Non-steroidal anti-inflammatory freeze-dried orally disintegrating tablet and preparation method thereof

Abstract

The invention discloses a non-steroidal anti-inflammatory drug freeze-dried orally disintegrating tablet and a preparation method thereof. The tablet comprises montelukast sodium, mannitol, pullulan, sucralose and water. The preparation method comprises the following steps: 1) weighing water accounting for about 70% of the total weight of the liquid medicine, adding pullulan, and stirring for dissolving; 2) adding mannitol and sucralose, stirring and dissolving to form a mixed solution; 3) adding montelukast sodium, stirring and dissolving, and fixing the volume to the required prescription dosage to obtain a liquid medicine; and 4) adding the obtained liquid medicine into a bubble cap mold according to the amount of 400 [mu] l / tablet. The preparation method comprises the following steps: mixing the raw materials, adding the mixture into a freeze dryer, setting freeze-drying process parameters, starting freeze-drying, and finishing freeze-drying to obtain the freeze-dried orally disintegrating tablet with good disintegration property and stability by optimizing the prescription and the preparation process.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical formulation technology, and specifically relates to a lyophilized orally disintegrating tablet of a nonsteroidal anti-inflammatory drug and its preparation method. Background Technology

[0002] Montelukast sodium, a new generation of nonsteroidal anti-inflammatory drug (NSAID), selectively antagonizes the binding of leukotrienes to their receptors, inhibiting the pro-inflammatory activity of leukotrienes. Montelukast sodium was first marketed by Merck & Co. in 1988 and is primarily used clinically to treat asthma and bronchitis. In 2015, MSD Corporation of Japan developed an orally disintegrating tablet, 10 mg, marketed under the brand name Singulair.

[0003] Currently, montelukast sodium is available in various dosage forms in China, including regular tablets, orally disintegrating tablets, chewable tablets, and granules. However, during an acute asthma attack, patients often experience difficulty taking the medication due to airway obstruction, and asthma patients are often elderly or children with weaker swallowing abilities. Lyophilized orally disintegrating tablets, due to their rich porosity and soluble matrix, offer advantages such as rapid disintegration and a pleasant taste, significantly improving patient compliance. Some medications can also be absorbed through the sublingual mucosa, bypassing the first-pass effect and improving bioavailability. Summary of the Invention

[0004] The purpose of this application is to provide a lyophilized orally disintegrating tablet of a nonsteroidal anti-inflammatory drug and its preparation method. Through formulation optimization and preparation process optimization, a lyophilized orally disintegrating tablet of a nonsteroidal anti-inflammatory drug and an optimal preparation method have been obtained. This product not only exhibits good stability, ensuring the effectiveness of the drug during storage and use, but also achieves rapid disintegration, greatly improving the convenience of use for patients and the rate of drug absorption, providing a more efficient and comfortable way of administration for the treatment of related diseases.

[0005] On one hand, this application provides a lyophilized orally disintegrating tablet of a nonsteroidal anti-inflammatory drug, the tablet comprising montelukast sodium, mannitol, pullulan, sucralose, and water, and the mass percentage content of each component is as follows:

[0006] Montelukast sodium 4%, mannitol 2.5%-4.5%, pullulan 2.2%-4.2%, sucralose 0.2%, water 3.8%-5.4%.

[0007] In one embodiment of lyophilized orally disintegrating tablets, the amount of mannitol used is 2.5%, 3%, 3.5%, 4%, or 4.5%. The amount of mannitol used is not limited to the specific data listed, and can be any value between the listed data.

[0008] In one embodiment of lyophilized orally disintegrating tablets, the pullulan dosage is 2.2%, 2.5%, 3%, 3.5%, 4%, or 4.2%. The pullulan dosage is not limited to the specific data listed, and can be any value between the listed data.

[0009] In one embodiment of the lyophilized orally disintegrating tablets, the amount of mannitol is 2.5%, and the amount of pullulan is 4.2%.

[0010] In one embodiment of the lyophilized orally disintegrating tablets, the amount of mannitol is 4.5%, and the amount of pullulan is 2.2%.

[0011] In one embodiment of lyophilized orally disintegrating tablets, the amount of mannitol is 3.5%, and the amount of pullulan is 3.5%.

