A method for preparing high-drug-load lyophilized orally disintegrating tablets

Abstract

This invention discloses a method for preparing high-drug-load lyophilized orally disintegrating tablets. The high-drug-load lyophilized orally disintegrating tablets of this invention contain, by weight percentage, 65-85% active pharmaceutical ingredient, 5-20% emulsifier, 5-20% matrix agent, 0.1-1% thickener, and 0.5-5% binder; the active pharmaceutical ingredient content per unit dosage of the high-drug-load lyophilized orally disintegrating tablet is ≥60mg; the preparation method includes solution preparation, filling, quick-freezing, lyophilization, and sealing; during the filling process, the sum of the total volume in the filling pipeline and the volume filled into the lyophilization tank per unit time is less than or equal to the volume of drug solution output by the peristaltic pump per unit time. This invention uses lyophilization flash-release technology to prepare lyophilized orally disintegrating tablets, which do not require water and dissolve instantly upon ingestion, solving the problem of inconvenient medication administration for patients. This invention also improves the equipment for lyophilization flash-release technology, greatly increasing the range of products that can be produced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and specifically relates to a method for preparing lyophilized orally disintegrating tablets with a large drug loading. Background Technology

[0002] Orally disintegrating tablets are tablets that rapidly disintegrate or dissolve in the mouth without the need for water. These tablets are convenient to take, rapidly absorbed, have high bioavailability, and cause minimal irritation to the digestive tract mucosa. They are generally suitable for drugs with small drug loadings and are often used for patients with difficulty swallowing or who are uncooperative with medication administration.

[0003] Orally disintegrating tablets are commonly prepared using methods such as lyophilization, direct compression, wet compression, and wet granulation compression. Among these, lyophilized orally disintegrating tablets can rapidly decompose in the oral cavity, are directly absorbed through the mucosa, and take effect quickly, improving medication compliance, reducing the first-pass effect in the liver, and minimizing toxic side effects.

[0004] Generally, the dispersion method is used to prepare lyophilized orally disintegrating tablet suspensions. This involves pulverizing coarse drug particles into microparticles of the required size and dispersing them in water, while dissolving excipients in a matrix aqueous solution. The two solutions are then combined and dispersed uniformly. After preparation, the solution is quantitatively filled using a metering pump. Before filling, the packaging material is first stamped into shape. Then, the filling needle is aligned with the groove in the stamped packaging material, and the filling program is started. The filling accuracy must meet the requirements for tablets in the Chinese Pharmacopoeia. During the filling process, the volume of the filled solution is sampled to ensure accuracy and consistency. Because suspensions have good homogeneity, ensuring filling accuracy and uniformity guarantees a consistent drug content in each compartment. After the solution is filled into the compartments, liquid nitrogen direct injection technology is used to instantly condense the solution. After rapid freezing, the solution is loaded into a freeze dryer and freeze-dried according to the freeze-drying curve.

[0005] Patent CN113750058A discloses a lyophilized orally disintegrating resorcinol tablet and its preparation method. The lyophilized orally disintegrating resorcinol tablet contains phloroglucinol, a lyophilization protectant, a disintegrant, and other pharmaceutical excipients, and is prepared using lyophilization flash-release technology. The lyophilized orally disintegrating resorcinol tablet provided by this patent has low dissolution, with a dissolution rate of only 99% after 20 minutes. Patent CN103690500B discloses a lyophilized oral resorcinol preparation and its preparation method. The 80mg lyophilized oral resorcinol preparation consists of phloroglucinol, excipients, antioxidants, and solvents. The preparation method includes preparing the solution, filling, lyophilizing, and packaging. The lyophilized oral resorcinol preparation provided by this patent contains antioxidants, which significantly reduces its safety.

[0006] Patent CN115054580A discloses a large-size lyophilized orally disintegrating tablet containing a unit dose greater than 60 mg of water-soluble or poorly soluble active ingredient, a specific amount of gelatin, and no conventional lyophilization support agent. This patent only discloses the beneficial use of gelatin in the preparation of large-size lyophilized orally disintegrating tablets and does not improve the filling or other preparation processes.

