A vildagliptin dry suspension and a method for preparing the same

Abstract

The present application relates to a kind of vericiguat dry suspensions and its preparation method, it includes the following steps: (1) vericiguat, first suspending agent, second suspending agent, filling agent and wetting agent are mixed with water, then form mixed solution, then carry out spray drying, obtain spray dried granules;(2) spray dried granules are mixed with third suspending agent, pH adjusting agent and flavouring agent evenly, obtain vericiguat dry suspension;Wherein, first suspending agent is selected from cellulose ether derivative;Second suspending agent is carboxymethyl chitosan;Third suspending agent is gellan gum.By developing vericiguat into dry suspension, the convenience of taking of special population is significantly improved, and by the system optimization of preparation process and prescription composition, the stability and redispersion of dry suspension and other key performances are effectively improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a velixika dry suspension and its preparation method. Background Technology

[0002] 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, and its structural formula is as follows: .

[0003] Vericigulet, the first oral sGC (soluble guanylate cyclase) stimulator for heart failure patients, possesses a unique dual regulatory mechanism. It directly stimulates sGC independently of endogenous nitric oxide levels, synergistically increasing sGC sensitivity to nitric oxide and repairing the damaged NO-sGC-cGMP pathway. This provides multiple benefits to the heart, blood vessels, and kidneys in heart failure patients, demonstrating good safety and tolerability. It can reduce the risk of death and readmission in patients with worsening heart failure. Based on the above mechanism of action, vericigulet is highly effective in preventing and treating heart failure relapses, providing a new treatment option for heart failure patients and further meeting the medical needs of patients experiencing recurrent symptoms after standard anti-heart failure treatment.

[0004] Currently, the main dosage form of Viliciguat on the market is tablets. As one of the most common oral solid dosage forms, tablets have significant advantages such as accurate dosage, high physicochemical stability, easy storage and portability, and mature production process, and play an important role in the long-term management of chronic heart failure in adults.

[0005] However, the epidemiological characteristics of heart failure determine the specific population that requires medication. Epidemiological data show that the incidence of heart failure increases significantly with age, with people aged 65 and above being the core high-risk group. Among existing heart failure patients, the elderly account for approximately 74%. With age, the elderly generally experience physiological changes such as decreased saliva secretion, weakened pharyngeal muscle strength, and reduced esophageal motility. They also often have multiple underlying diseases, leading to a decline in overall medication tolerance and practical difficulties in swallowing solid dosage forms. Furthermore, some heart failure patients may have esophageal diseases (such as esophageal stricture, esophageal motility disorders, severe gastroesophageal reflux, etc.) or neurological dysfunctions, further exacerbating the difficulty of swallowing tablets and resulting in significantly reduced medication compliance. It is worth noting that heart failure does not only occur in adults. Although the absolute incidence of heart failure in children is low, its causes are complex, mostly caused by congenital heart disease, fulminant myocarditis, dilated cardiomyopathy, metabolic diseases, or cardiotoxicity of antitumor drugs. In recent years, the detection rate and number of reported cases of heart failure in children have been increasing year by year, and they have become a population that cannot be ignored in clinical practice.

[0006] Although veliciguat tablets have a solid clinical foundation in the adult population, their applicability is significantly limited when considering a diverse patient population, primarily the elderly, and including a growing number of pediatric heart failure patients. Therefore, there is an urgent need to develop a new veliciguat formulation that is convenient to take, allows for flexible dosage adjustments, has a pleasant taste, and exhibits good stability.

[0007] Dry suspensions are solid dosage forms in which poorly soluble drugs are formulated into powder or granules with suitable excipients. They disperse into a suspension upon shaking with water before use and are ready for oral administration. The dispersed liquid form eliminates the need for swallowing solids, making it particularly suitable for elderly patients with swallowing difficulties, esophageal diseases, and children. It effectively improves medication compliance and allows for flexible dosage adjustments based on weight or age. Therefore, developing veliciguat into a dry suspension is a reasonable dosage form choice to expand its coverage of elderly and pediatric patients with heart failure.

[0008] However, the stability and dispersibility of veliximab dry suspension still face many technical challenges, which need to be systematically addressed in formulation design and process development in order to realize the clinical translational value of this dosage form.

[0009] The above background information is provided only to aid in understanding the concept and technical solution of this application. It does not necessarily belong to the prior art of this application, nor does it necessarily provide technical guidance. In the absence of clear evidence that the above information was disclosed before the filing date of this application, the above background information should not be used to evaluate the novelty and inventiveness of this application. Summary of the Invention

[0010] The purpose of this invention is to provide a velixicam dry suspension and its preparation method.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides a method for preparing a veliximab dry suspension, which includes the following steps: (1) After mixing veliximab, the first suspending agent, the second suspending agent, the filler and the wetting agent with water to form a mixture, the mixture is then spray-dried to obtain spray-dried particles; (2) The spray-dried granules are mixed evenly with the third suspending agent, pH adjuster and flavoring agent to obtain the Vilixigua dry suspension; The first suspending agent is selected from cellulose ether derivatives; The second suspending agent is carboxymethyl chitosan; The third suspending agent is gellan gum.

