Process for the preparation of ketorolac tromethamine sublingual tablets and tablet compositions prepared by the process

Abstract

The present disclosure relates to a method for preparing ketorolac tromethamine sublingual tablets and tablet compositions prepared by the method. The method includes dry mixing ketorolac tromethamine, a diluent, and an anti-static agent to form a dry mixed mixture; intermediate mixing a buffering agent, a sweetener, and a disintegrant to form an intermediate mixture; drug mixing the dry mixed mixture and the intermediate mixture to form a drug mixture; preparing a lubricated drug mixture comprising: sieving a lubricant, and lubricating the drug mixture with the lubricant to form a lubricated drug mixture; and compressing the lubricated drug mixture to form ketorolac tromethamine sublingual tablets.

Description

Technical Field

[0001] This disclosure generally relates to a method for preparing a sublingual tablet composition. More specifically, this disclosure relates to a method for preparing ketorolac tromethamine sublingual tablets and the tablet composition prepared by this method. Background Technology

[0002] Ketorazole tromethamine is the tromethamine salt of ketorazole (C 15 H 13 NO3. C4H 11 NO), its molecular formula is C 19 H 24 N2O6, also known chemically as "benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid". The IUPAC name for ketorolac tromethamine is "2-amino-2-(hydroxymethyl)propane-1,3-diol; 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid".

[0003] The chemical structure of ketorolac tromethamine is shown below:

[0004] Ketoroxytromethorphan is a synthetic pyrrolizidine carboxylic acid derivative with anti-inflammatory, analgesic, and antipyretic properties. Ketoroxytromethorphan is a non-selective inhibitor of cyclooxygenase (COX), inhibiting both COX-1 and COX-2 enzymes.

[0005] Ketoroxypropyl tromethamine, as the active ingredient, exhibits a strong bitter taste, thus requiring effective masking to improve its palatability.

[0006] Ketoroxytromethorphan in conventional tablet form is absorbed through the liver. In the liver, the drug is converted into metabolites and then excreted in bile. The drug then enters the digestive tract via bile, where it is either excreted in feces or reabsorbed back into the bloodstream. This process wastes a significant portion of the active drug. Furthermore, conventional preparation methods suffer from uneven distribution of ketoroxytromethorphan in the composition.

[0007] Therefore, there is a need for dosage forms of ketorolac tromethamine that offer rapid dispersion and a pleasant taste. Specifically, this requires dosage forms with good sensory properties and a positive effect on taste masking and mouthfeel. This need also includes dosage forms through which ketorolac tromethamine is directly absorbed and circulated through the bloodstream, with minimal waste.

[0008] This requirement also includes compositions containing pharmaceutical excipients that promote good sensory properties and have a positive effect on taste masking and mouthfeel; rapid oral disintegration time; suitable flowability of the drug mixture; and ease of handling during tableting. Furthermore, it is necessary to minimize or eliminate the disadvantage of uneven distribution of ketorolac tromethamine. Summary of the Invention

[0009] To achieve the above and other objectives and needs, this disclosure provides a method for preparing ketorolac tromethamine sublingual tablets and the ketorolac tromethamine sublingual tablets prepared by this method. The ketorolac tromethamine sublingual tablets developed by the inventors are rapidly dispersible and have a pleasant taste. Furthermore, this disclosure provides a ketorolac tromethamine sublingual tablet in which the drug reaches the systemic circulation directly via the blood vessels. In this way, drug waste of ketorolac tromethamine in this document is minimized.

[0010] This disclosure provides a method in which an effective masking agent is selected to improve the palatability of the drug, taking into account the bitterness of ketorolac tromethamine. Pharmaceutical excipients within a specific weight percentage range are selected to facilitate the formation of a tablet composition for sublingual or oral administration, thereby achieving rapid dispersibility and a pleasant taste.

[0011] The excipients in this ketorolac tromethamine sublingual tablet composition contribute to good sensory properties and have a positive effect on taste masking and mouthfeel. It exhibits rapid disintegration time in the oral cavity, suitable flowability of the drug mixture, and improved convenience during tableting. Furthermore, the selection of excipients does not result in die or mold wall adhesion during compression. Additionally, the use of excipients with similar particle sizes minimizes the risk of uneven distribution of ketorolac tromethamine.

