Lisdexamfetamine dimesylate orally dispersible tablet and process for preparation thereof

Abstract

To provide a lisdexamfetamine dimesylate orally dispensible tablet, and to provide a process for preparation thereof.SOLUTION: The process for preparation of the lisdexamfetamine dimesylate orally dispensible tablet includes: co-sieving lisdexamfetamine dimesylate, a binder, and a diluent; dry-mixing and blending the sieved lisdexamfetamine dimesylate, the binder, and the diluent to form a blended dry mixture; co-sieving and blending the diluent, a buffer, a disintegrant, a sweetener, and an antistatic agent to prepare an intermediate blend; blending the blended dry mixture with the intermediate blend; lubricating the blended dry mixture with the intermediate blend to form drug granules ready for compression; and compressing the ready-to-compress drug granules to form a compressed lisdexamfetamine dimesylate orally dispensible tablet.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure relates generally to orally disintegrating tablets. In particular, the present disclosure relates to lisdexamfetamine dimesylate orodispersible tablets and processes for their preparation. [Background technology]

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

[0003] The chemical structure of lisdexamfetamine dimesylate is shown below: [ka]

[0004] Lisdexamfetamine dimesylate is commonly indicated for the treatment of attention deficit hyperactivity disorder (ADHD) and moderate to severe binge eating disorder (BED) in adults.

[0005] Tablets and capsules have the disadvantage that they require water for ingestion and are less acceptable to the elderly and those with dysphagia. Dysphagia (difficulty swallowing) has been reported to be common in all age groups, and more specifically in the geriatric population, along with institutionalized patients and patients with nausea, vomiting, and motion sickness complications.

[0006] Over the past decade, there has been a need for the next generation of portable medicines and pharmaceuticals, including suitable types of formulations in orodispersible forms or with fast dissolving properties, dissolving or melting or disintegrating in the oral cavity in just a few seconds in the absence of water.

[0007] These preparations disintegrate or dissolve quickly in the oral cavity, making them suitable for the elderly and those with difficulty swallowing. Furthermore, because the preparations disintegrate in the oral cavity, the drug can be absorbed in the oral cavity, pharyngeal region, and gastrointestinal region.

[0008] Lisdexamfetamine dimesylate is, by its nature, a highly deliquescent material, and when exposed to moisture, it will absorb the moisture by any means and will not remain in a solid form.

[0009] Lisdexamfetamine dimesylate is commercially available in capsule and chewable tablet form. Many patient groups, such as the elderly, mentally retarded, uncooperative, nauseous, and those with limited fluid or food intake, have difficulty swallowing the available dosage forms of lisdexamfetamine dimesylate.

[0010] Therefore, there is a need for a lisdexamfetamine dimesylate orodispersible composition that addresses the deliquescence problem of lisdexamfetamine dimesylate. Therefore, it is highly desirable to develop an orally disintegrating lisdexamfetamine dimesylate orodispersible composition that allows for rapid release of the drug from the granules and allows for rapid absorption in the body after administration. Furthermore, it is desirable to develop a stable, palatable, and rapidly disintegrating lisdexamfetamine dimesylate orodispersible tablet. There is also a need for a manufacturing process that shortens the process time and reduces manufacturing costs for preparing lisdexamfetamine dimesylate orodispersible compositions. There is also a need for a humidity-controlled manufacturing process to minimize exposure of deliquescent materials to moisture during the manufacturing process. Summary of the Invention [Problem to be solved by the invention]

[0011] To achieve the above and other objectives and needs, the present disclosure provides a lisdexamfetamine dimesylate orodispersible composition in the form of a lisdexamfetamine dimesylate orodispersible tablet, and a process for preparing the same. The lisdexamfetamine dimesylate orodispersible tablet developed by the present inventors is an orally disintegrating tablet that allows for rapid release of the drug from the granules and allows for rapid absorption in the body after administration. Furthermore, the present disclosure provides a stable, palatable, and rapidly disintegrating lisdexamfetamine dimesylate orodispersible tablet. The present disclosure also provides a manufacturing process for preparing the lisdexamfetamine dimesylate orodispersible composition that has a short process time and low manufacturing costs. Furthermore, the present disclosure also provides a humidity-controlled manufacturing process to minimize exposure of deliquescent materials to moisture during the manufacturing process.

[0012] The present disclosure provides a synergistic combination of API and excipients in specific ratios to address the deliquescent nature of lisdexamfetamine dimesylate. This synergistic combination improves the disintegration time of orodispersible tablets. The present disclosure further imparts improved palatability to lisdexamfetamine dimesylate tablet formulations. The present disclosure provides a humidity-controlled manufacturing process in which tablet formulations are manufactured in a humidity-controlled environment to minimize exposure of deliquescent materials to moisture during the manufacturing process. In particular, the manufacturing process uses direct compression technology at a controlled humidity level of NMT 40% to reduce moisture exposure.

[0013] The present disclosure provides an orally disintegrating tablet lisdexamfetamine dimesylate composition that overcomes the shortcomings of capsules and chewable tablets. A synergistic combination of API and excipients in specific ratios is formulated to address the deliquescent nature of lisdexamfetamine dimesylate and provide a stable lisdexamfetamine dimesylate composition. The dissolution of the lisdexamfetamine orodispersible tablet composition is greater than 85% in 15 minutes. [Means for solving the problem]

[0014] In one embodiment, the present disclosure relates to a lisdexamfetamine dimesylate orodispersible tablet comprising about 8 to about 12% by weight of lisdexamfetamine dimesylate, about 45 to about 55% by weight of a diluent, about 10 to about 20% by weight of a binder, about 8 to about 12% by weight of a cushioning agent, about 6 to about 10% by weight of a disintegrating agent, about 1 to about 4% by weight of a sweetener, about 1 to about 2% by weight of an anti-static agent, and about 1 to about 2% by weight of a lubricant.

[0015] In one or more embodiments, the dosage of lisdexamfetamine dimesylate orodispersible 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.

[0016] In one or more embodiments, the diluent is mannitol granules 200SD and the binder is partially pregelatinized corn starch.

[0017] In one or more embodiments, the buffering agent is microcrystalline cellulose, the disintegrant is crospovidone, the sweetener is sucralose, the antistatic agent is colloidal anhydrous silica, and the lubricant is magnesium stearate.

[0018] In one or more embodiments, the particle size of the drug granules forming the lisdexamfetamine dimesylate orodispersible tablet is 400 microns or less.

[0019] In one or more embodiments, the friability is less than 2%, the disintegration time is less than 3 minutes at 37°C ± 2°C (without disc), and the hardness is from about 30N to about 70N.

[0020] In one or more embodiments, the dissolution is greater than 85% in 15 minutes.

[0021] In one or more embodiments, the particle size of the lisdexamfetamine dimesylate is 100 microns or less.