[0007] To address the aforementioned problems, this invention employs lyophilization flash-release technology to prepare lyophilized orally disintegrating tablets. These tablets require no water and dissolve instantly upon ingestion, resolving issues such as inconvenience for patients. This invention also improves the equipment used for lyophilization flash-release technology, significantly expanding the range of products that can be produced. Summary of the Invention

[0008] This invention provides a method for preparing high-drug-load lyophilized orally disintegrating tablets, which contain 65-85% active pharmaceutical ingredient, 5-20% emulsifier, 5-20% matrix agent, 0.1-1% thickener, and 0.5-5% binder by mass percentage. The active pharmaceutical ingredient content in each unit formulation of the high-drug-load lyophilized orally disintegrating tablet is ≥60mg. The preparation method includes solution preparation, filling, and lyophilization. The filling process uses a peristaltic pump and a distribution pipe to fill the drug solution. During the filling process, the sum of the total volume in the filling pipeline and the volume filled into the lyophilization tank per unit time is less than or equal to the volume of drug solution output by the peristaltic pump per unit time.

[0009] Furthermore, the active pharmaceutical ingredient content in a unit dosage form of the high-drug-load lyophilized orally disintegrating tablets is ≥60mg, preferably 60mg to 120mg, and more preferably 70mg to 90mg, such as 70mg, 75mg, 80mg, 85mg, or 90mg.

[0010] Furthermore, the aforementioned solution preparation refers to mixing the active pharmaceutical ingredient, emulsifier, matrix agent, thickener, and binder, adding water, and then shearing and degassing the resulting solution.

[0011] Furthermore, the weight ratio of the active pharmaceutical ingredient and excipients to water added to the liquid is 1:(2-4), preferably, the weight ratio of the active pharmaceutical ingredient and excipients to water is 1:(2.5-3).

[0012] Furthermore, the shearing is performed in an emulsifier.

[0013] Furthermore, the degassing is carried out in an emulsifier or a degassing bottle.

[0014] Furthermore, the filling refers to filling the degassed drug solution into a freeze-drying tank. Preferably, the volume of the freeze-drying tank is 0.3 to 0.8 ml, for example, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8 ml.

[0015] Furthermore, the preparation method also includes a quick-freezing step, where quick-freezing refers to quick-freezing the filled sample.

[0016] Furthermore, the quick-freezing method is selected from one of liquid nitrogen quick-freezing, liquid carbon dioxide quick-freezing, low-temperature cold storage quick-freezing, plate quick-freezing, and blower quick-freezing, with liquid nitrogen quick-freezing being preferred.

[0017] Furthermore, the freeze-drying refers to freeze-drying the quick-frozen sample according to a freeze-drying curve, which is as follows:

[0018] Cold trap temperature: -40℃~-70℃, vacuum degree <200μbar;

[0019] The temperature is initially set at -35℃ to -25℃. The temperature is then raised from -35℃ to -25℃ to -20℃ to -10℃ over 5 to 25 minutes, and maintained for 50 to 70 minutes. The temperature is then raised from -20℃ to -11℃ to -10℃ to 0℃ over 1 to 20 minutes, and maintained for 20 to 40 minutes. Finally, the temperature is raised from -10℃ to 0℃ to 5℃ to 15℃ over 5 to 25 minutes, and maintained for 20 to 40 minutes.

[0020] Preferably, the freeze-drying curve is as follows:

[0021] Cold trap temperature: -40℃~-70℃, vacuum degree <200μbar;

[0022] The chamber is set at -30℃. The temperature is raised from -30℃ to -15℃ over 15 minutes and maintained for 60 minutes. The temperature is then raised from -15℃ to -5℃ over 10 minutes and maintained for 30 minutes. The temperature is then raised from -5℃ to 10℃ over 15 minutes and maintained for 30 minutes.

[0023] Furthermore, the preparation method also includes a sealing step, wherein sealing refers to coating the freeze-dried sample with a film.

[0024] Furthermore, the shearing speed in the solution preparation step is 1000-6000 rpm; for example, the shearing speed is 1000 rpm, 1500 rpm, 2000 rpm, 2500 rpm, 3000 rpm, 3500 rpm, 4000 rpm, 4500 rpm, 5000 rpm, 5500 rpm, or 6000 rpm, preferably 2500 rpm.

[0025] Furthermore, the shearing time in the solution preparation step is 10 to 60 minutes; for example, the shearing time is 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 60 minutes, preferably 40 minutes.

[0026] Furthermore, the diameter of the diverter tube is 1.0 to 3.5 cm; for example, the diameter of the diverter tube is 1.0 cm, 1.5 cm, 2.0 cm, 2.5 cm, 3.0 cm, or 3.5 cm; preferably, the diameter of the diverter tube is 2.5 cm.

[0027] Furthermore, the active pharmaceutical ingredient is selected from one of phloroglucinol, oseltamivir or its salts, pregabalin and β-nicotinamide mononucleotide, preferably, the oseltamivir salt is oseltamivir phosphate.

