Pharmaceutical composition of PAR-1 inhibitor as well as preparation method and application of pharmaceutical composition

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of a PAR-1 inhibitor and a preparation method and application of the pharmaceutical composition. The preparation method comprises the following steps: weighing an oil phase, an emulsifier and a co-emulsifier, heating and stirring uniformly, then adding a PAR-1 inhibitor, and stirring until the mixture is clear and transparent; adding a penetration enhancer, and uniformly stirring and dispersing to obtain PAR-1 inhibitor liquid self-microemulsion; mixing the PAR-1 inhibitor liquid self-microemulsion with a polymer carrier solution, and converting the liquid self-microemulsion into solid particles by adopting a spray drying technology, namely solid self-microemulsion; according to the invention, an efficient, stable and convenient solution is provided for oral delivery of the PAR-1 inhibitor through an integrated strategy of a self-microemulsion drug delivery system, a penetration enhancer and spray drying and curing, and the self-microemulsion drug delivery system has important clinical application value and industrialization prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to pharmaceutical compositions of PAR-1 inhibitors, their preparation methods, and applications. Background Technology

[0002] Cardiovascular disease is the leading cause of death and disability worldwide. Particularly in my country, the prevalence of unhealthy diets, insufficient physical activity, and smoking, coupled with a large population at risk of cardiovascular disease and an accelerating aging population, has led to a continuous rise in the incidence and mortality rates of cardiovascular disease, posing a significant public health challenge. Antithrombotic therapy is one of the core strategies for the prevention and treatment of cardiovascular disease. Platelet activation is a key step in thrombus formation. PAR-1 (protease-activated receptor-1), as the main receptor for thrombin-mediated platelet activation, has a stronger activation effect than the thrombin-mediated platelet aggregation pathway (TxA2) and ADP pathway. It can selectively inhibit thrombin-induced platelet aggregation, blocking thrombus formation without interfering with normal hemostasis, thus becoming an ideal target for antithrombotic drug development.

[0003] Patent CN117362279A discloses a PAR-1 inhibitor, its chiral synthesis method, and the preparation method and uses of its salt crystal form. The chemical name of the PAR-1 inhibitor is ethyl((3aR,4aR,5S,6R,8aR,9R,9aS)-9-((E)(-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-5,8-dimethyl-3-oxododecanonaphtho[2,3-c]furan-6-yl)carbamate sulfate. Due to its molecular structure characteristics, oral administration faces problems such as low solubility, poor intestinal absorption, insufficient bioavailability, poor stability of traditional liquid formulations, and limited dosage forms, which seriously restricts its clinical translation. Summary of the Invention

[0004] To address the problems of low solubility and insufficient bioavailability of existing PAR-1 inhibitors when administered orally, as well as the poor stability and dosage form limitations of traditional liquid formulations, this invention provides a pharmaceutical composition for PAR-1 inhibitors. By optimizing the formulation composition and process, it achieves a synergistic improvement in drug solubility, bioavailability, and stability, while also facilitating industrial production into solid dosage forms such as tablets and capsules.

[0005] The present invention also provides a preparation method that is simple, easy to implement, and suitable for large-scale production.

[0006] The present invention also provides its application in the preparation of antithrombotic or cardiovascular disease treatment drugs.

[0007] The pharmaceutical composition of the PAR-1 inhibitor described in this invention has the chemical name of ethyl((3aR,4aR,5S,6R,8aR,9R,9aS)-9-((E)(-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-5,8-dimethyl-3-oxododecanonaphtho[2,3-c]furan-6-yl)carbamate sulfate, and its structural formula is shown in Formula I below:

[0008] Formula I; The pharmaceutical composition comprises the following raw materials: PAR-1 inhibitor, oil phase, emulsifier, co-emulsifier, penetration enhancer, and polymer carrier; The pharmaceutical composition comprises the following raw materials in the indicated mass fractions: PAR-1 inhibitors: 8-10%; Oil phase 10~30%; Emulsifier 30-50%; Co-emulsifier 20-30%; Penetration enhancer 1-4%; Polymer carrier 4-6%.