[0012] In one embodiment, this disclosure relates to a method for preparing ketorolac tromethamine sublingual tablets. The method includes dry mixing ketorolac tromethamine, a diluent, and an antistatic agent to form a dry mixture; intermediate mixing of a buffer, a sweetener, and a disintegrant to form an intermediate mixture; mixing the dry mixture and the intermediate mixture to form a drug mixture; preparing a lubricated drug mixture, including: sieving a lubricant, and lubricating the drug mixture with the lubricant to form a lubricated drug mixture; and compressing the lubricated drug mixture to form ketorolac tromethamine sublingual tablets.

[0013] In one or more embodiments, in the dry mixing step, the diluent is lactose monohydrate, and the content of the diluent is from about 55% to about 60% by weight; and the antistatic agent is colloidal anhydrous silica, and the content of the antistatic agent is from about 0.2% to about 0.8% by weight.

[0014] In one or more embodiments, in the intermediate mixing step, the buffer is microcrystalline cellulose, and the content of the buffer is from about 15% to about 20% by weight; the sweetener is sucralose, and the content of the sweetener is from about 3% to about 5% by weight; and the disintegrant is crospovidone, and the content of the disintegrant is from about 2% to about 7% by weight.

[0015] In one or more embodiments, in the step of lubricating the drug mixture, the lubricant is magnesium stearate, and the content of the lubricant is from about 1% to about 2% by weight.

[0016] In one or more embodiments, the molar ratio of lactose monohydrate to microcrystalline cellulose is 3:1.

[0017] In one or more embodiments, the particle size of lactose monohydrate is no greater than 150 micrometers.

[0018] In one or more embodiments, ketorolac tromethamine sublingual tablets are packaged in blister packs.

[0019] In another embodiment, this disclosure relates to a ketorolac tromethamine sublingual tablet. The ketorolac tromethamine sublingual tablet comprises about 10 to about 15% by weight of ketorolac tromethamine; about 55 to about 60% by weight of a diluent; about 0.2 to about 0.8% by weight of an antistatic agent; about 15 to about 20% by weight of a buffer; about 3 to about 5% by weight of a sweetener; about 2 to about 7% by weight of a disintegrant; and about 1 to about 2% by weight of a lubricant.

[0020] In one or more embodiments, the dose of ketorolac tromethamine sublingual tablets is 10 mg per tablet.

[0021] In one or more embodiments, the diluent is lactose monohydrate; the antistatic agent is colloidal anhydrous silica; the buffer is microcrystalline cellulose; the sweetener is sucralose; the disintegrant is crospovidone; and the lubricant is magnesium stearate.

[0022] In one or more embodiments, the molar ratio of lactose monohydrate to microcrystalline cellulose is 3:1.

[0023] In one or more embodiments, the particle size of lactose monohydrate is no greater than 150 micrometers.

[0024] In the implementation scheme, the friability is less than 1.5%; the disintegration time is less than 300 seconds; and the hardness is from about 20N to about 60N. Attached Figure Description

[0025] The advantages and features of this disclosure will be better understood by taking into account the accompanying drawings, the following detailed description, and the claims, wherein: Figure 1 A method flow for preparing ketorolac tromethamine sublingual tablets according to embodiments of the present disclosure is shown.

[0026] Figure 2 Details of a method for dry mixing ketorolac tromethamine, diluent, and antistatic agent according to embodiments of this disclosure are shown.

[0027] Figure 3 Details of a method for intermediately mixing buffers, sweeteners, and disintegrants according to embodiments of this disclosure are shown.

[0028] Figure 4 Details of the pharmaceutical mixture dry mix and intermediate mix according to embodiments of the present disclosure are shown.

[0029] Figure 5 Details of lubrication according to embodiments of this disclosure are shown.

[0030] Figure 6 Details of the compression according to the embodiments of this disclosure are shown.

[0031] Figure 7 Details of the packaging of ketorolac tromethamine sublingual tablets according to embodiments of the present disclosure are shown.

[0032] Figure 8A A graph illustrating the linear relationship between mean plasma concentrations of ketorolac tromethamine in the test and reference products according to embodiments of the present disclosure is shown.

[0033] Figure 8B A semi-logarithmic graph of the mean plasma concentration of ketorolac tromethamine in the test product and the reference product versus time is shown, according to an embodiment of the present disclosure. Detailed Implementation

[0034] The exemplary embodiments described in detail herein for illustrative purposes are subject to numerous variations in structure and design. However, it should be emphasized that this disclosure is not limited to the methods shown and described for preparing ketorolac tromethamine sublingual tablets and the tablet compositions prepared by such methods. It should be understood that expedient measures may be suggested or provided as appropriate, considering various omissions and substitutions of equivalents, and these omissions and substitutions are intended to cover the application or implementation without departing from the spirit or scope of the claims of this disclosure. Furthermore, it should be understood that the wording and terminology used herein are for descriptive purposes only and should not be considered restrictive.