[0028] Furthermore, the emulsifier is selected from one of maltodextrin, sodium lauryl sulfate, polyoxyethylene ether, polyoxypropylene ether, gum arabic, and lanolin; preferably, the emulsifier is maltodextrin.

[0029] Furthermore, the content of the emulsifier is 5-15%.

[0030] Furthermore, the skeleton agent is selected from one of mannitol, glycine, sorbitol, xylitol, lactitol, and erythritol, and preferably, the skeleton agent is mannitol.

[0031] Furthermore, the content of the skeleton agent is preferably 5-15%.

[0032] Furthermore, the thickener is selected from pullulan, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, starch, xanthan gum, and carrageenan, preferably pullulan.

[0033] Furthermore, the content of the thickener is preferably 0.1% to 0.5%.

[0034] Furthermore, the adhesive is selected from one of dextran-70, dextrin, vinyl acetate resin, shellac, and phenolic resin adhesive, preferably, the adhesive is dextran-70.

[0035] Furthermore, the adhesive content is preferably 0.5% to 2%.

[0036] Furthermore, the high-drug-load lyophilized orally disintegrating tablets may also include one or more of sweeteners, flavoring agents, and colorings.

[0037] Furthermore, the active pharmaceutical ingredient is phloroglucinol, and the lyophilized orally disintegrating tablets contain 70-80% phloroglucinol, 5-15% maltodextrin, 5-15% mannitol, 0.1-0.5% pullulan, and 0.5-2% dextran-70 by weight percentage.

[0038] In one embodiment of the present invention, the unit measurement of the phloroglucinol lyophilized orally disintegrating tablets includes:

[0039]

[0040]

[0041] In one embodiment of the present invention, the specific steps of the preparation method of the phloroglucinol lyophilized orally disintegrating tablets are as follows:

[0042] (1) Weighing: Weigh 80mg of phloroglucinol, 10mg of maltodextrin, 10mg of mannitol, 0.4mg of pullulan, and 2mg of dextran into a suitable container, and dry mix them evenly to obtain a mixture;

[0043] (2) Solution preparation: Add 277.6 mg of water to the mixture and stir to obtain the drug solution; use a vacuum emulsifier to homogenize and emulsify at 2500 rpm for 40 min; after shearing, degas the drug solution under vacuum until no more bubbles are generated.

[0044] (3) Filling: The degassed liquid medicine is filled into the freeze-drying tank. The filling process uses a peristaltic pump and a diversion pipe to fill the liquid medicine. During the filling process, the sum of the dead volume of the diversion pipe and the volume filled into the freeze-drying tank per unit time is less than or equal to the volume of liquid medicine output by the peristaltic pump per unit time.

[0045] (4) Quick freezing: The injected drug solution is quick frozen in a liquid nitrogen tunnel;

[0046] (5) Freeze-drying: The quick-frozen sample was freeze-dried according to the freeze-drying curve, which is as follows:

[0047] Cold trap temperature: -40℃~-70℃, vacuum degree <200μbar;

[0048] The chamber was initially set at -30℃, then gradually increased to -15℃ over 15 minutes and maintained for 60 minutes. The temperature was then gradually increased to -5℃ over 10 minutes and maintained for 30 minutes. Finally, the temperature was gradually increased to 10℃ over 15 minutes and maintained for 30 minutes.

[0049] (6) Sealing: The freeze-dried sample is coated with a film.

[0050] The present invention also provides lyophilized ortholytic tablets prepared by the aforementioned method for preparing high-capacity lyophilized ortholytic tablets.

[0051] This invention utilizes lyophilization flash-release technology to prepare lyophilized orally disintegrating tablets. These tablets dissolve instantly upon ingestion, eliminating the need for water and resolving issues such as inconvenience for patients. This invention also improves the equipment used in lyophilization flash-release technology, significantly expanding the range of products that can be produced. The formulation process (including formulation composition and preparation process, lyophilization curve) and equipment employed in this invention solve the technical problem of preparing lyophilized orally disintegrating tablets with large drug loadings (specification: 80mg), overcoming the limitations of lyophilized orally disintegrating tablets in terms of specification, tablet weight, and industrial-scale production. Attached Figure Description

[0052] Figure 1 The diagram shown is a schematic of a diversion pipe.

[0053] Figure 2 The diagram shows the working operation of the diversion pipe during the filling process when the diameter of the diversion pipe is 4cm.

