Vonoprazan fumarate suspension and preparation method thereof

Abstract

The invention discloses a fumaric acid Vonoprazan suspension and a preparation method thereof, the fumaric acid Vonoprazan suspension is prepared from fumaric acid Vonoprazan, a suspending aid, a wetting agent, an acidifying agent, a flavoring agent and essence, the prepared preparation is easier to swallow compared with tablets, proper auxiliary materials are screened and added through a prescription, the bitter taste of the fumaric acid Vonoprazan during oral administration is obviously reduced, and the oral administration effect of the fumaric acid Vonoprazan is improved. The clinical compliance of a patient is improved; and the defects that the tablet is taken after being broken apart, the dosage is not accurate enough, the coating is damaged and the taste masking effect is influenced are overcome. The oral suspension is packaged in unit dose, and is accurate in dose and convenient to administrate.

Description

Technical Field

[0001] The present invention relates to an oral preparation, in particular to a vonoprazan fumarate suspension. Background Art

[0002] Vonoprazan fumarate is a new potassium-competitive acid blocker (P-CAB) that reversibly inhibits H + , K + , -ATPase activity, can stay in the gastric wall cells for a long time to inhibit the production of gastric acid, and can effectively inhibit the formation of upper gastrointestinal mucosal damage.

[0003] Currently, only coated tablets of vonoprazan are available on the market. Vonoprazan fumarate itself has a strong bitter taste. The clinical application of tablets is limited for patients with swallowing difficulties or difficulty accessing water, such as the elderly and children. Furthermore, tablets undergo a disintegration and dissolution process, requiring time to exert their efficacy. For acute patients requiring rapid onset of action, tablets cannot meet the clinical need.

[0004] Therefore, there is an urgent need to develop a dosage form that can take effect quickly, is easy to swallow, and has good stability, so as to improve the clinical adaptability of patients and better meet clinical needs. Summary of the Invention

[0005] In view of this, one of the objects of the present invention is to provide a vonoprazan fumarate suspension; a second object of the present invention is to provide a method for preparing the vonoprazan fumarate suspension.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] Vonoprazan fumarate suspension is prepared from vonoprazan fumarate, a suspending agent, a wetting agent, an acidulant, a flavoring agent, and an essence according to the following method:

[0008] (1) dissolving the suspending agent in water and stirring to completely swell the suspension to obtain solution A;

[0009] (2) adding a wetting agent to vonoprazan fumarate and stirring thoroughly to allow the API to be completely coated and wetted by glycerol to obtain solution B;

[0010] (3) dissolving the acidulant, flavoring agent, and essence in water and stirring to dissolve to obtain solution C;

[0011] (4) Pour solution A into solution B and grind homogenously to obtain a white suspension;

[0012] (5) Pour solution C into the white suspension and stir evenly;

[0013] (6) Add water to the volume and stir until well mixed.

[0014] Preferably, the wetting agent is glycerol.

[0015] Preferably, the suspending agent is xanthan gum, tragacanth gum, sodium alginate or gum arabic.

[0016] Preferably, the acidulant is citric acid.

[0017] Preferably, the flavoring agent is sucralose.

[0018] Preferably, the flavor is orange flavor.

[0019] Preferably, the dosage of each component of the suspension is 5g of vonoprazan fumarate, 10g of suspending agent, 0.5g of wetting agent, 0.5g of acidifying agent, 2g of flavoring agent and 0.5g of essence per 100ml of suspension.

[0020] 2. The preparation method of the vonoprazan fumarate suspension comprises the following specific steps:

[0021] (1) dissolving the suspending agent in water and stirring to completely swell the suspending agent to obtain solution A;

[0022] (2) adding a wetting agent to the vonoprazan fumarate and stirring thoroughly to allow the vonoprazan fumarate to be completely coated and wetted by the glycerol to obtain a solution B;

[0023] (3) dissolving the acidulant, flavoring agent, and essence in water and stirring to dissolve to obtain solution C;

[0024] (4) Pour solution A into solution B and grind homogenously to obtain a white suspension;

[0025] (5) Pour solution C into the white suspension and stir evenly;

[0026] (6) Add water to 100ml and stir to mix.

[0027] The present invention has the beneficial effects of disclosing a vonoprazan fumarate suspension. Compared to tablets, the formulation is easier to swallow and, through prescription screening and the addition of appropriate excipients, significantly reduces the bitterness of vonoprazan fumarate during oral administration, thereby increasing patient clinical compliance. Furthermore, the present invention overcomes the problem of tablets being broken apart for administration, resulting in inaccurate dosage and damage to the coating, which affects the taste-masking effect. The oral suspension is packaged in unit doses, ensuring accurate dosage and convenient administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to make the purpose, technical solutions and beneficial effects of the present invention more clear, the present invention provides the following drawings for illustration:

[0029] Figure 1 The impurity chromatograms at 0°C are (A: blank control; B: prescription 1; C: prescription 5; D: prescription 6);

[0030] Figure 2 Impurity profiles at 60°C (A: blank control; B: prescription 1; C: prescription 5; D: prescription 6);

[0031] Figure 3 This is the pharmacokinetic curve. DETAILED DESCRIPTION

[0032] The present invention will be further described below with reference to the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it. However, the embodiments are not intended to limit the present invention.