[0012] On the other hand, the present invention provides a method for preparing lyophilized orally disintegrating tablets of nonsteroidal anti-inflammatory drugs, comprising the following steps:

[0013] 1) Weigh out water, which accounts for approximately 70% of the total weight of the liquid, and add pullulan polysaccharide while stirring to dissolve;

[0014] 2) Add mannitol and sucralose and stir to dissolve, forming a mixed solution;

[0015] 3) Add sodium montelukast and stir to dissolve, then bring the volume to the required prescription amount to obtain the drug solution;

[0016] 4) Add the obtained drug solution to the blister mold at a rate of 400 μl / tablet. Place it in a freeze dryer, set the freeze drying process parameters, start freeze drying, and when freeze drying is complete, you will get freeze-dried disintegrating tablets.

[0017] The freeze-drying process is as follows:

[0018]

[0019] In step 1) above, the temperature of the purified water can be in the range of room temperature and 60°C. Room temperature purified water or 60°C purified water is preferred.

[0020] In some embodiments of the above-described lyophilized orthotic tablets and their preparation methods, the moisture content of the lyophilized orthotic tablets is 3.8%-5.4%, for example 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, or 5.4%; preferably 3.8%-4.7%.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. Excipient Optimization: In the initial formulation stage of the montelukast sodium lyophilized orally disintegrating tablets of this invention, glycine or citric acid was initially considered as excipients. However, we found that maintaining the pH of the solution within the acidic range directly affected the solubility of montelukast sodium, making the API dissolution difficult. Therefore, the formulation was adjusted, removing glycine and citric acid to effectively maintain the appropriate solubility of the API. Simultaneously, the combination of other excipients was optimized to ensure the stability and efficacy of the formulation, providing patients with a more reliable treatment option.

[0023] 2. Carefully Selected Matrix Materials: In the molding of lyophilized orally disintegrating tablets, this invention selects pullulan and mannitol as the core matrix materials. Their synergistic effect plays a crucial role in enhancing the overall strength of the tablet. This not only ensures rapid disintegration of the lyophilized orally disintegrating tablet in the oral cavity but also guarantees its structural integrity and ease of use.

[0024] 3. Precise Moisture Management: This invention has conducted in-depth research on the effects of pullulan and mannitol dosages on the moisture content of lyophilized orally disintegrating tablets. By finely controlling the ratio of the two, precise control of moisture content has been achieved, thereby further improving the product's stability and shelf life, and bringing patients a safer and more effective medication experience. Attached Figure Description

[0025] Figure 1 This is a process flow diagram for freeze-dried orally disintegrating tablets of nonsteroidal anti-inflammatory drugs. Detailed Implementation

[0026] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0027] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments of this invention pertain. If any definition stated in this section is contrary to or otherwise inconsistent with a definition stated in a patent, patent application, published patent application, or other publication incorporated herein by reference, the definitions listed here shall prevail over those incorporated herein by reference.

[0028] Furthermore, the mass of the relevant components mentioned in the specification of the embodiments of this invention can refer not only to the specific content of each component, but also to the proportional relationship between the masses of the components. Therefore, any scaling up or down of the content of the relevant components according to the specification of the embodiments of this invention is within the scope disclosed in the specification of the embodiments of this invention. Specifically, the mass described in the specification of the embodiments of this invention can be a mass unit known in the chemical industry, such as μg, mg, g, or kg.

[0029] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available. This application will now be described in detail with reference to specific embodiments.

[0030] A lyophilized orally disintegrating tablet of a nonsteroidal anti-inflammatory drug comprises montelukast sodium, mannitol, pullulan, sucralose, and water, and the mass percentage content of each component is as follows:

[0031] Montelukast sodium 1%, mannitol 2.5%-4.5%, pullulan polysaccharide 2.2%-4.2%, sucralose 0.2%, and moisture 3.8%-5.4%.

[0032] A method for preparing a lyophilized orally disintegrating tablet of a nonsteroidal anti-inflammatory drug, comprising the following steps:

[0033] 1) Weigh out approximately 70% of the total weight of the liquid solution of purified water, add pullulan polysaccharide and stir to dissolve;

[0034] 2) Add mannitol and sucralose and stir to dissolve, forming a mixed solution;

[0035] 3) Add sodium montelukast and stir to dissolve, then bring the volume to the required prescription amount to obtain the drug solution;

[0036] 4) Add the obtained drug solution to the blister mold at a rate of 400 μl / tablet. Place it in a freeze dryer, set the freeze drying process parameters, start freeze drying, and when freeze drying is complete, you will get freeze-dried disintegrating tablets.

[0037] The freeze-drying process parameters are as follows:

[0038]

[0039] In one embodiment of lyophilized orally disintegrating tablets, the amount of mannitol used is 2.5%, 3%, 3.5%, 4%, or 4.5%. The amount of mannitol used is not limited to the specific data listed, and can be any value between the listed data.