[0054] Figure 3 The diagram shows the working operation of the diversion pipe during the filling process when the diameter of the diversion pipe is 2.5cm. Detailed Implementation

[0055] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0056] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0057] Example 1: Formulation screening of phloroglucinol lyophilized orally disintegrating tablets

[0058] 2.1 Initial formulation of phloroglucinol lyophilized orally disintegrating tablets

[0059] In the preparation of lyophilized orally disintegrating resorcinol tablets, dextran-70 (binder), mannitol (skeletonizer), maltodextrin (emulsifier), and pullulan (thickener) were used as the basic formulation, and the dosage of each excipient was initially determined. Following the established preparation process and evaluation criteria, lyophilized orally disintegrating resorcinol tablets were prepared, and a feasibility study was conducted. Specific experimental design and results are shown in Table 1.

[0060] Table 1 Initial Prescription

[0061]

[0062] Note*: Purified water is a solvent added during the solution preparation process, used in the process, and ultimately removed.

[0063] The quality evaluation criteria are shown in the table below:

[0064]

[0065]

[0066] As shown in Table 1, except for the suspension state of the drug solution and the difference in disintegration time, all other aspects meet the quality evaluation standards.

[0067] 2.2 Screening of active pharmaceutical ingredient particle size

[0068] Studies have found that raw material particle size not only affects the suspension state of the drug solution but also the disintegration time and dissolution of the finished product. Larger raw material particle sizes make it harder to maintain the suspension state, while smaller particle sizes alter the suspension viscosity, thus affecting sample injection. Therefore, the particle size of the raw material was investigated using solution state, appearance, and disintegration time as evaluation indicators. The specific experimental design and results are shown in Table 2.

[0069] Table 2. Particle size screening of phloroglucinol raw materials

[0070]

[0071]

[0072] Note*: Purified water is a solvent added during the solution preparation process, used in the process, and ultimately removed.

[0073] Table 2 shows that, under the same conditions, the drug solution state gradually stabilizes as the particle size of the active pharmaceutical ingredient (API) decreases, while the disintegration time slows down with decreasing particle size. Considering large-scale production, although larger API particle size results in better sample disintegration, poor stability during solution preparation leads to instability during filling and stratification. Therefore, taking all factors into account, an API particle size D90 ≤ 10 μm will be used for further research.

[0074] 2.3 Screening of Dextran-70 Dosage

[0075] In the preparation process, dextran-70 acts as a binder, and its dosage has a certain impact on the sample preparation process and sample quality. The specific experimental design and results are shown in Table 3.

[0076] Table 3 Screening of Dextran-70 Dosage

[0077]

[0078] Note*: Purified water is a solvent added during the solution preparation process, used in the process, and ultimately removed.

[0079] As shown in Table 3, the tablet texture gradually softens and the disintegration time shortens as the dosage of dextran-70 decreases. Considering the need to ensure the integrity of lyophilized orally disintegrating tablets during manufacturing, transportation, and use, and taking into account the characteristics of lyophilized orally disintegrating tablets, the dosage of dextran-70 was ultimately determined to be 2 mg per tablet.

[0080] 2.4 Screening of Mannitol Dosage

[0081] Mannitol is an important excipient in lyophilized orthotic tablets, acting as a matrix agent to create a structure with specific pores. This ensures that the lyophilized orthotic tablets maintain a full and stable shape while also exhibiting rapid disintegration. In industrial production, while ensuring the full shape of the lyophilized orthotic tablets, the impact of tablet size on the sealing of the inner aluminum socket should also be considered. Therefore, the dosage of mannitol needs to be investigated. The specific experimental design and results are shown in Table 4.

[0082] Table 4 Screening of Mannitol Dosage

[0083]

[0084] Note*: Purified water is a solvent added during the solution preparation process, used in the process, and ultimately removed.

[0085] As shown in Table 4, the different amounts of mannitol in formulations 7, 24, 25, and 29 have almost no impact on the appearance, adhesion to the tablet wall, or disintegration of the tablets. The above formulations were prepared at a concentration of 0.4 ml / tablet. After lyophilization, the top of the tablet was almost flush with the top edge of the blister pack, posing a risk of tablet adhesion to the sealing film during the sealing process.

[0086] In Formulation 39, after preparing the product at a dosage of 0.35 ml / tablet, the appearance and disintegration of the formulation remained unchanged, and there was a 2 mm distance between the top of the tablet and the top edge of the blister pack, meeting the design requirements. However, tablet shrinkage occurred after sealing. Analysis revealed that this phenomenon was caused by the disintegration characteristics of the lyophilized packaging and the manufacturing process. The supporting force of the matrix agent could not withstand the high temperature of the packaging material during sealing, thus causing structural collapse.

