A kind of ibuprofen suspension and preparation method thereof

Abstract

The invention discloses an ibuprofen suspension and a preparation method, and belongs to the technical field of pharmaceutical preparations. The ibuprofen suspension of the invention is composed of ibuprofen, sucrose, whey protein isolate / xanthan gum complex, pregelatinized starch, glycerol, Tween 80, citric acid, sodium benzoate, essence, pigment and water. Compared with the prior art, the invention adopts whey protein isolate / nicotinamide mononucleotide complex to replace xanthan gum, which can effectively solve the problem of uneven content of ibuprofen suspension and poor stability caused by uneven swelling of xanthan gum.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to an ibuprofen suspension and a preparation method thereof. Background Art

[0002] Ibuprofen suspension is a commonly used over-the-counter medicine mainly used to relieve fever and pain.

[0003] Xanthan gum and pregelatinized starch can play a role in thickening and suspending in suspensions, which is crucial to maintaining the stability of drugs. However, the uniform dispersion process of xanthan gum is relatively time-consuming and requires special attention. If the xanthan gum is not fully dispersed, lumps will form in the final product, which will interfere with the viscosity balance of the suspension, causing the ibuprofen component to float in the liquid and affect the overall uniformity. As a heterogeneous preparation, the dispersibility of ibuprofen in the suspension is easily affected by high-viscosity components such as xanthan gum and pregelatinized starch. Therefore, every step in the process must be carefully designed to ensure the uniform dispersion of the drug and the stability of the final product.

[0004] CN115770218A discloses a preparation process for improving the uniformity of ibuprofen suspension content, and the technical solution mainly solves the difficulty of xanthan gum dispersion by pre-treating and swelling xanthan gum for 8-20 hours in advance. In fact, pre-treating and swelling xanthan gum for 8-20 hours in advance will reduce the efficiency in industrial production.

[0005] CN114209650A discloses a process for improving the content uniformity of ibuprofen suspension. The technical solution mainly introduces a colloid mill to evenly disperse ibuprofen into a heterogeneous system, thus effectively solving the problem of product content uniformity. Summary of the invention

[0006] Different from the prior art, the present invention seeks a suitable substance to replace xanthan gum from the perspective of formulation, thereby solving the stability problem of ibuprofen suspension.

[0007] To achieve the above object, the present invention provides a method for preparing an ibuprofen suspension, comprising the following steps:

[0008] 1) 200-400 g of sucrose, 1-4 g of whey protein isolate / xanthan gum complex and 12-15 g of pregelatinized starch are mixed evenly, added to 500 mL of water, and stirred at 100-300 rpm for 5-20 min to obtain a slurry;

[0009] 2) adding 50-200 g of glycerol, 0.3-0.6 g of Tween 80 and 1-3 g of citric acid to 100 mL of water, stirring and mixing at 100-300 rpm for 2-10 min; adding 10-30 g of crushed ibuprofen, stirring and mixing at 100-300 rpm for 2-10 min to obtain a mixed solution; mixing the mixed solution and the slurry, and then adding 1-3 g of sodium benzoate, 1-5 g of flavor, 0.01-0.05 g of pigment, and 400 mL of water, stirring and mixing at 100-300 rpm for 5-20 min; standing and degassing to obtain the ibuprofen suspension.

[0010] Preferably, the preparation method of the whey protein isolate / xanthan gum complex is: uniformly mix the whey protein isolate, xanthan gum and water, react at 30-50°C for 1-5h; cool to room temperature, dialyze to remove unreacted raw materials, and freeze-dry the retained solution to obtain the whey protein isolate / xanthan gum complex; the mass ratio of whey protein isolate, xanthan gum and water is 0.3-1.5:0.5-2:96.5-99.2.

[0011] Further preferably, step 1) can also be: 200-400 g sucrose, 1-4 g whey protein isolate / xanthan gum / nicotinamide mononucleotide complex and 12-15 g pregelatinized starch are evenly mixed, added to 500 mL water, and stirred at 100-300 rpm for 5-20 min to obtain a slurry.

[0012] Preferably, the preparation method of the whey protein isolate / xanthan gum / nicotinamide mononucleotide complex is: uniformly mixing whey protein isolate, xanthan gum, nicotinamide mononucleotide and water, reacting at 30-50°C for 1-5h; cooling to room temperature, dialyzing to remove unreacted raw materials, and freeze-drying the entrapped solution to obtain the whey protein isolate / xanthan gum / nicotinamide mononucleotide complex; the mass ratio of whey protein isolate, xanthan gum, nicotinamide mononucleotide and water is 0.3-1.5:0.4-1:0.1-1:96.5-99.2.