[0009] The oil phase is at least one of medium-chain triglycerides, castor oil, oleic acid, ethyl oleate, isopropyl myristate, triacetin, caprylic / capric triglycerides, triethyl citrate, trioleic acid, pure olive oil, deep-sea shark oil, coconut oil, palm oil, soybean oil, clove oil, and monolinoleic acid glycerides.

[0010] The emulsifier is at least one of Tween 80, Tween 20, polyoxyethylene 35 castor oil, polyoxyethylene hydrogenated castor oil RH 40, propylene glycol monolaurate, propylene glycol octanoate, and polyethylene glycol glycerol octanoate / capric acid.

[0011] The co-emulsifier is at least one of 1,2-propanediol, polyethylene glycol 400, polyethylene glycol 300, diethylene glycol monoethyl ether, and glycerin.

[0012] The penetration enhancer is one or more of sodium decanoate, sodium octanoate, and sodium 8-(2-hydroxybenzamido)octanoate.

[0013] The preferred penetration enhancer is sodium 8-(2-hydroxybenzamido)octanoate.

[0014] The polymer carrier is at least one of the following: polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone, chitosan, hydroxypropyl methylcellulose, and polyethylene glycol.

[0015] The preferred material is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (CAS No. 402932-23-4), and a more preferred material is Soluplus®, a water-soluble graft polymer developed by BASF.

[0016] The preparation method of the PAR-1 inhibitor pharmaceutical composition of the present invention comprises the following steps: (1) Weigh out the oil phase, emulsifier, and co-emulsifier separately, heat and stir until uniform, then add the PAR-1 inhibitor and stir until clear and transparent; (2) Add the penetration enhancer to step (1), stir and disperse evenly to obtain PAR-1 inhibitor liquid self-microemulsion; (3) The PAR-1 inhibitor liquid self-microemulsion prepared in step (2) is mixed with the polymer carrier solution, and the liquid self-microemulsion is converted into solid particles by spray drying technology, which is the solid self-microemulsion; The heating temperature in step (1) is 30~50℃.

[0017] The process parameters for spray drying in step (3) are: inlet temperature 80~120℃, outlet temperature 40~60℃, and feed rate 5~20mL / min.

[0018] The polymer carrier solution in step (3) is a mixture of polymer carrier and aqueous acetic acid solution, and the mass ratio of PAR-1 inhibitor liquid microemulsion to polymer carrier solution is 1:2 to 1:5.

[0019] The acetic acid aqueous solution has a mass concentration of 0.5-2%.

[0020] The polymer carrier solution is prepared by adding the polymer carrier to a 0.5%~2wt.% acetic acid solution and stirring at 25-30℃ until completely dissolved to prepare a polymer carrier solution with a mass concentration of 1%-5%.

[0021] The solid microemulsion can be prepared as a solid dosage form, such as tablets, capsules, granules, or powders.

[0022] The solid self-microemulsion drug delivery system can spontaneously form microemulsions with a particle size of 10~200nm in the aqueous phase, and the particle size stability deviation is ≤10% within 24h.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention increases the solubility of novel PAR-1 inhibitors through a self-microemulsion system, and combined with the transcellular absorption enhancement effect of a penetration enhancer, significantly improving the oral bioavailability of the drug.

[0024] 2. The preferred polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer of the present invention is used as a polymer carrier and also as a precipitation inhibitor for liquid self-microemulsion, thereby improving the overall solubility.

[0025] 3. This invention uses spray drying technology to solidify liquid microemulsions into solid particles, which solves the problems of easy stratification and poor stability of traditional liquid formulations during storage, and extends the shelf life to more than 24 months.

[0026] 4. The solid particles obtained by this invention can be directly prepared into various solid dosage forms such as tablets, capsules, and granules to meet different clinical drug administration needs, and are easy to transport and store.