[0033] Example 1, Optimization of Vonoprazan Fumarate Suspension Process

[0034] Vonoprazan fumarate suspension is prepared from vonoprazan fumarate, a suspending agent, a wetting agent, an acidulant, a flavoring agent, and an essence. The following formula is designed:

[0035] Each 100 ml of suspension contains: 5 g of vonoprazan fumarate, 10 g of glycerin, 0.5 g of xanthan gum, 0.5 g of citric acid, 2 g of sucralose, and 0.5 g of orange flavor. This prescription is used as prescription 1.

[0036] The preparation process of vonoprazan fumarate suspension is as follows:

[0037] (1) Dissolve the suspending agent in 50 ml of water and stir until it is completely swollen to obtain solution A;

[0038] (2) adding a wetting agent to vonoprazan fumarate and stirring thoroughly to allow the API to be completely coated and wetted by glycerol to obtain solution B;

[0039] (3) Dissolve the acidulant, flavoring agent, and essence in 30 ml of water and stir to dissolve to obtain solution C;

[0040] (4) Pour solution A into solution B and grind homogenously to obtain a white suspension;

[0041] (5) Pour solution C into the white suspension and stir evenly;

[0042] (6) Add water to 100ml and stir to mix.

[0043] At the same time, the effects of different preparation methods were compared.

[0044] Comparison process 1:

[0045] (1) Glycerol was dissolved in 50 ml of water, and xanthan gum was added and stirred to completely swell to obtain solution A;

[0046] (2) Add the API to solution A and grind until homogenized;

[0047] (3) Add water to 100ml and stir to mix.

[0048] Comparison process 2:

[0049] (1) Dissolve xanthan gum in 50 ml of water and stir until it is completely swollen to obtain solution A;

[0050] (2) Dissolve glycerol in 30 ml of water, stir to dissolve, and add the API to obtain solution B;

[0051] (3) Pour solution B into solution A, mix, and grind until homogenous;

[0052] (4) Add water to 100ml and stir to mix.

[0053] The results of suspensions prepared by different processes are shown in Table 1:

[0054] Table 1. Comparison of suspensions prepared by different processes

[0055]

[0056] It can be seen from this that the suspension solution prepared by the process of the present invention is in a uniform suspension state, has no lumps, and is evenly dispersed. Therefore, the process of the present invention is used to prepare the suspension.

[0057] Example 2, Optimization of Vonoprazan Fumarate Suspension Formulation

[0058] The xanthan gum in prescription 1 was replaced by tragacanth gum, sodium alginate, and gum arabic, and the glycerol was replaced by Tween 80 and propylene glycol, respectively, to obtain prescriptions 2 to 6.

[0059] Prescription 2: Each 100ml suspension contains: 5g of vonoprazan fumarate, 10g of glycerin, 0.5g of tragacanth gum, 0.5g of citric acid, 2g of sucralose, and 0.5g of orange flavor.

[0060] Prescription 3: Each 100ml suspension contains: 5g of vonoprazan fumarate, 10g of glycerol, 0.5g of sodium alginate, 0.5g of citric acid, 2g of sucralose, and 0.5g of orange flavor.

[0061] Prescription 4: Each 100ml suspension contains: 5g of vonoprazan fumarate, 10g of glycerin, 0.5g of gum arabic, 0.5g of citric acid, 2g of sucralose, and 0.5g of orange flavor.

[0062] Prescription 5: Each 100ml suspension contains: 5g of vonoprazan fumarate, 10g of Tween 80, 0.5g of xanthan gum, 0.5g of citric acid, 2g of sucralose, and 0.5g of orange flavor.

[0063] Prescription 6: Each 100ml suspension contains: 5g of vonoprazan fumarate, 10g of propylene glycol, 0.5g of xanthan gum, 0.5g of citric acid, 2g of sucralose, and 0.5g of orange flavor.

[0064] Then the taste, sedimentation and dispersion of different prescriptions were tested, and the results are shown in Table 2.

[0065] Table 2. Taste, sedimentation and redispersibility of vonoprazan fumarate suspension

[0066]

[0067] Then test the impurity profiles of prescriptions 1, 5 and 6 at 0℃ and 60℃, and use blank solvent as a control. Figure 1 As shown, the chromatogram at 60°C is as follows Figure 2 shown.

