Tranexamic acid-coated granule composition and preparation process thereof

Abstract

To provide a tranexamic acid-coated granule composition and a preparation process thereof.SOLUTION: The present invention relates to a tranexamic acid-coated granule composition comprising an inner shell and an outer shell surrounding the inner shell. The inner shell comprises tranexamic acid, a sugar sphere, and a first portion of polyvinylpyrrolidone K30. The outer shell comprises Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, anhydrous colloidal silica, and purified talc. Here, the outer shell facilitates rapid release of 85% of tranexamic acid from the inner shell within 15 minutes. The present invention further relates to a process for preparing the tranexamic acid-coated granule composition.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions comprising tranexamic acid coated granules. In particular, the present invention relates to a particulate pharmaceutical composition for oral administration comprising the active agent tranexamic acid, as well as a method for preparing the same for sachet formulation. [Background technology]

[0002] Chemically, tranexamic acid is trans-4-(aminomethyl)cyclohexanecarboxylic acid, which has the following chemical structure: [ka]

[0003] It is commercially available as Cyklokapron® 500 mg oral tablets and Lysteda® 650 mg oral tablets. Tranexamic acid is a white crystalline powder. It is freely soluble in water. It helps prevent the lysis or dissolution of fibrin clots that form during the normal physiological process of hemostasis. Tranexamic acid thus helps stabilize the fibrin clot, which helps maintain clotting and slow bleeding. Lysteda® is indicated for the treatment of heavy menstrual bleeding. The Lysteda® dosing regimen is 1300 mg (two 650 mg tablets) three times daily (3900 mg / day) for up to five days during each monthly menstruation. It is highly desirable to prepare a high-dose composition to avoid frequent dosing.

[0004] If 1 gram of tranexamic acid were administered in the form of 250 mg or 500 mg tablets, the patient would need to swallow 4 or 2 tablets at a time. Alternatively, 1 gram tablets could be administered, but with a drug load of approximately 50%, the tablets would weigh approximately 2 grams and be difficult to swallow. Therefore, there is a need to provide a product that allows for the administration of large doses of medication without affecting patient compliance.

[0005] Therefore, there is a need for a dosage form containing tranexamic acid that can be taken by patients in need of tranexamic acid administration without difficulty in swallowing.

[0006] Therefore, a further need exists for a tranexamic acid dosage composition in a dosage form that facilitates the immediate release of a maximum amount of tranexamic acid in a minimum amount of time, and that further controls electrostatic charges generated during the preparation of the composition, thereby providing improved processability in the formulation of the composition. Summary of the Invention

[0007] To achieve the above and other objectives and needs, the present invention provides a pharmaceutical composition comprising tranexamic acid coated granules. In particular, the present invention provides a pharmaceutical composition comprising: The present invention relates to a particulate pharmaceutical formulation for oral administration comprising coated granules of the active agent tranexamic acid, as well as a method for preparing the same for sachet formulation.

[0008] In one embodiment, the present invention relates to a tranexamic acid-coated granule composition comprising an inner shell and an outer shell surrounding the inner shell. The inner shell comprises tranexamic acid, sugar spheres, and a first portion of polyvinylpyrrolidone K30. The outer shell comprises Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, anhydrous colloidal silica, and purified talc. The outer shell facilitates rapid release of 85% of the tranexamic acid from the inner shell within a 15-minute period.

[0009] In one or more embodiments, the solvent used in preparing the inner shell is a mixture of isopropyl alcohol and purified water.

[0010] In one or more embodiments, the solvent used in preparing the outer shell is purified water.

[0011] In one or more embodiments, the dosage is 1000 mg and 2000 mg.

[0012] In one or more embodiments, the particle size of the inner shell is in the range of 380 microns to 560 microns, and the particle size of the outer shell is in the range of 230 microns to 459 microns.

[0013] In one or more embodiments, the particle size of the tranexamic acid coated granules is less than 1.0 mm.

[0014] In one or more embodiments, the weight percent of the inner shell is between 94% (wt / wt) and 98% (wt / wt) of the total weight of the coated granule composition, and the weight percent of the outer shell is between 2% (wt / wt) and 6% (wt / wt) of the total weight of the coated granule composition.

[0015] In one or more embodiments, the inner shell comprises tranexamic acid, sugar spheres, and a first portion of polyvinylpyrrolidone K30 in various weight percents, wherein the weight percent of tranexamic acid is between 56% (w / w) and 58% (w / w) of the total weight of the coated granule composition, the weight percent of the sugar spheres is between 32% (w / w) and 33% (w / w) of the total weight of the coated granule composition, and the weight percent of the first portion of polyvinylpyrrolidone K30 is between 6% (w / w) and 7% (w / w) of the total weight of the coated granule composition.

[0016] In one or more embodiments, the outer shell comprises Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, anhydrous colloidal silica, and purified talc in various weight percentages, wherein the weight percentage of Eudragit NE 30D is between 2% (w / w) and 4% (w / w) of the total weight of the coated granule composition, the weight percentage of the second portion of polyvinylpyrrolidone K30 is between 0.25% (w / w) and 0.75% (w / w) of the total weight of the coated granule composition, the weight percentage of sucralose is between 0.05% (w / w) and 0.15% (w / w) of the total weight of the coated granule composition, and the weight percentage of anhydrous colloidal silica is between 0.20% (w / w) and 0.60% (w / w) of the total weight of the coated granule composition. The weight percentage of the refined talc is between 0.10% (w / w) and 0.30% (w / w) of the total weight of the coated granule composition.