[0027] 5. The PAR-1 inhibitor of the active pharmaceutical ingredient described in this invention has a shortened half-life after structural optimization, reducing the risk of bleeding. Combined with the efficient delivery of the formulation technology, it achieves synergistic optimization of antithrombotic efficacy and safety.

[0028] 6. The use of acetic acid aqueous solution as a solvent in the spray drying technology of this invention can increase the stability of the raw materials.

[0029] 7. This invention provides an efficient, stable, and convenient solution for the oral delivery of PAR-1 inhibitors through an integrated strategy of "self-microemulsion drug delivery system - penetration enhancer - spray drying and curing", which has important clinical application value and industrialization prospects. Attached Figure Description

[0030] Figure 1 This is a TEM image of the solid self-microemulsification forming a microemulsion in Example 4. Detailed Implementation

[0031] The present invention will be further described below with reference to the embodiments.

[0032] Unless otherwise specified, all raw materials used in the examples were commercially available.

[0033] The PAR-1 inhibitors used in the examples and comparative examples were prepared using the method described in Example 1 of patent CN117362279A.

[0034] Examples 1-3 (Exploration of the types of self-microemulsion excipients) This embodiment provides a pharmaceutical composition for a PAR-1 inhibitor, and explores the types of self-microemulsion phase, emulsifier, and co-emulsifier. The specific composition is shown in Table 1: Table 1. Prescription composition of Examples 1-3

[0035] The specific steps for preparing the PAR-1 inhibitor pharmaceutical composition are as follows: (1) Weigh 0.15g of oil phase, 0.45g of emulsifier and 0.25g of co-emulsifier, stir evenly under heating at 37°C, add 0.08g of PAR-1 inhibitor, and continue stirring until clear and transparent; (2) Add 0.02g of the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate to the mixture in step (1), stir and disperse evenly to obtain PAR-1 inhibitor liquid self-microemulsion; (3) Add chitosan to a 1 wt.% dilute acetic acid solution and stir at 25°C until completely dissolved to prepare a 3% chitosan carrier solution containing 0.05 g of chitosan. Mix the liquid microemulsion and the chitosan carrier solution at a mass ratio of 1:3 and stir at 300 rpm for 20 min until homogeneous. Add the mixture to the feed tank of a spray dryer and set the parameters as follows: inlet air temperature 100°C, outlet air temperature 60°C, feed rate 10 mL / min, and atomization pressure 0.2 MPa. Start the equipment for spray drying. The droplets evaporate the solvent quickly through the hot air to form chitosan solid particles loaded with the microemulsion. Collect the solid powder in the drying chamber and cyclone separator, remove large particles by passing through an 80-mesh sieve, and seal and store in a desiccator for later use to obtain the solid microemulsion.

[0036] Example 4 (Exploration of Polymer Carrier Types) This embodiment provides a pharmaceutical composition for a PAR-1 inhibitor, and explores the types of polymer carriers. The specific composition comparison with that of Example 3 is shown in Table 2: Table 2 Comparison of prescription composition in Examples 3 and 4

[0037] The specific steps for preparing the PAR-1 inhibitor pharmaceutical composition are as follows: (1) Weigh 0.15g of oil phase, 0.45g of emulsifier and 0.25g of co-emulsifier, stir evenly under heating at 37°C, add 0.08g of PAR-1 inhibitor, and continue stirring until clear and transparent; (2) Add 0.02g of the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate to the mixture in step (1), stir and disperse evenly to obtain PAR-1 inhibitor liquid self-microemulsion; (3) Chitosan and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer were added to a 1 wt.% dilute acetic acid solution and stirred at 25°C until completely dissolved to prepare a polymer carrier solution with a mass concentration of 3%. The chitosan carrier solution contained 0.05 g of chitosan. The liquid microemulsion and the polymer carrier solution were mixed at a mass ratio of 1:3 and stirred at 300 rpm for 20 min until homogeneous. The mixture was added to the feed tank of a spray dryer and the parameters were set as follows: inlet air temperature 100°C, outlet air temperature 60°C, feed rate 10 mL / min, and atomization pressure 0.2 MPa. The equipment was started for spray drying. The droplets were rapidly evaporated by hot air to form polymer solid particles loaded with the microemulsion. The solid powder in the drying chamber and cyclone separator was collected, and large particles were removed by passing through an 80-mesh sieve. The powder was sealed and stored in a desiccator for later use to obtain the solid microemulsion.

