Method for preparing lisdexamfetamine dimesylate dispersible tablets

Abstract

This disclosure relates to a method for preparing lisdexamfetamine dimesylate dispersible tablets. [Solution] The preparation method includes: dry mixing lisdexamfetamine dimesylate, a diluent, a binder, and an antistatic agent to form a dry mixture blend; blending a filler, a buffer, a disintegrant, and a sweetener into an intermediate granule blend to form an intermediate granule blend; adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend; lubricating the intermediate drug blend with a lubricant to form drug granules ready for compression; and compressing the drug granules ready for compression to form lisdexamfetamine dimesylate dispersible tablets.

Description

Technical Field

[0001] The present disclosure generally relates to a method for preparing dispersible tablets. In particular, the present disclosure relates to a method for preparing lisdexamfetamine dimesylate dispersible tablets.

Background Art

[0002] Molecular formula C 17 H 33 Lisdexamfetamine dimesylate, which is the dimesylate salt of L-lysyl-d-amphetamine having N3O7S2, is also known by the chemical name "(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]-hexanamide, dimethanesulfonate". The IUPAC name of lisdexamfetamine dimesylate is (2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide; methanesulfonic acid.

[0003] The chemical structure of lisdexamfetamine dimesylate is represented below.

Chemical Formula

[0004] Lisdexamfetamine dimesylate generally refers to the treatment of adult attention deficit hyperactivity disorder (ADHD) and moderate to severe binge eating disorder (BED).

[0005] Lisdexamfetamine dimesylate is, by its nature, a highly deliquescent material that absorbs moisture by any means and does not remain in solid form when exposed to moisture.

[0006] Lisdexamfetamine dimesylate is marketed in the form of capsules and chewable tablets. Many patient groups, including the elderly, patients with intellectual disability, uncooperative patients, patients with nausea, and patients on specific or customized diets, have difficulty swallowing the available capsule and chewable formulations of lisdexamfetamine dimesylate.

[0007] Over the past decade, there has been a need for next-generation pharmaceuticals and drugs in multiple dosages that are easily ingestible, rapidly dissolve, dissolve or melt or disintegrate in just a few seconds, and provide the desired therapeutic effect. This need further includes preferred types of methods for preparing formulations that improve the disintegration, dissolution, and free flow of components in the granules of the dosage form by employing physicochemical parameters during the process.

[0008] Therefore, there is a need for lisdexamfetamine dimesylate compositions and dosage forms that address the deliquescence problem of lisdexamfetamine dimesylate. It is therefore highly desirable to develop a lisdexamfetamine dimesylate dosage form that disintegrates rapidly, allows for rapid drug release from granules, and enables rapid absorption in the body after administration. Furthermore, it is desirable to develop a stable, palatable, and rapidly disintegrating lisdexamfetamine dimesylate dispersible tablet. Additionally, there is a need for a method for preparing lisdexamfetamine dimesylate compositions that has a short process time and low manufacturing costs. Moreover, a humidity-controlled manufacturing process is required to minimize exposure of the deliquescent material to moisture during the manufacturing process. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] To achieve the above and other objectives and needs, this disclosure provides a method for preparing lisdexamfetamine dimesylate dispersible tablets and lisdexamfetamine dimesylate dispersible tablets prepared thereby. The lisdexamfetamine dimesylate dispersible tablets developed by the inventors are dispersible tablets in multiple doses that are easy to ingest, dissolve rapidly, dissolve or melt or disintegrate in just a few seconds, and provide the desired therapeutic effect. This disclosure provides a method for preparing dispersible tablets that improves the disintegration, dissolution and free flow of components in the granules of the dosage form by employing physicochemical parameters during the method.

[0010] This disclosure provides a synergistic combination of API (active drug component) and excipients in specific ratios to address the deliquescence of lisdexamfetamine dimesylate. This synergistic combination improves the disintegration time of dispersible tablets. This disclosure further imparts improved palatability to tablet formulations of lisdexamfetamine dimesylate. This disclosure provides a humidity-controlled manufacturing method in which tablet formulations are manufactured in a humidity-controlled environment to minimize exposure of the deliquescent material to moisture during the manufacturing process. In particular, this manufacturing process uses a direct compression technique during the manufacturing process at a controlled humidity level of 40% NMT to reduce exposure to moisture.

[0011] This disclosure provides a method for producing a lisdexamfetamine dimesylate composition for dispersible tablets that overcomes the drawbacks of solid compositions such as capsules and chewable tablets. To address the deliquescence of lisdexamfetamine dimesylate and provide a stable lisdexamfetamine dimesylate dispersible composition, a synergistic combination of API and excipients in specific ratios is formulated. The lisdexamfetamine dispersible tablet composition dissolves by more than 75% in 15 minutes.

[0012] In one embodiment, the present disclosure relates to a method for preparing lisdexamfetamine dimesylate dispersible tablets. The method includes dry mixing lisdexamfetamine dimesylate with a diluent, a binder, and an anti-static agent to form a dry mixture blend. Subsequently, an intermediate granule blend is formed by blending a filler, a cushioning agent, a disintegrating agent, and a sweetener. Subsequently, the dry mixture blend and the intermediate granule blend are added and blended to form an intermediate drug blend. Subsequently, the intermediate drug blend is lubricated with a lubricant to form drug granules ready for compression, and finally, the drug granules ready for compression are compressed to form lisdexamfetamine dimesylate dispersible tablets.

[0013] In one or more embodiments, lisdexanfetamine dimesylate is present in an amount of about 8 to about 12% by weight.

[0014] In one or more embodiments, during the dry mixing step, the diluent is mannitol granules 200SD, present in an amount of about 18 to about 23% by weight. The binder is partially gelatinized corn starch, present in an amount of about 10 to about 20% by weight. The antistatic agent is colloidal anhydrous silica, present in an amount of about 1 to about 2% by weight.

[0015] In one or more embodiments, during the intermediate granule blending step, the filler is mannitol granules 200SD, and the diluent is present in an amount of about 28 to about 34% by weight. The buffer is microcrystalline cellulose, and the buffer is present in an amount of about 8 to about 12% by weight. The disintegrant is crospovidone, and the disintegrant is present in an amount of about 6 to about 10% by weight. The sweetener is sucralose, and the sweetener is present in an amount of about 1 to about 4% by weight.

[0016] In one or more embodiments, in the lubrication step, the lubricant is magnesium stearate and the lubricant is present in an amount of about 1% to about 2% by weight.

[0017] In one or more embodiments, the dosage of the lisdexamfetamine dimesylate dispersible tablets is 10 mg per tablet, 20 mg per tablet, 30 mg per tablet, 40 mg per tablet, 50 mg per tablet, 60 mg per tablet, and 70 mg per tablet.

[0018] In one or more embodiments, dissolution is 75% or more in 15 minutes.

[0019] In one or more embodiments, the friability is 1.5% or less, the disintegration time is less than 3 minutes at 15°C to 25°C (without disk), and the hardness is about 30 N to about 70 N.

[0020] In one or more embodiments, the compression step uses direct compression technology at a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0021] In one or more embodiments, the method further includes packaging the lisdexamfetamine dimesylate dispersible tablets in a moisture-resistant ALU peel blister package and / or in a moisture-resistant ALU-ALU blister package.

[0022] The advantages and features of the present disclosure will be better understood by referring to the following detailed description and the claims in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0023] [[ID=**30**]] [[ID=**31**]] [Figure 1] [[ID=**32**]]Figure 1 shows a method flow for preparing lisdexamfetamine dimesylate dispersible tablets according to an exemplary embodiment of the present disclosure.

[0024] [Figure 2] It should be noted that the tags to [Figure 2] are preserved as they are without translation as they seem to be some form of specific identifiers or tags in a particular context and not text to be translated. Also, the tag to seem to be in a non - standard or incomplete format in the original, but are preserved as is in the translation. If there is a specific format or meaning these are supposed to follow, it might need further clarification for a more precise translation in that regard.Figure 2 shows the details of a method for dry blending of lisdexamfetamine dimesylate, a binder, and a diluent, according to an exemplary embodiment of the present disclosure.

[0025] [Figure 3] Figure 3 shows the details of a method for intermediate granule blending, according to an exemplary embodiment of the present disclosure.

[0026] [Figure 4] Figure 4 shows the details of a method for preparing an intermediate drug blend, according to an exemplary embodiment of the present disclosure.

[0027] [Figure 5] Figure 5 shows the details of a method for preparing drug granules ready for compression, according to an exemplary embodiment of the present disclosure.

[0028] [Figure 6] Figure 6 shows the details of a method for preparing compressed lisdexamfetamine dimesylate dispersible tablets, according to an exemplary embodiment of the present disclosure.