[0040] In one embodiment of lyophilized orally disintegrating tablets, the pullulan dosage is 2.2%, 2.5%, 3%, 3.5%, 4%, or 4.2%. The pullulan dosage is not limited to the specific data listed, and can be any value between the listed data.

[0041] In one embodiment of the lyophilized orally disintegrating tablets, the amount of mannitol is 2.5%, and the amount of pullulan is 4.2%.

[0042] In one embodiment of the lyophilized orally disintegrating tablets, the amount of mannitol is 4.5%, and the amount of pullulan is 2.2%.

[0043] In one embodiment of the lyophilized orally disintegrating tablets, the amount of mannitol is 3.5%, and the amount of pullulan is 3.5%.

[0044] In one embodiment of the method for preparing lyophilized orally disintegrating tablets, the temperature of the purified water in step 1) can be in the range of room temperature and 60°C. Room temperature purified water or 60°C purified water is preferred.

[0045] In one embodiment of the freeze-dried orthotic tablets and its preparation method, the moisture content of the freeze-dried tablets is 3.8%-5.4%, for example 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, or 5.4%; preferably 3.8%-4.7%.

[0046] The features and performance of this application will be further described in detail below with reference to the embodiments.

[0047] Related substances detection methods - chromatographic conditions

[0048] Column: CAPCELL PAK C 18 (4.6mm×150mm, 3μm);

[0049] Mobile phase A: 0.15% trifluoroacetic acid aqueous solution;

[0050] Mobile phase B: 0.15% trifluoroacetic acid acetonitrile solution; perform gradient elution according to the table below;

[0051]

[0052]

[0053] Flow rate: 1.2 ml / min;

[0054] Detection wavelength: 238nm;

[0055] Column temperature: 30℃;

[0056] Injection volume: 10 μl;

[0057] Solvent: Methanol-water (9:1).

[0058] Content detection method - chromatographic conditions

[0059] Column: Phenomenex 3μm Phenyl-Hexy1, 4.6mm×100mm-132#, with pre-column: phenyl Phenyl, 3.0mm×4mm;

[0060] Mobile phase A: 0.15% trifluoroacetic acid aqueous solution;

[0061] Mobile phase B: 0.15% trifluoroacetic acid acetonitrile solution; perform gradient elution according to the table below;

[0062] Time (min) Mobile phase A (%) Mobile phase B (%) 0 60 40 3 60 40 16 49 51 30 49 51 30.1 60 40 40 60 40

[0063] Flow rate: 1.2 ml / min;

[0064] Detection wavelength: 238nm;

[0065] Column temperature: 30℃;

[0066] Injection volume: 10 μl.

[0067] Detection method for S-isomers - chromatographic conditions

[0068] Chromatographic column: AGP 5μm, 4.0mm×150mm;

[0069] Mobile phase A: 2.3 g / L ammonium acetate aqueous solution (pH adjusted to 5.7 with glacial acetic acid); Mobile phase B: methanol-acetonitrile (60:40); Gradient elution was performed according to the table below;

[0070] Time (min) Mobile phase A (%) Mobile phase B (%) 0 70 30 30 60 40 35 60 40 40 70 30 50 70 30

[0071] Flow rate: 0.9 ml / min;

[0072] Detection wavelength: 280nm;

[0073] Column temperature: 30℃;

[0074] Injection volume: 10 μl.

[0075] Example 1: Montelukast Sodium Lyophilized Orally Disintegrating Tablets (4mg)

[0076] 1. Composition of Montelukast Sodium Lyophilized Orally Disintegrating Tablets

[0077]

[0078]

[0079] The packaging material for this product is a cold-stamped solid pharmaceutical composite rigid sheet (double aluminum) made of polyamide / aluminum / polyvinyl chloride.

[0080] 2. The preparation process of montelukast sodium lyophilized orally disintegrating tablets includes the following steps:

[0081] 1) Weigh out water, which accounts for approximately 70% of the total weight of the liquid, and add pullulan polysaccharide while stirring to dissolve;

[0082] 2) Add mannitol and sucralose and stir to dissolve, forming a mixed solution;

[0083] 3) Add sodium montelukast and stir to dissolve, then bring the volume to the required prescription amount to obtain the drug solution;

[0084] 4) Add the obtained drug solution to the blister mold at a rate of 400 μl / tablet. Place it in a freeze dryer, set the freeze drying process parameters, start freeze drying, and when freeze drying is complete, you will get freeze-dried disintegrating tablets.