[0035] The terms “including,” “comprising,” or “having,” and variations thereof, as used herein, are intended to cover the items listed below and their equivalents, as well as additional items.

[0036] Furthermore, the terms “one” and “a” in this article do not represent a quantity limitation, but rather indicate that there is at least one of the cited items.

[0037] As used herein, the term "about" will be understood by those skilled in the art, and the term "about" will vary to some extent depending on the context in which it is used. If the use of the term is unclear to those skilled in the art, "about" will refer to a maximum of plus or minus 10% of that particular term, taking into account the context in which it is used.

[0038] This disclosure provides a method for preparing ketorolac tromethamine sublingual tablets and a tablet composition prepared by the method. To achieve the above and other objects and needs, this disclosure provides a method for preparing ketorolac tromethamine sublingual tablets and a tablet prepared by the method. The ketorolac tromethamine sublingual tablets developed by the inventors are rapidly dispersible and have a good taste. Furthermore, this disclosure provides a ketorolac tromethamine sublingual tablet in which the drug reaches the systemic circulation directly via the blood vessels. In this way, drug waste of ketorolac tromethamine in this document is minimized.

[0039] This disclosure provides a method in which an effective masking agent is selected to improve the palatability of the drug, taking into account the bitterness of ketorolac tromethamine. Pharmaceutical excipients within a specific weight percentage range are selected to facilitate the formation of a tablet composition for sublingual or oral administration, thereby achieving rapid dispersibility and a pleasant taste.

[0040] Pharmaceutical excipients contribute to good sensory properties and have a positive effect on taste masking and mouthfeel; they also ensure rapid oral disintegration time, suitable flowability of the drug mixture, and convenience during tableting. Furthermore, the selection of pharmaceutical excipients does not result in die or mold wall adhesion during compression. Additionally, using pharmaceutical excipients with similar particle sizes minimizes the risk of uneven distribution of ketorolac tromethamine.

[0041] In one embodiment, a method for preparing ketorolac tromethamine sublingual tablets is disclosed. Hereinafter, "ketorolac tromethamine sublingual tablets" and "ketorolac tromethamine ST" are used interchangeably without limitation. The method for preparing ketorolac tromethamine sublingual tablets includes dry mixing ketorolac tromethamine, a diluent, and an antistatic agent to form a dry mixture; intermediate mixing of a buffer, a sweetener, and a disintegrant to form an intermediate mixture; mixing the dry mixture and the intermediate mixture to form a drug mixture; preparing a lubricated drug mixture, including: sieving a lubricant, and lubricating the drug mixture with the lubricant to form a lubricated drug mixture; and compressing the lubricated drug mixture to form ketorolac tromethamine sublingual tablets.

[0042] refer to Figure 1 Method 100 relates to a method for preparing ketorolac tromethamine sublingual tablets. Step 102 of method 100 includes dry mixing ketorolac tromethamine, a diluent, and an antistatic agent to form a dry mixture. Step 104 of method 100 includes intermediate mixing a buffer, a sweetener, and a disintegrant to form an intermediate mixture. Step 106 of method 100 includes mixing the dry mixture and the intermediate mixture to form a drug mixture. Step 108 of method 100 includes preparing a lubricated drug mixture, including sieving a lubricant and lubricating the drug mixture with the lubricant to form a lubricated drug mixture. Step 110 of method 100 includes compressing the lubricated drug mixture to form ketorolac tromethamine sublingual tablets.

[0043] Figure 2 Detailed description Figure 1 Method step 102. Figure 3 Detailed description Figure 1 Method step 104. Figure 4 Detailed description Figure 1 Method step 106. Figure 5 Detailed description Figure 1 Method step 108. Figure 6 Detailed description Figure 1 Method step 110.

[0044] Refer again Figure 1 Step 102 of method 100 involves dry mixing ketorolac tromethamine, a diluent, and an antistatic agent to form a dry mixture. Figure 2 Detailed description Figure 1 Method step 102.

[0045] In one or more embodiments, in the dry mixing step, the diluent is lactose monohydrate, and the content of the diluent is from about 55% to about 60% by weight; and the antistatic agent is colloidal anhydrous silica, and the content of the antistatic agent is from about 0.2% to about 0.8% by weight.