[0022] In another embodiment, the present disclosure relates to a process for preparing lisdexamfetamine dimesylate orodispersible tablets, the process comprising co-sifting lisdexamfetamine dimesylate, a binder, and a diluent, dry mixing and blending the sieved lisdexamfetamine dimesylate, the binder, and the diluent to form a blended dry mixture, co-sifting and blending the diluent, a buffer, a disintegrant, a sweetener, and an antistatic agent to prepare an intermediate blend, blending the blended dry mixture with the intermediate blend, lubricating the blended dry mixture with the intermediate blend to form drug granulation ready for compression, and compressing the ready-to-compress drug granulation to form compressed lisdexamfetamine dimesylate orodispersible tablets.

[0023] In one or more embodiments, the dosage of lisdexamfetamine dimesylate orodispersible 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.

[0024] In one or more embodiments, the diluent is mannitol granules 200SD and the binder is partially pregelatinized corn starch.

[0025] In one or more embodiments, the buffering agent is microcrystalline cellulose, the disintegrant is crospovidone, the sweetener is sucralose, the antistatic agent is colloidal anhydrous silica, and the lubricant is magnesium stearate.

[0026] In one or more embodiments, the friability is less than 2%, the disintegration time is less than 3 minutes at 37°C ± 2°C (without disc), and the hardness is from about 30N to about 70N.

[0027] In one or more embodiments, the compressing step uses direct compression techniques at a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0028] In one embodiment, the method further comprises packaging compressed lisdexamfetamine dimesylate orodispersible tablets within a moisture-resistant ALU peel blister package.

[0029] In another embodiment, the method further comprises packaging compressed lisdexamfetamine dimesylate orodispersible tablets within the moisture resistant ALU-ALU package.

[0030] The advantages and features of the present disclosure will be better understood by referring to the following detailed description and claims in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0031] [Figure 1] FIG. 1 shows a process flow for preparing lisdexamfetamine dimesylate orodispersible tablets according to an exemplary embodiment of the present disclosure.

[0032] [Figure 2]FIG. 2 shows details of the process of dry blending lisdexamfetamine dimesylate, a binder, and a diluent according to an exemplary embodiment of the present disclosure.

[0033] [Figure 3] FIG. 3 shows process details for preparation of lubricated blend / compression ready drug granules according to an exemplary embodiment of the present disclosure.

[0034] [Figure 4] FIG. 4 shows details of the preparation of compressed lisdexamfetamine dimesylate orodispersible tablets according to an exemplary embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0035] The exemplary embodiments described in detail herein for illustrative purposes are susceptible to many variations in structure and design. It should be emphasized, however, that the present disclosure is not limited to the lisdexamfetamine dimesylate orodispersible tablets and the process for their preparation as shown and described. Various omissions and substitutions of equivalents are contemplated as circumstances may suggest or become expedient, but it is understood that these are intended to cover applications or implementations without departing from the spirit or scope of the claims of the present disclosure. It is also understood that the phraseology and terminology used herein are for the purpose of description and should not be regarded as limiting.

[0036] The use of the terms "including," "comprising," or "having," and variations thereof, herein is meant to encompass the items listed thereafter and equivalents thereof, as well as additional items.

[0037] 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.

[0038] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are any uses of the term that are not clear to persons of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term, given the context in which it is used.

[0039] The present disclosure provides a lisdexamfetamine dimesylate orodispersible tablet, an oral dosage form that has orodispersibility properties that allow it to rapidly disintegrate in saliva, eliminating the need to ingest lisdexamfetamine dimesylate with water, and a process for preparing the same. The lisdexamfetamine dimesylate orodispersible tablet developed by the present inventor is an orodispersible tablet that allows for rapid release of the drug from the granules and rapid absorption in the body after administration. Furthermore, the lisdexamfetamine dimesylate orodispersible tablet and the process for preparing the same require a short processing time for preparation, require a small number of excipients, have low manufacturing costs, are stable, have a good palatability, and are rapidly disintegrating.

[0040] The present disclosure provides a synergistic combination of API and excipients in specific ratios to address the deliquescent nature of lisdexamfetamine dimesylate. This synergistic combination improves the disintegration time of orodispersible tablets. The present disclosure further imparts improved palatability to lisdexamfetamine dimesylate tablet formulations. The present disclosure provides a humidity-controlled manufacturing process in which tablet formulations are manufactured in a humidity-controlled environment to minimize exposure of deliquescent materials to moisture during the manufacturing process. In particular, the manufacturing process uses direct compression technology at a controlled humidity level of NMT 40% to reduce moisture exposure.

[0041] In one embodiment, a lisdexamfetamine dimesylate orodispersible tablet is disclosed. Hereinafter, the terms "lisdexamfetamine dimesylate orodispersible tablet" and "lisdexamfetamine dimesylate ODT" will be used interchangeably without any limitation. The lisdexamfetamine dimesylate orodispersible tablet contains about 8 to about 12% by weight of lisdexamfetamine dimesylate, about 45 to about 55% by weight of a diluent, about 10 to about 20% by weight of a binder, about 8 to about 12% by weight of a buffer, about 6 to about 10% by weight of a disintegrant, about 1 to about 4% by weight of a sweetener, about 1 to about 2% by weight of an antistatic agent, and about 1 to about 2% by weight of a lubricant.

[0042] As used herein, lisdexamfetamine dimesylate is the active substance. Molecular formula C 17 H 33 Lisdexamfetamine dimesylate, the dimesylate salt of L-lysyl-d-amphetamine, having the formula N3O7S2, is also known by the chemical name "(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]-hexanamide, dimethanesulfonate." The IUPAC name for lisdexamfetamine dimesylate is (2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide; methanesulfonic acid.

[0043] The structural formula of lisdexamfetamine dimesylate shows that the molecule contains two chiral centers. Therefore, there are four possible enantiomers of this compound: (2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide; (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide; (2S)-2,6-diamino-N-[(2R)-1-phenylpropan-2-yl]hexanamide; and (2R)-2,6-diamino-N-[(2R)-1-phenylpropan-2-yl]hexanamide.

[0044] Lisdexamfetamine dimesylate is a white or almost white crystalline powder therapeutically classified as a CNS stimulant, also known as an amphetamine. It is freely soluble in methanol, soluble in ethanol, very slightly soluble in acetone, chloroform, and toluene, and practically insoluble in tetrahydrofuran.

[0045] Characteristically, lisdexamfetamine dimesylate is hygroscopic in nature and is commonly indicated for the treatment of attention deficit hyperactivity disorder (ADHD) and moderate to severe binge eating disorder (BED) in adults.

[0046] In one or more embodiments, the particle size of the lisdexamfetamine dimesylate is 100 microns or less.

[0047] In one or more embodiments, the dosage of lisdexamfetamine dimesylate orodispersible 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.

[0048] In one or more embodiments, the diluent is mannitol granules 200SD.

[0049] As used herein, mannitol granules 200SD are used in the preparation of lisdexamfetamine dimesylate orodispersible tablets. Mannitol granules 200SD are used to adjust the average weight of lisdexamfetamine dimesylate orodispersible tablets. Mannitol granules 200SD also improve the flow properties and mouthfeel of the lisdexamfetamine dimesylate orodispersible tablet formulation. Mannitol granules 200SD are divided into two parts to improve the uniformity and distribution of the drug in the formulation. In one example, the mannitol granules 200SD are Pearlitol® 200SD.