Mode for Carrying Out the Invention

[0029] The exemplary embodiments described in detail herein for illustrative purposes are subject to many variations in structure and design. However, it should be emphasized that the present disclosure is not limited to the method for preparing lisdexamfetamine dimesylate dispersible tablets as shown and described. Various omissions and substitutions of equivalents are contemplated as circumstances may suggest or make expedient, but it is understood that these are intended to cover the application or implementation without departing from the spirit or scope of the claims of the present disclosure. Also, it is understood that the expressions and terms used herein are for purposes of explanation and should not be regarded as limiting.

[0030] The use of the terms “including,” “comprising,” or “having” as used herein, and their variations thereof, means to include the items listed therein and their equivalents, as well as any additional items.

[0031] Furthermore, the terms "a" and "an" in this specification do not indicate a limit on quantity, but rather indicate the existence of at least one of the items being referenced.

[0032] Where used herein, the term “about” is to be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is any use of the term that is not clear to those skilled in the art, “about” means up to plus or minus 10% of the particular term, considering the context in which it is used.

[0033] This disclosure provides a method for preparing lisdexamfetamine dimesylate dispersible tablets and lisdexamfetamine dimesylate dispersible tablets prepared thereby. The lisdexamfetamine dimesylate dispersible tablets developed by the inventors are dispersible tablets in multiple dosages that are easy to ingest, dissolve rapidly, dissolve or melt or disintegrate in just a few seconds, and provide the desired therapeutic effect. This disclosure provides a method for preparing dispersible tablets that improves the disintegration, dissolution and free flow of components in the granules of the dosage form by employing physicochemical parameters during the method.

[0034] Lisdexamfetamine dimesylate dispersible tablets address the deliquescence problem of lisdexamfetamine dimesylate. Lisdexamfetamine dimesylate dispersible tablets rapidly disintegrate, allowing for rapid release of the drug from granules and rapid absorption in the body after administration. Furthermore, lisdexamfetamine dimesylate dispersible tablets are stable, palatable, and rapidly disintegrate. The preparation method for lisdexamfetamine dimesylate tablets also involves reduced process time and lower manufacturing costs. Additionally, the method controls humidity to minimize exposure of the deliquescent material to moisture during the production of dispersible tablets.

[0035] Lisdexamfetamine dimesylate dispersible tablets disintegrate or dissolve rapidly, and tablets in a form that can be dispersed upon ingestion allow for drug absorption within the gastrointestinal tract.

[0036] This disclosure provides a synergistic combination of API and excipients in specific ratios to address the deliquescence of lisdexamfetamine dimesylate. This synergistic combination improves the disintegration time of dispersible tablets. This disclosure further imparts improved palatability to tablet formulations of lisdexamfetamine dimesylate. This disclosure provides a humidity-controlled preparation method in which tablet formulations are manufactured in a humidity-controlled environment to minimize exposure of the deliquescent material to moisture during the manufacturing process. In particular, this manufacturing process uses a direct compression technique during the manufacturing process at a controlled humidity level of 40% NMT to reduce exposure to moisture.

[0037] This disclosure provides a method for preparing a lisdexamfetamine dimesylate composition for dispersible tablets that overcome the drawbacks of solid compositions such as capsules and chewable tablets. To address the deliquescence of lisdexamfetamine dimesylate and provide a stable lisdexamfetamine dimesylate dispersible composition, a synergistic combination of API and excipients in specific ratios is formulated. The lisdexamfetamine dispersible tablet composition dissolves by more than 75% in 15 minutes.

[0038] In one embodiment, a method for preparing lisdexamfetamine dimesylate dispersible tablets is disclosed. Hereinafter, "method for preparing lisdexamfetamine dimesylate dispersible tablets" and "method" will be used without any limitation or distinction. A method for preparing lisdexamfetamine dimesylate dispersible tablets, comprising: dry mixing lisdexamfetamine dimesylate, a diluent, a binder and an antistatic agent to form a dry mixture blend; forming an intermediate granule blend by blending a filler, a buffer and a disintegrant and a sweetener; adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend; lubricating the intermediate drug blend with a lubricant to form drug granules ready for compression; and finally compressing the drug granules ready for compression to form lisdexamfetamine dimesylate dispersible tablets. Here, the particle size of the drug granules forming the lisdexamfetamine dimesylate dispersible tablets is 400 microns or less.

[0039] The method for preparing lisdexamfetamine dimesylate dispersible tablets mainly comprises the steps of dry mixing, intermediate blending, lubrication, and compression. Specifically, this involves the preparation of a dry mixture blend, an intermediate granule blend, an intermediate drug blend, drug granules ready for compression, and the preparation of lisdexamfetamine dimesylate dispersible tablets.

[0040] Referring to Figure 1, Method 100 relates to the preparation of lisdexamfetamine dimesylate dispersible tablets. Step 102 of Method 100 includes dry mixing lisdexamfetamine dimesylate with a diluent, a binder and an antistatic agent to form a dry mixture blend. Step 104 of Method 100 includes blending a filler, a buffer and disintegrant and a sweetener into an intermediate granule blend to form an intermediate granule blend. Step 106 of Method 100 includes adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend. Step 108 of Method 100 includes lubricating the intermediate drug blend with a lubricant to form drug granules ready for compression. Step 110 of Method 100 includes compressing the drug granules ready for compression to form lisdexamfetamine dimesylate dispersible tablets. Subsequently, the lisdexamfetamine dimesylate dispersible tablets are packaged in a moisture-resistant ALU peel-off blister package / ALU-ALU blister package. The moisture-resistant ALU peel-off blister package / ALU-ALU blister package contributes to humidity control during preparation and packaging.

[0041] Step 102 of the method in Figure 1 is described in detail in Figure 2. Step 104 of the method in Figure 1 is described in detail in Figure 3. Step 106 of the method in Figure 1 is described in detail in Figure 4. Step 108 of the method in Figure 1 is described in detail in Figure 5. Step 110 of the method in Figure 1 is described in detail in Figure 6.

[0042] Referring again to Figure 1, step 102 involves method 100 dry mixing lisdexanfetamine dimesylate with a diluent, a binder, and an antistatic agent to form a dry mixture blend. The method for preparation step 102 in Figure 1 is described in detail in Figure 2.

[0043] Referring to Figure 2, in step 202, in part I, the diluent, which is mannitol granules 200SD, is passed through a 36-mesh vibrating sieve to obtain a lump of diluent that does not contain aggregates. In one example, mannitol granules 200SD is Pearlitol® 200SD.

[0044] Referring to Figure 2, in step 204, in part II, lisdexanfetamine dimesylate, a binder which is partially gelatinized corn starch, and an antistatic agent which is colloidal anhydrous silica are passed through a 36-mesh vibrating sieve and co-sifted to obtain aggregate-free lisdexanfetamine dimesylate, a binder, and an antistatic agent. In one example, the partially gelatinized corn starch is Starch1500®. In another example, the colloidal anhydrous silica is Aerosil® 200.

[0045] In step 206, as a first mixing level, the aggregate-free lumps of lisdexamfetamine dimesylate obtained in step 204, along with the binder and antistatic agent, are blended in a conta blender at 8 RPM for 30 minutes to form a blended mixture of lisdexamfetamine dimesylate, binder, and antistatic agent.

[0046] In step 208, as a second mixing level, the blended mixture obtained in step 206 is further blended in a contablender at 8 RPM for 15 minutes to obtain the blended material.

[0047] In step 210, the blended material obtained in step 208 is transferred to an HDPE container lined with a polyethylene bag, and a lump of the diluent obtained in step 202, free of aggregates, is added to form a dry mixture blend in step 212.

[0048] Referring again to Figure 1, step 104, following method 100, involves blending the filler, buffer, disintegrant, and sweetener into an intermediate granule blend to form an intermediate granule blend. The method for preparation step 104 in Figure 1 is described in detail in Figure 3.

[0049] Referring to Figure 3, in step 302, the filler (mannitol granules 200SD), buffer (microcrystalline cellulose), disintegrant (crospovidone), and sweetener (sucralose) are simultaneously sieved through a 36-mesh vibrating sieve to obtain a mass of the sieved filler, buffer, disintegrant, and sweetener that does not contain aggregates. In one example, the mannitol granules 200SD is Pearlitol® 200SD. In another example, the microcrystalline cellulose is Vivapur® 112. In another example, the crospovidone is Kollidone® CL.

[0050] In step 304, the sieved filler, buffer, disintegrant, and sweetener obtained in step 302, free of aggregates, are blended in a blender at 8 RPM for 15 minutes. Then, in step 306, an intermediate granule blend is obtained. Furthermore, the intermediate granule blend obtained in step 306 is divided into two parts: the first half of the intermediate granule blend and the second half of the intermediate granule blend.

[0051] In step 308, the first half of the intermediate granule blend is removed into an HDPE container lined with a polybag, which will hereafter be referred to as "50% of the removed intermediate granule blend," and the second half of the intermediate granule blend is left in the blender bin, which will hereafter be referred to as "50% of the intermediate granule blend contained in the blender bin."