[0038] Example 5 This embodiment provides a pharmaceutical composition for a PAR-1 inhibitor, the specific composition of which is shown in Table 3: Table 3. Prescription composition of Example 5

[0039] The specific steps for preparing the PAR-1 inhibitor pharmaceutical composition are as follows: (1) Weigh the oil phase, emulsifier, and co-emulsifier according to the proportion, stir evenly under heating at 50°C, add PAR-1 inhibitor, and continue stirring until clear and transparent; (2) Add the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate to the mixture in step (1), stir and disperse evenly to obtain PAR-1 inhibitor liquid self-microemulsion; (3) Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was added to a 2 wt.% dilute acetic acid solution and stirred at 25°C until completely dissolved to prepare a polymer carrier solution. The liquid microemulsion and the polymer carrier solution were mixed at a mass ratio of 1:5 and stirred at 300 rpm for 20 min until homogeneous. The mixture was added to the feed tank of a spray dryer and the parameters were set as follows: inlet air temperature 80°C, outlet air temperature 40°C, feed rate 6 mL / min, and atomization pressure 0.3 MPa. The equipment was started for spray drying. The droplets were rapidly evaporated by hot air to form polymer solid particles loaded with the microemulsion. The solid powder in the drying chamber and cyclone separator was collected, and large particles were removed by passing through an 80-mesh sieve. The powder was sealed and stored in a desiccator for later use to obtain the solid microemulsion.

[0040] Example 6 This embodiment provides a pharmaceutical composition for a PAR-1 inhibitor, the specific composition of which is shown in Table 4: Table 4. Prescription composition of Example 6

[0041] The specific steps for preparing the PAR-1 inhibitor pharmaceutical composition are as follows: (1) Weigh the oil phase, emulsifier, and co-emulsifier according to the proportion, stir evenly under heating at 30°C, add PAR-1 inhibitor, and continue stirring until clear and transparent; (2) Add the penetration enhancer sodium 8-(2-hydroxybenzamido)octanoate to the mixture in step (1), stir and disperse evenly to obtain PAR-1 inhibitor liquid self-microemulsion; (3) Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was added to a 2 wt.% dilute acetic acid solution and stirred at 25°C until completely dissolved to prepare a polymer carrier solution. The liquid microemulsion and the polymer carrier solution were mixed at a mass ratio of 1:2 and stirred at 300 rpm for 20 min until homogeneous. The mixture was added to the feed tank of a spray dryer and the parameters were set as follows: inlet air temperature 120°C, outlet air temperature 60°C, feed rate 15 mL / min, and atomization pressure 0.3 MPa. The equipment was started for spray drying. The droplets were rapidly evaporated by hot air to form polymer solid particles loaded with the microemulsion. The solid powder in the drying chamber and cyclone separator was collected, and large particles were removed by passing through an 80-mesh sieve. The powder was sealed and stored in a desiccator for later use to obtain the solid microemulsion.

[0042] Examples 7-8 Table 5. Prescription composition of Examples 7-8

[0043] This embodiment provides a pharmaceutical composition for a PAR-1 inhibitor, as detailed below: Sodium decanoate and sodium octanoate were used as penetration enhancers, respectively, and the rest of the preparation was the same as in Example 4.

[0044] Example 9 This embodiment provides a pharmaceutical composition for a PAR-1 inhibitor, as detailed below: Purified water was used as the solvent for the polymer carrier, and the rest of the preparation was the same as in Example 4.