[0050] In one or more embodiments, the binder is partially pregelatinized corn starch.

[0051] As used herein, partially pregelatinized corn starch is used to prepare lisdexamfetamine dimesylate orodispersible tablets. Lisdexamfetamine dimesylate as an active substance is a deliquescent molecule, and therefore, when maintained at room temperature, it turns into a liquid form. Therefore, in order to maintain the active lisdexamfetamine dimesylate in its solid form, a swellable partially pregelatinized corn starch is used in the lisdexamfetamine dimesylate orodispersible tablets. The partially pregelatinized corn starch improves the flow properties of the powder and ensures uniformity. When pregelatinized corn starch comes into contact with an aqueous dissolution medium, it swells and causes disintegration, which significantly reduces the adhesiveness of the powder. In one example, the partially pregelatinized corn starch is Starch 1500®.

[0052] In one or more embodiments, the buffering agent is microcrystalline cellulose.

[0053] As used herein, microcrystalline cellulose is used in the preparation of lisdexamfetamine dimesylate orodispersible tablets. Microcrystalline cellulose is crystalline in nature. It improves powder flow and aids in tablet compression to achieve the desired hardness. Microcrystalline cellulose also acts as a buffering agent. Due to the plasticity of microcrystalline cellulose, it is often used as an excipient for both tablet compression and pelleting processes. As a buffering agent, microcrystalline cellulose fills the interparticle spaces and attenuates the effects of compression forces occurring during the tableting process. In one example, the microcrystalline cellulose is Vivapur® 112.

[0054] In one or more embodiments, the disintegrant is crospovidone.

[0055] As used herein, crospovidone is used to prepare lisdexamfetamine dimesylate orodispersible tablets. Crospovidone is a water-insoluble tablet disintegrant and dissolving agent. Crospovidone has little tendency to form gels and exhibits high capillary activity and remarkable hydration ability. In one example, the crospovidone is Kollidone® CL.

[0056] In one or more embodiments, the sweetener is sucralose.

[0057] As used herein, sucralose is used in the preparation of lisdexamfetamine dimesylate orodispersible tablets. Sucralose is a white to off-white, free-flowing, crystalline powder with a sweetening power approximately 300 to 1000 times that of sucrose and no aftertaste.

[0058] In one or more embodiments, the antistatic agent is colloidal anhydrous silica.

[0059] As used herein, colloidal anhydrous silica is used in the preparation of lisdexamfetamine dimesylate orodispersible tablets. Colloidal anhydrous silica is an adsorbent, anti-caking agent, and lubricant. Colloidal anhydrous silica improves powder flow. In one example, the colloidal anhydrous silica is Aerosil® 200.

[0060] In one or more embodiments, the lubricant is magnesium stearate.

[0061] As used herein, magnesium stearate is used in the preparation of lisdexamfetamine dimesylate orodispersible tablets. Magnesium stearate is a fine powder with low bulk density. Magnesium stearate is very fine, greasy in texture, light, white, and essentially settles or breaks down. Functionally, magnesium stearate is used as a lubricant in the production of capsules and tablets. In the pharmaceutical industry, magnesium stearate powder, due to its characteristic oiliness, easily adheres to the surface of tablets, ensuring that the tablets are ejected cleanly without cracking or breaking.

[0062] In one or more embodiments, the particle size of the drug granules forming the tablet is 400 microns or less.

[0063] In one or more embodiments, the friability is less than 2%, the disintegration time is less than 3 minutes at 37°C ± 2°C (without disc), and the hardness is from about 30N to about 70N.

[0064] In one or more embodiments, the dissolution is greater than 85% in 15 minutes.

[0065] As used herein, the dissolution medium is 900 ml of 0.1 N hydrochloric acid at a temperature of 37° C.±0.5° C. with a collection time of 15 minutes.

[0066] In another embodiment, the present disclosure provides a process for preparing lisdexamfetamine dimesylate orodispersible tablets, the process comprising co-sieving lisdexamfetamine dimesylate, a binder, and a diluent, dry-blending the sieved lisdexamfetamine dimesylate with the binder and diluent, blending the dry-blended lisdexamfetamine dimesylate with the binder and diluent to prepare a blended dry blend, co-sieving and blending a diluent, a buffer, a disintegrant, a sweetener, and an antistatic agent to prepare an intermediate blend, blending the blended dry blend with the intermediate blend, lubricating the blended dry blend with the intermediate blend to form drug granulation ready for compression, and compressing the ready-to-compress drug granulation to form a compressed lisdexamfetamine dimesylate orodispersible tablet.

[0067] Referring to Figure 1, process 100 relates to a process for preparing lisdexamfetamine dimesylate orodispersible tablets. In step 102, process 100 comprises co-sieving lisdexamfetamine dimesylate, a binder, and a diluent. In step 104, process 100 comprises dry-mixing and blending the sieved lisdexamfetamine dimesylate, the binder, and the diluent to form a blended dry mixture. In step 106, process 100 comprises co-sieving and blending a diluent, a buffer, a disintegrant, a sweetener, and an antistatic agent to prepare an intermediate blend. In step 108, process 100 comprises blending the blended dry mixture with the intermediate blend. In step 110, process 100 comprises lubricating the blended dry mixture with the intermediate blend to form a drug granulation ready for compression. In step 112, process 100 includes compressing the ready-to-compress drug granulation to form compressed lisdexamfetamine dimesylate orodispersible tablets. The compressed lisdexamfetamine dimesylate orodispersible tablets are then packaged in moisture-resistant ALU peel blister packages / ALU-ALU packages. The moisture-resistant ALU peel blister packages / ALU-ALU packages contribute to a humidity-controlled manufacturing process and packaging.

[0068] Process steps 102 and 104 of Figure 1 are described in detail in Figure 2. Process steps 106, 108, and 110 of Figure 1 are described in detail in Figure 3. Process step 112 of Figure 1 is described in detail in Figure 4.

[0069] Referring again to Figure 1, in step 102, process 100 involves co-sieving lisdexamfetamine dimesylate, a binder, and a diluent, where lisdexamfetamine dimesylate is the active pharmaceutical ingredient (API). The binder is partially pregelatinized corn starch. The diluent is mannitol granules 200SD. In step 104, process 100 involves dry mixing and blending the agglomerate-free mass of the sieved lisdexamfetamine dimesylate partially pregelatinized corn starch and mannitol granules 200SD to form a blended dry mixture. Process steps 102 and 104 of Figure 1 are described in detail in Figure 2.

[0070] Referring to Figure 2, in step 202, the lisdexamfetamine dimesylate, partially pregelatinized corn starch, and mannitol granules 200SD are sieved to obtain an agglomerate-free mass. The sieved agglomerate-free mass of lisdexamfetamine dimesylate, partially pregelatinized corn starch, and mannitol granules 200SD is collected.