[0085] The freeze-drying process parameters are as follows:

[0086]

[0087] Example 2. Control drug

[0088] Table 1. Basic Information of the Reference Drug

[0089]

[0090]

[0091] Example 3: Investigation of the types and amounts of excipients in the prescription

[0092] (1) Examination of the types of excipients

[0093] The effects of the excipients glycine, mannitol, and citric acid on key quality attributes were investigated. Specific formulation parameters are shown in Table 1.

[0094] Table 1

[0095]

[0096] Solution preparation process:

[0097] Take 70g of hot water (about 60℃), add pullulan polysaccharide and stir to dissolve, then add excipients (glycine, mannitol, citric acid, sucralose) and stir to dissolve, and let it stand at room temperature. Add montelukast sodium and find that it does not dissolve.

[0098] Table 2 - Experimental Results

[0099]

[0100]

[0101] Based on the results in Table 2 above, during the formulation development process, we observed that when the pH of the drug solution was adjusted to an acidic range, the solubility of the active pharmaceutical ingredient (API) decreased significantly. This phenomenon is detrimental to the effective dispersion and absorption of the drug. Therefore, citric acid is not used in the optimized formulation to maintain the appropriate solubility of the API and ensure the stability and efficacy of the formulation.

[0102] (2) Screening of glycine and mannitol

[0103] The types and amounts of the molding agents glycine and mannitol were determined. Specific formulation parameters are shown in Table 3.

[0104]

[0105]

[0106] Table 4 - Experimental Results:

[0107]

[0108] Given that the formulation contains glycine, the pH of the solution is acidic, making montelukast sodium difficult to dissolve. Therefore, glycine is not added to the formulation of this application to avoid negatively impacting drug solubility.

[0109] (3) Investigation on the dosage of pullulan and mannitol

[0110] The effects of pullulan and mannitol dosages on dissolution and particle size were investigated. Specific formulation parameters are shown in Table 5.

[0111]

[0112] Solution preparation process:

[0113] Take 70g of hot water (approximately 60℃), add pullulan and stir to dissolve. Then add mannitol and stir to dissolve. Let it cool to room temperature, add sucralose and montelukast sodium and stir to dissolve. Make up to 100ml to obtain the drug solution. Use a pipette to take 400μL into a blister mold and begin lyophilization.

[0114] Freeze-drying process:

[0115]

[0116] Experimental results:

[0117] Table 6 - Tablet Properties

[0118]

[0119] Table 7 - Content Results

[0120] batch number 22082401 22082402 22082403 Tablet content 91.6 94.2 94.8 Intermediate drug content 95.2 93.6 97.3

[0121] Table 8 - Results of Related Substance Detection

[0122]

[0123]

[0124] Table 6 shows that the dosage of pullulan (2.2%-4.2%) and mannitol (2.5%-4.5%) has almost no effect on the tablet properties of the formulation. Table 7 compares the content data, showing that the content of the intermediate solution and the tablet content are basically the same, indicating that the freeze-drying process did not adversely affect the API content.

[0125] As can be seen from the results of related substance testing in Table 8, when the ratio of pullulan to mannitol changes, the impurity C also changes. This change is attributed to the difference in moisture content in the tablets. Therefore, in subsequent production and quality control, it is necessary to closely monitor and control the moisture content of the tablets to ensure product stability and quality consistency. (4) Effect of pullulan and mannitol dosage on tablet moisture content

[0126] The effects of different pullulan dosages on tablet moisture content, tablet appearance, and tablet strength were investigated, as well as the impact of using room temperature water to prepare the pharmaceutical solution on the process.

[0127] (i) Investigating the effect of reduced pullulan dosage on tablet moisture content

[0128]

[0129] Solution preparation process:

[0130] Take 70g of purified water at room temperature, add pullulan and stir to dissolve, then add mannitol and stir to dissolve, then add sucralose and montelukast sodium and stir to dissolve to obtain the drug solution. Use a pipette to take 400μL into a blister mold and begin freeze-drying.

[0131] Freeze-drying process:

[0132]

[0133]

[0134] Table 9 - Experimental Results:

[0135]

[0136] (ii) Investigate the effect of increasing pullulan dosage on tablet moisture content.

[0137]

[0138] Table 10 - Experimental Results

[0139]

[0140] Preparing the pharmaceutical solution with room temperature water has no impact on the process.