[0046] As used herein, lactose monohydrate is a water-soluble filler and diluent with good compressibility. Lactose monohydrate helps promote faster disintegration. Lactose monohydrate further contributes to improving the palatability of tablets. In the examples, the lactose monohydrate is Supertab 30 GR.

[0047] As used herein, colloidal anhydrous silica serves as an adsorbent, anti-caking agent, and flow aid. Colloidal anhydrous silica enhances powder flowability. In the examples, the colloidal anhydrous silica is Aerosil. ® 200. Colloidal anhydrous silica was selected in the preparation method to improve the flow properties of the drug mixture. The drug mixture is discussed in detail in the preceding paragraphs.

[0048] refer to Figure 2 In step 202, ketorolac tromethamine, lactose monohydrate, and colloidal anhydrous silica are co-sieved through a 40-mesh vibrating screen to obtain agglomerate-free material. The co-sieved agglomerate-free material of ketorolac tromethamine, lactose monohydrate, and colloidal anhydrous silica is collected.

[0049] Refer again Figure 2 In step 204, the co-sieved ketorolac tromethamine, lactose monohydrate, and colloidal anhydrous silica (agglomerates-free material) are loaded into a conta mixer and mixed at 8 RPM for 30 minutes. As a result, a dry mixture is obtained in step 206.

[0050] Step 104 of method 100 involves an intermediate mixture of buffers, sweeteners, and disintegrants to form an intermediate mixture. Figure 3 Detailed description Figure 1 Method step 104.

[0051] In one or more embodiments, in the intermediate mixing step, the buffer is microcrystalline cellulose, and the content of the buffer is from about 15% to about 20% by weight; the sweetener is sucralose, and the content of the sweetener is from about 3% to about 5% by weight; and the disintegrant is crospovidone, and the content of the disintegrant is from about 2% to about 7% by weight.

[0052] As used herein, microcrystalline cellulose is essentially crystalline. Microcrystalline cellulose enhances powder flow and facilitates tablet compression to achieve the desired stiffness. Microcrystalline cellulose also acts as a buffer. Due to its plasticity, it is commonly used as an excipient in both tablet compression and granulation processes. As a buffer, microcrystalline cellulose fills the voids between particles and mitigates the effects of compressive forces generated during tableting. In the examples, the microcrystalline cellulose is Vivapur.® 102.

[0053] As used in this article, sucralose is a white to off-white, free-flowing crystalline powder that is approximately 300 to 1000 times sweeter than sucrose and has no aftertaste.

[0054] As used herein, crospovidone is a water-insoluble tablet disintegrant or disintegrant and solubilizer. Crospovidone rapidly exhibits high capillary activity and significant hydration capacity, and forms virtually no gel. In the examples, the crospovidone is Kollidone. ® CL. Cross-linked povidone was chosen for this tablet composition to improve the dispersion time of the tablet in the oral cavity.

[0055] refer to Figure 3 In step 302, microcrystalline cellulose, sucralose, and crospovidone are co-sieved through a 40-mesh vibrating screen to obtain a non-agglomerated material. In step 304, the co-sieved material obtained in step 302 is mixed in a conta mixer at 8 RPM for 10 minutes to obtain an intermediate mixture in step 306. Subsequently, in step 308, 50% of the intermediate mixture obtained in step 306 (hereinafter referred to as "50% unloaded intermediate mixture") is unloaded, and the mixer chamber contains 50% of the intermediate mixture (hereinafter referred to as "mixer chamber containing 50% intermediate mixture"). Therefore, in step 310, a mixer chamber containing 50% of the intermediate mixture is obtained.

[0056] Refer again Figure 1 Step 106 of method 100 involves mixing a dry mixture and an intermediate mixture of drugs to form a drug mixture. Figure 4 Detailed description Figure 1 Method step 106.

[0057] refer to Figure 4 Method step 402 includes: Figure 2 The dry mixture obtained in step 206 is added to Figure 3 Step 310 yields a mixer chamber containing 50% intermediate mixture to obtain a mixture. Furthermore, the 50% unloaded intermediate mixture obtained in step 308 is added to the mixture in the mixer chamber containing the 50% intermediate mixture and the dry mixture to obtain an added mixture. Subsequently, in step 404, the added mixture is mixed in a conta mixer at a mixing speed of 8 RPM for 30 minutes to form a drug mixture.