[0071] 2, in step 204, the agglomerate-free mass of sieved lisdexamfetamine dimesylate, partially pregelatinized corn starch, and mannitol granules 200SD is charged into a contablender, where the agglomerate-free mass is dry mixed and blended to obtain a blended dry mixture, and then in step 206, the blended dry mixture is removed.

[0072] Referring again to FIG. 1, in step 106, the next step in process 100 involves co-sieving and blending a diluent, a buffer, a disintegrant, a sweetener, and an antistatic agent to prepare an intermediate blend. The diluent is Mannitol Granules 200SD. The buffer is microcrystalline cellulose. The disintegrant is crospovidone. The sweetener is sucralose. The antistatic agent is colloidal anhydrous silica. Process step 106 of FIG. 1 is described in detail in FIG. 3.

[0073] 1, in step 108, the next step in process 100 involves blending the blended dry mix obtained in step 204 with the intermediate blend obtained in step 304. Step 108 of FIG. 1 is described in detail in FIG. 3.

[0074] Referring again to Figure 1, the next step in process 100 involves lubricating the blended dry mixture with the intermediate blend to form drug granules ready for compression, at step 110. Step 110 of Figure 1 is described in detail in Figure 3.

[0075] 3, in step 302, mannitol granules 200SD, microcrystalline cellulose, crospovidone, sucralose, and colloidal anhydrous silica are simultaneously sieved through a 36 mesh vibratory sieve to obtain an agglomerate-free mass. In step 304, the sieved materials from step 302 are blended in a contablender at 8 RPM for 30 minutes to obtain an intermediate blend. Thereafter, in step 306, 50% of the intermediate blend from step 304 is removed.

[0076] Referring again to Figure 3, process step 308 includes adding the blended dry mix obtained in step 204 of Figure 2 with 50% of the intermediate blend obtained in step 304. Further, adding the removed 50% intermediate blend obtained in step 306 to a blender bin containing 50% of the intermediate blend and the blended dry mix. Further, in step 310, the added mix obtained in step 308 is blended.

[0077] Referring again to FIG. 3 , in step 312, a lubricant is used to lubricate the blended mixture obtained in step 308. Here, the lubricant is magnesium stearate. The magnesium stearate is sieved through a vibrating screen and added to the blended mixture in the Contablender to obtain a lubricated, blended mixture. In step 314, the lubricated, blended mixture is further blended to obtain a drug granulation ready for compression. The drug granulation ready for compression is removed. The drug granulation ready for compression is then transferred for compression.

[0078] In one or more embodiments, the compressing step uses direct compression techniques at a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0079] Referring again to Figure 1, in step 112, process 100 involves compressing the ready-to-compress drug granulation to form a compressed lisdexamfetamine dimesylate orodispersible tablet. Step 112 of Figure 1 is described in detail in Figure 4. Referring to Figure 4, in step 402, the ready-to-compress drug granulation obtained in step 314 is compressed through a compression machine to obtain a compressed lisdexamfetamine dimesylate orodispersible tablet. Compression as used herein is a direct compression technique during the manufacturing process at a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0080] After compression of the lisdexamfetamine dimesylate orodispersible tablets, in step 404, the bulk compressed tablets are stored in black double-lined polybags within HDPE drums containing silica gel bags as desiccants in pouches. The drums are stored at temperatures below 25°C in a quarantine area prior to primary packaging. In step 406, the compressed lisdexamfetamine dimesylate orodispersible bulk tablets are packaged. In one embodiment, the compressed lisdexamfetamine dimesylate orodispersible tablets are packaged in moisture-resistant ALU peel blister packaging. In another embodiment, the compressed lisdexamfetamine dimesylate orodispersible tablets are packaged in moisture-resistant ALU-ALU packaging.

[0081] Here, the compressive yield is greater than 95%.

[0082] In one or more embodiments, the compressed lisdexamfetamine dimesylate orodispersible tablets are packaged in moisture resistant (ALU) peel blister packages / ALU-ALU packages using a blister packaging machine. The moisture resistant ALU peel blister packages / ALU-ALU packages contribute to a humidity-controlled manufacturing process and packaging.

[0083] Table 1 shows the weight percentages of API and excipients for the presented batches. [Table 1]

[0084] The lisdexamfetamine dimesylate orodispersible tablets and processes for their preparation are further described by the following non-limiting examples. Those skilled in the art will recognize that the specific examples are intended to illustrate, but not limit, the scope of the present disclosure.

[0085] Table 2 shows the physical properties (mg / tablet) of lisdexamfetamine dimesylate orodispersible tablets at 10, 20, 30, 40, 50, 60 and 70 mg / tablet. [Table 2]

[0086] Example 1 Example 1 describes a process for preparing lisdexamfetamine dimesylate orodispersible tablets. In particular, a process for preparing lisdexamfetamine dimesylate orodispersible tablets having a strength of 10 mg per tablet is described.

[0087] Table 3 shows the amounts (mg / tablet) of API and excipients for lisdexamfetamine dimesylate (10 mg) orodispersible tablets. [Table 3]

[0088] The process begins by co-sieving lisdexamfetamine dimesylate, partially pregelatinized corn starch, and mannitol granules 200SD. Specifically, 10 mg of lisdexamfetamine dimesylate, 25 mg of mannitol granules 200SD, and 15 mg of partially pregelatinized corn starch are sieved through a vibrating sieve to obtain an agglomerate-free mass. The sieved agglomerate-free mass of lisdexamfetamine dimesylate, partially pregelatinized corn starch, and mannitol granules 200SD is collected.

[0089] The agglomerate-free mass of sieved lisdexamfetamine dimesylate, partially pregelatinized corn starch, and mannitol granules 200SD is then charged into a Contablender, and the agglomerate-free mass is dry mixed and blended in the Contablender to obtain a blended dry mixture, and the blended dry mixture is discharged.

[0090] Then, 26.75 mg of mannitol granules 200SD, 10 mg of microcrystalline cellulose, 8 mg of crospovidone, 2.5 mg of sucralose, and 1.5 mg of colloidal anhydrous silica are co-sieved through a vibrating sieve to obtain an agglomerate-free mass. The resulting sieved material is then blended in a contablender to obtain an intermediate blend. 50% of the resulting intermediate blend is then removed.

[0091] In the next step, the blended dry mixture is added to the blender bin of the Contablender containing 50% of the intermediate blend, and the removed 50% intermediate blend is added to the blender bin containing 50% of the intermediate blend and the blended dry mixture to blend the mixture.

[0092] Then, 1.25 mg of magnesium stearate is sieved through a vibrating sieve and added to the blended mixture in the Contablender to obtain a lubricated, blended mixture. The lubricated, blended mixture is further blended to obtain a compression-ready drug granulation. The compression-ready drug granulation is removed and transferred for compression.

[0093] Finally, the ready-to-compress drug granules are compressed through a compression machine to obtain compressed lisdexamfetamine dimesylate (10 mg) orodispersible tablets. The compression used herein is a direct compression technique during the manufacturing process at a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0094] Table 3A shows the product description for compressed lisdexamfetamine dimesylate (10 mg) orodispersible tablets. [Table 4]

[0095] Table 3B shows the physical properties of compressed lisdexamfetamine dimesylate (10 mg) orodispersible tablets. [Table 5]

[0096] Example 2 Example 2 describes a process for preparing lisdexamfetamine dimesylate orodispersible tablets, particularly for preparing lisdexamfetamine dimesylate orodispersible tablets having a strength of 20 mg per tablet.