[0045] Comparative Example 1 (Solid self-microemulsion composition without penetration enhancer) According to Example 4, without adding a penetration enhancer, a solid self-microemulsion was prepared using spray drying technology, and the solid particles were collected to obtain the microemulsion.

[0046] Comparative Example 2 (Liquid Self-Microemulsion Formulation) According to Example 4, a liquid self-microemulsion was prepared without using spray drying technology for curing.

[0047] Performance testing: a. Particle size and stability study Take Examples 1-9 and Comparative Examples 1-2, add them to purified water (0.5g sample added to 50mL purified water), centrifuge for 2min after emulsification, take the supernatant, and measure its average particle size with a laser particle size analyzer. Repeat the measurement after placing at 25℃ for 24h.

[0048] Table 6. Particle size and stability of the self-emulsified microemulsion

[0049] The test results are shown in Table 6. Compared with Examples 1-3, the formulation prepared using medium-chain triglycerides, polyoxyethylene hydrogenated castor oil RH40, and diethylene glycol monoethyl ether in the oil phase has a smaller particle size. Compared with Examples 3 and 4, the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is better than chitosan. Compared with Examples 4-6, the dosage and process parameters of the formulation in Example 4 are more effective. Compared with Example 4, in Examples 7-8, sodium decanoate and sodium octanoate were selected as penetration enhancers. The particle size of the samples prepared with sodium octanoate and sodium 8-(2-hydroxybenzamide)octanoate is not much different. However, since sodium 8-(2-hydroxybenzamide)octanoate has sufficient safety data, it is preferred. Compared with Example 4, Example 9 shows that using dilute acetic acid solution as the polymer carrier solvent is better; compared with Comparative Example 1, Example 4 shows that adding a penetration enhancer to the formulation is more effective; compared with Comparative Example 2, Example 4 produces similar particle sizes, therefore, the solid self-microemulsion prepared by spray drying technology does not affect the emulsification ability of the liquid self-microemulsion.

[0050] b. Transmission electron microscopy (TEM) morphological observation Take 0.1 g of the solid microemulsion of PAR-1 inhibitor prepared in Example 4, add it to 5 mL of purified water (37℃, 100 rpm), and after the self-emulsification is completed, centrifuge for 2 min, take the supernatant, drop it onto a copper grid covered with a support membrane, let it stand for 10 min, then use filter paper to absorb the excess liquid, add 2 wt.% phosphotungstic acid solution, negative stain for 5 min, let it dry naturally, and observe it under a transmission electron microscope.

[0051] The results are as follows Figure 1 The image shows the appearance of the PAR-1 inhibitor solid self-emulsifying microemulsion prepared in Example 4. The microemulsion is spherical, has a good morphology, is uniformly distributed and does not stick together, indicating that the formed nanoemulsion has physical stability.

[0052] c. Dissolution test The dissolution medium was 900 mL of pH 6.8 phosphate buffer, the rotation speed was 100 rpm, and the temperature was 37 ± 0.5 °C. The PAR-1 inhibitor raw material, the formulations prepared in Examples 1-9, and Comparative Examples 1-2 were used, and the dissolution curves of the PAR-1 inhibitor in pH 6.8 phosphate buffer were detected. The test results are shown in Table 7.

[0053] Table 7 Dissolution curve test results

[0054] As shown in Table 7, preparing PAR-1 inhibitors into solid self-microemulsions can significantly improve their dissolution rate, thereby improving their bioavailability.

[0055] d. Stability Study The solid self-microemulsion formulations of PAR-1 inhibitors prepared in Examples 1-6, 9 and Comparative Examples 1-2 were placed under accelerated conditions (temperature 40℃±2℃, relative humidity 75%±5%) for one month, and samples were taken to detect dissolution curves, particle size, and properties. Specific results are shown in Table 8.

[0056] Table 8. Results of stability determination of PAR-1 inhibitors under accelerated conditions.

