A vericiguat self-microemulsifying composition and a preparation method thereof

Abstract

The application discloses a venglustat self-microemulsion composition and a preparation method and application thereof. The composition comprises venglustat 0.2%-1.2% (w / w), an oil phase 3%-20% (w / w), a surfactant 20%-40% (w / w), a co-surfactant 45%-75% (w / w), and a precipitation inhibitor. The oil phase is selected from MCT, MCM, GMO or a mixture thereof; the surfactant is selected from RH40, Labrasol, Transcutol HP or a combination thereof; the co-surfactant is selected from PEG400, propylene glycol, glycerol or a mixture thereof; and the precipitation inhibitor is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), poloxamer 188, polyvinylpyrrolidone (PVP) or a mixture thereof. The composition can spontaneously form a microemulsion in the gastrointestinal tract, is expected to improve the bioavailability of venglustat in a fasting state, improve the food effect, reduce the inter-individual variation and improve the medication compliance of patients.

Description

Technical Field

[0001] This invention relates to velixigua self-microemulsion formulations, their preparation methods, and applications, and particularly to a velixigua self-microemulsion formulation that can improve food effects and increase fasting bioavailability. Background Technology

[0002] Vericiguat is a soluble guanylate cyclase (sGC) stimulant co-developed by Bayer AG and Merck & Co. It was first approved for marketing in the United States in 2021 and in China in 2022 under the brand name Verquvo®. This drug is indicated for adult patients with symptomatic chronic heart failure and reduced ejection fraction (<45%) whose condition has recently stabilized after intravenous therapy for decompensated heart failure, in order to reduce the risk of hospitalization for heart failure or the need for emergency intravenous diuretic therapy.

[0003] The chemical name of veliximab is methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate, with the molecular formula [missing information]. With a molecular weight of 426.39, its structure is shown in Formula I. According to the FDA product review report and related literature, veliciguat belongs to BCS Class II drugs, characterized by low solubility and high permeability. This drug is almost insoluble between pH 3 and 7, slightly soluble under more acidic pH conditions, and its solubility in pure water is approximately 0.12 mg / mL, classifying it as a very slightly soluble / poorly soluble drug.

[0004] The original drug, veliciguat tablets, exhibits a significant food effect. According to clinical trial data, compared to a fasting state, administration of 5 mg veliciguat tablets after a high-fat, high-calorie meal increased AUC and Cmax by 19% and 9%, respectively; administration of 10 mg after a meal increased AUC and Cmax by 44% and 41%, respectively. The original drug's instructions explicitly recommend "taken with food," achieving a bioavailability of 93%, while the bioavailability in a fasting state is only about 66%.

[0005] This food effect significantly impacts patient medication adherence. Heart failure patients often have comorbidities such as hypertension, diabetes, and chronic kidney disease, and elderly patients often have irregular eating habits; the restriction of taking medication after meals greatly reduces adherence. Furthermore, some patients need to take other medications on an empty stomach (such as thyroid hormone) or must fast after surgery, making it impossible for them to follow the requirement of taking medication after meals.

[0006] Self-Microemulsifying Drug Delivery System (SMEDDS) is a liquid formulation capable of spontaneously forming microemulsions in the gastrointestinal tract. It consists of an oil phase, surfactants, co-surfactants, and the drug. By preloading lipid components, this system can form mixed micelles without the need for food-stimulated bile secretion, promoting drug dissolution and transmembrane transport, thereby improving the bioavailability of poorly soluble drugs and enhancing the food effect.

[0007] Therefore, developing a self-microemulsion formulation of velixigua to improve food effects and increase fasting bioavailability is of great significance for improving patient compliance and optimizing treatment outcomes.

[0008]

[0009] I Summary of the Invention

[0010] The purpose of this invention is to provide a veliciguat self-microemulsifying composition. This formulation achieves effective solubilization and self-emulsification of veliciguat by optimizing the ratio of oil phase, surfactant, solubilizer and precipitation inhibitor, significantly improving fasting bioavailability, improving food effect, reducing inter-individual variability and improving patient medication compliance.