[0052] Referring again to Figure 1, step 106, the next step in method 100, involves adding and blending the dry mixture blend obtained in step 212 with the intermediate granule blend obtained in step 306 to form an intermediate drug blend. The method for preparation step 106 in Figure 1 is described in detail in Figure 4.

[0053] Referring to Figure 4, in step 402, the dry mixture blend obtained in step 212 of Figure 2 is added to "50% of the intermediate granule blend contained in the blender bin" (the second half), and then the "removed 50% of the intermediate granule blend" (the first half) separated in step 308 is added to the blender bin already containing the second half of the intermediate granule blend and the dry mixture blend. After successively adding the second half of the intermediate granule blend, the dry mixture blend, and the first half of the intermediate granule blend to the contablender bin, in step 404, the mixture is blended at 8 RPM for 30 minutes to obtain the intermediate drug blend in step 406.

[0054] Referring again to Figure 1, step 108, the next step of method 100, involves lubricating the intermediate drug blend with a lubricant to form drug granules ready for compression. The method of preparation step 108 in Figure 1 is described in detail in Figure 5.

[0055] Referring to Figure 5, in step 502, the lubricant, which is magnesium stearate, is sieved through a 40-mesh vibrating sieve to obtain a clump of sieved lubricant that does not contain aggregates. Furthermore, in step 504, the sieved lubricant obtained in step 502 is added to the intermediate drug blend obtained in step 406 in Figure 4, and blended in a contablender at 8 RPM for 10 minutes to obtain drug granules ready to be compressed in step 506.

[0056] Referring again to Figure 1, step 110 is the next step in method 100, which involves compressing the drug granules ready for compression to form lisdexamfetamine dimesylate dispersible tablets. The method of preparation step 110 in Figure 1 is described in detail in Figure 6.

[0057] Referring to Figure 6, in step 602, the drug granules ready to be compressed obtained in step 506 of Figure 5 are compressed by using a direct compression technique with a controlled humidity level of 40% NMT to reduce exposure to moisture, thereby forming lisdexamfetamine dimesylate dispersible tablets.

[0058] In one or more embodiments, lisdexanfetamine dimesylate is present in an amount of about 8 to about 12% by weight.

[0059] As used herein, lisdexamfetamine dimesylate is the active substance. Molecular formula C 17 H 33 Lisdexamfetamine dimesylate, a dimesylate salt of L-lysyl-d-amphetamine having N3O7S2, is also known by the chemical name "(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]-hexaneamide, dimethanesulfonate". The IUPAC name for lisdexamfetamine dimesylate is (2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexaneamide;methanesulfonic acid. When used in this disclosure, the particle size of lisdexamfetamine dimesylate is 100 microns or less.

[0060] The structural formula of lisdexamfetamine dimesylate shows that the molecule of lisdexamfetamine dimesylate contains two chiral centers. Therefore, there are four possible enantiomers of this compound: (2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexaneamide; (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexaneamide; (2S)-2,6-diamino-N-[(2R)-1-phenylpropan-2-yl]hexaneamide; and (2R)-2,6-diamino-N-[(2R)-1-phenylpropan-2-yl]hexaneamide.

[0061] Lisdexamfetamine dimesylate, also known as amphetamine, is a white or nearly white crystalline powder therapeutically classified as a CNS stimulant. Lisdexamfetamine dimesylate is freely soluble in methanol, soluble in ethanol, very slightly soluble in acetone, chloroform, and toluene, and practically insoluble in tetrahydrofuran.

[0062] Characteristically, lisdexamfetamine dimesylate is inherently hygroscopic and is generally used to treat attention deficit hyperactivity disorder (ADHD) and moderate to severe bulimia nervosa (BED) in adults.

[0063] In one or more embodiments, during the drying and mixing step, the diluent is mannitol granules 200SD, and the diluent is present in an amount of about 18 to about 23% by weight.

[0064] As used herein, Mannitol Granules 200SD is used in the preparation of lisdexamfetamine dimesylate dispersible tablets. Mannitol Granules 200SD is used to adjust the average weight of lisdexamfetamine dimesylate dispersible tablets. Mannitol Granules 200SD also improves the flow properties and mouthfeel of lisdexamfetamine dimesylate dispersible tablet formulations. In this disclosure, Mannitol Granules 200SD is used in two parts to improve the uniformity and distribution of the drug in the formulation: firstly as a diluent and secondly as a filler. In one example, Mannitol Granules 200SD is Pearlitol® 200SD.

[0065] In one or more embodiments, during the drying and mixing step, the binder is partially gelatinized corn starch, and the binder is present in an amount of about 10 to about 20% by weight.

[0066] As used herein, partially gelatinized corn starch is used in the preparation of lisdexamfetamine dimesylate dispersible tablets. Lisdexamfetamine dimesylate, as the active substance, is a hygroscopic molecule and therefore changes to a liquid form when maintained at room temperature. Thus, to maintain the active lisdexamfetamine dimesylate in its solid form, swellable partially gelatinized corn starch is used in these lisdexamfetamine dimesylate dispersible tablets. Partially gelatinized corn starch improves the flow properties of the powder and ensures uniformity. When gelatinized corn starch comes into contact with an aqueous dissolving medium, it swells and disintegrates. This significantly reduces the adhesion of the powder. One example of partially gelatinized corn starch is Starch1500®.

[0067] In one or more embodiments, the antistatic agent in the dry mixing step is colloidal anhydrous silica, and the antistatic agent is present in an amount of about 1 to about 2% by weight.

[0068] As used herein, colloidal anhydrous silica is used in the preparation of lisdexamfetamine dimesylate dispersible tablets. Colloidal anhydrous silica is an adsorbent, a caking inhibitor, and a lubricant. Colloidal anhydrous silica improves the flowability of powders. One example of colloidal anhydrous silica is Aerosil® 200.

[0069] In one or more embodiments, during the intermediate granule blending step, the filler is mannitol granules 200SD, and the filler is present in an amount of about 28 to about 34% by weight.

[0070] As used herein, Mannitol Granules 200SD is used as a filler in the intermediate granule blending process in the preparation of lisdexamfetamine dimesylate dispersible tablets. Mannitol Granules 200SD is used to adjust the average weight of the lisdexamfetamine dimesylate dispersible tablets. Mannitol Granules 200SD also improves the flow properties and mouthfeel of the lisdexamfetamine dimesylate dispersible tablet formulation. Mannitol Granules 200SD is used in this disclosure in two parts: firstly as a diluent and secondly as a filler to improve the uniformity and distribution of the drug in the formulation. In one example, Mannitol Granules 200SD is Pearlitol® 200SD.

[0071] In one or more embodiments, the buffer is microcrystalline cellulose in the intermediate granule blending step, and the buffer is present in an amount of about 8 to about 12% by weight.

[0072] As used herein, microcrystalline cellulose is used in the preparation of lisdexamfetamine dimesylate dispersible tablets. Microcrystalline cellulose is inherently crystalline. Microcrystalline cellulose improves powder flow and aids in tablet compression to give the desired hardness. Microcrystalline cellulose also acts as a buffer. Due to its plasticity, microcrystalline cellulose is often used as an excipient for both tablet compression and pelletizing processes. As a buffer, microcrystalline cellulose fills the spaces between particles and mitigates the effects of compressive forces generated throughout the tableting process. One example of microcrystalline cellulose is Vivapur® 112.

[0073] In one or more embodiments, the disintegrant in the intermediate granule blending step is crospovidone, and the disintegrant is present in an amount of about 6 to about 10% by weight.

[0074] As used herein, crospovidone is used in the preparation of lisdexamfetamine dimesylate dispersible tablets. Crospovidone is a water-insoluble tablet disintegrant and solvent. Crospovidone exhibits high capillary activity and remarkable hydration ability rapidly, with little tendency to form gels. For example, crospovidone is Kollidone® CL.

[0075] In one or more embodiments, the sweetener in the intermediate granule blending step is sucralose, and the sweetener is present in an amount of about 1 to about 4% by weight.

[0076] As used herein, sucralose is used in the preparation of lisdexamfetamine dimesylate dispersible tablets. Sucralose is a white to off-white, free-flowing crystalline powder with a sweetness level approximately 300 to 1000 times that of sucrose and no aftertaste.

[0077] In one or more embodiments, the lubricant in the lubrication step is magnesium stearate, and the lubricant is present in an amount of about 1 to about 2% by weight.

[0078] As used herein, magnesium stearate is used in the preparation of lisdexamfetamine dimesylate dispersible tablets. Magnesium stearate is a fine powder with low bulk density. It is very fine, has a greasy texture, is lightweight, white, and is essentially precipitated or pulverized. Functionally, magnesium stearate is used as a lubricant in the manufacture of capsules and tablets. In the pharmaceutical industry, magnesium stearate powder adheres readily to the surface of tablets due to its characteristic oiliness, ensuring that tablets are ejected cleanly without cracking or breaking.