[0013] Preferably, the molecular cutoff of the dialysis bag used for dialysis is 5 kDa.

[0014] Preferably, the particle size of ibuprofen is less than 100 μm.

[0015] Preferably, the flavor is a fruit flavor, specifically, it can be any one of strawberry flavor, cherry flavor, and orange flavor.

[0016] Preferably, the pigment may be any one of carmine, beetroot red and lemon yellow.

[0017] Beneficial effects of the present invention:

[0018] Compared with the prior art, the present invention adopts whey protein isolate / nicotinamide mononucleotide complex to replace xanthan gum, which can effectively solve the problems of uneven ibuprofen suspension content and poor stability caused by uneven swelling of xanthan gum. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The dissolution curves of the ibuprofen of Example 2 and Comparative Example 1 before and after 60 days of long-term storage. DETAILED DESCRIPTION

[0020] A method for preparing an ibuprofen suspension of the present invention comprises the following steps:

[0021] 1) 200-400 g of sucrose, 1-4 g of whey protein isolate / xanthan gum complex or whey protein isolate / xanthan gum / nicotinamide mononucleotide complex and 12-15 g of pregelatinized starch are mixed evenly, added to 500 mL of water, and stirred at 100-300 rpm for 5-20 min to obtain a slurry;

[0022] 2) adding 50-200 g of glycerol, 0.3-0.6 g of Tween 80 and 1-3 g of citric acid to 100 mL of water, stirring and mixing at 100-300 rpm for 2-10 min; adding 10-30 g of crushed ibuprofen, stirring and mixing at 100-300 rpm for 2-10 min to obtain a mixed solution; mixing the mixed solution and the slurry, and then adding 1-3 g of sodium benzoate, 1-5 g of flavor, 0.01-0.05 g of pigment, and 400 mL of water, stirring and mixing at 100-300 rpm for 5-20 min; standing and degassing to obtain the ibuprofen suspension.

[0023] Ibuprofen itself has a low melting point, is light in weight, and is easy to aggregate. Long-term storage may cause the drug to aggregate, settle, or float, affecting stability, which may cause the actual dosage to be inconsistent with expectations, causing drug poisoning or ineffectiveness. Moreover, in the preparation process of ibuprofen suspension, xanthan gum is used as a suspending agent, and its dispersion uniformity is crucial to product quality. If the xanthan gum is not evenly dispersed, it will affect the viscosity of the suspension, causing ibuprofen to float easily, affecting the uniform distribution of the drug. The formula of the present invention is mainly based on the commercially available product - Shanghai Johnson Pharmaceutical Co., Ltd. Improved.

[0024] The preparation method of the whey protein isolate / xanthan gum complex comprises the following steps: uniformly mixing the whey protein isolate, xanthan gum and water, reacting at 30-50° C. for 1-5 hours; cooling to room temperature, dialyzing with a dialysis bag having a molecular cutoff of 5 kDa to remove unreacted raw materials, freeze-drying the retained solution, and obtaining the whey protein isolate / xanthan gum complex; the mass ratio of the whey protein isolate, xanthan gum and water is 0.3-1.5:0.5-2:96.5-99.2.

[0025] The whey protein isolate / xanthan gum complex can enhance the interaction between ibuprofen particles and water molecules, reduce the sedimentation tendency of particles, and thus improve the stability of the suspension. Furthermore, the whey protein isolate / xanthan gum complex can form a three-dimensional network structure in the suspension system, effectively restricting the movement of ibuprofen particles and increasing the stability of the suspension.

[0026] The preparation method of the whey protein isolate / xanthan gum / nicotinamide mononucleotide complex comprises the following steps: uniformly mixing whey protein isolate, xanthan gum, nicotinamide mononucleotide and water, reacting at 30-50°C for 1-5h; cooling to room temperature, dialyzing to remove unreacted raw materials, and freeze-drying the retained solution to obtain the whey protein isolate / xanthan gum / nicotinamide mononucleotide complex; the mass ratio of whey protein isolate, xanthan gum, nicotinamide mononucleotide and water is 0.3-1.5:0.4-1:0.1-1:96.5-99.2.

[0027] The particle size of ibuprofen is less than 100 μm. Studies have shown that the ideal particle size of ibuprofen particles used in suspension should be less than 100 μm to effectively ensure the bioavailability, efficacy and safety of the drug.

[0028] Flavors are mainly used to cover up the unpleasant taste of drugs and improve children's compliance with medication. Just choose safe and edible flavors with fruity flavors to improve palatability. The same goes for pigments.