[0017] In another embodiment, the present invention relates to a process for preparing a coated granule composition that promotes the rapid release of tranexamic acid, the process comprising forming an inner shell and an outer shell surrounding the inner shell. The step for forming the inner shell comprises preparing a binder solution containing a first portion of polyvinylpyrrolidone K30 and applying tranexamic acid onto sugar spheres using the binder solution to thereby form the inner shell of the coated granule. The step for forming the outer shell comprises preparing a coating suspension by adding Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, and anhydrous colloidal silica, then applying the prepared coating suspension onto the inner shell and lubricating it with purified talc to form the outer shell.

[0018] In one or more embodiments, preparing the binder solution includes dissolving a first portion of polyvinylpyrrolidone K30 in a mixture of isopropyl alcohol and purified water.

[0019] In one or more embodiments, preparing the coating suspension includes filtering Eudragit NE 30D; dissolving a second portion of polyvinylpyrrolidone K30 in purified water and adding sucralose to form an intermediate solution; dispersing the filtered Eudragit NE 30D in the intermediate solution; and dispersing anhydrous colloidal silica to form the coating suspension. [Brief explanation of the drawings]

[0020] The advantages and features of the present invention will be better understood with reference to the following detailed description and claims taken in conjunction with the accompanying drawings, wherein:

[0021] [Figure 1]FIG. 1 illustrates a process flow for the preparation of a coated granule composition comprising an inner shell and an outer shell, according to an exemplary embodiment of the present invention. [Figure 1A] FIG. 1A further illustrates step 102 of process 100. [Figure 1B] FIG. 1B further illustrates step 104 of process 100.

[0022] [Figure 2] FIG. 2 illustrates details for forming the inner shell of the process of FIG. 1 according to an exemplary embodiment of the present invention.

[0023] [Figure 3] FIG. 3 shows details for preparing a coating suspension and applying the prepared coating suspension onto an inner shell to form an intermediate product according to an exemplary embodiment of the present invention.

[0024] [Figure 4] FIG. 4 illustrates details for lubrication of the intermediate product according to an exemplary embodiment of the present invention.

[0025] [Figure 5] FIG. 5 shows details for filling sachets with coated granules of lubricated tranexamic acid according to an exemplary embodiment of the present invention.

[0026] [Figure 6] FIG. 6 shows a summary of a bioavailability study between a coated granule composition promoting rapid release of tranexamic acid and a reference product, performed as described in Example 3, according to an exemplary embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0027] The advantages and features of the present invention will be better understood with reference to the following detailed description and claims taken in conjunction with the accompanying drawings, wherein:

[0028] The exemplary embodiments described in detail in this disclosure for illustrative purposes are subject to many variations in structure and design. However, it should be emphasized that the present invention is not limited to the described tranexamic acid coated granule compositions and processes for preparing coated granule compositions that promote the rapid release of tranexamic acid. It is understood that various omissions and substitutions of equivalents are contemplated as the circumstances suggest or prove useful, provided that they are intended to cover applications or practices without departing from the spirit or scope of the claims of the present invention. It should also be understood that the phraseology and terminology used in this disclosure should not be considered limiting, but are for illustrative purposes.

[0029] The use of the terms "including," "comprising," or "having," and variations thereof, in this disclosure is meant to cover the subsequently listed items and equivalents thereof, as well as additional items. Further, the use of the terms "a" and "an" in this disclosure does not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.

[0030] Furthermore, the terms "a" and "an" as used herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.

[0031] As used in this disclosure, "about" will be understood by one of ordinary skill in the art and will vary somewhat depending on the context in which "about" is used. If there is a use of the term that is not clear to a person of ordinary skill in the art given the context in which it is used, then "about" shall mean within plus or minus 10% of the particular term.

[0032] The present invention provides a tranexamic acid-coated granule composition having a patient-friendly dosing regimen, the tranexamic acid-coated granule composition comprising an inner shell and an outer shell surrounding the inner shell. The inventors have found that these properties can be obtained by preparing a sachet comprising a tranexamic acid-coated granule, which is a multi-layer composition, and containing a mixture of formulation excipients.

[0033] The present invention further provides a tranexamic acid coated granule composition comprising an inner shell and an outer shell, wherein the outer shell promotes rapid release of 85% of the tranexamic acid from the inner shell of the coated granule within a 15-minute period, which can further control electrostatic charges generated during the preparation of the composition, thereby providing improved processability for the composition formulation.

[0034] In one embodiment, the present invention relates to a tranexamic acid-coated granule composition comprising an inner shell and an outer shell surrounding the inner shell. The inner shell comprises tranexamic acid, sugar spheres, and a first portion of polyvinylpyrrolidone K30. The outer shell comprises Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, anhydrous colloidal silica, and purified talc. The outer shell facilitates rapid release of 85% of the tranexamic acid from the inner shell within a 15-minute period.