[0012] The pH adjuster includes citric acid and phosphate.

[0013] In some embodiments, step (1) specifically includes: adding the first suspending agent, the second suspending agent, and the wetting agent to water at 40°C to 60°C, dissolving until clear, then adding the filler and the velixigua to prepare a mixture with a mass concentration of 3% to 10%, and then spray drying the mixture, setting the inlet air temperature of the spray drying to 140°C to 160°C and the outlet air temperature to 90°C to 110°C to obtain the spray-dried particles.

[0014] In some embodiments, step (2) specifically includes: mixing the spray-dried particles obtained in step (1) with the third suspending agent, the pH adjuster and part of the flavoring agent to obtain a first mixed powder; and then mixing the remaining flavoring agent with the first mixed powder.

[0015] Furthermore, a portion of the flavoring agent constitutes 1 / 3 to 2 / 3 of the total mass of all the flavoring agents.

[0016] In some embodiments, the median particle size of the spray-dried particles is 30μm to 70μm, preferably 40μm to 60μm, such as 40μm, 45μm, 50μm, 55μm or 60μm.

[0017] In some embodiments, the mass ratio of the velixiva to the first suspending agent is 1:(1~3), preferably 1:(1.5~3).

[0018] In some embodiments, the first suspending agent is hydroxypropyl cellulose.

[0019] In some embodiments, the mass ratio of the velixiva to the second suspending agent is 1:(0.5~1).

[0020] In some embodiments, the mass ratio of the velixiva to the third suspending agent is 1:(0.2~0.5).

[0021] In some embodiments, the wetting agent is selected from one or more of sodium dodecyl sulfate, polysorbate (such as polysorbate-80), meglumine, and glycerin.

[0022] Further, the mass ratio of the velixicat to the wetting agent is 1:(0.3~0.8), preferably 1:(0.5~0.7).

[0023] In some embodiments, the filler is microcrystalline cellulose and / or mannitol.

[0024] Furthermore, the mass ratio of the veliximab to the filler is 1:(3~5), preferably 1:(3.5~4.5).

[0025] In some embodiments, the pH adjuster includes citric acid and phosphate.

[0026] Further, the mass ratio of the veliciguanide to the pH adjuster is 1:(4~8.5). Even further, the mass ratio of the citric acid to the phosphate is 1:(0.5~1.5), preferably 1:(0.7~1), such as 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0027] In some specific embodiments, the phosphate is disodium hydrogen phosphate.

[0028] In some embodiments, the flavoring agent includes a first flavoring agent, which is sucrose.

[0029] Furthermore, the mass ratio of the velixigua to the flavoring agent is 1:(10~33).

[0030] In some embodiments, the flavoring agent further includes a second flavoring agent, which includes one or more of strawberry flavoring, aspartame orange flavoring, and banana flavoring. The mass ratio of the first flavoring agent to the second flavoring agent is 1:(0.05~0.2), such as 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.15, or 1:0.2.

[0031] In some embodiments, based on the total mass of the veliximab dry suspension as 100%, it comprises: Viliximab 1.5%~4.5%, Flavoring agent 45%~65%, Filler 7%~20%, The first suspending agent is 5%~7%. The second suspending agent is 1.5%~2.5%. The third suspending agent is 0.5%~2%. Wetting agent 1%~3%, pH adjuster 13%~18%.

[0032] Furthermore, based on the total mass of the aforementioned veliximab dry suspension as 100%, it comprises: Viliximab 1.5%~4.5%, The first flavoring agent is 45-59%. The second flavoring agent is 0-6%. Filler 7%~20%, pH adjuster 13%~18% The first suspending agent is 5%~7%. The second suspending agent is 1.5%~2.5%. The third suspending agent is 0.5%~2%. Wetting agent 1%~3%.

[0033] In another aspect, the present invention provides a veliximab dry suspension prepared by the preparation method described above.

[0034] In some embodiments, the veliximab dry suspension, based on unit dosage, comprises the following: 2.5mg~10mg of veliciguanide, 10mg~40mg of microcrystalline cellulose, 59mg~118mg of sucrose, 7.5mg~15mg of hydroxypropyl cellulose, 2.5mg~5mg of carboxymethyl chitosan, 1mg~2.5mg of gellan gum, 11mg~22mg of citric acid, 9.5mg~19mg of disodium hydrogen phosphate, 1.5mg~6mg of sodium dodecyl sulfate, and 0mg~15mg of strawberry flavoring.

