Ridexamphetamine dimesylate oral dispersible tablet and preparation method thereof

Abstract

The invention relates to a ridexamphetamine dimesylate oral dispersible tablet and a preparation method thereof. The ridexamphetamine dimesylate oral dispersible tablet comprises the following components: co-sieved ridexamphetamine dimesylate; a binder and a diluent; dry-blending and blending the sieved ridexamphetamine dimesylate, a binder, and a diluent to form a blended dry blend; co-screening and blending a diluent, a buffer, a disintegrant, a sweetener, and an antistatic agent to prepare an intermediate blend; blending the blended dry blend and the intermediate blend; lubricating the blended dry blend and intermediate blend to form pharmaceutical particles for compression; and compressing the compressed medicine particles for later use to form the compressed ridexamphetamine dimesylate oral dispersible tablet.

Description

Technical Field

[0001] The present disclosure generally relates to orally disintegrating tablets. Specifically, the present disclosure relates to orodispersible tablets of lisdexamfetamine dimesylate and methods for preparing the same. Background Art

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

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

[0004]

[0005] Lisdexamfetamine dimesylate is commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) and moderate to severe Binge Eating Disorder (BED) in adults.

[0006] Tablets and capsules have the disadvantage that they require water for administration and are not well tolerated by the elderly and those with dysphagia. Dysphagia (difficulty swallowing) is reported to be common in all age groups and more particularly in the elderly population as well as in hospitalized patients and patients with complications of nausea, vomiting, and motion sickness.

[0007] Over the past decade, there has been a need for the next generation of pharmaceutical products and drugs that can be taken anywhere. This need also includes suitable types of formulations in orodispersible or rapidly dissolving forms, and having the characteristics of dissolving or melting or disintegrating in the mouth in just a few seconds without water.

[0008] These preparations disintegrate or dissolve rapidly when placed in the oral cavity and are therefore suitable for use by the elderly and those with dysphagia. In addition, since the preparations disintegrate in the oral cavity, the drug can be absorbed in the oral cavity, pharynx, and gastrointestinal tract.

[0009] Lisdexamfetamine dimesylate is a highly deliquescent material in nature and once exposed to moisture will absorb moisture in any manner and will not remain in solid form.

[0010] On the market, resoxamfetamine dimesylate exists with the form of capsule and chewable tablet.Many patient groups (such as, geriatric patient, mental retardation patient, uncooperative patient, nausea patient and fluid intake or the less patient of diet etc.) all have the difficulty of swallowing resoxamfetamine dimesylate in existing dosage form.

[0011] Therefore, need to solve the resoxamfetamine dimethylsulfonate oral dispersion composition of the deliquescence problem of resoxamfetamine dimethylsulfonate.Therefore, very expect to develop but oral disintegration, allow medicine from particle fast release and allow in vivo rapid absorption resoxamfetamine oral dispersion composition.In addition, expect to develop stable, palatable (palatable), disintegrate fast resoxamfetamine oral dispersible tablet.In addition, need to prepare the process time low and the manufacture method that production cost is low of resoxamfetamine dimethylsulfonate oral dispersion composition.In addition, need to have the manufacturing process of controlled humidity so that deliquescent material (deliquescent material) is minimized to the exposure of moisture in process of production. Summary of the Invention

[0012] In order to reach above-mentioned and other purposes and needs, the present disclosure provides dixamfetamine dimethanesulfonate oral dispersible composition and preparation method thereof, and the form of said composition is dixamfetamine dimethanesulfonate orodispersible tablet.The dixamfetamine dimethanesulfonate orodispersible tablet that the inventor developed is orally disintegrating tablet, and this tablet allows medicine to be quickly released from granule, and allows to absorb rapidly in vivo after using.In addition, the present disclosure provides a kind of dixamfetamine dimethanesulfonate orodispersible tablet that is stable, palatable and disintegrates quickly.The present disclosure also provides the manufacturing method that the process time of preparing dixamfetamine dimethanesulfonate oral dispersible composition is low and production cost is low.In addition, the present disclosure also provides the manufacturing process with controlled humidity so that the exposure of deliquescent material to moisture is minimized in production process.

[0013] The present disclosure provides a synergistic combination of API and excipient in a specific ratio to address the deliquescent nature of resoxamfetamine dimesylate. The synergistic combination increases the disintegration time of orally dispersible tablets. The present disclosure also imparts improved palatability to the tablet formulation of resoxamfetamine dimesylate. The present disclosure provides a humidity-controlled manufacturing method in which the tablet formulation is manufactured in a humidity-controlled environment to minimize the exposure of the deliquescent material to moisture during the production process. Particularly, during the manufacturing process, the manufacturing process adopts direct compression technology under a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0014] The present disclosure provides the orally disintegrating tablet of the rextroamphetamine dimethanesulfonate composition that overcomes capsule and chewable tablet shortcoming.Prepared the synergistic combination of API and excipient by specific ratio, to solve the deliquescent character of rextroamphetamine dimethanesulfonate, and provide stable rextroamphetamine dimethanesulfonate composition.In 15 minutes, the dissolution (dissolution) of rextroamphetamine dimethanesulfonate orally dispersible tablet composition was greater than 85%.