[0141] The above results show that the amount of pullulan has a significant effect on the moisture content and strength of lyophilized tablets. As the amount of pullulan decreases, the moisture content of lyophilized tablets prepared under the same process conditions decreases significantly, and the tablet strength tends to decrease. When the amount of pullulan is reduced to the range of 1.5-2.0%, although the moisture content is effectively reduced, the tablet strength also decreases. When the amount of pullulan increases, the moisture content in the tablets also increases, but the tablet strength decreases when the amount of pullulan exceeds 4.2%. In summary, when the amount of pullulan is in the range of 2.2-4.2%, it can play a role in water retention and effectively maintain the tablet strength. (5) Effect of moisture content of lyophilized tablets on formulation content and related substances

[0142] Samples were prepared by re-freezing the drug solutions of batches 22083001 and 22083005 of (4) which had significant differences in moisture content, and the effects of high temperature (40℃) and high temperature (60℃) on the content and related substances were investigated.

[0143] The content results are as follows:

[0144]

[0145]

[0146] The results for the relevant substances are as follows:

[0147]

[0148] The above stability assessment shows that:

[0149] (1) The content of active pharmaceutical ingredient (API) showed almost no significant change at 0 days, 40°C and 60°C, indicating that the content of the formulation is stable and can maintain its effectiveness under different temperature conditions.

[0150] (2) Data analysis of the relevant substances in the stability test revealed that the contents of impurities C and J increased significantly under high temperature (60°C) conditions in both the control drug and the formulation of this application. However, it is noteworthy that the growth trend of impurities C and J in the formulation of this application was significantly lower than that in the control drug. This result indicates that the formulation of this application exhibits better stability in terms of resistance to high temperature degradation, and its overall stability is superior to that of the control drug.

[0151] In summary, the montelukast sodium lyophilized orally disintegrating tablets of this application have achieved breakthrough optimizations in excipient selection, matrix material application, and moisture management.

[0152] The embodiments of this application have been described above with reference to the accompanying drawings. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A lyophilized orally disintegrating tablet of montelukast sodium, comprising montelukast sodium, mannitol, pullulan, sucralose, and water, wherein the mass percentage content of each component is as follows: Montelukast sodium 4%, mannitol 2.5%-4.5%, pullulan 2.2%-4.2%, sucralose 0.2%, water 3.8%-5.4%.

2. The montelukast sodium lyophilized orally disintegrating tablets according to claim 1, characterized in that, The amount of mannitol used is 2.5%, 3%, 3.5%, 4%, or 4.5%.

3. The montelukast sodium lyophilized orally disintegrating tablets according to claim 1, characterized in that, Pullulan was used at concentrations of 2.2%, 2.5%, 3%, 3.5%, 4%, or 4.2%.

4. The montelukast sodium lyophilized orally disintegrating tablets according to claim 1, characterized in that, The amount of mannitol used is 2.5%, and the amount of pullulan polysaccharide used is 4.2%.

5. The montelukast sodium lyophilized orally disintegrating tablets according to claim 1, characterized in that, The amount of mannitol used is 4.5%, and the amount of pullulan is 2.2%.

6. The montelukast sodium lyophilized orally disintegrating tablets according to claim 1, characterized in that, The amount of mannitol used is 3.5%, and the amount of pullulan polysaccharide used is 3.5%.

7. The montelukast sodium lyophilized orally disintegrating tablets according to claim 1, wherein the preparation method of the montelukast sodium lyophilized orally disintegrating tablets comprises the following steps: 1) Weigh out water, which accounts for approximately 70% of the total weight of the liquid, and add pullulan polysaccharide while stirring to dissolve; 2) Add mannitol and sucralose and stir to dissolve, forming a mixed solution; 3) Add sodium montelukast and stir to dissolve, then bring the volume to the required prescription amount to obtain the drug solution; 4) Add the obtained drug solution to the blister mold at a rate of 400 μl / tablet. Place it in a freeze dryer, set the freeze drying process parameters, start freeze drying, and when freeze drying is complete, you will get freeze-dried disintegrating tablets. in, The freeze-drying process is as follows:

8. The method for preparing montelukast sodium lyophilized orally disintegrating tablets according to claim 7, characterized in that, The temperature of the purified water mentioned in step 1) can be in the range of room temperature and 60°C. Room temperature purified water or 60°C purified water is preferred.

9. The montelukast sodium lyophilized orally disintegrating tablets according to claim 1 and the method for preparing montelukast sodium lyophilized orally disintegrating tablets according to claim 7, wherein the moisture content of the lyophilized orally disintegrating tablets is 3.8%-5.4%, preferably 3.8%-4.7%.

Images