[0035] Furthermore, according to unit dosage, the composition of the veliximab dry suspension is as follows: 2.5mg~10mg of veliciguanide, 10mg~40mg of microcrystalline cellulose, 59mg~118mg of sucrose, 7.5mg~15mg of hydroxypropyl cellulose, 2.5mg~5mg of carboxymethyl chitosan, 1mg~2.5mg of gellan gum, 11mg~22mg of citric acid, 9.5mg~19mg of disodium hydrogen phosphate, 1.5mg~6mg of sodium dodecyl sulfate, and 7.5mg~15mg of strawberry flavoring.

[0036] Due to the application of the above-mentioned technical solution, the present invention has the following advantages compared with the prior art: This invention significantly improves the ease of administration for special populations by developing veliciguat into a dry suspension. At the same time, through systematic optimization of the preparation process and formulation composition, it effectively enhances key properties such as the stability and redispersibility of the dry suspension, providing a reliable technical foundation for the clinical translation of this dosage form. Detailed Implementation

[0037] Although dry suspensions offer numerous advantages over tablets, such as improved user experience, increased bioavailability, and suitability for specific administration methods, the actual preparation of veliximab dry suspension still faces several technical challenges, primarily in the following aspects: Firstly, veliciguat's molecular structure contains a pyrimidine ring, a pyrazolopyridine fused ring, and multiple fluorine atoms, exhibiting strong hydrophobicity and low water solubility, classifying it as a poorly soluble drug. When formulated as a dry suspension, the drug particles need to be uniformly dispersed in water and maintain stable suspension for a certain period. This places stringent requirements on the particle size distribution and surface properties of the active pharmaceutical ingredient. Improper particle size control or insufficient surface wettability can easily lead to particle aggregation, floating, or rapid sedimentation, directly affecting the uniformity of the suspension and the accuracy of the dosage.

[0038] Secondly, when dry suspensions are dispersed in water, they form a thermodynamically unstable coarse dispersion system, and the particles will inevitably settle under gravity. The key lies in controlling the sedimentation rate and whether redispersion can be achieved through simple shaking after sedimentation. The active pharmaceutical ingredient (API) of veliciguat differs from commonly used excipients in terms of density and particle size. If the type or dosage of the suspending agent is not properly selected, two unfavorable situations may occur in the suspension: first, sedimentation is too rapid, resulting in stratification within a short time, making it difficult for patients to obtain a uniform dose within the prescribed time; second, the sediment forms a dense, hard precipitate at the bottom of the bottle, which cannot be restored to a uniform state even with vigorous shaking, leading to a lower actual dosage or greater fluctuations.

[0039] To address the above technical challenges, the inventors, through extensive experimentation, proposed a dual stabilization strategy combining internal and external approaches to synergistically improve the dispersion performance and stability of dry suspensions at both the particle and suspension system levels.

[0040] At the particle level, the inventors first formulated veliciguat with a first suspending agent, a second suspending agent, a filler, and a wetting agent to prepare a homogeneous mother liquor, which was then spray-dried to prepare drug-containing spray-dried granules. This process improves and enhances the dispersion uniformity of the API (the core active ingredient, veliciguat), ensuring the uniformity of the formulation content; it also reduces the particle size difference between the API and excipients, lowering the difficulty and complexity of process control. Furthermore, in this process, the first suspending agent (a cellulose ether derivative), the second suspending agent (carboxymethyl chitosan), and the filler work synergistically to encapsulate and fix veliciguat in a fine state within the spray-dried granules, effectively preventing direct contact and irreversible aggregation between API particles, thus controlling particle size growth from the source. Simultaneously, the wetting agent significantly reduces the surface tension of the hydrophobic veliciguat particles, improving their wettability in aqueous media, laying the foundation for rapid and uniform suspension during subsequent water dispersion.

[0041] At the suspension system level, the inventors further introduced gellan gum as an external phase suspending agent into the dry suspension. Gellan gum, on the one hand, physically binds suspended particles, effectively slowing down their settling rate; on the other hand, it has a synergistic thickening effect with carboxymethyl chitosan, imparting suitable shear-thinning rheological properties to the suspension. That is, the system has a high apparent viscosity when stationary, sufficient to maintain uniform particle suspension, and the viscosity decreases rapidly upon shaking, restoring good flowability for easy pouring and administration. As a result, both the sedimentation volume ratio and redispersibility of the dry suspension are simultaneously and significantly improved.

[0042] Dry suspensions are typically administered orally after being dispersed in water, unlike tablets which can be coated to prevent contact between the drug and taste buds. Veliciguat active pharmaceutical ingredient (API) may inherently possess an unpleasant bitter or astringent taste; without the introduction of flavoring agents to mask this, the desired effect is often difficult to achieve, especially for taste-sensitive children and elderly patients. However, introducing flavoring agents may introduce new compatibility risks or affect the stability of the suspension system. Therefore, achieving effective taste masking while ensuring formulation stability and dispersibility is a crucial challenge that must be balanced in formulation development.

