Pharmaceutical composition comprising SMTP derivative

Abstract

The present disclosure relates to a pharmaceutical composition comprising an SMTP derivative. Specifically, the present disclosure relates to a fat emulsion, comprising: a compound represented by formula I or a pharmaceutically acceptable salt thereof, an oil component, water, and a first emulsifier. The pharmaceutical composition can be better applied in clinic practice.

Description

Pharmaceutical compositions containing SMTP derivatives Technical Field

[0001] This disclosure pertains to the field of pharmaceutical formulations, and specifically relates to a pharmaceutical composition comprising an SMTP derivative. Background Technology

[0002] SMTP-7 (TMS-007, Stachybotrys microspore triprenyl phenol-7), extracted in 2000 from a special leaf mold (Stachybotrys microspora) on Iriomote Island, Okinawa Prefecture, is a small-molecule plasminogen activator with a structure similar to vitamin E. It possesses a novel mechanism of action for dissolving blood clots and is also believed to inhibit local inflammation at the thrombus site. Furthermore, SMTP-7 exhibits anti-tumor angiogenesis activity, antioxidant properties, and tissue regeneration-promoting activity.

[0003] SMTP-7 (TMS-007, Stachybotrys microspore triprenyl phenol-7), extracted in 2000 from a special leaf mold (Stachybotrys microspora) on Iriomote Island, Okinawa Prefecture, is a small-molecule plasminogen activator with a structure similar to vitamin E. It possesses a novel mechanism of action for dissolving blood clots and is also believed to inhibit local inflammation at the thrombus site. Furthermore, SMTP-7 exhibits anti-tumor angiogenesis activity, antioxidant properties, and tissue regeneration-promoting activity. Summary of the Invention

[0004] This disclosure provides a fat emulsion comprising: a compound of formula I or a pharmaceutically acceptable salt thereof, an oil component, water, and a first emulsifier.

[0005] in,

[0006] R1, R2, R3, R4, R5, R6, and R7 are each independently hydrogen or deuterium.

[0007] The first emulsifier is polyethylene glycol 15-hydroxystearate and / or poloxamer.

[0008] In some implementations, R1, R2, R3, R4, and R5 are all hydrogen, and R6 and R7 are each independently hydrogen or deuterium.

[0009] In some implementations, R1, R2, R3, R4, and R5 are all hydrogen, and R6 and R7 are deuterium.

[0010] In some embodiments, the compound represented by Formula I of this disclosure is

[0011] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt is present in a weight-volume ratio of 0.01% to 30%, or 0.1% to 10%. Non-limiting examples include 0.01%, 0.02%, 0.05%, 0.08%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1 0.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 18.0%, 20.0%, 22.0%, 25.0%, 28.0%, 30.0%, and any range between these point values.

[0012] In some embodiments, the oil component comprises natural oils and / or synthetic oils. The natural oils may be selected from soybean oil, safflower oil, jojoba oil, olive oil, sweet almond oil, coconut oil, castor oil, sunflower seed oil, and fish oil, such as those selected from castor oil and fish oil. The synthetic oils may be selected from medium-chain triglycerides, isooctyl palmitate, isooctyl palmitate, isopropyl palmitate, such as medium-chain triglycerides.

[0013] In some embodiments, the oil component may also include other oily substances, such as oily stabilizers.

[0014] In some embodiments, the oil component has a weight-to-volume ratio of 1% to 50%, for example, 5% to 40%, and non-limiting embodiments include 2%, 4%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 18.0%, 20.0%, 22.0%, 25.0%, 28.0%, 30.0%, 32.0%, 35.0%, 38.0%, 40.0%, 50.0%, 60.0%, and any range between these point values.

[0015] In some embodiments, the oil component comprises natural oils and synthetic oils. The weight ratio of the natural oils to the synthetic oils can be 1:0.1 to 1:30, for example 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, and any range between these values.