[0079] In one or more embodiments, the dosage of lisdexamfetamine dimesylate dispersible tablets is 10 mg per tablet, 20 mg per tablet, 30 mg per tablet, 40 mg per tablet, 50 mg per tablet, 60 mg per tablet, and 70 mg per tablet.

[0080] In one or more embodiments, dissolution is 75% or more in 15 minutes.

[0081] In one or more embodiments, the fracturability is 1.5% or less, the disintegration time is less than 3 minutes at 15°C to 25°C (without disc), and the hardness is approximately 30N to approximately 70N.

[0082] In one or more embodiments, the compression step uses a direct compression technique at a controlled humidity level of 40% NMT to reduce exposure to moisture.

[0083] Referring again to Figure 6, after compression of the lisdexamfetamine dimesylate dispersible tablets in step 602, lisdexamfetamine dimesylate dispersible tablets are obtained in step 604. The lisdexamfetamine dimesylate dispersible tablets obtained in step 604 are stored in a black double-lined polybag inside an HDPE drum containing a silica gel bag as a desiccant. Before primary packaging, the drum is stored in a quarantine area at a temperature below 25°C. Here, the compression yield exceeds 95%.

[0084] In one or more embodiments, the preparation method further includes packaging lisdexamfetamine dimesylate dispersible tablets in a moisture-resistant ALU peel blister package and / or a moisture-resistant ALU-ALU blister package.

[0085] Referring again to Figure 6, step 606 involves packaging the lisdexamfetamine dimesylate dispersible tablets obtained in step 604. In one embodiment, the compressed lisdexamfetamine dimesylate dispersible tablets are packaged in a moisture-resistant ALU peel-off blister package. In another embodiment, the compressed lisdexamfetamine dimesylate dispersible tablets are packaged in a moisture-resistant ALU-ALU blister package.

[0086] Lisdexamfetamine dimesylate dispersible tablets disperse rapidly in water, producing a uniform dispersion that ensures dose consistency and the desired therapeutic outcome.

[0087] Dispersible tablets, as defined in Ph.Eur, are uncoated or film-coated tablets intended to be dispersed in water before administration to obtain a uniform dispersion. Typically, dispersible tablets are dispersed in approximately 5–15 ml of water, and the resulting dispersion is administered to the patient. Dispersible tablets must disintegrate within 3 minutes in water at 15–25°C. Furthermore, the dispersion produced from the dispersible tablets should pass through a sieve screen with a nominal mesh opening of 710 microns. The dosage form offers the advantages of both tablets and liquid formulations. They are convenient to carry, easy to manufacture, and highly stable.

[0088] Table 1 shows the weight percentages of APIs and excipients at various stages of the preparation method. [Table 1]

[0089] The alternative embodiment of the method for preparing lisdexamfetamine dimesylate can be used as a method for preparing lisdexamfetamine dimesylate orally dispersible tablets or ODT tablets.

[0090] Table 2 shows the physical properties (mg / tablet) of lisdexamfetamine dimesylate dispersible tablets at 10, 20, 30, 40, 50, 60, and 70 mg / tablet concentrations. [Table 2]

[0091] The following non-limiting examples further illustrate lisdexamfetamine dimesylate dispersible tablets and processes for their preparation. Those skilled in the art will recognize that the specific examples are intended to be illustrative and not limit the scope of this disclosure.

[0092] Example 1 Example 1 describes a method for preparing lisdexamfetamine dimesylate dispersible tablets. In particular, it describes a method for preparing lisdexamfetamine dimesylate dispersible tablets having a strength of 10 mg per tablet.

[0093] Table 3 shows the amounts of API and excipients (mg / tablet) for lisdexamfetamine dimesylate (10 mg) dispersible tablets. [Table 3]

[0094] The method begins by dry mixing lisdexamfetamine dimesylate with a diluent, a binder, and an antistatic agent to form a dry mixture blend. Specifically, in Part I, 20.75 mg of 200 SD mannitol granules are sieved through a 36-mesh vibrating sieve to obtain a clump of sieved 200 SD mannitol granules free of aggregates. Then, in Part II, 10 mg of lisdexamfetamine dimesylate, 15 mg of partially gelatinized corn starch, and 1.50 mg of colloidal anhydrous silica are simultaneously sieved through a 36-mesh vibrating sieve to obtain a clump of sieved lisdexamfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica free of aggregates.

[0095] Subsequently, as a first mixing level, the sieved lisdexanfetamine dimesylate obtained in the previous step, along with partially gelatinized corn starch and colloidal anhydrous silica, is blended in a blender at 8 RPM for 30 minutes to form a blended mixture of lisdexanfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica.

[0096] Subsequently, as a second mixing level, the blended mixture is further blended in a contablender at 8 RPM for 15 minutes to obtain the blended material. The blended material is then transferred to an HDPE container lined with a polyethylene bag, and sieved mannitol granules (200 SD), free of aggregates, are added to form a dry mixture blend.

[0097] In the next step, the filler, buffer, disintegrant, and sweetener are blended to form an intermediate granular blend.

[0098] Specifically, 31 mg of mannitol granules 200SD, 10 mg of microcrystalline cellulose, 8 mg of crospovidone, and 2.50 mg of sucralose are passed through a 36-mesh vibrating sieve and simultaneously sieved to obtain a mass of mannitol granules 200SD, microcrystalline cellulose, crospovidone, and sucralose that does not contain aggregates.

[0099] Subsequently, the sieved mannitol granules 200SD obtained in the previous step, along with microcrystalline cellulose, crospovidone, and sucralose, free of aggregates, are blended in a contablender at 8 RPM for 15 minutes to obtain an intermediate granule blend. This intermediate granule blend is further divided into two parts: the first half and the second half. The first half is transferred to an HDPE container lined with a polybag, while the second half remains in the contablender bottle.

[0100] The next step in the preparation method involves adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend. In this step, the dry mixture blend is added to the latter half of the intermediate granule blend, followed by the first half of the intermediate granule blend. The latter half of the intermediate granule blend, the dry mixture blend, and the first half of the intermediate granule blend are successively added to a contablender bottle, and the mixture is blended at 8 RPM for 30 minutes to obtain the intermediate drug blend.

[0101] The next step in the method involves lubricating the intermediate drug blend with magnesium stearate to form drug granules ready for compression. Here, 1.25 mg of magnesium stearate is sieved through a 40-mesh vibrating sieve to obtain a clump of sieved magnesium stearate that does not contain aggregates. Furthermore, the sieved magnesium stearate is added to the intermediate drug blend obtained in the previous step and blended in a contablender at 8 RPM for 10 minutes to obtain drug granules ready for compression.

[0102] Subsequently, the drug granules ready for compression are compressed using a direct compression technique with a controlled humidity level of 40% NMT to reduce moisture exposure, simultaneously forming 10 mg lisdexamfetamine dimesylate dispersible tablets.

[0103] Table 4A shows the product description for compressed lisdexamfetamine dimesylate (10 mg) dispersible tablets. [Table 4]

[0104] In one embodiment, the disintegration time of a lisdexamfetamine dimesylate (10 mg) dispersible tablet is 58 seconds.

[0105] Table 4B shows the physical properties of lisdexamfetamine dimesylate (10 mg) dispersible tablets. [Table 5]

[0106] Example 2 Example 2 describes a method for preparing lisdexamfetamine dimesylate dispersible tablets. In particular, it describes a method for preparing lisdexamfetamine dimesylate dispersible tablets having a strength of 20 mg per tablet.

[0107] Table 5 shows the amounts of API and excipients (mg / tablet) for lisdexamfetamine dimesylate (20 mg) dispersible tablets. [Table 6]

[0108] The method begins by dry mixing lisdexamfetamine dimesylate with a diluent, a binder, and an antistatic agent to form a dry mixture blend. Specifically, in Part I, 41.50 mg of 200 SD mannitol granules are sieved through a 36-mesh vibrating sieve to obtain a clump of sieved 200 SD mannitol granules free of aggregates. Then, in Part II, 20 mg of lisdexamfetamine dimesylate, 30 mg of partially gelatinized corn starch, and 3 mg of colloidal anhydrous silica are simultaneously sieved through a 36-mesh vibrating sieve to obtain a clump of sieved lisdexamfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica free of aggregates.

[0109] Subsequently, as a first mixing level, the sieved lisdexanfetamine dimesylate obtained in the previous step, along with partially gelatinized corn starch and colloidal anhydrous silica, is blended in a blender at 8 RPM for 30 minutes to form a blended mixture of lisdexanfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica.

[0110] Subsequently, as a second mixing level, the blended mixture is further blended in a contablender at 8 RPM for 15 minutes to obtain the blended material. The blended material is then transferred to an HDPE container lined with a polyethylene bag, and sieved mannitol granules (200 SD), free of aggregates, are added to form a dry mixture blend.