[0043] Furthermore, the inventors have introduced suitable flavoring agents and pH adjusters into the formulation to synergistically improve the taste and acceptability of the preparation through multiple mechanisms.

[0044] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other. Unless otherwise specified, the reagents used in the following embodiments and comparative examples are all commercially available products or can be prepared with reference to existing technology.

[0045] Unless explicitly excluded or the context clearly indicates otherwise, the term 'about' as used below, when used to modify an endpoint of a numerical value or range, shall be interpreted to include the numerical value or endpoint, and the range by which it reasonably deviates from the endpoint due to tolerances necessary for carrying out the invention, measurement uncertainties, or routine variations between raw materials and production batches. This deviation shall be limited to a range that does not affect the overall function, effect, and reproducibility of the technical solution. Furthermore, when the numerical value relates to process conditions such as reaction temperature, pressure, or time, the deviation covered by 'about' should not cause the process step to deviate from its intended reaction kinetics or thermodynamic mechanism.

[0046] Example 1: This embodiment provides a velixika dry suspension with a theoretical batch yield of 100 bags, each bag containing 10 mg of the active ingredient.

[0047] The specific prescription composition of this embodiment is shown in Table 1 below.

[0048] Table 1 This embodiment also provides a method for preparing veliximab dry suspension, as detailed below: Preparation of mother liquor for velixigua spray-dried product: Hydroxypropyl cellulose, sodium dodecyl sulfate, and carboxymethyl chitosan were added sequentially to hot purified water at 40℃~60℃ while stirring until they were dissolved and clear. Then, microcrystalline cellulose and velixigua were added while stirring, and the mixture was stirred for about 1 hour to prepare a 5% velixigua spray-dried product mother liquor for later use.

[0049] Preparation of the spray-dried material from the VeriSilicon spray dryer: Turn on the SODA-25 spray dryer and set the parameters as follows: inlet air temperature 140℃~160℃, outlet air temperature 90℃~110℃, inlet air frequency 32Hz~40Hz, atomizer frequency 37Hz~45Hz, tower pressure 0.15kPa~0.30kPa, air delivery frequency 32Hz~40Hz, air delivery temperature 40℃~60℃. Spray purified water until all parameters stabilize. After the parameters stabilize, switch to spraying the material and begin spray drying. Control the drying loss to ≤3.5% during the spray drying process. After the material spraying is completed, switch to spraying purified water, and stop spraying the liquid after about 10 minutes.

[0050] Premix 1: The spray-dried velixicam obtained by spray drying, along with gellan gum, citric acid, disodium hydrogen phosphate, strawberry flavoring, and about 1 / 2 of the prescribed amount of sucrose, were added sequentially into an SHR-10 experimental mixer and mixed at 6 rpm for 15 min. After passing through a 1.0 mm sieve granulator, the mixture was further mixed in an SHR-10 experimental mixer at 6 rpm for 20 min to obtain powder mix 1.

[0051] Premix 2: Add the remaining sucrose and powder 1 to the SHR-10 experimental mixer in sequence, mix at 6 rpm for 15 min, pass through a 1.0 mm sieve granulator, and continue to mix at 6 rpm for 20 min using the SHR-10 experimental mixer to obtain the total powder mixture.

[0052] Granule dispensing: The total powder mixture is evenly fed into the S-180D horizontal fully automatic packaging machine through a feeder. The screw feeding speed is controlled at 100rpm~400rpm, the production speed is 25Hz~45Hz, and the heat sealing temperature is 150℃~190℃. The granules are then dispensed to obtain the Vilixi Gua dry suspension.

[0053] Example 2: This embodiment provides a velixika dry suspension with a theoretical batch yield of 100 bags, each bag containing 5 mg of the active ingredient.

[0054] The specific prescription composition of this embodiment is shown in Table 2 below.

[0055] Table 2 This embodiment also provides a method for preparing veliximab dry suspension, as detailed below: Preparation of mother liquor for velixigua spray-dried product: Hydroxypropyl cellulose, sodium dodecyl sulfate, and carboxymethyl chitosan were added sequentially to hot purified water at 40℃~60℃ while stirring until they were dissolved and clear. Then, microcrystalline cellulose and velixigua were added while stirring, and the mixture was stirred for about 1 hour to prepare a 5% velixigua spray-dried product mother liquor for later use.