[0097] Table 4 shows the amounts (mg / tablet) of API and excipients for lisdexamfetamine dimesylate (20 mg) orodispersible tablets. [Table 6]

[0098] The process begins by co-sieving lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch. Specifically, 20 mg of lisdexamfetamine dimesylate, 50.0 mg of mannitol granules 200SD, and 30.0 mg of partially pregelatinized corn starch are sieved through a vibrating sieve to obtain an agglomerate-free mass. The sieved agglomerate-free mass of lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch is collected.

[0099] The agglomerate-free mass of sieved lisdexamfetamine dimesylate, mannitol granules 200SD and partially pregelatinized corn starch is then charged into a Contablender, the agglomerate-free mass is dry mixed and blended in the Contablender to obtain a blended dry mixture, and the blended dry mixture is discharged.

[0100] Then, 53.50 mg of mannitol granules 200SD, 20 mg of microcrystalline cellulose, 16 mg of crospovidone, 5 mg of sucralose, and 3 mg of colloidal anhydrous silica are co-sieved through a vibratory sieve to obtain an agglomerate-free mass. The resulting sieved material is then blended in a contablender to obtain an intermediate blend. 50% of the resulting intermediate blend is then removed.

[0101] In the next step, the blended dry mixture is added to the blender bin of the Contablender containing 50% of the intermediate blend, and the removed 50% intermediate blend is added to the blender bin containing 50% of the intermediate blend and the blended dry mixture to blend the mixture.

[0102] Then, 2.5 mg of magnesium stearate is sieved through a vibrating sieve and added to the blended mixture in the Contablender to obtain a lubricated, blended mixture. The lubricated, blended mixture is further blended to obtain a compression-ready drug granulation. The compression-ready drug granulation is removed and transferred for compression.

[0103] Finally, the ready-to-compress drug granules are compressed through a compression machine to obtain compressed lisdexamfetamine dimesylate (20 mg) orodispersible tablets. The compression used is a direct compression technique during the manufacturing process with a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0104] Table 4A shows the product description for compressed lisdexamfetamine dimesylate (20 mg) orodispersible tablets. [Table 7]

[0105] Table 4B shows the physical properties of compressed lisdexamfetamine dimesylate (20 mg) orodispersible tablets. [Table 8]

[0106] Example 3 Example 3 describes a process for preparing lisdexamfetamine dimesylate orodispersible tablets, particularly for preparing lisdexamfetamine dimesylate orodispersible tablets having a strength of 30 mg per tablet.

[0107] Table 5 shows the amounts (mg / tablet) of API and excipients for lisdexamfetamine dimesylate (30 mg) orodispersible tablets. [Table 9]

[0108] The process begins by co-sieving lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch. Specifically, 30 mg of lisdexamfetamine dimesylate, 75 mg of mannitol granules 200SD, and 45 mg of partially pregelatinized corn starch are sieved through a vibrating sieve to obtain an agglomerate-free mass. The sieved agglomerate-free mass of lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch is collected.

[0109] The agglomerate-free mass of sieved lisdexamfetamine dimesylate, mannitol granules 200SD and partially pregelatinized corn starch is then charged into a Contablender, the agglomerate-free mass is dry mixed and blended in the Contablender to obtain a blended dry mixture, and the blended dry mixture is discharged.

[0110] Then, 80.25 mg of mannitol granules 200SD, 30 mg of microcrystalline cellulose, 24 mg of crospovidone, 7.5 mg of sucralose, and 4.5 mg of colloidal anhydrous silica are co-sieved through a vibrating sieve to obtain an agglomerate-free mass. The resulting sieved material is then blended in a contablender to obtain an intermediate blend. 50% of the resulting intermediate blend is then removed.

[0111] In the next step, the blended dry mixture is added to the blender bin of the Contablender containing 50% of the intermediate blend, and the removed 50% intermediate blend is added to the blender bin containing 50% of the intermediate blend and the blended dry mixture to blend the mixture.

[0112] Then, 3.75 mg of magnesium stearate is sieved through a vibrating sieve and added to the blended mixture in the Contablender to obtain a lubricated, blended mixture. The lubricated, blended mixture is further blended to obtain a compression-ready drug granulation. The compression-ready drug granulation is removed and transferred for compression.

[0113] Finally, the ready-to-compress drug granules are compressed through a compression machine to obtain compressed lisdexamfetamine dimesylate (30 mg) orodispersible tablets. The compression used is a direct compression technique during the manufacturing process with a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0114] Table 5A shows the amounts (mg / tablet) of API and excipients for lisdexamfetamine dimesylate (30 mg) orodispersible tablets. [Table 10]

[0115] Table 5B shows the physical properties of compressed lisdexamfetamine dimesylate (30 mg) orodispersible tablets. [Table 11]

[0116] Example 4 Example 4 describes a process for preparing lisdexamfetamine dimesylate orodispersible tablets, particularly for preparing lisdexamfetamine dimesylate orodispersible tablets having a strength of 40 mg per tablet.

[0117] Table 6 shows the amounts (mg / tablet) of API and excipients for lisdexamfetamine dimesylate (40 mg) orodispersible tablets. [Table 12]

[0118] The process begins by co-sieving lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch. Specifically, 40 mg of lisdexamfetamine dimesylate, 100 mg of mannitol granules 200SD, and 60 mg of partially pregelatinized corn starch are sieved through a vibrating sieve to obtain an agglomerate-free mass. The sieved agglomerate-free mass of lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch is collected.

[0119] The agglomerate-free mass of sieved lisdexamfetamine dimesylate, mannitol granules 200SD and partially pregelatinized corn starch is then charged into a Contablender, the agglomerate-free mass is dry mixed and blended in the Contablender to obtain a blended dry mixture, and the blended dry mixture is discharged.

[0120] Then, 107 mg of mannitol granules 200SD, 40 mg of microcrystalline cellulose, 32 mg of crospovidone, 10 mg of sucralose, and 6 mg of colloidal anhydrous silica are co-sieved through a vibrating sieve to obtain an agglomerate-free mass. The resulting sieved material is then blended in a contablender to obtain an intermediate blend. 50% of the resulting intermediate blend is then removed.

[0121] In the next step, the blended dry mixture is added to the blender bin of the Contablender containing 50% of the intermediate blend, and the removed 50% intermediate blend is added to the blender bin containing 50% of the intermediate blend and the blended dry mixture to blend the mixture.

[0122] 5 mg of magnesium stearate is then sieved through a vibrating sieve and added to the blended mixture in the Contablender to obtain a lubricated, blended mixture. The lubricated, blended mixture is further blended to obtain a compression-ready drug granulation. The compression-ready drug granulation is removed and transferred for compression.