[0029] Example 1

[0030] A method for preparing an ibuprofen suspension comprises the following steps:

[0031] 1) 300 g of sucrose, 2.5 g of whey protein isolate / xanthan gum complex and 13.1 g of pregelatinized starch were mechanically stirred and mixed for 5 min, then added to 500 mL of purified water and stirred and mixed at 200 rpm for 15 min to obtain a slurry;

[0032] 2) adding 100 g of glycerol, 0.5 g of Tween 80 and 1.921 g of citric acid to 100 mL of purified water, stirring and mixing at 200 rpm for 5 min; adding 20 g of crushed ibuprofen, stirring and mixing at 200 rpm for 5 min to obtain a mixed solution; mixing the mixed solution and the slurry, and then adding 2 g of sodium benzoate, 3 g of strawberry flavor, 0.03 g of carmine, and 400 mL of purified water, stirring and mixing at 200 rpm for 10 min; standing and degassing for 12 h to obtain the ibuprofen suspension.

[0033] The preparation method of the whey protein isolate / xanthan gum complex is as follows: 0.7g of whey protein isolate, 1.5g of xanthan gum and 97.8g of purified water solution are uniformly mixed, reacted at 40°C for 3h, cooled to room temperature, dialyzed with a dialysis bag with a molecular cutoff of 5kDa for 12h, the purified water is replaced every 2h, and the retained solution in the dialysis bag is freeze-dried to obtain the whey protein isolate / xanthan gum complex.

[0034] Comparative Example 1

[0035] A method for preparing an ibuprofen suspension comprises the following steps:

[0036] 1) 300 g of sucrose, 2.5 g of xanthan gum and 13.1 g of pregelatinized starch were mechanically stirred and mixed for 5 min, then added to 500 mL of purified water and stirred and mixed at 200 rpm for 15 min to obtain a slurry;

[0037] 2) adding 100 g of glycerol, 0.5 g of Tween 80 and 1.921 g of citric acid to 100 mL of purified water, stirring and mixing at 200 rpm for 5 min; adding 20 g of crushed ibuprofen, stirring and mixing at 200 rpm for 5 min to obtain a mixed solution; mixing the mixed solution and the slurry, and then adding 2 g of sodium benzoate, 3 g of strawberry flavor, 0.03 g of carmine, and 400 mL of purified water, stirring and mixing at 200 rpm for 10 min; standing and degassing for 12 h to obtain the ibuprofen suspension.

[0038] Comparative Example 2

[0039] A method for preparing an ibuprofen suspension comprises the following steps:

[0040] 1) 300 g of sucrose, 2.5 g of whey protein isolate and 13.1 g of pregelatinized starch were mechanically stirred and mixed for 5 min, then added to 500 mL of purified water and stirred and mixed at 200 rpm for 15 min to obtain a slurry;

[0041] 2) adding 100 g of glycerol, 0.5 g of Tween 80 and 1.921 g of citric acid to 100 mL of purified water, stirring and mixing at 200 rpm for 5 min; adding 20 g of crushed ibuprofen, stirring and mixing at 200 rpm for 5 min to obtain a mixed solution; mixing the mixed solution and the slurry, and then adding 2 g of sodium benzoate, 3 g of strawberry flavor, 0.03 g of carmine, and 400 mL of purified water, stirring and mixing at 200 rpm for 10 min; standing and degassing for 12 h to obtain the ibuprofen suspension.

[0042] Example 2

[0043] A method for preparing an ibuprofen suspension comprises the following steps:

[0044] 1) 300 g of sucrose, 2.5 g of whey protein isolate / xanthan gum / nicotinamide mononucleotide complex and 13.1 g of pregelatinized starch were mechanically stirred and mixed for 5 min, then added to 500 mL of purified water and stirred and mixed at 200 rpm for 15 min to obtain a slurry;

[0045] 2) adding 100 g of glycerol, 0.5 g of Tween 80 and 1.921 g of citric acid to 100 mL of purified water, stirring and mixing at 200 rpm for 5 min; adding 20 g of crushed ibuprofen, stirring and mixing at 200 rpm for 5 min to obtain a mixed solution; mixing the mixed solution and the slurry, and then adding 2 g of sodium benzoate, 3 g of strawberry flavor, 0.03 g of carmine, and 400 mL of purified water, stirring and mixing at 200 rpm for 10 min; standing and degassing for 12 h to obtain the ibuprofen suspension.