[0035] In one or more embodiments, the solvent used in preparing the inner shell is a mixture of isopropyl alcohol and purified water.

[0036] In one or more embodiments, the solvent used in preparing the outer shell is purified water.

[0037] As used in this disclosure, tranexamic acid includes the free base as well as its pharmaceutically acceptable salts, enantiomers, and polymorphic forms.

[0038] The "inert material" or "core material" is a material onto which tranexamic acid is applied using the binder solution to form the inner shell of the coated granule composition. The inert material or core material according to the present invention is a particle or spherical carrier. The material used for the core material is chemically inert in the sense that it does not react with any of the other components in the coated granule composition according to the present invention and, in particular, does not interfere with the intended pharmacological mechanism exerted by the pharmaceutically active ingredient of the coated granule composition.

[0039] Examples of materials that can be used for the inert or core material include cellulose, especially microcrystalline cellulose, starch, lactose, sugar spheres, mannitol or mixtures thereof, or any other granular material, such as granular mannitol, sugar crystals, etc. Commercially available inert / core materials can also be used. It has been found to be advantageous to use particles with a particle size (diameter) of about 200 μm to 600 μm, preferably with a small variation in size.

[0040] As described in more detail below and demonstrated by the examples of this application, the coated granule compositions of the present invention are taste-masked while at the same time exhibiting advantageous dissolution profiles. In particular, the exemplary material poly(meth)acrylate has been found to be a very good outer coating layer, allowing the particles to disintegrate and release the drug. They also provide an acceptable mouth feel, i.e., no grittiness for the patient.

[0041] The percentage of inactive or core material in the final formulation (i.e., the tranexamic acid coated granule composition) is 10% (w / w) to 50% (w / w), more preferably 15% (w / w) to 40% (w / w), and most preferably 20% (w / w) to 35% (w / w) of the final formulation.

[0042] Pharmaceutically acceptable binders are soluble or insoluble binders. For soluble binders, water or a hydro-alcoholic solvent is used as the dissolution medium, and for insoluble binders, an organic solvent is used as the dissolution medium.

[0043] Binders that can be used in accordance with the present invention include, but are not limited to, tragacanth, acacia, gelatin, starch, cellulose materials such as methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, povidone, sucrose, alginic acid and its salts, polyethylene glycol, PVP, guar gum, polysaccharide acids, sugars, invert sugars, etc. In one embodiment, the water-soluble binder used is povidone, which is the first part of polyvinylpyrrolidone K30 (Kollidon 30).

[0044] The binder may be used in an amount of 20% (w / w) or less. In the tranexamic acid coated granule composition, the binder is present in an amount of 15% (w / w) or less, preferably 4% (w / w) to 10% (w / w).

[0045] The tranexamic acid coated granule composition may further include an outer shell surrounding the inner shell, which prevents drug loss from the inner shell during handling and sachet filling operations. The outer shell may also serve for taste masking. The outer shell comprises a poly(meth)acrylate copolymer (as the coating polymer), a water-soluble pore-forming material, a sweetener, an antistatic agent, and a lubricant. As described above, the outer shell facilitates the rapid release of 85% of the tranexamic acid from the inner shell of the coated granule composition.

[0046] In one embodiment, the poly(meth)acrylate copolymer used is Eudragit NE 30D. In the tranexamic acid composition, the poly(meth)acrylate copolymer is present in an amount between 2% (w / w) and 4% (w / w).

[0047] The water-soluble pore-forming material includes a polymeric material such as povidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, or sugar. In one embodiment, the water-soluble pore-forming material is povidone. The povidone used is the second part of polyvinylpyrrolidone K30 (Kollidon 30).

[0048] In the tranexamic acid coated granule composition, the water-soluble pore-forming material is present in an amount between 0.25% (w / w) and 0.75% (w / w).

[0049] "Palatability" and "mouth feel" are among the most important properties to consider when providing a sachet dosage form for a drug. Unfortunately, many drugs have a bitter or other unpleasant taste, or an unacceptable mouth feel, which makes them unsuitable for administration as a sachet. Much research has been devoted to designing technologies and approaches to mask the bitter taste of drugs in dosage forms. Simple approaches include adding chemical mediators, flavorings, or sweetening ingredients to the composition, thereby masking the bitter taste of the drug.

[0050] Anhydrous colloidal silica is used as an antistatic agent. Antistatic agents include, but are not limited to, micronized and non-micronized talc, fumed silica (Aerosil® 972), colloidal silica (Aerosil® 200), precipitated silica (Syloid® FP 244), and combinations thereof. The antistatic agent is present in the formulation in an amount ranging from 0.5 to 5.0%. The antistatic agent is incorporated into granules to improve material flow. In certain embodiments, the antistatic agent is Aerosil® 200. In tranexamic acid compositions, anhydrous colloidal silica is present in an amount between 0.2% (w / w) and 0.6% (w / w).

