.

[0028] The present disclosure also provides a lyophilized preparation obtained by freeze-drying the aforementioned pharmaceutical composition.

[0029] The present disclosure also provides a reconstituted solution, wherein the reconstituted solution is prepared by reconstituted the aforementioned lyophilized preparation.

[0030] The present disclosure also provides a method for preparing the aforementioned reconstituted solution, which comprises the step of reconstituted the aforementioned lyophilized preparation, wherein the solution used for reconstitution is selected from but not limited to water for injection, physiological saline or glucose solution.

[0031] The present disclosure further provides use of the pharmaceutical composition of the present disclosure in the preparation of a medicament for preventing or treating diseases and conditions affected by neuronal damage.

[0032] The present disclosure further provides use of the pharmaceutical composition described in the present disclosure in the preparation of a medicament for treating acute stroke, traumatic brain injury, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular arrhythmia, ischemic injury, hypoxia / ischemia, and Parkinson's disease.

[0033] The present disclosure provides a method for preparing the aforementioned pharmaceutical composition, comprising the step of mixing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof with a stabilizer and a buffer.

[0034] In some embodiments, the method further comprises the steps of adjusting pH and lyophilizing.

[0035] The pharmaceutical compositions provided herein exhibit excellent stability. The pH of the lyophilized formulation exhibits minimal pH shift after reconstitution, allowing direct injection after dilution. Pharmaceutical compositions without buffers exhibit poor stability and experience a significant pH drop after reconstitution, posing a risk of precipitation of the active ingredient.

[0036] As used herein, the terms "about" and "approximately" refer to values ​​that are within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, in each practice in the art, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%. In addition, particularly for biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. Unless otherwise indicated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[0037] The numerical values ​​in this disclosure are instrumentally measured or calculated after instrumental measurement, and are subject to a certain degree of error. Generally speaking, a value within a reasonable error range of plus or minus 10% is within this range. The context in which the value is used must be considered. For example, the total impurity content, where the error after measurement does not exceed plus or minus 10%, may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0038] The “weight to volume ratio” (w / v) described in the present disclosure refers to the weight (in g) of the component contained in every 100 mL of liquid system, that is, g / 100 mL. DETAILED DESCRIPTION

[0039] The present disclosure is further described in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0040] Example 1

[0041] Experimental method: Prepare sodium hydroxide solution or phosphate buffer at the prescribed pH value, take 80% of the prescribed amount of the above solution, weigh the compound represented by formula (I) and add it to the solution, stir until completely dissolved, add the prescribed amount of mannitol or trehalose, stir until completely dissolved, add sodium hydroxide solution or phosphate buffer at the prescribed pH to the full amount, mix well, sterilize and filter, fill and half-stopper, freeze-dry, and cap.

[0042] Table 1 Components of each composition

[0043] Chemical stability test of freeze-dried preparations:

[0044] The prepared samples were stored at 40°C for 30 days. The results are shown in Table 2. The results show that the active ingredient purity of Formulation 1, which does not contain a buffer, decreased rapidly and showed poor stability. Formulations 2 and 3, which contain a buffer, showed better stability.

[0045] Table 2

[0046] pH stability test of reconstituted solution:

[0047] The samples were reconstituted with water for injection, and the results are shown in Table 3. The results showed that the pH of formulation 1 without a buffer fluctuated greatly after reconstitution, while the pH of formulations 2 and 3 was relatively stable.

[0048] Table 3

[0049] Example 2

[0050] According to the method of Example 1, pre-lyophilization solutions and lyophilized preparations with different pH values ​​were prepared.

[0051] Table 4 Components of each composition

[0052] Chemical stability test of freeze-dried preparations:

[0053] The prepared samples were placed at 40°C for 30 days, and the results are shown in Table 5. The results show that the samples have good stability.

[0054] Table 5

[0055] pH stability test of reconstituted solution:

[0056] Samples prepared from pre-lyophilized solutions with different pH values ​​were placed at 40°C for 30 days, and the pH of the reconstituted solutions was investigated. The results are shown in Table 6. The results show that the pH values ​​of all samples were relatively stable.

[0057] Table 6

[0058] Experimental conclusion: Each composition showed good stability in all tests. After reconstitution and dilution with a small amount of water, the pH of the solution was close to neutral, making it suitable for clinical use.

[0059] Example 3

[0060] According to the method of Example 1, pre-lyophilized solutions and lyophilized preparations with different mannitol contents were prepared.