[0087] The dosage of mannitol in Formulation 41 was further optimized. When the dosage of mannitol was 10 mg / tablet, and the product was prepared at a dosage of 0.35 ml / tablet, the resulting tablet structure was the most stable, and the appearance and disintegration met the design requirements without affecting the inner packaging seal. Therefore, the final dosage of mannitol was determined to be 10 mg / tablet.

[0088] 2.5 Screening of pullulan dosage

[0089] Pullulan acts as a thickener in this product, and its dosage directly determines the viscosity of the solution. High viscosity leads to droplet adhesion during filling, while low viscosity results in leakage, both affecting filling accuracy. Furthermore, increasing solution viscosity also impacts disintegration time. Therefore, the dosage of pullulan was investigated; the specific experimental design and results are shown in Table 5.

[0090] Table 5 Screening of pullulan dosage

[0091]

[0092] Note*: Purified water is a solvent added during the solution preparation process, used in the process, and ultimately removed.

[0093] Table 5 shows that pullulan dosage has almost no effect on tablet appearance and adhesion to the tablet wall. However, significant differences in filling state and disintegration time occur with variations in pullulan dosage. Both excessive and insufficient dosage negatively impact filling and tablet disintegration. In Formulation 35, the drug solution stability and tablet disintegration time are optimal when the pullulan dosage is 0.4 mg / tablet. Therefore, the final pullulan dosage was determined to be 0.4 mg / tablet.

[0094] 2.6 Screening of Maltodextrin Dosage

[0095] Maltodextrin plays an emulsifying and skeletal support role in this product. Its dosage may affect the stability of the drug solution and the disintegration of the tablets. The specific experimental design and results are shown in Table 6.

[0096] Table 6: Screening of Maltodextrin Dosage

[0097]

[0098]

[0099] Note*: Purified water is a solvent added during the solution preparation process, used in the process, and ultimately removed.

[0100] Table 6 shows that when the dosage of maltodextrin is between 5 mg / tablet and 12 mg / tablet, there is almost no difference in the stability of the solution, the appearance of the tablets, and the disintegration time. However, when maltodextrin is not added, the appearance of the tablets is slightly worse than that of the formulation with maltodextrin, and the tablets are more prone to powdering. Taking all factors into consideration, the dosage of maltodextrin is determined to be 10 mg / tablet.

[0101] 2.7 Optimization of solution volume

[0102] During the pilot-scale amplification process, while taking into account the product's impact on sealing and disintegration, there is still room for optimization of the liquid preparation volume. The specific experimental design and results are shown in Table 7.

[0103] Table 7: Optimization and Confirmation of Solution Volume

[0104]

[0105] Table 7 shows that increasing the solution volume from 0.35 ml / tablet to 0.38 ml / tablet did not change the appearance or disintegration time of the tablets, nor did it affect the sealing or the shape of the sealed tablets. Comparing the state of the 0.35 ml and 0.38 ml tablets in the aluminum foil, it was found that the 0.38 ml tablets appeared more full and uniform in the aluminum foil. Therefore, the final solution volume was set at 0.38 ml / tablet.

[0106] 2.8 Final Formulation of Phloroglucinol Lyophilized Orally Disintegrating Tablets

[0107] Based on the studies in Examples 2.1 to 2.7, the final formulation of phloroglucinol lyophilized orally disintegrating tablets was determined, with a specification of 80 mg (calculated as C6H6O3·2H2O), as detailed in Table 8.

[0108] Table 8. Prescription for Phloroglucinol Lyophilized Orally Disintegrating Tablets

[0109]

[0110]

[0111] Note*: Purified water is a solvent added during the solution preparation process, used in the process, and ultimately removed.

[0112] Example 2: Investigation of the preparation process of lyophilized ortholytic tablets

[0113] The preparation process of the lyophilized disintegrating tablets described in this application mainly includes the following five steps: solution preparation, filling, quick freezing, lyophilization, and sealing. This experiment used the optimal formulation and focused on investigating the two key preparation processes of filling and lyophilization, determining the range of parameters for each process step, and providing a reference for large-scale production.