[0058] Refer again Figure 1Step 108 of method 100 relates to preparing a lubricated drug mixture, comprising: sieving a lubricant and lubricating the drug mixture with the lubricant to form a lubricated drug mixture. The lubricant is magnesium stearate. Figure 5 Detailed description Figure 1 Method step 108.

[0059] In one or more embodiments, in the step of lubricating the drug mixture, the lubricant is magnesium stearate, and the content of the lubricant is from about 1% to about 2% by weight.

[0060] As used herein, magnesium stearate is an intangible powder with low bulk density. Magnesium stearate is fine-textured, oily, lightweight, white in color, and is produced through natural precipitation or grinding. Functionally, magnesium stearate is used as a lubricant in capsule and tablet manufacturing. Due to its inherent oiliness, magnesium stearate powder readily adheres to tablet surfaces, ensuring clean ejection without breakage or fragmentation in the pharmaceutical industry. Magnesium stearate is chosen to prevent die and mold wall adhesion during the compression process of ketorolac tromethamine sublingual tablets. Compression is discussed in detail in the preceding paragraphs.

[0061] refer to Figure 5 In step 502, magnesium stearate is sieved through a 40-mesh vibrating screen to obtain agglomerate-free magnesium stearate material. Subsequently, in step 504, the drug mixture obtained in step 404 is lubricated in a conta mixer with the agglomerate-free magnesium stearate material at a speed of 8 RPM and a mixing time of 5 minutes. In step 506, the lubricated drug mixture is obtained.

[0062] Refer again Figure 1 Step 110 of method 100 involves compressing and lubricating a drug mixture to form ketorolac tromethamine sublingual tablets. Figure 6 Detailed illustration Figure 1 Method step 110.

[0063] refer to Figure 6 In step 602, the lubricated drug mixture obtained in step 506 is compressed in a compressor at a standard speed of 50 ± 10 RPM to obtain ketorolac tromethamine sublingual tablets in step 604.

[0064] In one or more embodiments, the molar ratio of lactose monohydrate to microcrystalline cellulose is 3:1.

[0065] Choosing a combination of lactose monohydrate and microcrystalline cellulose to have free-flowing material during the tableting process ultimately helps the tablet composition disperse more quickly and has a better taste.

[0066] In this direct compression formulation of sublingual tablets, the molar ratio of lactose monohydrate to microcrystalline cellulose is 3:1. This specific ratio is primarily based on the balance between the hardness, compressibility, and disintegration time of the sublingual tablets.

[0067] Regarding compressibility, lactose monohydrate is a well-known filler and diluent with good compressibility; however, when used alone in sublingual tablets, it may not provide optimal tablet stiffness. On the other hand, microcrystalline cellulose exhibits excellent compressibility and helps improve tablet stiffness, which is crucial for maintaining structural integrity during manufacturing and processing.

[0068] Microcrystalline cellulose is somewhat coarse in terms of improving texture. Therefore, a higher proportion of lactose monohydrate helps to improve the texture of sublingual tablets.

[0069] Regarding disintegration, lactose monohydrate is a water-soluble excipient that helps promote faster disintegration. Furthermore, while microcrystalline cellulose is insoluble in water, it helps form a porous tablet matrix, enabling rapid water absorption and ultimately promoting disintegration. A molar ratio of lactose monohydrate to microcrystalline cellulose of 3:1 promotes the disintegration of sublingual tablets, as sublingual tablets must disintegrate rapidly in the oral cavity to ensure the rapid release of the active pharmaceutical ingredient (API), in this case, ketorolac tromethamine.

[0070] In terms of flowability, microcrystalline cellulose improves the overall flowability of the powder mixture during direct compression; however, a high proportion of microcrystalline cellulose may affect the disintegration time. Therefore, a molar ratio of 3:1 balances the flow properties and the desired disintegration rate.

[0071] In one or more embodiments, the particle size of lactose monohydrate is no greater than 150 micrometers.

[0072] Table 1 shows the test results that meet the standard specifications for lactose monohydrate particle size distribution (PSD).

[0073]

[0074] The specific particle size of lactose monohydrate helps to minimize the risk of uneven distribution of ketorolac tromethamine in the tablet composition.

[0075] In one or more embodiments, ketorolac tromethamine sublingual tablets are packaged in blister packs.

[0076] refer to Figure 7The ketorolac tromethamine sublingual tablets obtained in step 604 are packaged through a two-step packaging process. These two steps are the first packaging process and the second packaging process. In step 702, during the first packaging process, a blister packing machine is used, with the following temperature parameters: bagging temperature 160℃±10℃; and sealing temperature 180℃±20℃. Subsequently, in step 704, the ketorolac tromethamine sublingual tablets obtained in the first packaging process are further packaged through a second packaging process.