[0056] Preparation of the spray-dried material for Vilixigua: Turn on the SODA-25 spray dryer and set the parameters as follows: inlet air temperature 140℃~160℃, outlet air temperature 90℃~110℃, inlet air frequency 32Hz~40Hz, atomizer frequency 37Hz~45Hz, tower pressure 0.15 kPa~0.30 kPa, air delivery frequency 32Hz~40Hz, air delivery temperature 40℃~60℃. Spray purified water until all parameters stabilize. After the parameters stabilize, switch to spraying the material and start spray drying. Control the drying loss to ≤3.5% during the spray drying process. After the material spraying is completed, switch to spraying purified water, and stop spraying the liquid after about 10 minutes.

[0057] Premix 1: The spray-dried velixicam obtained by spray drying, along with gellan gum, citric acid, disodium hydrogen phosphate, strawberry flavoring, and about 1 / 2 of the prescribed amount of sucrose, were added sequentially into an SHR-10 experimental mixer and mixed at 6 rpm for 15 min. After passing through a 1.0 mm sieve granulator, the mixture was further mixed in an SHR-10 experimental mixer at 6 rpm for 20 min to obtain powder mix 1.

[0058] Premix 2: Add the remaining sucrose and powder 1 to the SHR-10 experimental mixer in sequence, mix at 6 rpm for 15 min, pass through a 1.0 mm sieve granulator, and continue to mix at 6 rpm for 20 min using the SHR-10 experimental mixer to obtain the total powder mixture.

[0059] Granule dispensing: The total powder mixture is evenly fed into the S-180D horizontal fully automatic packaging machine through a feeder. The screw feeding speed is controlled at 100rpm~400rpm, the production speed is 25Hz~45Hz, and the heat sealing temperature is 150℃~190℃. The granules are then dispensed to obtain the Vilixi Gua dry suspension.

[0060] Example 3: This embodiment provides a velixika dry suspension with a theoretical batch yield of 100 bags, each bag containing 2.5 mg of the active ingredient.

[0061] The specific prescription composition of this embodiment is shown in Table 3 below.

[0062] Table 3 This embodiment also provides a method for preparing veliximab dry suspension, as detailed below: Preparation of mother liquor for velixigua spray-dried product: Hydroxypropyl cellulose, sodium dodecyl sulfate, and carboxymethyl chitosan were added sequentially to hot purified water at 40℃~60℃ while stirring until they were dissolved and clear. Then, microcrystalline cellulose and velixigua were added while stirring, and the mixture was stirred for about 1 hour to prepare a 5% velixigua spray-dried product mother liquor for later use.

[0063] Preparation of the spray-dried material for Vilixigua: Turn on the SODA-25 spray dryer and set the parameters as follows: inlet air temperature 120℃~140℃, outlet air temperature 80℃~100℃, inlet air frequency 28Hz~38Hz, atomizer frequency 32Hz~40Hz, tower pressure 0.15kPa~0.30kPa, air delivery frequency 30Hz~40Hz, air delivery temperature 40℃~50℃. Spray purified water until all parameters stabilize. After the parameters stabilize, switch to spraying the material and start spray drying. Control the drying loss to ≤3.5% during the spray drying process. After the material spraying is completed, switch to spraying purified water, and stop spraying the liquid after about 10 minutes.

[0064] Premix 1: The spray-dried velixicam obtained by spray drying, gellan gum, citric acid, sodium dihydrogen phosphate, strawberry flavoring and about 1 / 2 of the prescription amount of sucrose were added sequentially to an SHR-10 experimental mixer and mixed at 6 rpm for 15 min. After passing through a 1.0 mm sieve granulator, the mixture was further mixed at 6 rpm for 20 min using an SHR-10 experimental mixer to obtain powder mix 1.

[0065] Premix 2: Add the remaining sucrose and powder 1 to the SHR-10 experimental mixer in sequence, mix at 6 rpm for 15 min, pass through a 1.0 mm sieve granulator, and continue to mix at 6 rpm for 20 min using the SHR-10 experimental mixer to obtain the total powder mixture; Granule dispensing: The total powder mixture is evenly fed into the S-180D horizontal fully automatic packaging machine through a feeder. The screw feeding speed is controlled at 100rpm~400rpm, the production speed is 25Hz~45Hz, and the heat sealing temperature is 150℃~190℃. The granules are then dispensed to obtain the Vilixi Gua dry suspension.

[0066] Example 4: This embodiment provides a velixika dry suspension, which is prepared in the same way as in Example 2, except that the formulation is different.

[0067] The specific prescription composition of this embodiment is shown in Table 4 below.

[0068] Table 4 Example 5: This embodiment provides a velixika dry suspension, which is prepared in the same way as in Example 2, except that the formulation is different.

[0069] The specific prescription composition of this embodiment is shown in Table 5 below.

[0070] Table 5 Example 6: This embodiment provides a velixika dry suspension, which is prepared in the same way as in Example 2, except that the formulation is different.

[0071] The specific prescription composition of this embodiment is shown in Table 6 below.

[0072] Table 6 Example 7: This embodiment provides a velixika dry suspension, which is prepared in the same way as in Example 2, except that the formulation is different.