[0046] The preparation method of the whey protein isolate / xanthan gum / nicotinamide mononucleotide complex is as follows: 0.7g of whey protein isolate, 1.0g of xanthan gum, 0.5g of nicotinamide mononucleotide, and 97.8g of purified aqueous solution are mixed evenly, reacted at 40°C for 3h, cooled to room temperature, dialyzed with a dialysis bag with a molecular cutoff of 5kDa, the dialysis time is 12h, purified water is replaced every 2h, and the retained solution in the dialysis bag is freeze-dried to obtain the whey protein isolate / xanthan gum / nicotinamide mononucleotide complex.

[0047] Comparative Example 3

[0048] A method for preparing an ibuprofen suspension comprises the following steps:

[0049] 1) 300 g of sucrose, 2.5 g of nicotinamide mononucleotide and 13.1 g of pregelatinized starch were mechanically stirred and mixed for 5 min, then added to 500 mL of purified water and stirred and mixed at 200 rpm for 15 min to obtain a slurry;

[0050] 2) adding 100 g of glycerol, 0.5 g of Tween 80 and 1.921 g of citric acid to 100 mL of purified water, stirring and mixing at 200 rpm for 5 min; adding 20 g of crushed ibuprofen, stirring and mixing at 200 rpm for 5 min to obtain a mixed solution; mixing the mixed solution and the slurry, and then adding 2 g of sodium benzoate, 3 g of strawberry flavor, 0.03 g of carmine, and 400 mL of purified water, stirring and mixing at 200 rpm for 10 min; standing and degassing for 12 h to obtain the ibuprofen suspension.

[0051] The ibuprofen used in the examples of the present invention is of pharmaceutical grade, with a particle size of about 70 μm. The other raw materials not mentioned are all common commercial products of pharmaceutical grade.

[0052] Test Example 1

[0053] The sedimentation volume ratio test refers to the method in "Chinese Pharmacopoeia 2020 Edition Four General Rules 0123-Oral Suspension". The specific method is: use a stoppered measuring cylinder to measure 50 ml of the test sample, seal it, shake it vigorously for 1 minute, write down the starting height H0 of the suspension, let it stand for 6 hours, write down the final height H of the suspension, and calculate it according to the following formula: sedimentation volume ratio = H / H0. After 60 days of sealed storage at room temperature and protected from light, the sedimentation volume ratio was measured again. According to the actual situation of the present invention, the standing time in the specific method is extended by 1 times compared with the time specified in the pharmacopoeia to highlight the differences between the embodiments.

[0054] Table 1 Sedimentation volume ratio of ibuprofen suspension

[0055]

[0056] It can be seen from the comparison example 1 and the comparative example 1 that replacing conventional xanthan gum with the whey protein isolate / xanthan gum complex of the present invention can effectively improve the stability of the ibuprofen suspension. The whey protein isolate and xanthan gum form a whey protein isolate / xanthan gum complex through hydrogen bonds, which can improve the interfacial effect between the ibuprofen particles and the aqueous phase, enhance the interaction between the ibuprofen particles and the water molecules, and reduce the sedimentation trend of the particles. Furthermore, the whey protein isolate / xanthan gum complex may form a three-dimensional network structure in the suspension system, effectively restrict the movement of the particles, and increase the stability of the suspension. It can be seen from the test results that the addition of nicotinamide mononucleotide can further enhance the stability of the ibuprofen suspension. It may be because nicotinamide mononucleotide enhances the interaction between whey protein isolate and xanthan gum, and by forming additional hydrogen bonds or other non-covalent bonds, the stability of the complex is improved, thereby achieving a further improvement in the stability of the ibuprofen suspension.

[0057] Test Example 2

[0058] The potential of the ibuprofen suspension in the examples and comparative examples was measured using a Malvern laser particle size analyzer.

[0059] Table 2 Potential of ibuprofen suspension

[0060] Potential (mV) Example 1 -26.4 Comparative Example 1 -23.1 Example 2 -29.5

[0061] Generally speaking, the higher the absolute value of the Zeta potential, the greater the repulsive force between particles and the more stable the suspension.

[0062] Zeta potential analysis further confirmed that replacing conventional xanthan gum with whey protein isolate / xanthan gum complex could improve the stability of ibuprofen suspension.

[0063] Test Example 3

[0064] The dissolution determination was carried out with reference to the "Chinese Pharmacopoeia 2020 Edition Part 4 0931 Dissolution and Release Determination Method 2 (Pulp Method)", with pH 7.2 phosphate buffer solution as the dissolution medium, medium volume 900 mL, rotation speed 50 rpm, and medium temperature 37 °C.