[0111] As the next step in the preparation method, the filler, buffer, disintegrant, and sweetener are blended to form an intermediate granule blend.

[0112] Specifically, 62 mg of mannitol granules 200SD, 20 mg of microcrystalline cellulose, 16 mg of crospovidone, and 5 mg of sucralose are passed through a 36-mesh vibrating sieve and simultaneously sieved to obtain a mass of mannitol granules 200SD, microcrystalline cellulose, crospovidone, and sucralose that does not contain aggregates.

[0113] Subsequently, the sieved mannitol granules 200SD obtained in the previous step, along with microcrystalline cellulose, crospovidone, and sucralose, free of aggregates, are blended in a contablender at 8 RPM for 15 minutes to obtain an intermediate granule blend. This intermediate granule blend is further divided into two parts: the first half and the second half. The first half is transferred to an HDPE container lined with a polybag, while the second half remains in the contablender bottle.

[0114] The next step in the preparation method involves adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend. In this step, the dry mixture blend is added to the latter half of the intermediate granule blend, followed by the first half of the intermediate granule blend. The latter half of the intermediate granule blend, the dry mixture blend, and the first half of the intermediate granule blend are successively added to a contablender bottle, and the mixture is blended at 8 RPM for 30 minutes to obtain the intermediate drug blend.

[0115] The next step in the preparation method involves lubricating the intermediate drug blend with magnesium stearate to form drug granules ready for compression. Here, 2.50 mg of magnesium stearate is sieved through a 40-mesh vibrating sieve to obtain a clump of sieved magnesium stearate that does not contain aggregates. Furthermore, the sieved magnesium stearate is added to the intermediate drug blend obtained in the previous step and blended in a contablender at 8 RPM for 10 minutes to obtain drug granules ready for compression.

[0116] Subsequently, the drug granules ready for compression are compressed using a direct compression technique with a controlled humidity level of 40% NMT to reduce moisture exposure, simultaneously forming 20 mg lisdexamfetamine dimesylate dispersible tablets.

[0117] Table 6A shows the product description for compressed lisdexamfetamine dimesylate (20 mg) dispersible tablets. [Table 7]

[0118] In one embodiment, the disintegration time for a compressed lisdexamfetamine dimesylate (20 mg) dispersible tablet is 35 seconds.

[0119] Table 6B shows the physical properties of compressed lisdexamfetamine dimesylate (20 mg) dispersible tablets. [Table 8]

[0120] Example 3 Example 3 describes a method for preparing lisdexamfetamine dimesylate dispersible tablets. In particular, it describes a method for preparing lisdexamfetamine dimesylate dispersible tablets having a strength of 30 mg per tablet.

[0121] Table 7 shows the amounts of API and excipients (mg / tablet) for lisdexamfetamine dimesylate (30 mg) dispersible tablets. [Table 9]

[0122] The method begins by dry mixing lisdexamfetamine dimesylate with a diluent, a binder, and an antistatic agent to form a dry mixture blend. Specifically, in Part I, 62.25 mg of 200 SD mannitol granules are sieved through a 36-mesh vibrating sieve to obtain a clump of sieved 200 SD mannitol granules free of aggregates. Then, in Part II, 30 mg of lisdexamfetamine dimesylate, 45 mg of partially gelatinized corn starch, and 4.50 mg of colloidal anhydrous silica are simultaneously sieved through a 36-mesh vibrating sieve to obtain a clump of sieved lisdexamfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica free of aggregates.

[0123] Subsequently, as a first mixing level, the sieved lisdexanfetamine dimesylate obtained in the previous step, along with partially gelatinized corn starch and colloidal anhydrous silica, is blended in a blender at 8 RPM for 30 minutes to form a blended mixture of lisdexanfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica.

[0124] Subsequently, as a second mixing level, the blended mixture is further blended in a contablender at 8 RPM for 15 minutes to obtain the blended material. The blended material is then transferred to an HDPE container lined with a polyethylene bag, and 200 SD of mannitol granules, free of aggregates, is added to form a dry mixture blend.

[0125] In the next step, the filler, buffer, disintegrant, and sweetener are blended to form an intermediate granular blend.

[0126] Specifically, 93 mg of mannitol granules 200SD, 30 mg of microcrystalline cellulose, 24 mg of crospovidone, and 7.50 mg of sucralose are passed through a 36-mesh vibrating sieve and simultaneously sieved to obtain a mass of mannitol granules 200SD, microcrystalline cellulose, crospovidone, and sucralose that does not contain aggregates.

[0127] Subsequently, the sieved mannitol granules 200SD obtained in the previous step, along with microcrystalline cellulose, crospovidone, and sucralose, free of aggregates, are blended in a contablender at 8 RPM for 15 minutes to obtain an intermediate granule blend. This intermediate granule blend is further divided into two parts: the first half and the second half. The first half is transferred to an HDPE container lined with a polybag, while the second half remains in the contablender bottle.

[0128] The next step in the method involves adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend. In this step, the dry mixture blend is added to the latter half of the intermediate granule blend, followed by the first half of the intermediate granule blend. The latter half of the intermediate granule blend, the dry mixture blend, and the first half of the intermediate granule blend are successively added to a contablender bottle, and the mixture is blended at 8 RPM for 30 minutes to obtain the intermediate drug blend.

[0129] The next step in the preparation method involves lubricating the intermediate drug blend with magnesium stearate to form drug granules ready for compression. Here, 3.75 mg of magnesium stearate is sieved through a 40-mesh vibrating sieve to obtain a clump of sieved magnesium stearate that does not contain aggregates. Furthermore, the sieved magnesium stearate is added to the intermediate drug blend obtained in the previous step and blended in a contablender at 8 RPM for 10 minutes to obtain drug granules ready for compression.

[0130] Subsequently, the drug granules ready for compression are compressed using a direct compression technique with a controlled humidity level of 40% NMT to reduce moisture exposure, simultaneously forming 30 mg lisdexamfetamine dimesylate dispersible tablets.

[0131] Table 8A shows the amounts of API and excipients (mg / tablet) for lisdexamfetamine dimesylate (30 mg) dispersible tablets. [Table 10]

[0132] In one embodiment, for a compressed lisdexamfetamine dimesylate (30 mg) dispersible tablet, the disintegration time is 30 seconds.

[0133] Table 8B shows the physical properties of compressed lisdexamfetamine dimesylate (30 mg) dispersible tablets. [Table 11]

[0134] Example 4 Example 4 describes a method for preparing lisdexamfetamine dimesylate dispersible tablets. In particular, it describes a method for preparing lisdexamfetamine dimesylate dispersible tablets having a strength of 40 mg per tablet.

[0135] Table 9 shows the amounts of API and excipients (mg / tablet) for lisdexamfetamine dimesylate (40 mg) dispersible tablets. [Table 12]

[0136] The method begins by dry mixing lisdexamfetamine dimesylate with a diluent, a binder, and an antistatic agent to form a dry mixture blend. Specifically, in Part I, 83 mg of 200 SD of mannitol granules is sieved through a 36-mesh vibrating sieve to obtain a clump of sieved 200 SD of mannitol granules that does not contain aggregates. Then, in Part II, 40 mg of lisdexamfetamine dimesylate, 60 mg of partially gelatinized corn starch, and 6 mg of colloidal anhydrous silica are simultaneously sieved through a 36-mesh vibrating sieve to obtain a clump of sieved lisdexamfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica that does not contain aggregates.

[0137] Subsequently, as a first mixing level, the sieved lisdexanfetamine dimesylate obtained in the previous step, along with partially gelatinized corn starch and colloidal anhydrous silica, is blended in a blender at 8 RPM for 30 minutes to form a blended mixture of lisdexanfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica.

[0138] Subsequently, as a second mixing level, the blended mixture is further blended in a contablender at 8 RPM for 15 minutes to obtain the blended material. The blended material is then transferred to an HDPE container lined with a polyethylene bag, and 200 SD of mannitol granules, free of aggregates, is added to form a dry mixture blend.

[0139] In the next step, the filler, buffer, disintegrant, and sweetener are blended to form an intermediate granular blend.

[0140] Specifically, 124 mg of mannitol granules 200SD, 40 mg of microcrystalline cellulose, 32 mg of crospovidone, and 10 mg of sucralose are passed through a 36-mesh vibrating sieve and simultaneously sieved to obtain a mass of mannitol granules 200SD, microcrystalline cellulose, crospovidone, and sucralose that does not contain aggregates.

[0141] Subsequently, the sieved mannitol granules 200SD obtained in the previous step, along with microcrystalline cellulose, crospovidone, and sucralose, free of aggregates, are blended in a contablender at 8 RPM for 15 minutes to obtain an intermediate granule blend. This intermediate granule blend is further divided into two parts: the first half and the second half. The first half is transferred to an HDPE container lined with a polybag, while the second half remains in the contablender bottle.