[0016] In some embodiments, the oil component comprises castor oil and medium-chain triglycerides. The weight ratio of the castor oil to the medium-chain triglycerides can be 1:0.1 to 1:30, for example 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, and any range between these values.

[0017] In some embodiments, the first emulsifier is present in a weight-volume ratio of 0.01% to 10%, or 0.1% to 5%, with non-limiting examples including 0.02%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, and any range between these values.

[0018] In some embodiments, the fat emulsions described in this disclosure may also contain other emulsifiers, including but not limited to Tween 80, lecithin, sodium oleate, Span 20, Tween 20, polyoxyethylene monostearate, polyoxyethylene stearate, polyoxyethylene 40 stearate, polyoxyethylene 400 monolaurate, polyoxyethylene 400 monostearate, polyoxyethylene 400 monooleate, polyoxyethylene lauryl ether, polyoxyethylene hexadecyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkylphenol, polyoxyethylene fatty alcohol ether, polyoxyethylene nonylphenol ether, polyoxyethylene octylphenyl ether, polyoxyethylene lauryl ether, etc., such as lecithin. The weight-volume ratio of the other emulsifiers may be from 0.01% to 10%, or from 0.1% to 5%.

[0019] In some embodiments, the fat emulsion described in this disclosure may further include stabilizers. The stabilizers include, but are not limited to, one or more of oleic acid, sodium oleate, sodium caprylate, cholesterol, cholic acid, deoxycholic acid and its sodium salt, vitamin A, vitamin C, and vitamin E. The stabilizer is present in a weight-volume ratio of 0.001% to 10%, or 0.01% to 5%, with non-limiting embodiments including 0.002%, 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, and any range between these values.

[0020] In some embodiments, the fat emulsion described in this disclosure may further comprise an osmotic pressure regulator, including but not limited to sodium chloride, glucose, sorbitol, glycerol, PEG, propylene glycol, etc. The weight-volume ratio of the osmotic pressure regulator is 0.01% to 10%, or 0.1% to 5%.

[0021] In some embodiments, the fat emulsions described in this disclosure may further comprise buffers, including but not limited to acid salt buffers, carbonate buffers, citrate buffers, acetate buffers, glycine / hydrochloric acid buffers, phthalate buffers, borate buffers, lactate buffers, succinate buffers, and tartrate buffers. The weight-to-volume ratio of the buffers is 0.01% to 2%, or 0.05% to 1%, or 0.1% to 0.5%.

[0022] In some embodiments, the pH of the fat emulsion described in this disclosure is from 6.0 to 11.0, and non-limiting examples include 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 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, and 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, and any range between these values. In some implementations, the pH is from 6.0 to 8.5.

[0023] In some embodiments, the fat emulsion may further comprise other protective excipients, such as one or more of amino acids, sugars, polymeric sugars, cyclodextrins, and inorganic salts, including but not limited to histidine, lysine, glycine, sucrose, glucose, lactose, trehalose, maltose, inositol, hydroxyethyl starch, PEG, dextran, sulfobutyl-β-cyclodextrin, and sodium chloride. In some embodiments, the other protective excipients are present in a weight-volume ratio of 0.01% to 30%, or 0.1% to 20%, or 1% to 15%.

[0024] In some embodiments, the fat emulsion described herein comprises a weight-to-volume ratio of:

[0025] (a) 0.05% to 10% of the compound of formula I or a pharmaceutically acceptable salt thereof,

[0026] (b) 1% to 25% castor oil,

[0027] (c) 1% to 25% medium-chain glycerides,

[0028] (d) 0.1% to 10% of a first emulsifier, which is polyethylene glycol 15-hydroxystearate and / or poloxamer.

[0029] (e) 50% to 97% water,

[0030] Optional (f) 0.01% to 10% stabilizer,

[0031] Optional 0.01% to 5% (g) of osmotic pressure regulator,

[0032] Optional (h) 0.1% to 10% of other emulsifiers.