[0011] To achieve the above objectives, the present invention adopts the following technical solution: a veliximab self-microemulsion composition, comprising the following components, Viliximab: 0.2%-1.2% (w / w), preferably 0.5%-1.2%; Oil phase: 3%-20% (w / w), preferably 4%-10%; Surfactant: 20%-40% (w / w), preferably 25%-35%; Co-surfactant: 45%-75% (w / w), preferably 50%-70%; Precipitation inhibitor: 2%-10% (w / w), preferably 3%-8%.

[0012] The oil phase is selected from MCT, MCM, GMO or mixtures thereof, with MCM being preferred.

[0013] The surfactant is selected from polyoxyethylene hydrogenated castor oil (RH40), polyethylene glycol-8 octanoic acid / capric acid glyceride (Labrasol), diethylene glycol monoethyl ether (Transcutol HP), or combinations thereof. Preferred combinations are: ① Labrasol alone; ② RH40 and Labrasol in combination at a mass ratio of 1:5 to 1:1; ③ RH40, Labrasol, and Transcutol HP in combination at a mass ratio of (0.8-1.2):(0.8-1.2):1.

[0014] The co-surfactant is selected from PEG400, propylene glycol, glycerin or a mixture thereof, preferably PEG400.

[0015] The precipitation inhibitor is selected from Soluplus, poloxamer 188, PVP, or a mixture thereof, with Soluplus being preferred.

[0016] Another object of the present invention is to provide a method for preparing a veliximab self-microemulsion composition, comprising the following steps: (1) Dispersion: Add the precipitation inhibitor to the co-surfactant, stir at 40-60℃ until it is clear, and add velixiva to disperse it completely; (2) Mixing: Add the oil phase and surfactant in sequence and stir for 1-2 hours to obtain a clear and uniform self-microemulsion composition.

[0017] Another object of the present invention is to provide a veliximab self-microemulsion formulation comprising the above-described veliximab self-microemulsion composition and its pharmaceutical excipients.

[0018] Preferably, the self-microemulsion formulation of the present invention is selected from one of soft capsules, single-dose oral solutions, or solidified tablets.

[0019] Preferably, the self-microemulsion formulation is a soft capsule, a single-dose oral solution, or a tablet; the solidification is achieved by adsorption using a porous adsorbent.

[0020] Compared with the prior art, the present invention has the following advantages: (1) Improved food effect: Effective solubilization and self-emulsification are achieved by optimizing the ratio of excipients. Transcutol HP is generally classified as a co-solvent or co-solvent in the art, but in the velixigua self-microemulsion system of the present invention, Transcutol HP, RH40, and Labrasol participate in the formation of self-microemulsion as surfactant components. In addition to its solubilizing effect, Transcutol HP, together with RH40 and Labrasol, reduces the oil-water interfacial tension, promotes spontaneous emulsification, significantly reduces the microemulsion particle size, and lowers the PDI. In vitro tests show that the formulation of the present invention can spontaneously form microemulsions with a particle size of less than 100 nm at pH 1.2-6.8. The expected fasting bioavailability is more than 90% of that after meal administration.

[0021] (2) Improve compliance: It does not need to be taken with meals and can be taken at any time. It is suitable for patients with irregular diet, those who need to take other medications on an empty stomach, or those who are fasting after surgery.

[0022] (3) Reduced variability: Self-emulsification forms a uniform microemulsion system, and the drug exists in a molecular or nanoscale dispersed state. Absorption is not affected by food, and the expected inter-individual coefficient of variation is comparable to or better than that of postprandial administration. Attached Figure Description

[0023] Figure 1 The appearance of the self-microemulsion compositions of components 1-3 in Examples 1-3 is shown.

[0024] Figure 2 The image shows the appearance of each component after dilution with purified water in Example 6. Detailed Implementation

[0025] The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention.