[0051] Sweeteners play an important role in developing a palatable, taste-masked formulation. Sweeteners can help reduce bitterness, but are most effective when combined with an acidity buffer and a sodium salt for saltiness. Sweeteners include dextrose, fructose, sucrose, erythritol, maltitol, mannitol, sorbitol, xylitol, aspartame, saccharin, saccharin sodium, sucralose, and the like. In one embodiment, the sweetener used is sucralose. In the tranexamic acid-coated granule composition, the sweetener is used in the range of 0.05% (w / w) to 0.5% (w / w).

[0052] The lubricant may be selected from lubricants conventionally known in the art, such as, but not limited to, Mg (magnesium), Al (aluminum), Ca (calcium), or Zn (zinc) stearates, sodium stearyl fumarate, stearic acid, sodium benzoate, micronized macrogol, and other materials known to those skilled in the art, as well as combinations thereof. The amount of lubricant is 0% (w / w) to 3% (w / w), preferably 0% (w / w) to 2% (w / w), and more preferably 1% (w / w). In one embodiment, the lubricant used in the present invention is refined talc.

[0053] The present invention provides a tranexamic acid coated granule composition comprising an inner shell and an outer shell, wherein the outer shell facilitates rapid release of 85% of the tranexamic acid from the inner shell of the coated granule within a 15-minute period, which can further control electrostatic charges generated during the preparation of the composition, thereby providing improved processability for the composition formulation.

[0054] In one or more embodiments, the dosage is 1000 mg and 2000 mg.

[0055] In one or more embodiments, the particle size of the inner shell is in the range of 380 microns to 560 microns, and the particle size of the outer shell is in the range of 230 microns to 459 microns.

[0056] In a preferred embodiment, the inner shell has an average particle size of 481 microns and the outer shell has an average particle size of 370 microns.

[0057] In one or more embodiments, the particle size of the tranexamic acid coated granules is less than 1.0 mm.

[0058] In one or more embodiments, the weight percent of the inner shell is between 94% (wt / wt) and 98% (wt / wt) of the total weight of the coated granule composition, and the weight percent of the outer shell is between 2% (wt / wt) and 6% (wt / wt) of the total weight of the coated granule composition.

[0059] In one or more embodiments, the inner shell comprises tranexamic acid, sugar spheres, and polyvinylpyrrolidone K30 in various weight percentages, wherein the weight percentage of tranexamic acid is between 56% (w / w) and 58% (w / w) of the total weight of the coated granule composition, the weight percentage of the sugar spheres is between 32% (w / w) and 33% (w / w) of the total weight of the coated granule composition, and the weight percentage of the first portion of polyvinylpyrrolidone K30 is between 6% (w / w) and 7% (w / w) of the total weight of the coated granule composition.

[0060] In one or more embodiments, the outer shell comprises Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, anhydrous colloidal silica, and purified talc in various weight percentages, wherein the weight percentage of Eudragit NE 30D is between 2% (w / w) and 4% (w / w) of the total weight of the coated granule composition, the weight percentage of the second portion of polyvinylpyrrolidone K30 is between 0.25% (w / w) and 0.75% (w / w) of the total weight of the coated granule composition, the weight percentage of sucralose is between 0.05% (w / w) and 0.15% (w / w) of the total weight of the coated granule composition, and the weight percentage of anhydrous colloidal silica is between 0.20% (w / w) and 0.60% (w / w) of the total weight of the coated granule composition. The weight percentage of the refined talc is between 0.10% (w / w) and 0.30% (w / w) of the total weight of the coated granule composition.

[0061] The coated granule compositions of the present invention involve fluidized bed coating, a process in which coated particles are produced in a single device by spraying a binder as a solution, suspension, or melt onto a fluidized powder bed. This process is often classified as a one-pot system, which offers several advantages, including uniform coating, good process control, and good edge coverage.

[0062] In another embodiment, the present invention relates to a process for preparing a coated granule composition that promotes the rapid release of tranexamic acid, the process comprising forming an inner shell and an outer shell surrounding the inner shell. The step for forming the inner shell comprises preparing a binder solution containing a first portion of polyvinylpyrrolidone K30 and applying tranexamic acid onto sugar spheres using the binder solution to thereby form the inner shell of the coated granule. The step for forming the outer shell comprises preparing a coating suspension by adding Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, and anhydrous colloidal silica, then applying the prepared coating suspension onto the inner shell and lubricating it with purified talc to form a coated granule composition.

[0063] 1, in step 102, process 100 includes forming an inner shell. In step 104, process 100 includes forming an outer shell surrounding the inner shell. Process 100 begins by forming the inner shell, followed by forming the outer shell surrounding the inner shell of the coated granules.

[0064] Step 102 of process 100 is further illustrated in Figure 1A. Referring to Figure 1A, in step 102A, the process includes preparing a binder solution including a first portion of polyvinylpyrrolidone K30. Also referring to Figure 1A, in step 102B, the process includes applying tranexamic acid onto sugar spheres using the binder solution, thereby forming the inner shell of the coated granules.

[0065] Step 104 of process 100 is further illustrated in Figure 1B. Referring to Figure 1B, in step 104A, the process includes preparing a coating suspension by adding Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, and anhydrous colloidal silica. Also referring to Figure 1B, in step 104B, the process includes applying the prepared coating suspension onto an inner shell to form an intermediate shell. Also referring to Figure 1B, in step 104C, the process includes lubricating the intermediate shell with refined talc to form a coated granule composition.