[0033] In some embodiments, the fat emulsion described herein comprises a weight-to-volume ratio of:

[0034] (a) 0.05% to 10% of the compound of formula I or a pharmaceutically acceptable salt thereof,

[0035] (b) 3% to 20% castor oil,

[0036] (c) 3% to 20% medium-chain glycerides,

[0037] (d) 0.1% to 10% of a first emulsifier, which is polyethylene glycol 15-hydroxystearate and / or poloxamer.

[0038] (e) 50% to 90% water,

[0039] Optional (f) 0.01% to 10% stabilizer, selected from oleic acid, sodium oleate, sodium caprylate, cholesterol, and bile acids.

[0040] Optional osmotic pressure regulator (0.01% to 5% by weight), selected from sodium chloride, glucose, sorbitol, glycerol, and propylene glycol.

[0041] Optional (h) 0.1% to 10% of other emulsifiers, selected from Tween 80, lecithin and Tween 20.

[0042] In some embodiments, the weight ratio of castor oil to medium-chain glycerides is 1:0.1 to 1:10.

[0043] The fat emulsions described in this disclosure may be used in pharmaceuticals for the prevention and treatment of cardiovascular and cerebrovascular diseases in mammals, including humans. In some embodiments, the diseases are selected from thromboembolic diseases. In some embodiments, the diseases are selected from myocardial infarction, angina pectoris, restenosis and re-occlusion after angioplasty or aortocoronary shunt, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.

[0044] Hemolysis refers to the rupture of red blood cells, resulting in the release of hemoglobin, a process known as erythrocyte dissolution. Human plasma is isotonic, with a concentration of 0.9% NaCl. In solutions with NaCl concentrations below 0.45%, red blood cells swell and rupture due to water infiltration, releasing hemoglobin. In the human body, hemolysis can be caused by hemolytic bacteria or certain snake venoms, antigen-antibody reactions (such as transfusion of incompatible blood), various mechanical injuries, intrinsic red blood cell defects (membrane, enzymes), and certain drugs. In vitro hemolysis tests have shown that SMTP-7 series molecules pose a significant risk of hemolysis.

[0045] The fat emulsions comprising the compound of Formula I or its pharmaceutically acceptable salts disclosed herein exhibit good stability, and the drug loading in the composition is significantly increased. During clinical administration, this allows for a reduction in infusion rate and volume, thereby decreasing local irritation at the infusion site and improving clinical application and patient compliance. Furthermore, the fat emulsions of this disclosure maintain good safety while increasing drug loading, avoiding the risk of hemolysis.

[0046] The “w / v” in this disclosure refers to the mass (in g) of the component contained in every 100 mL of liquid system, i.e., g / 100 mL.

[0047] As used herein, the terms “about” and “approximately” mean a numerical value within the acceptable margin of error of a specific value determined by a person skilled in the art, the numerical value depending in part on how it is measured or determined (i.e., the limits of the measurement system). For example, in every practice in the art, “about” may mean within or above 1 standard deviation. Alternatively, “about” or “substantially includes” may mean a range of up to 20%. Furthermore, particularly for biological systems or processes, the term may mean up to an order of magnitude or up to five times the numerical value. Unless otherwise stated, when a specific value appears in this application and claims, the meaning of “about” or “substantially includes” should be assumed to be within the acceptable margin of error of that specific value.

[0048] The values ​​in this disclosure are instrument measurements or calculated values ​​after instrument measurement, and are subject to a certain degree of error. Generally speaking, ±10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, for the content of total impurities, the value is defined as having an error variation of no more than ±10% after measurement, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0049] "Optional" or "optional" means that the event or situation described below may, but does not have to, occur, including the circumstances in which the event or situation may or may not occur.

[0050] In this disclosure, "mixing" or "mixing" means that the order of addition of components is not limited. For example, mixing A into B can mean that A is added to B or that B is added to A. Mixing A and B can mean that A is added to B or that B is added to A. Detailed Implementation

[0051] The present disclosure is further described in detail through the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0052] The structure of the SMTP derivative used in the examples is shown below:

[0053] Compound A

[0054] Compound B

[0055] The SMTP derivatives described in this disclosure can be prepared with reference to methods disclosed in the prior art, such as WO2022171151.