[0061] Table 7 Composition

[0062] Chemical stability test of freeze-dried preparations:

[0063] The prepared samples were placed at 40°C for 30 days, and the results are shown in Table 8. The results show that the samples have good stability.

[0064] Table 8

[0065] pH stability test of reconstituted solution:

[0066] The samples were reconstituted with water for injection, and the pH of the reconstituted solutions was tested. The results are shown in Table 9. The results showed that the pH of each sample after reconstitution was relatively stable.

[0067] Table 9

[0068] Experimental conclusion: Each composition has good stability in each test.

[0069] Example 4

[0070] According to the method of Example 1, pre-lyophilization solutions and lyophilized preparations with different buffer concentrations were prepared.

[0071] Table 10 Composition

[0072] Chemical stability test of freeze-dried preparations:

[0073] The prepared samples were placed at 40°C for 30 days, and the results are shown in Table 11. The results show that the samples have good stability.

[0074] Table 11

[0075] Example 5

[0076] According to the method of Example 1, pre-lyophilization solutions and lyophilized preparations containing different buffers were prepared.

[0077] Table 12 Composition

[0078] 1) pH buffering capacity test results

[0079] The raw and auxiliary materials were mixed under conditions of equivalent raw and auxiliary material concentrations and pH. The results showed that except for the phosphate buffer group (prescription 11), the pH of the other groups decreased significantly, indicating that the buffering capacity of phosphate with the same molar concentration was better than that of the other groups.

[0080] 2) Accelerated stability of freeze-dried preparations at 25°C (impurity content) (%)

[0081] It can be seen that the impurity changes in the phosphate buffer group (prescription 11) were significantly lower than those in the other groups, and the stability was good.

Claims

1. A pharmaceutical composition characterized in that it contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, a stabilizer and a phosphate-based buffering agent, .

2. The pharmaceutical composition according to claim 1, characterized in that the stabilizer is selected from one or more of mannitol, sucrose, trehalose, maltose, dextrose and lactose, preferably mannitol or trehalose.

3. A pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition additionally contains a pH regulator, preferably hydrochloric acid or sodium hydroxide.

4. A pharmaceutical composition according to any one of claims 1-3, characterized in that the concentration of the buffering agent in the pharmaceutical composition is 5-200 mM, preferably 5-100 mM and more preferably 10-50 mM.

5. A pharmaceutical composition according to any one of claims 1-4, characterized in that the concentration of the stabilizer is from 1 mg / ml to 150 mg / ml, preferably from 10 mg / ml to 80 mg / ml.

6. A pharmaceutical composition according to any one of claims 1-5, characterized in that the composition is characterized by a pH of 7-12, preferably 8-12.

7. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that the concentration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is from 0.01 mg / ml to 50 mg / ml, preferably from 0.1 mg / ml to 20 mg / ml and more preferably from 0.3 mg / ml to 10 mg / ml.

8. A pharmaceutical composition characterized in that it contains from 0.1 mg / ml to 20 mg / ml of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; from 10 mg / ml to 80 mg / ml mannitol or trehalose as a stabilizer; 10-50 mM phosphate buffer and optionally a pH regulator, where the composition is characterized by a pH of 8-12.

9. A lyophilized composition, characterized in that the lyophilized composition, upon reconstitution, ensures the formation of a pharmaceutical composition according to any of paragraphs 1-8.

10. A lyophilized composition, characterized in that the lyophilized composition is obtained by lyophilizing a pharmaceutical composition according to any of paragraphs 1-8.

11. A reconstituted solution, characterized in that the reconstituted solution is obtained by reconstituting the lyophilized composition according to paragraph 9 or 10.

12. A product characterized in that it provides a container containing a pharmaceutical composition according to any of paragraphs 1-8, a lyophilized composition according to paragraph 9 or paragraph 10, or a reconstituted solution according to paragraph 11.

13. The use of a pharmaceutical composition according to any of claims 1-8, a lyophilized composition according to claim 9 or 10, a reconstituted solution according to claim 11, or a product according to claim 12 in the production of a medicinal product for the treatment of diseases and conditions caused by damage to neurons.

14. The use of a pharmaceutical composition according to any one of claims 1-8, a lyophilized composition according to claim 9 or 10, a reconstituted solution according to claim 11, or a product according to claim 12 in the preparation of a medicinal product for the treatment of acute cerebral stroke, traumatic brain injury, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular arrhythmias, ischemic injury, hypoxia / ischemia, and Parkinson's disease.

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