[0073] The specific prescription composition of this embodiment is shown in Table 7 below.

[0074] Table 7 Comparative Example 1: This comparative example provides a velixika dry suspension, which is prepared in the same way as in Example 2, except that the formulation is different.

[0075] The specific prescription composition for this comparative example is shown in Table 8 below.

[0076] Table 8 Comparative Example 2: This comparative example provides a velixika dry suspension, which is prepared in the same way as in Example 2, except that the formulation is different.

[0077] The specific prescription composition for this comparative example is shown in Table 9 below.

[0078] Table 9 Comparative Example 3: This comparative example provides a velixika dry suspension, which is prepared in the same way as in Example 2, except that the formulation is different.

[0079] The specific prescription composition for this comparative example is shown in Table 10 below.

[0080] Table 10 Comparative Example 4: This comparative example provides a velixika dry suspension with the same formulation components as Example 2, the only difference being the preparation method.

[0081] The preparation method for this comparative example is as follows: Gellan gum and about half the amount of microcrystalline cellulose were mixed at high speed in a wet granulator to obtain powder I; carboxymethyl chitosan and the remaining microcrystalline cellulose were mixed at high speed in a wet granulator to obtain powder II.

[0082] Hydroxypropyl cellulose, sodium lauryl sulfate, veliciguanidine, Mix I, Mix II, citric acid, disodium hydrogen phosphate, strawberry flavoring, and about half the prescribed amount of sucrose were added sequentially to an SHR-10 experimental mixer and mixed at 6 rpm for 15 min. After passing through a 1.0 mm sieve granulator, the mixture was further mixed at 6 rpm for 20 min using an SHR-10 experimental mixer to obtain Mix III.

[0083] Add the remaining sucrose and Mixed Powder III to the SHR-10 experimental mixer in sequence, mix at 6 rpm for 15 min, pass through a 1.0 mm sieve granulator, and continue mixing in the SHR-10 experimental mixer at 6 rpm for 20 min to obtain the total mixed powder.

[0084] The total powder is evenly fed into the S-180D horizontal fully automatic packaging machine through a feeder. The screw feeding speed is controlled at 100rpm~400rpm, the production speed is 25Hz~45Hz, and the heat sealing temperature is 150℃~190℃. The product is then packaged to obtain the Vilixi Gua dry suspension.

[0085] Performance testing: 1. Sedimentation volume ratio: Take approximately 125 mg of sample and place it in a 100 mL stoppered graduated cylinder. Add water and shake to prepare a suspension. Tick the volume to the mark, mix well, and let stand for 3 hours. Record the sedimentation height at 0 hours, 1 hour, and 3 hours. Calculate the sedimentation volume ratio using the following formula: Settlement volume ratio = H3 / H0; Where H0 is the initial suspension height, and H3 is the sediment height after standing for 3 hours. The larger the sediment volume ratio, the more stable the suspension.

[0086] 2. Redispersibility: Take the sample after the sedimentation volume ratio has been determined (after standing for 3 hours), and rotate the graduated cylinder up and down at a frequency of 30 times per minute for 30 seconds. Visually observe whether the sediment can be redispersed uniformly. If the sediment is completely redispersed after shaking without obvious lumps or agglomerates, it indicates good redispersibility; if the sediment forms hard lumps and cannot be completely dispersed after shaking or if there are visible lumps, it indicates poor redispersibility.

[0087] 3. Content: Determined by high performance liquid chromatography. This product contains veliciguanidine (C14). 19 H 16 F2N8O2 should be 95.0%-105.0% of the labeled amount.

[0088] 4. Alkalinity: Take approximately 1.0 g of each sample, add 20 mL of water to prepare a suspension, and determine the pH value. Limit: pH 4.5~6.5.

[0089] 5. Taste: Take an appropriate amount of this product, dissolve it in warm water, and have 10 healthy subjects (aged 18-65 years, without taste disorders) evaluate the taste. The score is based on a 100-point scale. A comprehensive evaluation score <80 points is considered poor taste, a comprehensive evaluation score ≥80 and <90 points is considered average taste, and a comprehensive evaluation score ≥90 points is considered good taste.

[0090] The test results of the above embodiments and comparative examples are summarized in Table 11 below.

[0091] Table 11 Comparative Example 4 involved direct mixing of the active pharmaceutical ingredient (API) and excipients. The lack of effective separation between the veliciguat particles led to easy aggregation due to interparticle interactions, resulting in uneven distribution of the API in the formulation. After reconstitution, this resulted in rapid sedimentation and severe clumping. In this invention, veliciguat is first formulated into a mother liquor with suspending agents hydroxypropyl cellulose and carboxymethyl chitosan, wetting agent sodium dodecyl sulfate, and filler microcrystalline cellulose. After spray drying, hydroxypropyl cellulose, carboxymethyl chitosan, and microcrystalline cellulose can fix veliciguat in a fine state within the spray-dried particles, effectively preventing the aggregation of the API particles. Sodium dodecyl sulfate reduces the surface tension of the veliciguat particles, improving their wettability and dispersibility in the liquid phase.