[0057] Comparing the stability test results of the above comparative examples and embodiments, since the liquid self-microemulsion is directly dissolved in the liquid during storage, it is easily degraded. However, the solid self-microemulsion is fixed in a solid carrier by solidification technology, which improves its stability. At the same time, during the solidification process, the solvent used is aqueous acetic acid, which can improve the stability of the raw materials compared with purified water.

Claims

1. A pharmaceutical composition for a PAR-1 inhibitor, characterized in that, The chemical name of the PAR-1 inhibitor is ethyl((3aR,4aR,5S,6R,8aR,9R,9aS)-9-((E)(-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-5,8-dimethyl-3-oxododecanonaphtho[2,3-c]furan-6-yl)carbamate sulfate, and its structural formula is shown in Formula I below: Formula I; The pharmaceutical composition comprises the following raw materials: PAR-1 inhibitor, oil phase, emulsifier, co-emulsifier, penetration enhancer, and polymer carrier.

2. The pharmaceutical composition of the PAR-1 inhibitor according to claim 1, characterized in that, The pharmaceutical composition comprises the following raw materials in the indicated mass fractions: PAR-1 inhibitors: 8-10%; Oil phase 10~30%; Emulsifier 30-50%; Co-emulsifier 20-30%; Penetration enhancer 1-4%; Polymer carrier 4-6%.

3. The pharmaceutical composition of the PAR-1 inhibitor according to claim 1, characterized in that, The emulsifier is at least one of Tween 80, Tween 20, polyoxyethylene 35 castor oil, polyoxyethylene hydrogenated castor oil RH 40, propylene glycol monolaurate, propylene glycol octanoate, and polyethylene glycol glycerol octanoate / capric acid.

4. The pharmaceutical composition of the PAR-1 inhibitor according to claim 1, characterized in that, The co-emulsifier is at least one of 1,2-propanediol, polyethylene glycol 400, polyethylene glycol 300, diethylene glycol monoethyl ether, and glycerin.

5. The pharmaceutical composition of the PAR-1 inhibitor according to claim 1, characterized in that, The penetration enhancer is at least one of sodium decanoate, sodium octanoate, and sodium 8-(2-hydroxybenzamido)octanoate.

6. The pharmaceutical composition of the PAR-1 inhibitor according to claim 1, characterized in that, The polymer carrier is at least one of the following: polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone, chitosan, hydroxypropyl methylcellulose, and polyethylene glycol.

7. A method for preparing a pharmaceutical composition of the PAR-1 inhibitor according to any one of claims 1 to 6, characterized in that, It is prepared by the following steps: (1) Weigh out the oil phase, emulsifier, and co-emulsifier separately, heat and stir until uniform, then add the PAR-1 inhibitor and stir until clear and transparent; (2) Add the penetration enhancer to step (1), stir and disperse evenly to obtain PAR-1 inhibitor liquid self-microemulsion; (3) The PAR-1 inhibitor liquid self-microemulsion prepared in step (2) is mixed with the polymer carrier solution, and the liquid self-microemulsion is converted into solid particles by spray drying technology to obtain solid self-microemulsion.

8. The method for preparing the pharmaceutical composition of the PAR-1 inhibitor according to claim 7, characterized in that, The heating temperature in step (1) is 30~50℃, and the process parameters for spray drying in step (3) are: inlet temperature 80~120℃, outlet temperature 40~60℃, and feed rate 5~20mL / min.

9. The method for preparing the pharmaceutical composition of the PAR-1 inhibitor according to claim 7, characterized in that, The polymer carrier solution in step (3) is a mixture of polymer carrier and aqueous acetic acid solution, and the mass ratio of PAR-1 inhibitor liquid microemulsion to polymer carrier solution is 1:2 to 1:

5.

10. The use of a pharmaceutical composition of any one of claims 1 to 6 of a PAR-1 inhibitor in the preparation of an antithrombotic or cardiovascular disease treatment medicament.

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