[0142] The next step in the preparation method involves adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend. In this step, the dry mixture blend is added to the latter half of the intermediate granule blend, followed by the first half of the intermediate granule blend. The latter half of the intermediate granule blend, the dry mixture blend, and the first half of the intermediate granule blend are successively added to a contablender bottle, and the mixture is blended at 8 RPM for 30 minutes to obtain the intermediate drug blend.

[0143] The next step in the preparation method involves lubricating the intermediate drug blend with magnesium stearate to form drug granules ready for compression. Here, 5 mg of magnesium stearate is sieved through a 40-mesh vibrating sieve to obtain a clump of sieved magnesium stearate that does not contain aggregates. Furthermore, the sieved magnesium stearate is added to the intermediate drug blend obtained in the previous step and blended in a contablender at 8 RPM for 10 minutes to obtain drug granules ready for compression.

[0144] Subsequently, the drug granules ready for compression are compressed using a direct compression technique with a controlled humidity level of 40% NMT to reduce moisture exposure, simultaneously forming 40 mg lisdexamfetamine dimesylate dispersible tablets.

[0145] Table 10A shows the product description for compressed lisdexamfetamine dimesylate (40 mg) dispersible tablets. [Table 13]

[0146] In one embodiment, the disintegration time for a compressed lisdexamfetamine dimesylate (40 mg) dispersible tablet is 45 seconds.

[0147] Table 10B shows the physical properties of compressed lisdexamfetamine dimesylate (40 mg) dispersible tablets. [Table 14]

[0148] Example 5 Example 5 describes a method for preparing lisdexamfetamine dimesylate dispersible tablets. In particular, it describes a method for preparing lisdexamfetamine dimesylate dispersible tablets having a strength of 50 mg per tablet.

[0149] Table 11 shows the amounts of API and excipients (mg / tablet) for lisdexamfetamine dimesylate (50 mg) dispersible tablets. [Table 15]

[0150] The method begins by dry mixing lisdexamfetamine dimesylate with a diluent, a binder, and an antistatic agent to form a dry mixture blend. Specifically, in Part I, 103.75 mg of 200 SD of mannitol granules is sieved through a 36-mesh vibrating sieve to obtain a clump of sieved 200 SD of mannitol granules that does not contain aggregates. Then, in Part II, 50 mg of lisdexamfetamine dimesylate, 75 mg of partially gelatinized corn starch, and 7.5 mg of colloidal anhydrous silica are simultaneously sieved through a 36-mesh vibrating sieve to obtain a clump of sieved lisdexamfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica that does not contain aggregates.

[0151] Subsequently, as a first mixing level, the sieved lisdexanfetamine dimesylate obtained in the previous step, along with partially gelatinized corn starch and colloidal anhydrous silica, is blended in a blender at 8 RPM for 30 minutes to form a blended mixture of lisdexanfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica.

[0152] Subsequently, as a second mixing level, the blended mixture is further blended in a contablender at 8 RPM for 15 minutes to obtain the blended material. The blended material is then transferred to an HDPE container lined with a polyethylene bag, and sieved mannitol granules (200 SD), free of aggregates, are added to form a dry mixture blend.

[0153] In the next step, the filler, buffer, disintegrant, and sweetener are blended to form an intermediate granular blend.

[0154] Specifically, 155 mg of mannitol granules 200SD, 50 mg of microcrystalline cellulose, 40 mg of crospovidone, and 12.5 mg of sucralose are passed through a 36-mesh vibrating sieve and simultaneously sieved to obtain a mass of mannitol granules 200SD, microcrystalline cellulose, crospovidone, and sucralose that does not contain aggregates.

[0155] Subsequently, the sieved mannitol granules 200SD obtained in the previous step, along with microcrystalline cellulose, crospovidone, and sucralose, free of aggregates, are blended in a contablender at 8 RPM for 15 minutes to obtain an intermediate granule blend. This intermediate granule blend is further divided into two parts: the first half and the second half. The first half is transferred to an HDPE container lined with a polybag, while the second half remains in the contablender bottle.

[0156] The next step in the preparation method involves adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend. In this step, the dry mixture blend is added to the latter half of the intermediate granule blend, followed by the first half of the intermediate granule blend. The latter half of the intermediate granule blend, the dry mixture blend, and the first half of the intermediate granule blend are successively added to a contablender bottle, and the mixture is blended at 8 RPM for 30 minutes to obtain the intermediate drug blend.

[0157] The next step in the preparation method involves lubricating the intermediate drug blend with magnesium stearate to form drug granules ready for compression. Here, 6.25 mg of magnesium stearate is sieved through a 40-mesh vibrating sieve to obtain a clump of sieved magnesium stearate that does not contain aggregates. Furthermore, the sieved magnesium stearate is added to the intermediate drug blend obtained in the previous step and blended in a contablender at 8 RPM for 10 minutes to obtain drug granules ready for compression.

[0158] Subsequently, the drug granules ready for compression are compressed using a direct compression technique with a controlled humidity level of 40% NMT to reduce moisture exposure, simultaneously forming 50 mg lisdexamfetamine dimesylate dispersible tablets.

[0159] Table 12A shows the product description for compressed lisdexamfetamine dimesylate (50 mg) dispersible tablets. [Table 16]

[0160] In one embodiment, the disintegration time for a compressed lisdexamfetamine dimesylate (50 mg) dispersible tablet is 48 seconds.

[0161] Table 12B shows the physical properties of compressed lisdexamfetamine dimesylate (50 mg) dispersible tablets. [Table 17]

[0162] Example 6 Example 6 describes a method for preparing lisdexamfetamine dimesylate dispersible tablets. In particular, it describes a method for preparing lisdexamfetamine dimesylate dispersible tablets having a strength of 60 mg per tablet.

[0163] Table 13 shows the amounts of API and excipients (mg / tablet) for lisdexamfetamine dimesylate (60 mg) dispersible tablets. [Table 18]

[0164] The method begins by dry mixing lisdexamfetamine dimesylate with a diluent, a binder, and an antistatic agent to form a dry mixture blend. Specifically, in Part I, 124.50 mg of 200 SD mannitol granules are sieved through a 36-mesh vibrating sieve to obtain a clump of sieved 200 SD mannitol granules free of aggregates. Then, in Part II, 60 mg of lisdexamfetamine dimesylate, 90 mg of partially gelatinized corn starch, and 9 mg of colloidal anhydrous silica are simultaneously sieved through a 36-mesh vibrating sieve to obtain a clump of sieved lisdexamfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica free of aggregates.

[0165] Subsequently, as a first mixing level, the sieved lisdexanfetamine dimesylate obtained in the previous step, along with partially gelatinized corn starch and colloidal anhydrous silica, is blended in a blender at 8 RPM for 30 minutes to form a blended mixture of lisdexanfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica.

[0166] Subsequently, as a second mixing level, the blended mixture is further blended in a contablender at 8 RPM for 15 minutes to obtain the blended material. The blended material is then transferred to an HDPE container lined with a polyethylene bag, and sieved mannitol granules (200 SD), free of aggregates, are added to form a dry mixture blend.

[0167] In the next step, the filler, buffer, disintegrant, and sweetener are blended to form an intermediate granular blend.

[0168] Specifically, 186 mg of mannitol granules 200SD, 60 mg of microcrystalline cellulose, 48 mg of crospovidone, and 15 mg of sucralose are passed through a 36-mesh vibrating sieve and simultaneously sieved to obtain a mass of mannitol granules 200SD, microcrystalline cellulose, crospovidone, and sucralose that does not contain aggregates.

[0169] Subsequently, the sieved mannitol granules 200SD obtained in the previous step, along with microcrystalline cellulose, crospovidone, and sucralose, free of aggregates, are blended in a contablender at 8 RPM for 15 minutes to obtain an intermediate granule blend. This intermediate granule blend is further divided into two parts: the first half and the second half. The first half is transferred to an HDPE container lined with a polybag, while the second half remains in the contablender bottle.

[0170] The next step in the preparation method involves adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend. In this step, the dry mixture blend is added to the latter half of the intermediate granule blend, followed by the first half of the intermediate granule blend. The latter half of the intermediate granule blend, the dry mixture blend, and the first half of the intermediate granule blend are successively added to a contablender bottle, and the mixture is blended at 8 RPM for 30 minutes to obtain the intermediate drug blend.

[0171] The next step in the preparation method involves lubricating the intermediate drug blend with magnesium stearate to form drug granules ready for compression. Here, 7.50 mg of magnesium stearate is sieved through a 40-mesh vibrating sieve to obtain a clump of sieved magnesium stearate that does not contain aggregates. Furthermore, the sieved magnesium stearate is added to the intermediate drug blend obtained in the previous step and blended in a contablender at 8 RPM for 10 minutes to obtain drug granules ready for compression.