[0077] In one or more embodiments, this disclosure relates to a ketorolac tromethamine sublingual tablet or tablet composition. The ketorolac tromethamine sublingual tablet comprises about 10 to about 15% by weight of ketorolac tromethamine; about 55 to about 60% by weight of a diluent; about 0.2 to about 0.8% by weight of an antistatic agent; about 15 to about 20% by weight of a buffer; about 3 to about 5% by weight of a sweetener; about 2 to about 7% by weight of a disintegrant; and about 1 to about 2% by weight of a lubricant.

[0078] Ketorazole tromethamine is the tromethamine salt of ketorazole (C 15 H 13 NO3. C4H 11 NO), its molecular formula is C 19 H 24 N2O6, also known chemically as "benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid". The IUPAC name for ketorolac tromethamine is "2-amino-2-(hydroxymethyl)propane-1,3-diol; 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid".

[0079] Ketoroxytromethorphan is a synthetic pyrrolizidine carboxylic acid derivative with anti-inflammatory, analgesic, and antipyretic properties. Ketoroxytromethorphan is a non-selective inhibitor of cyclooxygenase (COX), inhibiting both COX-1 and COX-2 enzymes. As the active ingredient, ketoroxytromethorphan exhibits a strong bitter taste.

[0080] In one or more embodiments, the dose of ketorolac tromethamine sublingual tablets is 10 mg per tablet.

[0081] In one or more embodiments, the diluent is lactose monohydrate; the antistatic agent is colloidal anhydrous silica; the buffer is microcrystalline cellulose; the sweetener is sucralose; the disintegrant is crospovidone; and the lubricant is magnesium stearate.

[0082] In one or more embodiments, the molar ratio of lactose monohydrate to microcrystalline cellulose is 3:1.

[0083] In one or more embodiments, the particle size of lactose monohydrate is no greater than 150 micrometers.

[0084] In one or more embodiments, the friability is less than 1.5%; the disintegration time is less than 300 seconds; and the hardness is about 20N to about 60N.

[0085] Table 2 shows the weight percentage of API and excipients used to represent the batch.

[0086]

[0087] Example 1

[0088] Example 1 describes a method for preparing ketorolac tromethamine sublingual tablets. Specifically, a method for preparing ketorolac tromethamine sublingual tablets with a strength of 10 mg per tablet is described.

[0089] Table 3 shows the amount of API and excipients (mg / tablet) for Ketoroxyprotein Tromethamine (10 mg) sublingual tablets.

[0090]

[0091] The method is initiated by preparing a dry mixture by dry mixing 10 mg of ketorolac tromethamine, 46.2 mg of diluent, and 0.4 mg of antistatic agent. Subsequently, an intermediate mixture is prepared by intermediate mixing 15 mg of buffer, 3.2 mg of sweetener, and 4.0 mg of disintegrant. Then, a drug mixture is prepared by mixing the dry mixture and the intermediate mixture prepared in the above steps. Next, a lubricated drug mixture is prepared by first sieving 1.2 mg of lubricant, and then lubricating the drug mixture with the lubricant. Finally, ketorolac tromethamine sublingual tablets are prepared by compressing the lubricated drug mixture.

[0092] Specifically, 10 mg of ketorolac tromethamine, 46.2 mg of lactose monohydrate, and 0.4 mg of colloidal anhydrous silica were co-sieved through a 40-mesh vibrating sieve to obtain agglomerate-free material. The co-sieved agglomerate-free material of ketorolac tromethamine, lactose monohydrate, and colloidal anhydrous silica was collected.

[0093] Subsequently, the co-sieved ketorolac tromethamine, lactose monohydrate, and colloidal anhydrous silica, which are free of agglomerates, are loaded into a conta mixer and mixed at 8 RPM for 30 minutes to prepare a dry mixture.

[0094] Subsequently, 15 mg of microcrystalline cellulose, 3.2 mg of sucralose, and 4.0 mg of crospovidone were co-sieved through a 40-mesh vibrating sieve to obtain agglomerate-free co-sieved material. The obtained co-sieved material was then mixed in a conta mixer at 8 RPM for 10 minutes to form an intermediate mixture.