[0123] Finally, the ready-to-compress drug granules are compressed through a compression machine to obtain compressed lisdexamfetamine dimesylate (40 mg) orodispersible tablets. The compression used is a direct compression technique during the manufacturing process with a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0124] Table 6A shows the product description for compressed lisdexamfetamine dimesylate (40 mg) orodispersible tablets. [Table 13]

[0125] Table 6B shows the physical properties of compressed lisdexamfetamine dimesylate (40 mg) orodispersible tablets. [Table 14]

[0126] Example 5 Example 5 describes a process for preparing lisdexamfetamine dimesylate orodispersible tablets, particularly for preparing lisdexamfetamine dimesylate orodispersible tablets having a strength of 50 mg per tablet.

[0127] Table 7 shows the amounts (mg / tablet) of API and excipients for lisdexamfetamine dimesylate (50 mg) orodispersible tablets. [Table 15]

[0128] The process begins by co-sieving lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch. Specifically, 50 mg of lisdexamfetamine dimesylate, 125 mg of mannitol granules 200SD, and 75 mg of partially pregelatinized corn starch are sieved through a vibrating sieve to obtain an agglomerate-free mass. The sieved agglomerate-free mass of lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch is collected.

[0129] The agglomerate-free mass of sieved lisdexamfetamine dimesylate, mannitol granules 200SD and partially pregelatinized corn starch is then charged into a Contablender, the agglomerate-free mass is dry mixed and blended in the Contablender to obtain a blended dry mixture, and the blended dry mixture is discharged.

[0130] Then, 133.75 mg of mannitol granules 200SD, 50 mg of microcrystalline cellulose, 40 mg of crospovidone, 12.5 mg of sucralose, and 7.5 mg of colloidal anhydrous silica are co-sieved through a vibrating sieve to obtain an agglomerate-free mass. The resulting sieved material is then blended in a contablender to obtain an intermediate blend. 50% of the resulting intermediate blend is then removed.

[0131] In the next step, the blended dry mixture is added to the blender bin of the Contablender containing 50% of the intermediate blend, and the removed 50% intermediate blend is added to the blender bin containing 50% of the intermediate blend and the blended dry mixture to blend the mixture.

[0132] Then, 6.25 mg of magnesium stearate is sieved through a vibrating sieve and added to the blended mixture in the Contablender to obtain a lubricated, blended mixture. The lubricated, blended mixture is further blended to obtain a compression-ready drug granulation. The compression-ready drug granulation is removed and transferred for compression.

[0133] Finally, the ready-to-compress drug granules are compressed through a compression machine to obtain compressed lisdexamfetamine dimesylate (50 mg) orodispersible tablets. The compression used is a direct compression technique during the manufacturing process with a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0134] Table 7A shows the product description for compressed lisdexamfetamine dimesylate (50 mg) orodispersible tablets. [Table 16]

[0135] Table 7B shows the physical properties of compressed lisdexamfetamine dimesylate (50 mg) orodispersible tablets. [Table 17]

[0136] Example 6 Example 6 describes a process for preparing lisdexamfetamine dimesylate orodispersible tablets, particularly for preparing lisdexamfetamine dimesylate orodispersible tablets having a strength of 60 mg per tablet.

[0137] Table 8 shows the amounts (mg / tablet) of API and excipients for lisdexamfetamine dimesylate (60 mg) orodispersible tablets. [Table 18]

[0138] The process begins by co-sieving lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch. Specifically, 60 mg of lisdexamfetamine dimesylate, 150 mg of mannitol granules 200SD, and 90 mg of partially pregelatinized corn starch are sieved through a vibrating sieve to obtain an agglomerate-free mass. The sieved agglomerate-free mass of lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch is collected.

[0139] The agglomerate-free mass of sieved lisdexamfetamine dimesylate, mannitol granules 200SD and partially pregelatinized corn starch is then charged into a Contablender, the agglomerate-free mass is dry mixed and blended in the Contablender to obtain a blended dry mixture, and the blended dry mixture is discharged.

[0140] Then, 160.5 mg of mannitol granules 200SD, 60 mg of microcrystalline cellulose, 48 mg of crospovidone, 15 mg of sucralose, and 9 mg of colloidal anhydrous silica are co-sieved through a vibratory sieve to obtain an agglomerate-free mass. The resulting sieved material is then blended in a contablender to obtain an intermediate blend. 50% of the resulting intermediate blend is then blended.

[0141] In the next step, the blended dry mixture is added to the blender bin of the Contablender containing 50% of the intermediate blend, and the removed 50% intermediate blend is added to the blender bin containing 50% of the intermediate blend and the blended dry mixture to blend the mixture.

[0142] Then, 7.5 mg of magnesium stearate is sieved through a vibrating sieve and added to the blended mixture in the Contablender to obtain a lubricated, blended mixture. The lubricated, blended mixture is further blended to obtain a compression-ready drug granulation. The compression-ready drug granulation is removed and transferred for compression.

[0143] Finally, the ready-to-compress drug granules are compressed through a compression machine to obtain compressed lisdexamfetamine dimesylate (60 mg) orodispersible tablets. The compression used is a direct compression technique during the manufacturing process with a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0144] Table 8A shows the product description for compressed lisdexamfetamine dimesylate (60 mg) orodispersible tablets. [Table 19]

[0145] Table 8B shows the physical properties of compressed lisdexamfetamine dimesylate (60 mg) orodispersible tablets. [Table 20]

[0146] Example 7 Example 7 describes a process for preparing lisdexamfetamine dimesylate orodispersible tablets. In particular, a process for preparing lisdexamfetamine dimesylate orodispersible tablets having a strength of 70 mg per tablet is described.

[0147] Table 9 shows the amounts (mg / tablet) of API and excipients for lisdexamfetamine dimesylate (70 mg) orodispersible tablets. [Table 21]

[0148] The process begins by co-sieving lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch. Specifically, 70 mg of lisdexamfetamine dimesylate, 175 mg of mannitol granules 200SD, and 105 mg of partially pregelatinized corn starch are sieved through a vibrating sieve to obtain an agglomerate-free mass. The sieved agglomerate-free mass of lisdexamfetamine dimesylate, mannitol granules 200SD, and partially pregelatinized corn starch is collected.

[0149] The agglomerate-free mass of sieved lisdexamfetamine dimesylate, mannitol granules 200SD and partially pregelatinized corn starch is then charged into a Contablender, the agglomerate-free mass is dry mixed and blended in the Contablender to obtain a blended dry mixture, and the blended dry mixture is discharged.

[0150] Then, 187.25 mg of mannitol granules 200SD, 70 mg of microcrystalline cellulose, 56 mg of crospovidone, 17.5 mg of sucralose, and 10.5 mg of colloidal anhydrous silica are co-sieved through a vibrating sieve to obtain an agglomerate-free mass. The resulting sieved material is then blended in a contablender to obtain an intermediate blend. 50% of the resulting intermediate blend is then removed.

[0151] In the next step, the blended dry mixture is added to the blender bin of the Contablender containing 50% of the intermediate blend, and the removed 50% intermediate blend is added to the blender bin containing 50% of the intermediate blend and the blended dry mixture to blend the mixture.