[0056] Example 1

[0057] According to the formulation composition in Table 1, weigh out the prescribed amounts of each excipient. Heat in a water bath at 60–70°C, mix compound A with castor oil, medium-chain glycerides, and other oil components, and add stabilizer oleic acid or sodium oleate to obtain the oil phase. Heat in a water bath at 70°C, mix with emulsifier, glycerol, and water for injection to obtain the aqueous phase. Under 60°C water bath conditions, slowly add the oil phase to the aqueous phase, and shear at 12000 rpm for 5–10 min using a high-speed shear mill. Homogenize in a high-pressure homogenizer with an initial homogenization pressure of 200 bar, homogenize 5 times, then adjust the homogenization pressure to 650–800 bar, homogenize 8–15 times to obtain a homogeneous emulsion. Adjust the pH to 8.0 using hydrochloric acid or sodium hydroxide to obtain the target fat emulsion.

[0058] Table 1. Composition of the composition (w / v)

[0059] Example 2

[0060] The target fat emulsion was prepared according to the formulation composition in Tables 2 and 3 and the method in Example 1.

[0061] Table 2 Composition of the composition (w / v)

[0062] Table 3. Composition of the composition (w / v)

[0063] Example 3

[0064] The compositions prepared in Examples 1 and 2 were subjected to hemolysis tests, and the results are shown in Table 4. Some compositions were diluted with physiological saline or 5% glucose solution.

[0065] Add 1 ml of drug-loaded fat emulsion to a 2 ml centrifuge tube and preheat in a 37°C water bath for 1–2 min. Then add 100 μl of mouse whole blood and incubate the tube in a 37°C water bath for 1 min. Centrifuge at 3500 rpm for 2 min. Take 0.5 ml of the supernatant or upper emulsion and dilute to 5 ml with a demulsifier (anhydrous ethanol-concentrated hydrochloric acid, 399:1). The solution will become clear. Take 100 μl of the sample and measure its absorbance at 530 nm. Calculate the hemolysis rate as follows: (AA negative control) / (A positive control - A negative control) * 100%. The positive control is purified water with whole blood, and the negative control is physiological saline or 5% glucose solution with whole blood.

[0066] Table 4 Note: A hemolysis rate >20% is defined as a risk of hemolysis.

[0067] Example 4

[0068] The compositions prepared in Examples 1 and 2 were stored under different conditions, and the stability of the fat emulsion was observed. The results are shown in Table 5.

[0069] Table 5 Composition Stability

[0070] The results showed that after two months of storage, the particle size, distribution, potential, pH and other parameters of the tested fat emulsions were not significantly abnormal, indicating that the fat emulsions had good quality stability.

Claims

1. A fat emulsion comprising: a compound represented by Formula I or a pharmaceutically acceptable salt thereof, an oil component, water, and a first emulsifier, wherein R1, R2, R3, R4, R5, R6and R7are each independently hydrogen or deuterium, the first emulsifier is 15-hydroxypolyoxyl stearate and / or poloxamer.

2. The fat emulsion of claim 1, wherein, R1, R2, R3, R4, and R5are each hydrogen, and R6and R7are each independently hydrogen or deuterium, preferably the compound of formula I is:

3. The fat emulsion according to claim 1 or 2, wherein the weight / volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof is 0.01 to 30%, preferably 0.1 to 10%.

4. The fat emulsion according to any one of claims 1 to 3, wherein the oil component comprises natural oil and / or synthetic oil, preferably the natural oil is selected from one or more of soybean oil, safflower oil, jojoba oil, olive oil, sweet almond oil, coconut oil, castor oil, sunflower oil, fish oil, and preferably the synthetic oil is selected from one or more of medium-chain glycerides, isooctyl palmitate, isooctyl palmitate, isopropyl palmitate.