[0095] Next, 50% of the intermediate mixture is unloaded as “50% unloaded intermediate mixture”, and the remaining 50% of the intermediate mixture is retained in the mixer compartment of the conta mixer as “mixer compartment containing 50% intermediate mixture”.

[0096] Subsequently, the pre-prepared dry mixture is added to a mixer chamber containing 50% intermediate mixture to obtain a mixture. The unloaded intermediate mixture is then added to the above mixture to prepare an added mixture. The added mixture is then mixed in a conta mixer at a mixing speed of 8 RPM for 30 minutes to form a drug mixture.

[0097] Subsequently, 1.2 mg of magnesium stearate was sieved through a 40-mesh vibrating sieve to obtain agglomerated magnesium stearate material. Then, the agglomerated magnesium stearate material was used to lubricate the previously prepared drug mixture in a conta mixer at a speed of 8 RPM and a mixing time of 5 minutes, thereby preparing a lubricated drug mixture.

[0098] Finally, the lubricated drug mixture is compressed by a compressor at a standard speed of 50 ± 10 RPM to form ketorolac tromethamine sublingual tablets. This composition is the final tablet composition of ketorolac tromethamine sublingual tablets, which achieves improved palatability and rapid dispersion of the active drug.

[0099] Table 4 shows the analytical results of the final tablet composition of ketorolac tromethamine sublingual tablets.

[0100]

[0101] The final tablet composition of ketorolac tromethamine sublingual tablets was tested in two batches for mixing and compression purposes.

[0102] Tables 5A and 5B show the analytical results of two batches of 10 mg ketorolac tromethamine sublingual tablets; Tables 5A and 5B show the results for batch 1 and batch 2, respectively.

[0103] Table 5A

[0104] test: The bioavailability of the prepared ketorolac tromethamine 10 mg sublingual tablets (hereinafter referred to as the "test product") was compared with that of the reference product, and the pharmacokinetic profile was characterized to assess the bioequivalence of the test product. This test aims to further monitor adverse events to ensure consumer safety.

[0105] Cross-bioequivalence studies

[0106] An open-label, balanced, randomized, dual-treatment, dual-sequence, dual-period, single-dose, crossover bioequivalence study of the test product and reference product was conducted on normal, healthy adult male and female volunteers under fasting conditions.

[0107] Table 6 shows the results of the cross-bioequivalence study.

[0108]

[0109] Test observations indicate that, according to the standards set forth in the protocol, under fasting conditions, the tested product meets the requirements for Cmax and AUC of ketorolac tromethamine compared to the reference product. 0-t Bioequivalence standards.

[0110] In summary, the pharmacokinetic profile of the test product was improved compared to the reference product administered at the same dose of the oral pharmaceutical composition. Here, improved pharmacokinetic profile means improved Cmax or AUC of ketorolac tromethamine. 0-t Increase.

[0111] Plot the mean plasma concentration versus nominal time for the test and reference products of ketorolac tromethamine to determine the bioequivalence of the test and reference products.

[0112] refer to Figure 8A A linear graph was plotted for the test and reference products of ketorolac tromethamine, with one axis (Y-axis) representing the average plasma concentration and the other axis (X-axis) representing time.

[0113] Analysis of the linear curves showed that the bioequivalence of the test article was enhanced compared to that of the reference article.

[0114] refer to Figure 8B A semi-logarithmic plot was plotted for the test and reference products of ketorolac tromethamine, with one axis (Y-axis) representing average plasma concentration and the other axis (X-axis) representing time.

[0115] Analysis of the semi-logarithmic plot curves showed that the bioequivalence of the test article was enhanced compared with that of the reference article.

[0116] The sublingual tablets prepared in this disclosure for sublingual administration of ketorolac tromethamine refer to placing the drug under the tongue. The sublingual route bypasses first-pass metabolism, thereby promoting rapid absorption of the drug into the systemic circulation. The drug reaches the systemic circulation directly via blood vessels. The sublingual region has a rich vascular source, with these vessels running parallel to the mucosal surface. The sublingual artery supplies blood to the salivary glands. In this way, the waste of the drug ketorolac tromethamine in this invention is minimized.

[0117] As used herein, the active ingredient, ketorolac tromethamine, exhibits a strong bitter taste, and therefore an effective masking agent was chosen to improve palatability. Specifically, diluents, antistatic agents, buffers, sweeteners, disintegrants, and lubricants (collectively, “pharmaceutical excipients”) within specific weight percentage ranges are used in tablet compositions for sublingual or oral administration to achieve rapid dispersion and a pleasant taste in sublingual tablets.