[0066] Steps 102A and 102B are described in detail in Figure 2. Referring to Figure 2, in step 202, a first portion of polyvinylpyrrolidone K30 (Kollidon 30) is dissolved in a mixture of isopropyl alcohol and purified water by continuous stirring until a clear solution is obtained. The final solution is filtered through No. 60 / nylon cloth to obtain the binder solution.

[0067] In step 204, the tranexamic acid is applied to the inactive / core materials using the binder solution to form the inner shell of the coated granules. Specifically, the binder solution is continuously sprayed onto the sugar spheres (i.e., the inactive / core materials) in a rotating coating pan. Tranexamic acid is intermittently added to the pan and mixed thoroughly to distribute the tranexamic acid and adhere it to the sugar spheres. Once all of the tranexamic acid is adhered to the sugar spheres, in step 206, the tranexamic acid-coated sugar spheres are dried in the rotating coating pan with hot air at pre-40°C until the moisture content of the inner shell (loss on drying) is less than 3%, resulting in the dried inner shell of the coated granules. Then, in step 208, the dried inner shell of the coated granules is sieved through a 1000-micron screen to remove agglomerates. The dried and sieved inner shell of the coated granules is again sieved through a 500 micron screen to remove fines, after which the inner shell of the coated granules is obtained in step 210. In a preferred embodiment, the layering or coating or application of tranexamic acid onto the inactive material / core material is done in a solid coating pan.

[0068] Referring again to FIG. 1B, the next step in process 100 involves preparing a coating suspension by adding Eudragit NE 30D, the second portion of polyvinylpyrrolidone K30, sucralose, and anhydrous colloidal silica in step 104A. Step 104A is illustrated in detail in FIG. 3. Referring to FIG. 3, in step 302, the Eudragit NE 30D suspension is filtered through a 60 mesh to form a lump-free suspension in step 304. Simultaneously, a suitable SS tank with a stirrer is prepared to which purified water is added, after which the second portion of polyvinylpyrrolidone is added with continuous stirring to form a solution in step 306. Thereafter, sucralose is added to the solution and dissolved with continuous stirring to form an intermediate solution in step 308.

[0069] Thereafter, in step 310, the previously filtered Eudragit NE 30D suspension from step 302 is dispersed into the intermediate solution obtained in step 308 and continuously dispersed until a white to off-hazy suspension is obtained. Thereafter, in step 312, anhydrous colloidal silica (e.g., Aerosil 200) is added to the solution obtained in step 310 and dispersed by a stirring process until a white to off-hazy suspension is obtained. In this step (i.e., step 312), a coating suspension is obtained.

[0070] Referring again to Figure 1B, the next step in process 100 involves applying the prepared coating suspension onto the inner shell at step 104B. Step 104B is shown in detail in Figure 3. Referring again to Figure 3, at step 314, the prepared coating suspension is applied onto the inner shell by continuous stirring at predetermined parameters in a fluidized bed coater.

[0071] As used in this disclosure, the predetermined parameters, in non-limiting examples, include an inlet temperature of about 30° C. to about 50° C., a product temperature of about 25° C. to about 35° C., a damper opening of about 30% to about 90%, a spray rate of the prepared taste mask coating suspension of about 200 g / min to about 500 g / min, and a spray rate of about 1.0 kg / cm 2 to approximately 3.0 kg / cm 2 Although certain predetermined parameters are set forth above, it will be apparent to one skilled in the art to modify the predetermined parameters based on obvious variations.

[0072] Next, in step 316, drying is performed in a fluidized bed coater under predetermined parameters for one hour. As used in this disclosure, the predetermined parameters, by way of non-limiting example, include an inlet temperature of about 30°C to about 50°C, a product temperature of about 25°C to about 35°C, and a damper opening of about 30% to about 90%. While certain predetermined parameters are described above, it will be apparent to those skilled in the art to modify the predetermined parameters based on obvious variations. Then, in step 318, the mixture is sifted and sieved through a 1000-micron screen set on a vibrating screen to remove agglomerated granules. The sieved product (less than 1000 microns) is collected in an HDPE container lined with a polybag and weighed. Finally, in step 320, the intermediate product is obtained.

[0073] 1B, in step 104C, the process 100 lubricates the intermediate product. Step 104C is described in detail in Figure 4. Next, in step 402, the intermediate product is lubricate with refined talc in a conta blender bin and mixed for about 5 minutes to form the outer shell of the coated granules.

[0074] Here, the tranexamic acid coated granules include an inner shell surrounded by an outer shell. Thereafter, in step 404, the tranexamic acid coated granules are unloaded into appropriate drums labeled with the product name, batch number, and weight and transferred to a coated granule storage area. Thereafter, in step 406, the tranexamic acid coated granules are unloaded.

[0075] 5, in step 502, the tranexamic acid coated granules are filled or packaged into sachets using a sachet filling machine. Finally, in step 504, the filled sachets are manually placed into cartons for final product analysis.

[0076] For the preparation of coated granules of tranexamic acid, conventional equipment such as blenders, sieves, coating equipment and sachet machines are used.