[0114] 2.1 Examination of the filling process

[0115] In the preparation of lyophilized orthotic tablets, the filling process is one of the most important steps in production. It uses a peristaltic pump to circulate the drug solution within the filling pipeline for automatic and continuous filling. The state of the drug solution's movement within the filling pipeline directly affects its uniformity. This experiment used a qualified drug solution obtained from the optimal formulation. After the drug solution circulation stabilized, the tablet weight was monitored online and the tablet weight difference was calculated at the beginning, middle, and end of the filling process to determine whether the filling process was stable.

[0116] Testing methods and indicators: During the continuous automatic filling process, the tablet weight difference is checked once at the beginning, middle and end. The filling volume variation range is ±5%. No more than 2 filling needles exceed the filling volume range, and no one needle exceeds twice the filling volume range.

[0117] 2.1.1 First filling

[0118] Table 9 Tablet weight and tablet weight variation data for the first filling

[0119] stage Average weight of 50 tablets Difference in slice weight result forward 0.375g -15.19％～10.21％ Non-compliant middle 0.385g -13.73％～12.95％ Non-compliant back 0.371g -14.82％～13.65％ Non-compliant

[0120] Analysis of the data in Table 9 shows that the average tablet weight of 50 tablets varied greatly in the early, middle and late stages of filling, and the difference in tablet weight within the group of 50 tablets reached more than ±10%, which did not meet the requirements.

[0121] 2.1.2 Second filling

[0122] By analyzing the operating phenomena and principles of the filling machine, it can be determined that adjusting the power of the peristaltic pump increases the liquid supply in the filling pipeline, ensuring that the liquid fills the entire circulation pipeline during the filling process, thereby guaranteeing filling stability. To this end, the efficiency of the peristaltic pump was increased from 60% to 90%, and the pumping volume per minute was increased from 4000 cm³ / min. 3 Increase to 6000cm 3 A filling test was conducted.

[0123] Table 10 Tablet weight and tablet weight difference data for the second filling.

[0124]

[0125]

[0126] Analysis of the data in Table 10 shows that after adjusting the peristaltic pump power, the average weight of 50 tablets varied greatly in the early, middle and late stages of filling, and the weight difference of the 50 tablets in the group was still more than ±10%, which did not meet the requirements.

[0127] In response, the drug solution system and filling process were analyzed separately.

[0128] 2.1.2.1 Determination of drug solution

[0129] Using the sedimentation ratio determination method, the sedimentation time of an existing product was measured and recorded for 80mg and 40mg samples prepared according to the formulation in Table 8. Then, a filling test was conducted (the 40mg sample was prepared by adjusting the amount of phloroglucinol to 40mg while keeping other excipients unchanged). Specific data are shown in the table below:

[0130]

[0131] Sedimentation ratio determination method: Measure 50 ml of the test sample using a stoppered graduated cylinder, stopper tightly, shake vigorously for 1 min, record the initial height Ho of the suspension, let stand for 3 hours, record the final height H of the suspension, and calculate using the following formula: Sedimentation volume ratio = H / Ho.

[0132] 2.1.2.2 Investigation of factors related to the shunt pipe

[0133] The filling process uses a peristaltic pump and a distribution pipe to fill the medicine solution. The entire pipeline consists of a peristaltic pump, a distribution pipe, and a connecting pipe 3 that connects the peristaltic pump and the distribution pipe. The distribution pipe is shown in the image below. Figure 1 As shown, it includes a flow divider and flow dividers, with the flow dividers located below the flow divider distributing the flow at equal intervals.

[0134] The peristaltic pump can pump in approximately 6000 cm³ of liquid medicine per minute. 3 The peristaltic pump and connecting pipe volume (dead volume) is 3000 cm³. 3 When the diameter of the manifold is 4cm and the length is 220cm, the dead volume of the manifold is 2800cm³. 3 The distributor head fills 300 cm³ of water into the reservoir per minute. 3 Up to 800cm 3 At this point, the peristaltic pump can pump in a total volume of liquid medicine per minute (6000 cm³). 3 () is lower than the total pipe volume (5800cm³) 3 ) and the filling volume per minute of the diverter head (300 cm³) 3 Up to 800cm 3 The sum of these factors indicates a mismatch between the diameter of the distribution tube and the peristaltic pump's liquid supply speed. This prevents the liquid from circulating sufficiently during filling, significantly shortening the liquid stratification time and resulting in inconsistent liquid proportions in each freeze-drying tank, leading to substantial differences in tablet weight. A schematic diagram is shown below. Figure 2 As shown.