[0068] Because the chromatographic column was replaced during the 10-day sample test, the chromatograms of the blank solutions at day 0 and day 10 differed. Comparing Prescriptions 1, 5, and 6 after subtracting the blank, multiple unknown impurities appeared between 40 and 50 minutes in Prescriptions 5 and 6, with larger peak areas. Prescription 1, however, showed no significant impurity peaks at this time point. Furthermore, after 10 days at 60°C, the impurity levels in Prescriptions 5 and 6 increased significantly.

[0069] Example 3. Pharmacokinetic study

[0070] The pharmacokinetics of vonoprazan fumarate oral solution prepared in prescription 1 and vonoprazan fumarate tablets produced by Takeda Pharmaceutical Company of Japan were studied in Beagle dogs:

[0071] Beagle dogs were randomly divided into two groups according to body weight, with 4 dogs in each group, half male and half female. The drug was administered orally. The dogs were fasted for 12 hours before administration and had free access to water. After administration, they were deprived of water for 2 hours and fasted for 4 hours.

[0072] Tablet group: Before administration, moisten the dog's mouth and esophagus with 15 ml of purified water, then place the drug at the root of the dog's tongue. After the dog swallows, administer the drug with 15 ml of purified water. Solution group: After moistening the catheter with warm water, insert the gavage tube along the gap at the corner of the dog's mouth about 20 cm to 30 cm. After confirming that the outer end of the catheter is placed in clean water without bubbles, connect the syringe and slowly inject the drug solution. After the drug solution is pushed out, push 15 ml of purified water to flush all the remaining drug solution in the catheter into the stomach. Blood samples were collected from each experimental animal before administration and 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration. About 2 ml of whole blood was collected from the cephalic vein of the Beagle dog's forelimb into a pre-labeled heparinized blood collection tube. The blood sample was temporarily stored in an ice box and then centrifuged at 4500 rpm for 10 minutes to separate the plasma for testing. The results are shown in Table 1 and Figure 3 shown.

[0073] Table 1. Blood drug concentration detection

[0074] parameter unit Tablet group Suspension group AUC(0-t) ug / L*h 1152.371 1305.278 t1 / 2z h 2.023 2.51 Tmax h 1.375 1 Cmax ng / ml 212.254 270.299

[0075] The results showed that the blood drug concentration of the suspension prepared by the present invention was consistent with that of the existing tablets, and therefore it can be used clinically.

[0076] The above embodiments are merely preferred embodiments for the purpose of fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are within the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

Claims

1. Vonoprazan fumarate suspension, characterized in that: The suspension is prepared from vonoprazan fumarate, a suspending agent, a wetting agent, an acidulant, a flavoring agent and an essence according to the following method: (1) dissolving the suspending agent in water and stirring to completely swell the suspension to obtain solution A; (2) adding a wetting agent to vonoprazan fumarate and stirring thoroughly to allow the API to be completely coated and wetted by glycerol to obtain solution B; (3) dissolving the acidulant, flavoring agent, and essence in water and stirring to dissolve to obtain solution C; (4) Pour solution A into solution B and grind homogenously to obtain a white suspension; (5) Pour solution C into the white suspension and stir evenly; (6) Add water to the volume and stir until evenly mixed.

2. The vonoprazan fumarate suspension according to claim 1, wherein: The wetting agent is glycerin.

3. The vonoprazan fumarate suspension according to claim 1, wherein: The suspending agent is xanthan gum, tragacanth gum, sodium alginate or gum arabic.

4. The vonoprazan fumarate suspension according to claim 1, wherein: The acidifying agent is citric acid.

5. The vonoprazan fumarate suspension according to claim 1, wherein: The flavoring agent is sucralose.

6. The vonoprazan fumarate suspension according to claim 1, wherein: The flavor is orange flavor.

7. The vonoprazan fumarate suspension according to claim 1, wherein: The dosage of each component of the suspension is as follows: per 100 ml of suspension, 5 g of vonoprazan fumarate, 10 g of suspending agent, 0.5 g of wetting agent, 0.5 g of acidifying agent, 2 g of flavoring agent, and 0.5 g of essence.

8. The method for preparing the vonoprazan fumarate suspension according to any one of claims 1 to 7, characterized in that: The specific steps are as follows: (1) dissolving the suspending agent in water and stirring to completely swell the suspension to obtain solution A; (2) adding a wetting agent to the vonoprazan fumarate and stirring thoroughly to allow the vonoprazan fumarate to be completely coated and wetted by the glycerol to obtain a solution B; (3) dissolving the acidulant, flavoring agent, and essence in water and stirring to dissolve to obtain solution C; (4) Pour solution A into solution B and grind homogenously to obtain a white suspension; (5) Pour solution C into the white suspension and stir evenly; (6) Add water to 100ml and stir to mix.

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