[0077] Description of pharmaceutical compositions and processes for preparing same in accordance with the present invention are further illustrated in the following non-limiting examples, which one of ordinary skill in the art will recognize are intended to illustrate, but not limit, the scope of the invention.

[0078] Example 1 In Example 1, a process for preparing a tranexamic acid coated granule composition is described. In particular, the process is described for preparing a tranexamic acid composition having a strength of 1000 mg per sachet, wherein the tranexamic acid is in a weight ratio of 50% (w / w) to 60% (w / w) of the composition.

[0079] The process begins by preparing a binder solution containing a first portion of polyvinylpyrrolidone K30. 108.85 mg of the first portion of polyvinylpyrrolidone (Kollidon 30) is dissolved in a mixture of isopropyl alcohol and purified water. The final solution is filtered through a No. 60 nylon cloth to obtain the binder solution.

[0080] The next step is to apply tranexamic acid to the inactive / core materials using the binder solution to form the inner shell of the coated granules. Specifically, the binder solution is continuously sprayed onto 567.65 mg of sugar spheres (i.e., the inactive / core materials) in a rotating coating pan. 1000 mg of tranexamic acid is intermittently added to the pan and mixed thoroughly to distribute the tranexamic acid and adhere it to the sugar spheres. Once the tranexamic acid is completely attached to the sugar spheres, the tranexamic acid-coated sugar spheres are dried in the rotating coating pan with hot air at 40°C until the moisture content of the inner shell (loss on drying) is less than 3%, resulting in a dried inner shell. The dried inner shell of the coated granules is then sieved through a 1000-micron screen to remove agglomerates. The dried and sieved inner shell is again sieved through a 500 micron screen to remove fines. In a preferred embodiment, the layering or coating or application of tranexamic acid onto the inactive material / core material is done in a solid coating pan.

[0081] Table 1A below shows various raw materials for preparing the binder solution, applying tranexamic acid onto an inert material with the binder solution in a coating pan, drying, and sieving and classifying. [Table 1A]

[0082] In the next step of the process, a coating suspension is prepared by adding Eudragit NE 30D, the second portion of polyvinylpyrrolidone K30, sucralose, and anhydrous colloidal silica. Specifically, 52.50 mg of the Eudragit NE 30D suspension is filtered through a 60 mesh to form a lump-free suspension. Simultaneously, a suitable SS tank equipped with a stirrer is prepared, and purified water is added. 8.75 mg of the second portion of polyvinylpyrrolidone is added with continuous stirring to form a solution. 1.75 mg of sucralose is then added to the solution and dissolved with continuous stirring to form an intermediate solution. The previously filtered Eudragit NE 30D suspension is then dispersed into the intermediate solution and continuously stirred. 7 mg of anhydrous colloidal silica (e.g., Aerosil 200) is then dispersed into the solution and dissolved by stirring.

[0083] In Table 1B, the various ingredients for preparing the intermediate product are given. [Table 1B]

[0084] The prepared coating suspension is then applied onto the inner shell by continuous stirring in a fluidized bed coater under predetermined parameters. As used herein, the predetermined parameters, in non-limiting examples, include an inlet temperature of about 30° C. to about 50° C., a product temperature of about 25° C. to about 35° C., a damper opening of about 30% to about 90%, a spray rate of the prepared taste mask coating suspension of about 200 g / min to about 500 g / min, and a spray rate of about 1.0 kg / cm. 2 to approximately 3.0 kg / cm 2 Although certain predetermined parameters are set forth above, it will be apparent to one skilled in the art to modify the predetermined parameters based on obvious variations.

[0085] This is followed by drying in a fluidized bed coater under predetermined parameters for 1 hour. As used in this disclosure, the predetermined parameters, in non-limiting examples, include an inlet temperature of about 30°C to about 50°C, a product temperature of about 25°C to about 35°C, and a damper opening of about 30% to about 90%. While certain predetermined parameters are described above, it will be apparent to one skilled in the art to modify the predetermined parameters based on obvious variations. Finally, sieving is performed using a vibrating sieve.

[0086] The next step in the process is to lubricate the blender in a conta blender bin with 3.50 mg of purified talc for approximately 5 minutes to form an outer shell surrounding the inner shell of tranexamic acid coated granules.

[0087] Table 1C shows the lubricating finishes using actual amounts of refined talc. [Table 1C]

[0088] The weight percentages for the inner and outer shells of the tranexamic acid coated granule composition (1000 mg) are given in the table below. [Table 2]

[0089] The weight percentages for the inner shell of the tranexamic acid coated granule composition (1000 mg) are given in the table below. [Table 2A]

[0090] The weight percentages for the outer shell of the tranexamic acid coated granule composition (1000 mg) are given in the table below. [Table 2B]

[0091] The actual amount of coated granules (kg) and the actual amount of coated granules (kg) for 125,000 sachets are shown in the table below. [Table 3]

[0092] Example 2 In Example 2, a process for preparing a tranexamic acid coated granule composition is described. In particular, the process is described for preparing a tranexamic acid composition having a strength of 2000 mg per sachet, wherein the tranexamic acid is in a weight ratio of 50% (w / w) to 60% (w / w) of the composition.