[0118] The selection of pharmaceutical excipients is primarily aimed at ensuring that the tablet matrix formulation possesses good sensory properties and has a positive effect on taste masking and mouthfeel; rapid oral disintegration time; suitable flowability of the drug mixture; and ease of tableting. Furthermore, the selection of pharmaceutical excipients should prevent die or mold wall adhesion during compression.

[0119] Here, the tablet composition consists of excipients with similar particle sizes to minimize the risk of uneven distribution of ketorolac tromethamine.

[0120] For purposes of illustration and description, the above description of specific embodiments of this disclosure has been given. These descriptions are not intended to be exhaustive or to strictly limit this disclosure to the precise form disclosed, and it will be apparent that many modifications and variations can be made in accordance with the above teachings. The embodiments were chosen and described in order to best explain the principles of this disclosure and its practical application, thereby enabling others skilled in the art to best utilize this disclosure and various embodiments with various modifications for their intended specific use. (It should be understood that expedient measures may be suggested or provided as appropriate, considering various omissions and substitutions of equivalents, and these omissions and substitutions are intended to cover this application or implementation without departing from the spirit or scope of the claims of this disclosure.)

Claims

1. A method for preparing ketorolac tromethamine sublingual tablets, comprising: Dry-mix ketorolac tromethamine, diluent and antistatic agent to form a dry mixture; Intermediate mixtures of buffers, sweeteners, and disintegrants are used to form intermediate mixtures; The drug mixture is prepared by mixing the dry mixture and the intermediate mixture to form a drug mixture; The preparation of a lubricating pharmaceutical mixture includes: Screening lubricant, The drug mixture is lubricated with the lubricant to form a lubricated drug mixture; as well as The lubricated drug mixture is compressed to form ketorolac tromethamine sublingual tablets.

2. The method according to claim 1, wherein in the dry mixing step: The diluent is lactose monohydrate, and the content of the diluent is from about 55% by weight to about 60% by weight; and The antistatic agent is colloidal anhydrous silica, and the content of the antistatic agent is from about 0.2% by weight to about 0.8% by weight.

3. The method of claim 1, wherein in the intermediate mixing step: The buffer is microcrystalline cellulose, and the content of the buffer is from about 15% to about 20% by weight. The sweetener is sucralose, and the content of the sweetener is from about 3% to about 5% by weight; and The disintegrant is crospovidone, and the content of the disintegrant is from about 2% to about 7% by weight.

4. The method according to claim 1, wherein in the step of lubricating the drug mixture: The lubricant is magnesium stearate, and the content of the lubricant is from about 1% to about 2% by weight.

5. The method according to claims 2 and 3, wherein the molar ratio of lactose monohydrate to microcrystalline cellulose is 3:

1.

6. The method according to claim 2, wherein the particle size of the lactose monohydrate is not greater than 150 micrometers.

7. The method according to claim 1, wherein the ketorolac tromethamine sublingual tablets are packaged in blister packs.

8. A ketorolac tromethamine sublingual tablet, wherein the ketorolac tromethamine sublingual tablet comprises: Ketorazole tromethamine, approximately 10% by weight to approximately 15% by weight; Diluent of approximately 55% to approximately 60% by weight; An antistatic agent comprising approximately 0.2% to approximately 0.8% by weight; Approximately 15% by weight to approximately 20% by weight of the buffer; Sweeteners: about 3% to about 5% by weight; Disintegrant of about 2% to about 7% by weight; and Lubricant of about 1% to about 2% by weight.

9. The ketorolac tromethamine sublingual tablet according to claim 8, wherein the dose of the ketorolac tromethamine sublingual tablet is 10 mg per tablet.

10. The ketorolac tromethamine sublingual tablet according to claim 8, wherein the diluent is lactose monohydrate; the antistatic agent is colloidal anhydrous silica; the buffer is microcrystalline cellulose; the sweetener is sucralose; the disintegrant is crospovidone; and the lubricant is magnesium stearate.

11. The ketorolac tromethamine sublingual tablet according to claim 10, wherein the molar ratio of lactose monohydrate to microcrystalline cellulose is 3:

1.

12. The ketorolac tromethamine sublingual tablet according to claim 10, wherein the particle size of the lactose monohydrate is not greater than 150 micrometers.

13. The ketorolac tromethamine sublingual tablet according to claim 8, wherein the friability is less than 1.5%; the disintegration time is less than 300 seconds; and the hardness is about 20 N to about 60 N.

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