[0172] Subsequently, the drug granules ready for compression are compressed using a direct compression technique with a controlled humidity level of 40% NMT to reduce moisture exposure, simultaneously forming 60 mg lisdexamfetamine dimesylate dispersible tablets.

[0173] Table 14A shows the product description for compressed lisdexamfetamine dimesylate (60 mg) dispersible tablets. [Table 19]

[0174] In one embodiment, the disintegration time for a compressed lisdexamfetamine dimesylate (60 mg) dispersible tablet is 48 seconds.

[0175] Table 14B shows the physical properties of compressed lisdexamfetamine dimesylate (60 mg) dispersible tablets. [Table 20]

[0176] Example 7 Example 7 describes a method for preparing lisdexamfetamine dimesylate dispersible tablets. In particular, it describes a method for preparing lisdexamfetamine dimesylate dispersible tablets having a strength of 70 mg per tablet.

[0177] Table 15 shows the amounts of API and excipients (mg / tablet) for lisdexamfetamine dimesylate (70 mg) dispersible tablets. [Table 21]

[0178] The method begins by dry mixing lisdexamfetamine dimesylate with a diluent, a binder, and an antistatic agent to form a dry mixture blend. Specifically, in Part I, 145.25 mg of 200 SD mannitol granules are sieved through a 36-mesh vibrating sieve to obtain a clump of sieved 200 SD mannitol granules free of aggregates. Then, in Part II, 70 mg of lisdexamfetamine dimesylate, 105 mg of partially gelatinized corn starch, and 10.50 mg of colloidal anhydrous silica are simultaneously sieved through a 36-mesh vibrating sieve to obtain a clump of sieved lisdexamfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica free of aggregates.

[0179] Subsequently, as a first mixing level, the sieved lisdexanfetamine dimesylate obtained in the previous step, along with partially gelatinized corn starch and colloidal anhydrous silica, is blended in a blender at 8 RPM for 30 minutes to form a blended mixture of lisdexanfetamine dimesylate, partially gelatinized corn starch, and colloidal anhydrous silica.

[0180] Subsequently, as a second mixing level, the blended mixture is further blended in a contablender at 8 RPM for 15 minutes to obtain the blended material. The blended material is then transferred to an HDPE container lined with a polyethylene bag, and 200 SD of mannitol granules, free of aggregates, is added to form a dry mixture blend.

[0181] As the next step in the preparation method, the filler, buffer, disintegrant, and sweetener are blended to form an intermediate granule blend.

[0182] Specifically, 217 mg of mannitol granules 200SD, 70 mg of microcrystalline cellulose, 56 mg of crospovidone, and 17.50 mg of sucralose are passed through a 36-mesh vibrating sieve and simultaneously sieved to obtain a mass of mannitol granules 200SD, microcrystalline cellulose, crospovidone, and sucralose that does not contain aggregates.

[0183] Next, the sieved mannitol granules 200SD obtained in the previous step, along with microcrystalline cellulose, crospovidone, and sucralose, which are free of aggregates, are blended in a contablender at 8 RPM for 15 minutes to obtain an intermediate granule blend. The intermediate granule blend obtained in this step is further divided into two parts: the first half and the second half. The first half of the intermediate granule blend is removed into an HDPE container lined with a polybag, while the second half is left in the contablender bottle.

[0184] The next step in the preparation method involves adding and blending the dry mixture blend and the intermediate granule blend to form an intermediate drug blend. In this step, the dry mixture blend is added to the latter half of the intermediate granule blend, followed by the first half of the intermediate granule blend. The latter half of the intermediate granule blend, the dry mixture blend, and the first half of the intermediate granule blend are successively added to a contablender bottle, and the mixture is blended at 8 RPM for 30 minutes to obtain the intermediate drug blend.

[0185] The next step in the preparation method involves lubricating the intermediate drug blend with magnesium stearate to form drug granules ready for compression. Here, 8.75 mg of magnesium stearate is sieved through a 40-mesh vibrating sieve to obtain a clump of sieved magnesium stearate that does not contain aggregates. Furthermore, the sieved magnesium stearate is added to the intermediate drug blend obtained in the previous step and blended in a contablender at 8 RPM for 10 minutes to obtain drug granules ready for compression.

[0186] Subsequently, the drug granules ready for compression are compressed using a direct compression technique with a controlled humidity level of 40% NMT to reduce moisture exposure, simultaneously forming 70 mg lisdexamfetamine dimesylate dispersible tablets.

[0187] Table 16A shows the product description for compressed lisdexamfetamine dimesylate (70 mg) dispersible tablets. [Table 22]

[0188] In one embodiment, the disintegration time for a compressed lisdexamfetamine dimesylate (70 mg) dispersible tablet is 46 seconds.

[0189] Table 16B shows the physical properties of compressed lisdexamfetamine dimesylate (70 mg) dispersible tablets. [Table 23]

[0190] test: The data included in the test results represent readings for moisture-controlled tablet compositions, i.e., tablets where the deliquescence of the API is taken into account; in other words, data on how the exact combination of the drug with any different excipients results in formulations / compositions that have no or slight deliquescence.

[0191] To demonstrate that compositions containing lisdexamfetamine dimesylate do not exhibit deliquescence, a series of tests were conducted to evaluate the stability, durability, and resistance to various forms of degradation of tablet compositions containing lisdexamfetamine dimesylate.

[0192] The tests include accelerated degradation tests to evaluate resistance to degradation over time; chemical resistance / compatibility tests to evaluate the suitability of the excipient material to lisdexamfetamine dimesylate tablets; and hygroscopic tests to demonstrate that there is no significant increase in moisture absorption levels due to tablets containing lisdexamfetamine dimesylate.

[0193] (Accelerated degradation test) The tablet composition was subjected to accelerated stability conditions, such as high temperature of 40°C and humidity of 75% RH, to simulate long-term environmental exposure. To evaluate resistance to degradation over time, the performance of tablets containing lisdexamfetamine dimesylate was evaluated before and after degradation.

[0194] Table 17 shows the results of accelerated degradation tests conducted on tablet compositions containing lisdexamfetamine dimesylate. [Table 24]

[0195] The results clearly show that there is no change in the hardness of the tablet composition containing lisdexamfetamine dimesylate. The absence of a decrease or change in the hardness of the tablets confirms the mechanical properties of the material, as well as its ability to withstand stress and deformation without showing any signs of deliquescence.

[0196] (Chemical resistance test / Conformity test) Tablet compositions were exposed to a range of chemicals commonly used in DT formulations to evaluate the tablets' resistance to chemical attack, including changes in appearance, physical properties, or structural integrity.

[0197] To perform conformity testing, the tablets are exposed to a high temperature of 40°C and a humidity of 75% RH under open and closed conditions, and to a temperature of 25°C and a humidity of 75% RH under open and closed conditions.

[0198] The results reveal a positive interpretation, indicating a high level of compatibility between the tablet composition containing lisdexamfetamine dimesylate and chemicals commonly used in DT formulations. The positive results obtained from the compatibility tests provide strong evidence supporting the suitability of the excipient materials for their intended use.

[0199] (Moisture absorption test) To determine the ability of a tablet composition containing lisdexamfetamine dimesylate to withstand moisture absorption, subject it to controlled humidity or water immersion tests. The amount of moisture absorbed by the tablet is measured, and its effect on dimensional stability, strength, and other relevant properties is evaluated.

[0200] Tablet compositions containing lisdexanfetamine dimesylate, as determined by using a KF analyzer under various storage conditions: 40°C / 75% relative humidity, 30°C / 75% relative humidity, 30°C / 65% relative humidity, and 25°C / 60% relative humidity.

[0201] The results clearly show that the water absorption content of tablet compositions containing lisdexamfetamine dimesylate remains the same. In summary, the tablets do not show a significant increase in water absorption levels.

[0202] Table 18 shows the results of the moisture absorption test for the tablet composition containing lisdexamfetamine dimesylate from BATCH1. [Table 25]

[0203] Table 19 shows the results of the moisture absorption test for the tablet composition containing lisdexamfetamine dimesylate from BATCH2. [Table 26]

[0204] Table 20 shows the results of the moisture absorption test for the tablet composition containing lisdexamfetamine dimesylate from BATCH3. [Table 27]

[0205] The stability reports for BATCH1, BATCH2, and BATCH3 emphasize the non-hygroscopicity of the lisdexamfetamine dimesylate dispersible composition. Based on the stability data (shown in Tables 18, 19, and 20), it can be concluded that there is no significant increase in water content under the storage conditions mentioned. Therefore, in other words, it can be concluded that the lisdexamfetamine dimesylate composition for dispersible tablets is stable.

[0206] Fineness test of disintegration and dispersion As mentioned, the dispersible tablets disintegrate within 3 minutes using water R at 15-25°C as the liquid medium.

[0207] The European Pharmacopoeia further instructs to add 2 tablets to 100 mL of water and stir until completely dispersed. This produces a smooth dispersion that passes through a sieve screen with a nominal mesh opening of 710 μm.