[0152] Then, 8.75 mg of magnesium stearate is sieved through a vibrating sieve and added to the blended mixture in the Contablender to obtain a lubricated, blended mixture. The lubricated, blended mixture is further blended to obtain a compression-ready drug granulation. The compression-ready drug granulation is removed and transferred for compression.

[0153] Finally, the ready-to-compress drug granules are compressed through a compression machine to obtain compressed lisdexamfetamine dimesylate (70 mg) orodispersible tablets. The compression used is a direct compression technique during the manufacturing process with a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0154] Table 9A shows the product description for compressed lisdexamfetamine dimesylate (70 mg) orodispersible tablets. [Table 22]

[0155] Table 9B shows the physical properties of compressed lisdexamfetamine dimesylate (70 mg) orodispersible tablets. [Table 23]

[0156] The present disclosure provides a lisdexamfetamine dimesylate orodispersible composition in the form of a lisdexamfetamine dimesylate orodispersible tablet, and a process for preparing the same. The lisdexamfetamine dimesylate orodispersible tablet developed by the present inventor is an orally disintegrating tablet that allows for rapid release of the drug from the granules and rapid absorption in the body after administration. Furthermore, the present disclosure provides a stable, palatable, and rapidly disintegrating lisdexamfetamine dimesylate orodispersible tablet. The present disclosure also provides a manufacturing process for preparing the lisdexamfetamine dimesylate orodispersible composition that has a short process time and low manufacturing costs. Furthermore, the present disclosure also provides a humidity-controlled manufacturing process to minimize exposure of deliquescent materials to moisture during the manufacturing process.

[0157] test: The data included for the test results show readings for moisture-controlled tablet compositions, i.e., tablets where API deliquescence is taken into account, in other words, data on how the correct combination of drug with all the different excipients results in a formulation / composition with no or little deliquescence.

[0158] To demonstrate that compositions containing lisdexamfetamine dimesylate do not exhibit deliquescent properties, a series of studies were conducted to evaluate the stability, durability, and resistance to various forms of degradation of tablet compositions containing lisdexamfetamine dimesylate.

[0159] The tests include an accelerated aging test to assess resistance to degradation over time; a chemical resistance / compatibility test to assess the compatibility of excipient materials with lisdexamfetamine dimesylate tablets; and a moisture absorption test to demonstrate that there is no significant increase in moisture absorption levels by tablets containing lisdexamfetamine dimesylate.

[0160] (Accelerated aging test) Tablet compositions were subjected to accelerated stability conditions, such as elevated temperatures of 40°C and humidity of 75% RH exposure, to simulate long-term environmental exposure. To assess resistance to degradation over time, the performance of tablets containing lisdexamfetamine dimesylate is evaluated before and after degradation.

[0161] Table 10 shows the results of accelerated degradation tests performed on tablet compositions containing lisdexamfetamine dimesylate. [Table 24]

[0162] The results demonstrate no change in hardness of tablet compositions containing lisdexamfetamine dimesylate. The lack of a decrease or change in tablet hardness confirms the mechanical properties of the material and its ability to withstand stress and deformation without showing signs of deliquescence.

[0163] (Chemical resistance test / compatibility test) The tablet compositions were exposed to a series of chemicals commonly used in ODT formulations to evaluate the tablet's resistance to chemical attack, including changes in appearance, physical properties, or structural integrity.

[0164] To perform the compatibility test, the tablets are exposed to an elevated temperature of 40°C and humidity of 75% RH exposure in open and closed conditions, and to a temperature of 25°C and humidity of 75% RH exposure in open and closed conditions.

[0165] The results reveal a positive interpretation indicating a high level of compatibility between tablet compositions containing lisdexamfetamine dimesylate and chemicals commonly used in ODT formulations. Positive results obtained from compatibility testing provide strong evidence supporting the suitability of excipient materials for their intended use.

[0166] (Moisture absorption test) The ability of a tablet composition containing lisdexamfetamine dimesylate to resist moisture absorption is determined by subjecting it to a controlled humidity or water immersion test, measuring the amount of moisture absorbed by the tablet and assessing its effect on dimensional stability, strength, and other relevant properties.

[0167] Tablet composition containing lisdexamfetamine dimesylate by using KF analyzer at various storage conditions temperature 40°C / relative humidity 75%, temperature 30°C / relative humidity 75%, temperature 30°C / relative humidity 65%, and temperature 25°C / relative humidity 60%.

[0168] The results reveal that the water absorption content of the tablet compositions containing lisdexamfetamine dimesylate remains the same. In summary, the tablets do not show a significant increase in water absorption levels.

[0169] Table 11 shows the results of the moisture absorption test for the tablet compositions containing lisdexamfetamine dimesylate of BATCH 1. [Table 25]

[0170] Table 12 shows the results of moisture absorption testing of tablet compositions containing lisdexamfetamine dimesylate from BATCH 2. [Table 26]

[0171] Table 13 shows the results of moisture absorption testing of tablet compositions containing lisdexamfetamine dimesylate from BATCH 3. [Table 27]

[0172] The stability reports for BATCH 1, BATCH 2, and BATCH 3 highlight the non-deliquescent nature of the lisdexamfetamine dimesylate orodispersible compositions. From the stability data (shown in Tables 11, 12, and 13), it can be interpreted that there is no significant increase in water content under the mentioned storage conditions. Therefore, in other words, it can be concluded that the lisdexamfetamine dimesylate compositions for orodispersible tablets are stable.

[0173] The present disclosure provides a synergistic combination of API and excipients in specific ratios to address the deliquescent nature of lisdexamfetamine dimesylate. This synergistic combination improves the disintegration time of orodispersible tablets. The present disclosure further imparts improved palatability to lisdexamfetamine dimesylate tablet formulations. The present disclosure provides a humidity-controlled manufacturing process in which tablet formulations are manufactured in a humidity-controlled environment to minimize exposure of deliquescent materials to moisture during the manufacturing process. In particular, the manufacturing process uses direct compression technology at a controlled humidity level of NMT 40% to reduce moisture exposure.

[0174] The present disclosure provides an orally disintegrating tablet lisdexamfetamine dimesylate composition that overcomes the shortcomings of capsules and chewable tablets. A synergistic combination of API and excipients in specific ratios is formulated to address the deliquescent nature of lisdexamfetamine dimesylate and provide a stable lisdexamfetamine dimesylate composition. The dissolution of the lisdexamfetamine orodispersible tablet composition is greater than 85% in 15 minutes.

[0175] 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 those skilled in the art to best utilize the disclosure and various embodiments, with various modifications suited to the particular uses contemplated. (Various omissions and substitutions of equivalents are contemplated as circumstances may suggest or become expedient, it being understood that these are intended to cover applications or implementations without departing from the spirit or scope of the claims of the present disclosure.)