[0093] The process begins by preparing a binder solution containing a first portion of polyvinylpyrrolidone K30. 217.7 mg of the first portion of polyvinylpyrrolidone (Kollidon 30) is dissolved in a mixture of isopropyl alcohol and purified water. The final solution is filtered through a No. 60 nylon cloth to obtain the binder solution.

[0094] The next step is to apply tranexamic acid to the inactive / core materials using the binder solution to form the inner shell of the coated granules. Specifically, the binder solution is continuously sprayed onto 1135.3 mg of sugar spheres (i.e., the inactive / core materials) in a rotating coating pan. 2000 mg of tranexamic acid is intermittently added to the pan and mixed thoroughly to distribute the tranexamic acid and adhere it to the sugar spheres. Once the tranexamic acid is completely attached to the sugar spheres, the tranexamic acid-coated sugar spheres are dried in the rotating coating pan with hot air at 40°C until the moisture content of the inner shell (loss on drying) is less than 3%, resulting in a dried inner shell. The dried inner shell is then sieved through a 1000-micron screen to remove agglomerates. The dried and sieved inner shell is again sieved through a 500 micron screen to remove fines. In a preferred embodiment, the layering or coating or application of tranexamic acid onto the inactive / core material is done in a solid coating pan.

[0095] Table 4A below shows various raw materials for preparing the binder solution, applying tranexamic acid onto an inert material with the binder solution in a coating pan, drying, and sieving and classifying. [Table 4A]

[0096] In the next step of the process, a coating suspension is prepared by adding Eudragit NE 30D, the second portion of polyvinylpyrrolidone K30, sucralose, and anhydrous colloidal silica. Specifically, 105 mg of the Eudragit NE 30D suspension is filtered through a 60 mesh to form a lump-free suspension. Simultaneously, a suitable SS tank with a stirrer is prepared, to which purified water is added, and 17.5 mg of the second portion of polyvinylpyrrolidone is added with continuous stirring to form a solution. 3.5 mg of sucralose is then added to the solution and dissolved with continuous stirring to form an intermediate solution. The previously filtered Eudragit NE 30D suspension is then dispersed into the intermediate solution and continuously stirred. 14 mg of anhydrous colloidal silica (e.g., Aerosil 200) is then dispersed into the solution and dissolved by stirring.

[0097] In Table 4B, the various ingredients for preparing the intermediate product are given. [Table 4B]

[0098] The prepared coating suspension is then applied onto the inner shell by continuous stirring in a fluidized bed coater under predetermined parameters. As used herein, the predetermined parameters, in non-limiting examples, include an inlet temperature of about 30° C. to about 50° C., a product temperature of about 25° C. to about 35° C., a damper opening of about 30% to about 90%, a spray rate of the prepared taste mask coating suspension of about 200 g / min to about 500 g / min, and a spray rate of about 1.0 kg / cm. 2 to approximately 3.0 kg / cm 2 Although certain predetermined parameters are set forth above, it will be apparent to one skilled in the art to modify the predetermined parameters based on obvious variations.

[0099] This is followed by drying in a fluidized bed coater under predetermined parameters for 1 hour. As used in this disclosure, the predetermined parameters, in non-limiting examples, include an inlet temperature of about 30°C to about 50°C, a product temperature of about 25°C to about 35°C, and a damper opening of about 30% to about 90%. While certain predetermined parameters are described above, it will be apparent to one skilled in the art to modify the predetermined parameters based on obvious variations. Finally, sieving is performed using a vibrating sieve.

[0100] The next step in the process is to lubricate the blender in a conta blender bin with 7 mg of purified talc for approximately 5 minutes to form an outer shell surrounding the inner shell of tranexamic acid coated granules.

[0101] Table 4C shows the lubricating finishes using actual amounts of refined talc. [Table 4C]

[0102] The weight percentages for the inner and outer shells of the tranexamic acid coated granule composition (2000 mg) are given in the table below. [Table 5]

[0103] The weight percentages for the inner shell of the tranexamic acid coated granule composition (2000 mg) are given in the table below. [Table 5A]

[0104] The weight percentages for the outer shell of the tranexamic acid coated granule composition (2000 mg) are given in the table below. [Table 5B]

[0105] The actual amount of coated granules (mg) per sachet is shown in the table below. [Table 6]

[0106] Example 3 In Example 3, a bioavailability study was conducted between the test product, tranexamic acid 1 g coated granules in a sachet, and the reference product, Cyclof 500 mg film-coated tablets from Meda AB, Sweden. An open-label, balanced, randomized, single-dose, two-treatment, two-period, two-sequence, two-way crossover comparative bioavailability study was conducted between tranexamic acid granules (1 g) in a sachet from Athena Drug Delivery Solutions Pvt. Ltd., India, and Cyclof 500 mg film-coated tablets from Meda AB, Box 906, 170 09, Solna, in healthy, adult, human subjects under fasting conditions.

[0107] In this study, the pharmacokinetic parameters of the test product, tranexamic acid coated granules 1 g sachet, are bioequivalent to those of the reference drug, tranexamic acid 500 mg tablets, two tablets.

[0108] FIG. 7 shows a summary of the bioavailability study carried out according to Example 3 between tranexamic acid coated granule sachets and a reference product.