[0208] When lisdexamfetamine dimesylate dispersible tablets prepared in accordance with the European Pharmacopoeia according to the preparation method disclosed herein are tested for disintegration and dispersion fineness, the tests reveal that the disintegration time and dispersion fineness comply with the acceptable criteria referred to in the European Pharmacopoeia.

[0209] Table 21 shows the results of tests conducted on the disintegration of dispersible tablets and the fineness of the dispersion. [Table 28]

[0210] This disclosure provides a method for preparing lisdexamfetamine dimesylate dispersible tablets and lisdexamfetamine dimesylate dispersible tablets prepared thereby. The lisdexamfetamine dimesylate dispersible tablets developed by the inventors are dispersible tablets in multiple dosages that are easy to ingest, dissolve rapidly, dissolve or melt or disintegrate in just a few seconds, and provide the desired therapeutic effect. This disclosure provides a method for preparing dispersible tablets that improves the disintegration, dissolution and free flow of components in the granules of the dosage form by employing physiological and chemical parameters during the method.

[0211] Lisdexamfetamine dimesylate dispersible tablets address the deliquescence problem of lisdexamfetamine dimesylate. Lisdexamfetamine dimesylate dispersible tablets rapidly disintegrate, allowing for rapid drug release from granules and rapid absorption in the body after administration. Furthermore, lisdexamfetamine dimesylate dispersible tablets are stable, palatable, and rapidly disintegrate. The preparation method for lisdexamfetamine dimesylate tablets also involves reduced process time and lower manufacturing costs. Additionally, the preparation method controls humidity to minimize exposure of the deliquescent material to moisture during the manufacturing of the dispersible tablets.

[0212] Lisdexamfetamine dimesylate dispersible tablets disintegrate or dissolve rapidly, and tablets in a form that can be dispersed upon ingestion allow for drug absorption within the gastrointestinal tract.

[0213] This disclosure provides a synergistic combination of API and excipients in specific ratios to address the deliquescence of lisdexamfetamine dimesylate. This synergistic combination improves the disintegration time of dispersible tablets. This disclosure further imparts improved palatability to tablet formulations of lisdexamfetamine dimesylate. This disclosure provides a humidity-controlled manufacturing method in which tablet formulations are manufactured in a humidity-controlled environment to minimize exposure of the deliquescent material to moisture during the manufacturing process. In particular, this manufacturing process uses a direct compression technique during the manufacturing process at a controlled humidity level of 40% NMT to reduce exposure to moisture.

[0214] This disclosure provides a method for preparing a lisdexamfetamine dimesylate composition in the form of dispersible tablets that overcome the drawbacks of solid compositions such as capsules and chewable tablets. To address the deliquescence of lisdexamfetamine dimesylate and provide a stable lisdexamfetamine dimesylate dispersible composition, a synergistic combination of API and excipients in specific ratios is formulated. The dissolution of the lisdexamfetamine dispersible tablet composition is 75% or more in 15 minutes.

[0215] The foregoing descriptions of specific embodiments of this disclosure are presented for illustrative and illustrative purposes only. They are not intended to be exhaustive or to limit this disclosure to the exact form disclosed, and many modifications and variations are obviously possible in light of the foregoing teachings. The embodiments have been selected and described to best illustrate the principles of this disclosure and their practical application, thereby enabling those skilled in the art to best utilize this disclosure and various embodiments with various modifications suited to the particular intended use. (Various omissions and substitutions of equivalents are contemplated where circumstances may suggest or may be advantageous, but it is understood that they are intended to cover the application or practice without departing from the spirit or scope of the claims of this disclosure).

[0216] This disclosure includes the following aspects: <1> Dry mixing of lisdexanfetamine dimesylate, diluent, binder, and antistatic agent to form a dry mixture blend. The process involves blending fillers, buffers, disintegrants, and sweeteners into an intermediate granular blend to form an intermediate granular blend. The dry mixture blend and the intermediate granule blend are added and blended to form an intermediate drug blend. The intermediate drug blend is lubricated with a lubricant to form drug granules ready for compression, and The drug granules prepared for compression are compressed to form lisdexamfetamine dimesylate dispersible tablets. A method for preparing lisdexamfetamine dimesylate dispersible tablets containing the above. <2> The aforementioned lisdexanfetamine dimesylate is present in an amount of approximately 8% to approximately 12% by weight. <1> Methods used. <3> In the dry mixing step, The diluent is mannitol granules 200SD, and the diluent is present in an amount of approximately 18% to approximately 23% by weight. The binder is partially gelatinized corn starch, and the binder is present in an amount of about 10% to about 20% by weight. The antistatic agent is colloidal anhydrous silica, and the antistatic agent is present in an amount of about 1% to about 2% by weight. <1> Methods used. <4> In the aforementioned intermediate granule blending step, The filler is mannitol granules 200SD, and the filler is present in an amount of approximately 28% to approximately 34% by weight. The buffer is microcrystalline cellulose, and the buffer is present in an amount of approximately 8% to approximately 12% by weight. The disintegrant is crospovidone, and the disintegrant is present in an amount of approximately 6% to approximately 10% by weight. The sweetener is sucralose, and the sweetener is present in an amount of approximately 1% to approximately 4% by weight. <1> Methods used. <5> In the lubrication process, the lubricant is magnesium stearate, and the lubricant is present in an amount of about 1% to about 2% by weight. <1> Methods used. <6> The dosages of the lisdexamfetamine dimesylate dispersible tablets are 10 mg per tablet, 20 mg per tablet, 30 mg per tablet, 40 mg per tablet, 50 mg per tablet, 60 mg per tablet, and 70 mg per tablet. <1> Methods used. <7> Dissolution is 75% or more in 15 minutes. <1> Methods used. <8> The material has a fracture rate of 1.5% or less, a disintegration time of less than 3 minutes at 15°C to 25°C (without discs), and a hardness of approximately 30N to 70N. <1> Methods used. <9> The aforementioned compression process uses a direct compression technique at a controlled humidity level of 40% NMT to reduce exposure to moisture. <1> Methods used. <10> The further method includes packaging lisdexamfetamine dimesylate dispersible tablets in a moisture-resistant ALU peel blister package and / or a moisture-resistant ALU-ALU blister package. <1> Methods used.

Claims

1. Dry mixing of lisdexanfetamine dimesylate, diluent, binder, and antistatic agent to form a dry mixture blend. The process involves blending fillers, buffers, disintegrants, and sweeteners into an intermediate granular blend to form an intermediate granular blend. The dry mixture blend and the intermediate granule blend are added and blended to form an intermediate drug blend. The intermediate drug blend is lubricated with a lubricant to form drug granules ready for compression, and The drug granules prepared for compression are compressed to form lisdexamfetamine dimesylate dispersible tablets. A method for preparing lisdexamfetamine dimesylate dispersible tablets containing the above.

2. The method according to claim 1, wherein the lisdexanfetamine dimesylate is present in an amount of about 8% to about 12% by weight.

3. In the dry mixing step, The diluent is mannitol granules 200SD, and the diluent is present in an amount of approximately 18% to approximately 23% by weight. The binder is partially gelatinized corn starch, and the binder is present in an amount of about 10% to about 20% by weight. The method according to claim 1, wherein the antistatic agent is colloidal anhydrous silica, and the antistatic agent is present in an amount of about 1% to about 2% by weight.

4. In the aforementioned intermediate granule blending step, The filler is mannitol granules 200SD, and the filler is present in an amount of approximately 28% to approximately 34% by weight. The buffer is microcrystalline cellulose, and the buffer is present in an amount of about 8% to about 12% by weight. The disintegrant is crospovidone, and the disintegrant is present in an amount of about 6% to about 10% by weight. The method according to claim 1, wherein the sweetener is sucralose and is present in an amount of about 1% to about 4% by weight.

5. The method according to claim 1, wherein in the lubrication step, the lubricant is magnesium stearate and is present in an amount of about 1% to about 2% by weight.

6. The method according to claim 1, wherein the dosage of the lisdexamfetamine dimesylate dispersible tablets is 10 mg per tablet, 20 mg per tablet, 30 mg per tablet, 40 mg per tablet, 50 mg per tablet, 60 mg per tablet, and 70 mg per tablet.

7. The method according to claim 1, wherein dissolution is 75% or more in 15 minutes.

8. The method according to claim 1, wherein the crushability is 1.5% or less, the disintegration time is less than 3 minutes at 15°C to 25°C (without disc), and the hardness is approximately 30N to approximately 70N.

9. The method according to claim 1, wherein the compression step uses a direct compression technique at a controlled humidity level of 40% NMT to reduce exposure to moisture.

10. The method according to claim 1, further comprising packaging lisdexamfetamine dimesylate dispersible tablets in a moisture-resistant ALU peel blister package and / or a moisture-resistant ALU-ALU blister package.

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