[0026] In the following specific embodiments, the reagents, excipients, and their sources are as follows: MCM, short for caprylic acid glyceride, was purchased from Abitec and is pharmaceutical grade. RH40, whose full Chinese name is Polyoxyethylene 40 Hydrogenated Castor Oil, was purchased from BASF and is pharmaceutical grade. PEG400, whose full Chinese name is polyethylene glycol 400, was purchased from Alpha High-Tech Co., Ltd., and is pharmaceutical grade. Soluplus, whose full Chinese name is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, was purchased from BASF and is pharmaceutical grade. Labrasol, whose full Chinese name is polyethylene glycol-8 caprylic / capric glyceride, was purchased from Giafass Corporation and is pharmaceutical grade. Transcutol HP, whose full Chinese name is diethylene glycol monoethyl ether, was purchased from Gefion and is pharmaceutical grade. Vericiguar, purchased from HETERO LABS LIMITED, with a purity of 99.80%; Unless otherwise specified, all other reagents and excipients are commercially available; reagents are of analytical grade, and excipients all meet pharmaceutical standards or pharmacopoeia standards.

[0027] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods.

[0028] Example 1: Preparation of a Velixika self-microemulsion composition A veliciguane self-microemulsion composition, the first component of which is as follows: veliciguane 40 mg (1.0%), polyethylene glycol 400 (PEG400) 2400 mg (60%), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) 200 mg (5%), polyethylene glycol-8 caprylic / capric triglyceride (Labrasol) 1160 mg (29%), and caprylic / capric triglyceride monocaprylate (MCM) 200 mg (5%). The total mass of the components is 4000 mg.

[0029] The preparation process is as follows: Soluplus was added to PEG400 and stirred in a 50°C water bath for 45 minutes until dissolved and clear; veliciguanidine was added and stirring was continued for 30 minutes to ensure complete dispersion; finally, MCM and Labrasol were added and stirred for 45 minutes to obtain a clear and homogeneous self-microemulsion composition, such as... Figure 1 As shown.

[0030] Example 2: Preparation of a Velixito self-microemulsion composition A veliciguat self-microemulsion composition, the second component of which is as follows: veliciguat 40 mg (1.0%), PEG400 2400 mg (60%), Soluplus 200 mg (5%), polyoxyethylene hydrogenated castor oil (RH40) 580 mg (14.5%), Labrasol 580 mg (14.5%), and MCM 200 mg (5%). The total mass of the formulation is 4000 mg.

[0031] The preparation process is as follows: Soluplus was added to PEG400 and stirred in a 55°C water bath for 40 minutes until dissolved and clear; veliciguanidine was added and stirring was continued for 30 minutes to ensure complete dispersion; MCM, RH40, and Labrasol were added sequentially and stirred for 50 minutes to obtain a clear and homogeneous self-microemulsion composition, such as... Figure 1 As shown.

[0032] Example 3: Preparation of a Velixika self-microemulsion composition A veliciguat self-microemulsion composition, the third component of which is as follows: veliciguat 40 mg (1.0%), PEG400 2400 mg (60%), Soluplus 240 mg (6%), RH40 400 mg (10%), Labrasol 400 mg (10%), diethylene glycol monoethyl ether (Transcutol HP) 320 mg (8%), and MCM 200 mg (5%). The total mass of the formulation is 4000 mg.

[0033] The preparation process is as follows: Soluplus was added to PEG400 and stirred in a 50°C water bath for 50 minutes until dissolved and clear; veliciguanidine was added and stirring was continued for 40 minutes to ensure complete dispersion; MCM, RH40, Labrasol, and Transcutol HP were added sequentially and stirred for 60 minutes to obtain a clear and homogeneous self-microemulsion composition, such as... Figure 1 As shown.

[0034] Example 4: Preparation of a Velixika self-microemulsion composition A veliciguane self-microemulsion composition, comprising the following components and dosages: veliciguane 20 mg (0.5%), PEG4002 420 mg (60%), Soluplus 200 mg (5%), Labrasol 1160 mg (29%), and MCM 200 mg (5%). The total mass of the components is 4000 mg.

[0035] The preparation process is the same as in Example 1.

[0036] Example 5: Preparation of a Velixito self-microemulsion composition A veliciguane self-microemulsion composition, comprising the following components and dosages: veliciguane 48 mg (1.2%), PEG4002 392 mg (59.8%), Soluplus 200 mg (5%), Labrasol 1160 mg (29%), and MCM 200 mg (5%). The total mass of the formulation is 4000 mg.