[0065] Specific operation method: The ibuprofen suspensions of the embodiments and comparative examples were sucked into 10 mL syringes respectively, and when the paddles rotated, the above suspensions were added into each dissolution cup (the weight of the syringe was recorded before and after the suction). Sampling time points: 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min. 5 ml was sampled at 60 min, filtered through a 0.45 μm microporous membrane, the primary filtrate was discarded, and the chromatographic injection analysis was performed, the peak area of ​​ibuprofen was recorded, and the dissolution rate of ibuprofen was calculated by the external standard method.

[0066] Chromatographic conditions: AICHROM Bond C18 column (250 mm×4.6 mm, 5 μm); mobile phase: sodium acetate buffer-acetonitrile (40:60); detection wavelength: 222 nm; column temperature: room temperature; flow rate: 1.0 ml / min; injection volume: 20 μL.

[0067] Sodium acetate buffer solution is prepared by adding 950 mL of water to 6.13 g of sodium acetate, shaking to dissolve, adjusting the pH to 2.5 with glacial acetic acid, and fixing the volume to 1 L.

[0068] The ibuprofen suspensions of Example 2 and Comparative Example 1 were subjected to dissolution tests with reference to the above method, and dissolution curves were drawn.

[0069] The ibuprofen suspensions of Example 2 and Comparative Example 1 were stored in the dark at room temperature for 60 days, then manually shaken for 1 minute, and the above dissolution test was repeated to draw a dissolution curve.

[0070] from Figure 1It can be seen that the dissolution curve of the ibuprofen suspension of the present invention is close to that of the ibuprofen suspension of Reference Example 1. After 60 days of storage, the dissolution curve of the ibuprofen suspension of the present invention is better than that of the ibuprofen suspension of Reference Example 1.

Claims

1. A method for preparing an ibuprofen suspension, characterized in that: The steps include: 1) 200-400 g of sucrose, 1-4 g of whey protein isolate / xanthan gum complex and 12-15 g of pregelatinized starch are mixed evenly, added to 500 mL of water, and stirred at 100-300 rpm for 5-20 min to obtain a slurry; Alternatively, 200-400 g of sucrose, 1-4 g of whey protein isolate / xanthan gum / nicotinamide mononucleotide complex and 12-15 g of pregelatinized starch are mixed evenly, added to 500 mL of water, and stirred at 100-300 rpm for 5-20 min to obtain a slurry; 2) adding 50-200 g glycerol, 0.3-0.6 g Tween 80 and 1-3 g citric acid to 100 mL water, stirring and mixing at 100-300 rpm for 2-10 min; adding 10-30 g crushed ibuprofen, stirring and mixing at 100-300 rpm for 2-10 min to obtain a mixed solution; mixing the mixed solution and the slurry, and then adding 1-3 g sodium benzoate, 1-5 g flavor, 0.01-0.05 g pigment, and 400 mL water, stirring and mixing at 100-300 rpm for 5-20 min; standing for degassing to obtain the ibuprofen suspension; The preparation method of the whey protein isolate / xanthan gum complex comprises: uniformly mixing whey protein isolate, xanthan gum and water, reacting at 30-50° C. for 1-5 hours; cooling to room temperature, dialyzing to remove unreacted raw materials, and freeze-drying the retained solution to obtain the whey protein isolate / xanthan gum complex; the mass ratio of whey protein isolate, xanthan gum and water is 0.3-1.5:0.5-2:96.5-99.2; The preparation method of the whey protein isolate / xanthan gum / nicotinamide mononucleotide complex comprises: uniformly mixing whey protein isolate, xanthan gum, nicotinamide mononucleotide and water, reacting at 30-50° C. for 1-5 hours; cooling to room temperature, dialyzing to remove unreacted raw materials, and freeze-drying the retained solution to obtain the whey protein isolate / xanthan gum / nicotinamide mononucleotide complex; The mass ratio of whey protein isolate, xanthan gum, nicotinamide mononucleotide and water is 0.3-1.5:0.4-1:0.1-1:96.5-99.

2.

2. The preparation method of ibuprofen suspension as claimed in claim 1, characterized in that: The molecular cutoff of the dialysis bag used for dialysis was 5 kDa.

3. The preparation method of ibuprofen suspension as claimed in claim 1, characterized in that: The particle size of ibuprofen is less than 100 μm.

4. The preparation method of ibuprofen suspension as claimed in claim 1, characterized in that: The flavor is any one of strawberry flavor, cherry flavor and orange flavor.

5. The preparation method of ibuprofen suspension as claimed in claim 1, characterized in that: The pigment may be any one of carmine, beetroot red and lemon yellow.

6. An ibuprofen suspension, characterized in that Prepared by the method according to any one of claims 1 to 5.

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