[0092] Furthermore, gellan gum is introduced into the dry suspension as an external phase suspension aid system to further enhance the steric hindrance system and effectively delay particle sedimentation. At the same time, gellan gum has a synergistic thickening effect, giving the suspension suitable rheological properties. It is sufficient to maintain particle suspension when standing and restores fluidity when shaken, thereby simultaneously improving sedimentation volume ratio and redispersibility.

[0093] In addition, the inventors improved the taste of the medicine by introducing flavoring agents, thereby increasing patient compliance.

[0094] 6. Particle size: The particle size was determined by laser diffraction using a dry dispersion system. For specific determination conditions and operating procedures, please refer to the General Chapter 0982, Method III (Light Scattering Method), of the Chinese Pharmacopoeia 2025 Edition and the following provisions.

[0095] The test results of the active pharmaceutical ingredient (API) and its spray-dried product of velixigua are shown in Table 12 below.

[0096] Table 12 As can be seen, the velixicat spray-dried product prepared by the method of this invention has a narrow particle size distribution, with D50 controllable between 45 μm and 44 μm. This particle size design avoids both the inherent defect of easy aggregation of nanoparticles and the process bottleneck that prevents nanoparticles from being directly used in powder mixtures.

[0097] 7. Detection of the intermediate or finished product of the dried suspension of Viliximab: The content is determined by high performance liquid chromatography; the loss on drying is checked according to the General Chapter 0831 (Determination of Loss on Drying) of the 2025 edition of the Chinese Pharmacopoeia, Part IV; the properties are determined by visual observation and olfaction under bright natural light by taking an appropriate amount of the test sample; the moisture content is determined according to the Karl Fischer method of the General Chapter 0832 (Determination of Loss on Drying) of the 2025 edition of the Chinese Pharmacopoeia, Part IV.

[0098] The test results are shown in Table 13 below.

[0099] Table 13 8. Quality Study of Velixigua Dry Suspension: Appearance was determined by visual inspection and olfactory examination under bright natural light using an appropriate amount of the sample; alkalinity was determined as above; related substances were determined under the chromatographic conditions specified in the Content Assay section; dissolution was determined according to the Dissolution and Release Assay method; content uniformity was checked according to Chinese Pharmacopoeia General Chapter 0941, with A+2.2S not exceeding 15.0 to be considered compliant, otherwise non-compliant (where A is the absolute value of the difference between the labeled amount and the mean, and S is the standard deviation); microbiology was determined using the plate method, with the total aerobic bacteria count not exceeding 1000 CFU, the total mold and yeast count not exceeding 100 CFU per 1g of sample, and no Escherichia coli detected per 1g of sample; moisture, content, and taste were determined as above.

[0100] The measurement results are shown in Table 14 below.

[0101] Table 14 9. Cumulative dissolution percentage in different pH media: (1) Cumulative dissolution percentage in pH 1.2 medium: According to the dissolution test method, samples were taken at specified time points and the cumulative dissolution percentage at each time point is shown in Table 15 below.

[0102] Table 15 (2) Cumulative dissolution percentage in pH 2.0 medium: According to the dissolution test method, samples were taken at specified time points and the cumulative dissolution percentage at each time point is shown in Table 16 below.

[0103] Table 16 (3) Cumulative dissolution percentage in pH 4.5 medium: According to the dissolution test method, samples were taken at specified time points and the cumulative dissolution percentage at each time point is shown in Table 17 below.

[0104] Table 17 (4) Cumulative dissolution percentage in pH 6.8 medium: According to the dissolution test method, samples were taken at specified time points and the cumulative dissolution percentage at each time point is shown in Table 18 below.

[0105] Table 18 In Tables 15-18, Control Examples 1-3 used commercially available Vilicitracin tablets as reference formulations. Control Example 1: Reference formulation information: Trade name: Vilicitracin, batch number 25M012; strength 10mg; manufacturer: Bayer AG. Control Example 2: Reference formulation information: Trade name: Vilicitracin, batch number BXK54L1; strength 5mg; manufacturer: Bayer AG. Control Example 3: Reference formulation information: Trade name: Vilicitracin, batch number BJ88551; strength 2.5mg; manufacturer: Bayer AG.

[0106] Selection of dissolution conditions for dissolution curves: Dissolution media: 0.1 mol / L hydrochloric acid solution, pH 2.0 hydrochloric acid solution, pH 4.5 acetate solution, pH 6.8 phosphate solution; Media volume: 900 mL; Dissolution method: Paddle method, 50 rpm (75 rpm for pH 2.0 hydrochloric acid solution).