[0037] The preparation process is the same as in Example 1.

[0038] Comparative Example 1: Preparation of a Veliximab Self-Microemulsion Composition A veliciguane self-microemulsion composition, comprising the following components and dosages: veliciguane 60 mg (1.5%), PEG4002 380 mg (59.5%), Soluplus 200 mg (5%), Labrasol 1160 mg (29%), and MCM 200 mg (5%). The total mass of the formulation is 4000 mg.

[0039] The preparation process is the same as in Example 1.

[0040] The results showed that after stirring at 50°C for 2 hours, undissolved drug particles remained in the system, and a white precipitate was visible at the bottom, making it impossible to obtain a clear and transparent self-microemulsion composition. Even after extending the stirring time to 4 hours, the precipitate still did not completely dissolve.

[0041] Comparative Example 2: Preparation of a Velixito Self-Microemulsion Composition A veliciguane self-microemulsion composition, comprising the following components and dosages: veliciguane 40 mg (1.0%), PEG400 2600 mg (65%), Labrasol 1160 mg (29%), and MCM 200 mg (5%). The total mass of the formulation is 4000 mg.

[0042] Preparation process: Vectisil was added to PEG400 and stirred at 50°C for 30 minutes; MCM and Labrasol were added and stirred for 45 minutes to obtain a clear composition.

[0043] The results showed that the obtained composition was initially clear and transparent, but after being diluted 50 times with purified water, a white flocculent precipitate appeared after standing for 2 hours. The precipitation was obvious after 6 hours and the precipitate separated after 12 hours.

[0044] Table 1 Components of each embodiment

[0045] Example 6 Performance evaluation of a veliximab self-microemulsion composition The in vitro self-emulsifying properties of a veliximab self-microemulsifying composition are evaluated as follows: Take 0.1 mL of each of the self-microemulsion compositions prepared in Examples 1-3, and add them to 35 mL of pH 1.2 simulated fasting gastric juice (without enzymes), 600 mL of pH 4.5 simulated satiated gastric juice (without enzymes), and 80 mL of pH 6.8 simulated intestinal juice, respectively. Stir gently at 37°C and observe the emulsification. Dilute each component 50 times with purified water, stir gently at 37°C, and observe the appearance.

[0046] The results showed that the appearance after dilution with purified water was as follows: Figure 2As shown, the formulations obtained from the three components all exhibit a translucent, pale blue opalescence. All three components spontaneously formed milky white microemulsions within 1 minute in various pH media. The particle size distribution, as determined by a laser particle size analyzer, is as follows: Table 2. Particle size distribution of each component after emulsification from the microemulsion.

[0047] The results showed that all five components could rapidly and spontaneously form nanoscale microemulsions under various pH conditions in the gastrointestinal tract, with particle sizes ranging from 50 to 100 nm. Among them, component 3 (containing Transcutol HP) formed the microemulsion with the smallest particle size and the lowest PDI, indicating that it had the best emulsifying performance. Comparative Example 1 lacked self-emulsifying ability because the drug loading was too high, resulting in incomplete drug dissolution; Comparative Example 2 failed to form a stable microemulsion due to the lack of precipitation inhibitors.

[0048] Example 7: Stability Study of a Veliximab Self-Microemulsion Composition The dilution stability of a veliximab self-microemulsion composition is investigated as follows: The stability of the stock solutions and diluents (diluted with purified water 10, 50, and 100 times) of the microemulsion formulations obtained in Examples 1-5 and Comparative Examples 1-2 was observed after being placed at room temperature for 24 h. The results are shown in Table 3.

[0049] Table 3. Results of stability studies for each component

[0050] The results showed that Examples 1-4 remained stable at all dilution ratios, while Example 5 showed trace precipitation at a 100-fold dilution, indicating that the 1.2% drug loading was close to the upper limit of the present invention. Comparative Example 1 was unstable at all dilution ratios due to incomplete drug dissolution; Comparative Example 2 precipitated rapidly after dilution due to the lack of a precipitation inhibitor. These results confirm that the Soluplus precipitation inhibitor and the 0.5%-1.2% drug loading range in the composition of the present invention are crucial for maintaining the dilution stability of the formulation.