[0135] When the diameter of the manifold is adjusted to 2.5cm, the dead volume of the manifold is 1080cm³. 3 At this point, the peristaltic pump can pump in a total volume of liquid medicine per minute (6000 cm³). 3 ) higher than the total pipe volume within the pipeline (4080cm³) 3 ) and the filling volume per minute of the diverter head (300 cm³) 3 Up to 800cm 3 The sum of the two components. The diameter of the distribution pipe is matched with the liquid supply speed of the peristaltic pump, allowing the liquid to circulate fully during the filling process. This significantly increases the time for liquid stratification, ensuring that the proportion of liquid filling each freeze-drying tank is nearly uniform, thus ensuring that the tablet weight variation meets the requirements. A schematic diagram is shown below. Figure 3 As shown.

[0136] 2.1.3 Third filling

[0137] Table 11 Tablet weight and tablet weight variation data for the third filling

[0138] stage Average weight of 50 tablets Difference in slice weight Difference in slice weight forward 0.381g -2.21％～1.28％ Compliant middle 0.385g -1.41％～1.33％ Compliant back 0.388g -1.01％～3.14％ Compliant

[0139] Analysis of the data in Table 11 confirms that the average tablet weight change of 50 tablets and the difference in tablet weight within the group of 50 tablets met the design requirements in the pre-filling, mid-filling, and late-filling stages. Compared with the pipeline modification, the accuracy and stability of tablet weight have been significantly improved. Therefore, the modification of the diversion pipe has met the design requirements, and all results comply with the regulations.

[0140] This restructuring not only significantly improved product production efficiency but also reduced material waste.

[0141] state Waste materials Before the reform 3.1kg After the reform 1.2kg

[0142] 2.2 Investigation of the freeze-drying process

[0143] Freeze-drying is the core process in this production, and the proper setting of the freeze-drying profile directly affects product quality and production costs. During the sublimation stage, the freeze-drying profile needs to remove most of the water from the product; an improperly designed sublimation time can cause the product to melt and collapse. Simultaneously, the product's moisture content also directly affects the drug's stability. By designing different heating stages and durations, and evaluating the product's appearance, adhesion to the wall, disintegration time, and tablet weight variation as indicators, the final freeze-drying profile used for subsequent studies was determined. Details are shown in Table 12.

[0144] Table 12 Freeze-drying curve design

[0145]

[0146]

[0147] As shown in Table 12, when other formulation processes are the same and only the freeze-drying curve is changed, the optimal freeze-drying curve is curve 4. The samples freeze-dried under this curve are superior to those under other curves in terms of both appearance and disintegration time. Therefore, curve 4 can be used as the freeze-drying curve for later production validation.

[0148] 2.3 Preparation process of lyophilized ortholytic tablets

[0149] Through the studies in Examples 2.1-2.2, the preparation process of lyophilized orally disintegrating tablets was finally determined. Taking phloroglucinol lyophilized orally disintegrating tablets as an example, the preparation method includes the following steps:

[0150] (1) Weighing: Weigh 80mg of phloroglucinol, 10mg of maltodextrin, 10mg of mannitol, 0.4mg of pullulan, and 2mg of dextran into a suitable container, and dry mix them evenly to obtain a mixture;

[0151] (2) Solution preparation: Add 277.6 mg of purified water to the mixture, stir and mix well to obtain the drug solution; use a vacuum emulsifier to homogenize and emulsify at 2500 rpm for 40 min; after shearing, degas the drug solution under vacuum until no more bubbles are generated in the drug solution.

[0152] (3) Filling: The degassed liquid is filled into specific aluminum sockets using an automatic filling machine according to the planned injection volume;

[0153] (4) Quick freezing: The injected drug solution is quick frozen in a liquid nitrogen tunnel;

[0154] (5) Freeze-drying: The quick-frozen sample was freeze-dried according to the freeze-drying curve, which is as follows:

[0155] Cold trap temperature: -40℃~-70℃, vacuum degree <200μbar;

[0156] The chamber was initially set at -30℃, then gradually increased to -15℃ over 15 minutes and maintained for 60 minutes. The temperature was then gradually increased to -5℃ over 10 minutes and maintained for 30 minutes. Finally, the temperature was gradually increased to 10℃ over 15 minutes and maintained for 30 minutes.

[0157] (6) Sealing: The freeze-dried sample is coated with a film and the batch number is printed after coating.

[0158] Example 3: Evaluation of Large-Scale Samples

[0159] Based on the confirmed prescription and process, a sample with batch number T2206001 and a batch size of 75,000 tablets was prepared on a large scale and the sample was evaluated. Specific data are shown in Tables 13 and 14.