[0107] Under the same dissolution conditions in each of the above-mentioned pH media (pH 1.2, pH 2.0, pH 4.5, pH 6.8), the cumulative dissolution percentage of the reference formulation was determined. The results showed that the dissolution behavior of this product in each pH medium was similar to that of the reference formulation, and the dissolution rate of this product in the weakly acidic medium was better than that of the reference formulation.

[0108] The present invention has been described in detail above, with the aim of enabling those skilled in the art to understand and implement the invention. However, this description should not be construed as limiting the scope of protection of the invention. All equivalent changes or modifications made in accordance with the spirit and essence of the invention should be included within the scope of protection of the invention.

Claims

1. A method for preparing a veliximab dry suspension, characterized in that, Includes the following steps: (1) After mixing veliximab, the first suspending agent, the second suspending agent, the filler and the wetting agent with water to form a mixture, the mixture is then spray-dried to obtain spray-dried particles; (2) The spray-dried granules are mixed evenly with the third suspending agent, pH adjuster and flavoring agent to obtain the Vilixigua dry suspension; The first suspending agent is selected from cellulose ether derivatives; The second suspending agent is carboxymethyl chitosan; The third suspending agent is gellan gum.

2. The method for preparing the veliximab dry suspension according to claim 1, characterized in that, Step (1) specifically includes: adding the first suspending agent, the second suspending agent, and the wetting agent to water at 40°C~60°C, dissolving until clear, then adding the filler and the velixiguat to prepare a mixture with a mass concentration of 3%~10%, and then spray-drying the mixture, setting the inlet air temperature of the spray drying to 140°C~160°C and the outlet air temperature to 90°C~110°C to obtain the spray-dried particles; and / or, Step (2) specifically includes: mixing the spray-dried granules obtained in step (1) with the third suspending agent, the pH adjuster and part of the flavoring agent to obtain a first mixed powder; and then mixing the remaining flavoring agent with the first mixed powder.

3. The method for preparing the veliximab dry suspension according to claim 1, characterized in that, The median particle size of the spray-dried particles is 30 μm to 70 μm.

4. The method for preparing the veliximab dry suspension according to claim 1, characterized in that, The mass ratio of the veliximab to the first suspending agent is 1:(1~3); and / or, The mass ratio of the veliximab to the second suspending agent is 1:(0.5~1); and / or, The mass ratio of the veliximab to the third suspending agent is 1:(0.2~0.5); and / or, the first suspending agent is hydroxypropyl cellulose.

5. The method for preparing the veliximab dry suspension according to claim 1, characterized in that, The filler is microcrystalline cellulose and / or mannitol; and / or, The wetting agent is selected from one or more of sodium dodecyl sulfate, polysorbate, meglumine, and glycerin; and / or, The pH adjuster includes citric acid and phosphate; and / or, The flavoring agent includes a first flavoring agent, which is sucrose.

6. The method for preparing the veliximab dry suspension according to claim 5, characterized in that, The mass ratio of the veliximab to the filler is 1:(3~5); and / or, The mass ratio of the veliximab to the wetting agent is 1:(0.3~0.8); and / or, The mass ratio of the veliximab to the pH adjuster is 1:(4~8.5); and / or, The mass ratio of the velixiguat to the flavoring agent is 1:(10~33).

7. The method for preparing the veliximab dry suspension according to claim 5, characterized in that, The mass ratio of citric acid to phosphate is 1:(0.5~1.5); and / or, The phosphate is disodium hydrogen phosphate; and / or, The flavoring agent further includes a second flavoring agent, which includes one or more of strawberry flavoring, aspartame orange flavoring and banana flavoring, and the mass ratio of the first flavoring agent to the second flavoring agent is 1:(0.05~0.2).

8. The method for preparing veliximab dry suspension according to any one of claims 1 to 7, characterized in that, Based on the total mass of the aforementioned veliximab dry suspension as 100%, it comprises: Viliximab 1.5%~4.5%, Flavoring agent 45%~65%, Filler 7%~20%, The first suspending agent is 5%~7%. The second suspending agent is 1.5%~2.5%. The third suspending agent is 0.5%~2%. Wetting agent 1%~3%, pH adjuster 13%~18%.

9. The method for preparing the veliximab dry suspension according to claim 8, characterized in that, Based on the total mass of the aforementioned veliximab dry suspension as 100%, it comprises: Viliximab 1.5%~4.5%, The first flavoring agent is 45-59%. The second flavoring agent is 0-6%. Filler 7%~20%, pH adjuster 13%~18% The first suspending agent is 5%~7%. The second suspending agent is 1.5%~2.5%. The third suspending agent is 0.5%~2%. Wetting agent 1%~3%.

10. The veliximab dry suspension prepared by any one of claims 1 to 9.

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