[0051] Example 8: In vitro self-emulsifying properties of a veliximab self-microemulsifying composition The in vitro self-emulsifying properties of a veliximab self-microemulsifying composition are evaluated as follows: The self-microemulsion compositions prepared in Examples 1-5 were dispersed in pH 6.8 phosphate buffer to form microemulsions. After standing at 37°C, samples were taken at 0, 1, 2, 4, and 6 hours to determine the drug concentration and calculate the supersaturation maintenance rate.

[0052] Results: All five components maintained high supersaturation levels within 6 hours. Example 3 (containing Transcutol HP) exhibited the strongest supersaturation maintenance, retaining over 85% of its initial concentration after 6 hours, indicating that the synergistic effect of Soluplus and Transcutol HP effectively inhibits drug precipitation. Examples 4 and 5 showed supersaturation maintenance rates comparable to Example 1, confirming good physical stability of the formulations within the 0.5%-1.2% drug loading range.

Claims

1. A veliximab self-microemulsion composition, characterized in that, In in vitro dispersion tests, the composition spontaneously forms microemulsions with a particle size of less than 100 nm in an aqueous medium with a pH of 1.2-6.8, and comprises the following components: Viliximab: 0.2%-1.2% (w / w); Oil phase: 3%-20% (w / w); Surfactant: 20%-40% (w / w); Co-surfactant: 45%-75% (w / w); Precipitation inhibitor: 2%-10% (w / w).

2. The veliximab self-microemulsion composition according to claim 1, characterized in that: The oil phase is selected from MCT, MCM, GMO or mixtures thereof; the surfactant is selected from RH40, Labrasol, Transcutol HP or combinations thereof; the co-surfactant is selected from PEG400, propylene glycol, glycerol or mixtures thereof; and the precipitation inhibitor is selected from Soluplus, poloxamer 188, PVP or mixtures thereof.

3. The veliximab self-microemulsion composition according to claim 2, characterized in that: The preferred oil phase is MCM; The preferred combination of surfactants is: ① Labrasol alone; or ② RH40 and Labrasol in combination at a mass ratio of 1:5 to 1:1; or ③ RH40, Labrasol and Transcutol HP in combination at a mass ratio of (0.8-1.2):(0.8-1.2):

1. The co-surfactant is PEG400; the precipitation inhibitor is preferably Soluplus.

4. The veliximab self-microemulsion composition according to any one of claims 1 to 3, characterized in that, The oil phase content is 3%-10% (w / w), the surfactant content is 25%-35% (w / w), the co-surfactant content is 50%-70% (w / w), and the precipitation inhibitor content is 3%-8% (w / w).

5. The veliximab self-microemulsion composition according to claim 4, characterized in that, The oil phase contains 4%-6% (w / w), the surfactant contains 27%-32% (w / w), the co-surfactant contains 55%-65% (w / w), and the precipitation inhibitor contains 4%-6% (w / w).

6. The veliximab self-microemulsion composition according to claim 1, characterized in that, The composition comprises: Viliximab: 0.2%-1.2% (w / w); MCM: 3%-10% (w / w); RH40: 5%-15% (w / w); Labrasol: 5%-15% (w / w); Transcutol HP: 5%-15% (w / w); PEG400: 50%-70% (w / w); Soluplus: 3%-8% (w / w); The total amount of RH40, Labrasol, and Transcutol HP is 25%-35% (w / w).

7. A method for preparing the veliximab self-microemulsion composition of claim 1, characterized in that, Includes the following steps: (1) After dissolving the precipitation inhibitor in the co-surfactant, add veliciguanine and stir at 40-60℃ to dissolve it, thus obtaining a drug solution; (2) Add the oil phase and surfactant to the above drug solution, stir and mix until completely dissolved to obtain a clear self-microemulsion composition.

8. A self-microemulsion formulation of velixiva, characterized in that, The composition comprises the velixigua self-microemulsion composition and its pharmaceutical excipients as described in any one of claims 1.

9. The self-microemulsion formulation according to claim 8, characterized in that, The veliximab self-microemulsion formulation is one of a soft capsule, a single-dose oral solution, or a tablet.

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