[0176] The present disclosure includes the following aspects. <1> about 8 to about 12% by weight of lisdexamfetamine dimesylate; about 45 to about 55 weight percent of a diluent; about 10 to about 20 weight percent of a binder; about 8 to about 12 wt. % of a buffer; about 6 to about 10% by weight of a disintegrant; about 1 to about 4% by weight of a sweetener; about 1 to about 2 wt. % of an antistatic agent; about 1 to about 2 weight percent of a lubricant; 1. A lisdexamfetamine dimesylate orodispersible tablet comprising: <2> the dosages of the lisdexamfetamine dimesylate orodispersible 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> 1. A lisdexamfetamine dimesylate orodispersible tablet according to claim 1. <3> The diluent is mannitol granules 200SD and the binder is partially pregelatinized corn starch. <1> 1. A lisdexamfetamine dimesylate orodispersible tablet according to claim 1. <4> the buffering agent is microcrystalline cellulose, the disintegrant is crospovidone, the sweetener is sucralose, the antistatic agent is colloidal anhydrous silica, and the lubricant is magnesium stearate; <1> 1. A lisdexamfetamine dimesylate orodispersible tablet according to claim 1. <5> the particle size of the drug granules forming the lisdexamfetamine dimesylate orodispersible tablet is 400 microns or less; <1> 1. A lisdexamfetamine dimesylate orodispersible tablet according to claim 1. <6> The friability is less than 2%, the disintegration time is less than 3 minutes at 37°C ± 2°C (without disc), and the hardness is about 30N to about 70N. <1> 1. A lisdexamfetamine dimesylate orodispersible tablet according to claim 1. <7> Dissolution is greater than 85% in 15 minutes; <1> 1. A lisdexamfetamine dimesylate orodispersible tablet according to claim 1. <8> the particle size of the lisdexamfetamine dimesylate is 100 microns or less; <1> 1. A lisdexamfetamine dimesylate orodispersible tablet according to claim 1. <9> co-sieving the lisdexamfetamine dimesylate, the binder and the diluent; dry mixing and blending the sieved lisdexamfetamine dimesylate, the binder, and the diluent to form a blended dry mixture; co-sieving and blending the diluent, buffer, disintegrant, sweetener and antistatic agent to prepare an intermediate blend; blending the blended dry mixture with the intermediate blend; lubricating the blended dry mixture with the intermediate blend to form drug granulation ready for compression; and compressing the ready-to-compress drug granulation to form a compressed lisdexamfetamine dimesylate orodispersible tablet; 1. A process for the preparation of lisdexamfetamine dimesylate orodispersible tablets, comprising: <10> the dosages of the lisdexamfetamine dimesylate orodispersible 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; <9> The process described in <11> The diluent is mannitol granules 200SD and the binder is partially pregelatinized corn starch. <9> The process described in <12> the buffering agent is microcrystalline cellulose, the disintegrant is crospovidone, the sweetener is sucralose, the antistatic agent is colloidal anhydrous silica, and the lubricant is magnesium stearate; <9> The process described in <13> The friability is less than 2%, the disintegration time is less than 3 minutes at 37°C ± 2°C (without disc), and the hardness is about 30N to about 70N. <9> The process described in <14> said compressing step using direct compression technology at a controlled humidity level of NMT 40% to reduce exposure to moisture; <9> The process described in <15> further comprising packaging the compressed lisdexamfetamine dimesylate orodispersible tablets in a moisture-resistant ALU peel blister package. <9> The process described in <16> further comprising packaging the compressed lisdexamfetamine dimesylate orodispersible tablets in a moisture-resistant ALU-ALU package. <9> The process described in

Claims

1. about 8 to about 12% by weight of lisdexamfetamine dimesylate; about 45 to about 55 wt. % of a diluent; about 10 to about 20 weight percent of a binder; about 8 to about 12 wt. % of a buffering agent; about 6 to about 10% by weight of a disintegrant; about 1 to about 4% by weight of a sweetener; about 1 to about 2 weight percent of an antistatic agent; about 1 to about 2 weight percent of a lubricant; 1. A lisdexamfetamine dimesylate orodispersible tablet comprising:

2. 2. The lisdexamfetamine dimesylate orodispersible tablet of claim 1, wherein the dosage of the lisdexamfetamine dimesylate orodispersible tablet 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.

3. 2. The lisdexamfetamine dimesylate orodispersible tablet of claim 1, wherein the diluent is mannitol granules 200SD and the binder is partially pregelatinized corn starch.

4. 2. The lisdexamfetamine dimesylate orodispersible tablet of claim 1, wherein the buffering agent is microcrystalline cellulose, the disintegrant is crospovidone, the sweetener is sucralose, the antistatic agent is colloidal anhydrous silica, and the lubricant is magnesium stearate.

5. 2. The lisdexamfetamine dimesylate orodispersible tablet of claim 1, wherein the particle size of the drug granules forming the lisdexamfetamine dimesylate orodispersible tablet is 400 microns or less.

6. 2. The lisdexamfetamine dimesylate orodispersible tablet of claim 1, having a friability of less than 2%, a disintegration time of less than 3 minutes at 37°C ± 2°C (without discs), and a hardness of about 30N to about 70N.

7. 2. The lisdexamfetamine dimesylate orodispersible tablet of claim 1, wherein the dissolution is greater than 85% in 15 minutes.

8. 2. The lisdexamfetamine dimesylate orodispersible tablet of claim 1, wherein the particle size of the lisdexamfetamine dimesylate is 100 microns or less.

9. co-sieving the lisdexamfetamine dimesylate, the binder and the diluent; dry mixing and blending the sieved lisdexamfetamine dimesylate, the binder, and the diluent to form a blended dry mixture; co-sieving and blending the diluent, buffer, disintegrant, sweetener and antistatic agent to prepare an intermediate blend; blending the blended dry mixture with the intermediate blend; lubricating the blended dry mixture with the intermediate blend to form drug granulations ready for compression; and compressing the ready-to-compress drug granulation to form a compressed lisdexamfetamine dimesylate orodispersible tablet; 1. A process for the preparation of lisdexamfetamine dimesylate orodispersible tablets, comprising:

10. 10. The process of claim 9, wherein the dosage of the lisdexamfetamine dimesylate orodispersible 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.

11. 10. The process of claim 9, wherein the diluent is mannitol granules 200SD and the binder is partially pregelatinized corn starch.

12. 10. The process of claim 9, wherein the buffering agent is microcrystalline cellulose, the disintegrating agent is crospovidone, the sweetener is sucralose, the antistatic agent is colloidal anhydrous silica, and the lubricant is magnesium stearate.

13. 10. The process of claim 9, wherein the friability is less than 2%, the disintegration time is less than 3 minutes at 37°C ± 2°C (without discs), and the hardness is from about 30N to about 70N.

14. 10. The process of claim 9, wherein said compressing step uses direct compression techniques at a controlled humidity level of NMT 40% to reduce exposure to moisture.

15. 10. The process of claim 9, further comprising packaging the compressed lisdexamfetamine dimesylate orodispersible tablets in a moisture-resistant ALU peel blister package.

16. 10. The process of claim 9, further comprising packaging the compressed lisdexamfetamine dimesylate orodispersible tablets in a moisture resistant ALU-ALU package.

Images