[0160] Table 13 Evaluation data of self-made samples

[0161]

[0162] Table 14 Test data of self-made samples

[0163]

[0164] Note*: Purified water is a solvent added during the solution preparation process, used in the process, and ultimately removed.

[0165] Product Name Phloroglucinol orally disintegrating tablets with batch number N2068 and a strength of 80 mg were used as the reference preparation. A comparative experiment was conducted between the above reference preparation and a self-made sample with batch number T2206001 and a strength of 80 mg. The specific experimental design and results are shown in Tables 15-18.

[0166] Table 15 Dissolution curves in aqueous medium

[0167]

[0168]

[0169] Table 16 Dissolution curves in hydrochloric acid medium at pH 1.0

[0170]

[0171] Table 17 Dissolution curves in acetate medium at pH 4.5

[0172]

[0173] Table 18 Dissolution curves in phosphate medium at pH 6.8

[0174]

[0175]

[0176] Experiments have demonstrated that the formulation and process of phloroglucinol lyophilized orally disintegrating tablets are stable, the drug solution is in good condition, and the appearance, wall adhesion, and disintegration time of the prepared samples all meet the design targets. Results regarding properties, tablet weight variation, moisture content, dissolution rate, and content all comply with standard requirements. The dissolution curves of the self-made scaled-up sample and the reference formulation in different media are similar, and f2 meets the requirements.

[0177] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a high-drug-load lyophilized orally disintegrating tablet, characterized in that, The high-drug-load lyophilized orally disintegrating tablets are composed of 70-80% active pharmaceutical ingredient, 5-15% emulsifier, 5-15% matrix agent, 0.1-0.5% thickener, and 0.5-2% binder by weight percentage; the active pharmaceutical ingredient is phloroglucinol, the emulsifier is maltodextrin, the matrix agent is mannitol, the thickener is pullulan, and the binder is dextran-70; the particle size D90 of the phloroglucinol is ≤10μm; the active pharmaceutical ingredient content per unit formulation of the high-drug-load lyophilized orally disintegrating tablets is ≥60mg; The preparation method includes solution preparation, filling, and freeze-drying; The filling process uses a peristaltic pump and a distribution tube to fill the liquid medicine. The diameter of the distribution tube is 2.5 cm, the efficiency of the peristaltic pump is 90%, and the pumping volume of the peristaltic pump is 6000 cm³. 3 / min; During the filling process, the sum of the total volume in the filling pipeline and the volume filled into the freeze-drying tank per unit time is less than or equal to the volume of liquid medicine output by the peristaltic pump per unit time. The freeze-drying curve is as follows: Cold trap temperature: -40℃~-70℃, vacuum degree <200μbar; The temperature was raised from -30℃ to -15℃ in 15 minutes and maintained for 60 minutes; from -15℃ to -5℃ in 10 minutes and maintained for 30 minutes; and from -5℃ to 10℃ in 15 minutes and maintained for 30 minutes.

2. The preparation method according to claim 1, characterized in that, The aforementioned solution preparation refers to mixing the active pharmaceutical ingredient, emulsifier, matrix agent, thickener, and binder, adding water, and then shearing and degassing the resulting solution.

3. The preparation method according to claim 2, characterized in that, The weight ratio of the added active pharmaceutical ingredient and excipients to water is 1:(2~4).

4. The preparation method according to claim 3, characterized in that, The weight ratio of the added active pharmaceutical ingredient and excipients to water is 1:(2.5~3).

5. The preparation method according to claim 2, characterized in that, The filling process refers to filling the degassed liquid medicine into a freeze-drying tank.

6. The preparation method according to claim 5, characterized in that, The volume of the freeze-drying chamber is 0.3~0.8 ml.

7. The preparation method according to claim 2, characterized in that, The shearing speed is 1000~6000 rpm, and the shearing time is 10~60 min.

8. The preparation method according to claim 7, characterized in that, The shearing speed is 2500 rpm, and the shearing time is 40 min.

9. The preparation method according to claim 1, characterized in that, The preparation method also includes a quick-freezing step, where quick-freezing refers to quick-freezing the filled sample.

10. The preparation method according to any one of claims 1 to 9, characterized in that, The unit dosage of the lyophilized orally disintegrating tablets includes: 80 mg phloroglucinol, 10 mg maltodextrin, 10 mg mannitol, 0.4 mg pullulan, and 2 mg dextran-70.

11. The lyophilized orally disintegrating tablets prepared by the preparation method according to any one of claims 1 to 10.

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