[0109] A summary of the study is given in the table below. [Table 7]

[0110] Therefore, in this study, the pharmacokinetic parameters of the test drug, tranexamic acid coated granules 1 g sachet, were bioequivalent to the pharmacokinetics of the reference drug, tranexamic acid 500 mg tablets, two 2 g sachets, and were dose proportional.

[0111] The present invention provides a tranexamic acid-coated granule composition comprising an inner shell and an outer shell surrounding the inner shell, the tranexamic acid-coated granule composition having a patient-friendly dosing regimen. The applicant has discovered that these properties can be obtained by preparing a sachet containing tranexamic acid-coated granules that are multi-layer compositions and contain a mixture of formulation excipients. The present invention also provides a tranexamic acid-coated granule composition comprising an inner shell and an outer shell, wherein the outer shell promotes rapid release of 85% of the tranexamic acid from the inner shell of the coated granule within a 15-minute period. This further allows for the control of electrostatic charges generated during the preparation of the composition, thereby providing improved processability for the formulation of the composition.

[0112] The foregoing descriptions of specific embodiments of the present disclosure have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the disclosure to the precise forms disclosed, and obviously, many modifications and variations are possible in light of the above teachings. The embodiments have been chosen and described to best explain the principles of the present disclosure and its practical application, thereby enabling others skilled in the art to best utilize the present disclosure and various embodiments with various modifications as suited to the specific uses envisioned. (Various omissions and substitutions of equivalents are contemplated as the circumstances suggest or are useful under the circumstances, however, it being understood that these are intended to cover applications or practices without departing from the spirit or scope of the appended claims.)

Claims

1. tranexamic acid, sugar spheres, and First part of polyvinylpyrrolidone K30 Including an inner shell, an outer shell surrounding the inner shell, Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, anhydrous colloidal silica, and Refined talc An outer shell including wherein the outer shell promotes rapid release of 85% of the tranexamic acid from the inner shell within a 15 minute period.

2. 2. The coated granule composition according to claim 1, wherein the solvent used in preparing the inner shell is a mixture of isopropyl alcohol and purified water.

3. 10. The coated granule composition of claim 1, wherein the solvent used in preparing the outer shell is purified water.

4. The coated granule composition of claim 1, wherein the dosage is 1000 mg and 2000 mg.

5. 2. The coated granule composition of claim 1, wherein the particle size of the inner shell is in the range of 380 microns to 560 microns and the particle size of the outer shell is in the range of 230 microns to 459 microns.

6. 2. The coated granule composition according to claim 1, wherein the particle size of the tranexamic acid coated granules is less than 1.0 mm.

7. 2. The coated granule composition of claim 1, wherein the weight percentage of the inner shell is between 94% (wt / wt) and 98% (wt / wt) of the total weight of the coated granule composition, and the weight percentage of the outer shell is between 2% (wt / wt) and 6% (wt / wt) of the total weight of the coated granule composition.

8. In the inner shell, the weight percentage of tranexamic acid is between 56% (w / w) and 58% (w / w) of the total weight of the coated granule composition; the weight percentage of the sugar spheres is between 32% (w / w) and 33% (w / w) of the total weight of the coated granule composition; The weight percentage of polyvinylpyrrolidone K30 is between 6% (w / w) and 7% (w / w) of the total weight of the coated granule composition. The coated granule composition of claim 1.

9. In the outer shell, the weight percentage of Eudragit NE 30D is between 2% (w / w) and 4% (w / w) of the total weight of the coated granule composition; the weight percentage of the second portion of polyvinylpyrrolidone K30 is between 0.25% (w / w) and 0.75% (w / w) of the total weight of the coated granule composition; the weight percentage of sucralose is between 0.05% (w / w) and 0.15% (w / w) of the total weight of the coated granule composition; the weight percentage of the anhydrous colloidal silica is between 0.20% (w / w) and 0.60% (w / w) of the total weight of the coated granule composition; 10. The coated granule composition of claim 1, wherein the weight percentage of purified talc is between 0.10% (w / w) and 0.30% (w / w) of the total weight of the coated granule composition.

10. forming an inner shell, this step comprising: preparing a binder solution comprising a first portion of polyvinylpyrrolidone K30; applying tranexamic acid onto sugar spheres using the binder solution; Includes; forming an outer shell surrounding the inner shell, this step comprising: preparing a coating suspension by adding Eudragit NE 30D, a second portion of polyvinylpyrrolidone K30, sucralose, and anhydrous colloidal silica; applying the prepared coating suspension onto the inner shell; and Lubricate with refined talc, Including, 1. A process for preparing a coated granule composition that promotes rapid release of tranexamic acid, comprising:

11. 11. The process of claim 10, wherein preparing the binder solution comprises dissolving a first portion of polyvinylpyrrolidone K30 in a mixture of isopropyl alcohol and purified water.

12. The preparation of the coating suspension comprises: Filtering Eudragit NE 30D; dissolving a second portion of polyvinylpyrrolidone K30 in purified water and adding sucralose to form an intermediate solution; Dispersing filtered Eudragit NE 30D into the intermediate solution; and dispersing anhydrous colloidal silica to form a coating suspension; The process of claim 10, comprising:

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