5. The fat emulsion according to any one of claims 1 to 4, wherein the weight / volume ratio of the oil component is 1 to 50%, preferably 5 to 40%.

6. The fat emulsion according to any one of claims 1 to 5, wherein the oil component comprises natural oil and synthetic oil, and the weight ratio of the natural oil to the synthetic oil is 1:0.1 to 1:30, preferably the oil component comprises castor oil and medium-chain glycerides.

7. The fat emulsion according to any one of claims 1 to 6, wherein the weight / volume ratio of the first emulsifier is 0.01 to 10%, preferably 0.1 to 5%.

8. The fat emulsion according to any one of claims 1 to 7, wherein the fat emulsion further comprises an additional emulsifier, and the additional emulsifier is selected from one or more of Tween 80, lecithin, sodium oleate, Span 20, Tween 20, polyoxyethylene monostearate, polyoxyethylene stearate, polyoxyethylene 40 stearate, polyoxyethylene 400 monolaurate, polyoxyethylene 400 monostearate, polyoxyethylene 400 monooleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl phenol, polyoxyethylene fatty alcohol ether, polyoxyethylene nonyl phenol ether, polyoxyethylene octyl phenyl ether, polyoxyethylene lauryl ether, and preferably the weight / volume ratio of the additional emulsifier is 0.01 to 10%.

9. The fat emulsion according to any one of claims 1 to 8, wherein the fat emulsion further comprises a stabilizer, and the stabilizer is selected from one or more of oleic acid, sodium oleate, sodium caprylate, cholesterol, cholic acid, deoxycholic acid and its sodium salt, vitamin A, vitamin C, vitamin E, and preferably the weight / volume ratio of the stabilizer is 0.001 to 10%.

10. The fat emulsion according to any one of claims 1 to 9, wherein the fat emulsion further comprises an osmotic pressure regulator, and the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, sorbitol, glycerol, PEG, propylene glycol, and preferably the weight / volume ratio of the osmotic pressure regulator is 0.01 to 10%.

11. The fat emulsion according to any one of claims 1 to 10, wherein the pH of the fat emulsion is from 6.0 to 11.0, preferably from 6.0 to 8.

5.

12. The fat emulsion according to any one of claims 1 to 11, comprising in weight by volume: (a) 0.05% to 10% of the compound of formula I or a pharmaceutically acceptable salt thereof, (b) 1% to 25% of castor oil, (c) 1% to 25% of medium chain glycerides, (d) 0.1% to 10% of a first emulsifier which is 15-hydroxystearic acid polyethylene glycol ester and / or poloxamer, (e) 50% to 97% of water, optionally (f) 0.01% to 10% of a stabilizer, optionally (g) 0.01% to 5% of an osmotic pressure adjusting agent, optionally (h) 0.1% to 10% of a further emulsifier; preferably the fat emulsion comprises in weight by volume: (a) 0.05% to 10% of the compound of formula I or a pharmaceutically acceptable salt thereof, (b) 3% to 20% of castor oil, (c) 3% to 20% of medium chain glycerides, (d) 0.1% to 10% of a first emulsifier which is 15-hydroxystearic acid polyethylene glycol ester and / or poloxamer, (e) 50% to 90% of water, optionally (f) 0.01% to 10% of a stabilizer selected from the group consisting of oleic acid, sodium oleate, sodium caprylate, cholesterol and cholic acid, optionally (g) 0.01% to 5% of an osmotic pressure adjusting agent selected from the group consisting of sodium chloride, dextrose, sorbitol, glycerol and propylene glycol, optionally (h) 0.1% to 10% of a further emulsifier selected from the group consisting of Tween 80, lecithin and Tween 20.

13. Use of the fat emulsion according to any one of claims 1 to 12 for the preparation of a medicament for the treatment of cardiovascular diseases in a mammal, preferably thromboembolic diseases, more preferably myocardial infarction, angina pectoris, restenosis and reocclusion after angioplasty or aortocoronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

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