[0015] In embodiments, present disclosure relates to resoxamfetamine dimethanesulfonate orodispersible tablets.Resoxamfetamine dimethanesulfonate orodispersible tablets include the resoxamfetamine dimethanesulfonate of approximately 8 % by weight to approximately 12 % by weight; The diluent of approximately 45 % by weight to approximately 55 % by weight; The binding agent (binder) of approximately 10 % by weight to approximately 20 % by weight; The buffer (cushioning agent) of approximately 8 % by weight to approximately 12 % by weight; The disintegrant of approximately 6 % by weight to approximately 10 % by weight; The sweetener of approximately 1 % by weight to approximately 4 % by weight; The antistatic agent of approximately 1 % by weight to approximately 2 % by weight; And the lubricant of approximately 1 % by weight to approximately 2 % by weight.

[0016] In one or more embodiments, the dosage of the rextroamphetamine 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.

[0017] In one or more embodiments, the diluent is mannitol granules 200SD and the binder is partially pregelatinized maize starch.

[0018] 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.

[0019] In one or more embodiments, the particle size of the drug particles used to form the rextroamphetamine dimesylate orodispersible tablet does not exceed 400 microns.

[0020] 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.

[0021] In one or more embodiments, the dissolution rate exceeds 85% within 15 minutes.

[0022] In one or more embodiments, the particle size of the rextroamphetamine dimesylate does not exceed 100 microns.

[0023] In another embodiment, the disclosure relates to a method for preparing rextroamphetamine dimethanesulfonate orodispersible tablets. The method comprises sieving (co-sifting) rextroamphetamine dimethanesulfonate, adhesive and diluent together; Dry mixing (dry mixing) also blends rextroamphetamine dimethanesulfonate, adhesive and diluent through sieving, to form the dry blend (blended dry mix) through blending; Sieve together and blend diluent, buffer, disintegrant, sweetener and antistatic agent, to prepare intermediate blend; Blend through blended dry blend and intermediate blend; Lubrication through blended dry blend and intermediate blend, to form the drug granules (ready to compress drug granules) of standby compression; And compress the standby compressed drug granules, to form compressed rextroamphetamine dimethanesulfonate orodispersible tablets.

[0024] In one or more embodiments, the dosage of the rextroamphetamine 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.

[0025] In one or more embodiments, the diluent is mannitol granules 200SD and the binder is partially pregelatinized corn starch.

[0026] 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 silicon dioxide, and the lubricant is magnesium stearate.

[0027] 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 flakes), and the hardness is from about 30N to about 70N.

[0028] In one or more embodiments, the compressing step utilizes direct compression techniques at a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0029] In an embodiment, the method further comprises packaging the compressed orodispersible tablets of rextroamphetamine dimesylate in a moisture-proof ALU peel off blister package.

[0030] In another embodiment, the method further comprises packaging the compressed orodispersible tablets of rextroamphetamine dimesylate in a moisture-proof ALU-ALU package. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Advantages and features of the present disclosure will become better understood with reference to the following detailed description and claims taken in conjunction with the accompanying drawings, in which:

[0032] Figure 1 The present invention shows a process flow for preparing orodispersible tablets of rextroamphetamine dimesylate according to an exemplary embodiment of the present disclosure.

[0033] Figure 2 Details of a process for dry mixing of rextroamphetamine dimesylate, a binder, and a diluent according to an exemplary embodiment of the present disclosure are shown.

[0034] Figure 3 Details of a method for preparing a lubricated blend / drug granules ready for compression are shown according to an exemplary embodiment of the present disclosure.

[0035] Figure 4 Shown are the preparation details of a compressed orodispersible tablet of rextroamphetamine dimesylate according to an exemplary embodiment of the present disclosure. DETAILED DESCRIPTION

[0036] The exemplary embodiments described in detail for illustrative purposes have many variations in structure and design. However, it should be emphasized that the disclosure is not limited to as shown and described dimethicone orodispersible tablets and preparation method thereof. Should be understood that, according to circumstances, can suggest or provide convenience, can consider the replacement of various omissions and equivalents, but these are intended to contain application or enforcement, and do not depart from the spirit or scope of the claims of the present disclosure. In addition, should be understood that the phrases and terms used herein are for the purpose of description, and should not be considered as restrictive.

[0037] The terms "including," "comprising," or "having" and variations thereof used herein are meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0038] Furthermore, the terms "a" and "an" herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.

[0039] As used herein, the term "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of the term is unclear to one of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term, given the context in which the term is used.

[0040] The invention provides rextroamphetamine dimethanesulfonate orodispersible tablets and preparation method thereof, it is an oral dosage form with oral disintegration property, and this oral dosage form eliminates the needs of consuming rextroamphetamine dimethanesulfonate with the help of water, and disintegrates rapidly in saliva.The rextroamphetamine dimethanesulfonate orodispersible tablets developed by the inventor are orally disintegrating tablets, and this tablet allows medicine to be quickly released from particles, and allows to absorb rapidly in vivo after using. In addition, rextroamphetamine dimethanesulfonate orodispersible tablets and preparation method thereof need less preparation process time, less excipient dosage and lower production cost, and are stable, palatable and disintegrate fast.

[0041] The present disclosure provides a synergistic combination of API and excipient in a specific ratio to address the deliquescent nature of resoxamfetamine dimesylate. The synergistic combination increases the disintegration time of orodispersible tablets. The present disclosure also imparts improved palatability to the tablet formulation of resoxamfetamine dimesylate. The present disclosure provides a humidity-controlled manufacturing method in which the tablet formulation is manufactured in a humidity-controlled environment to minimize the exposure of the deliquescent material to moisture during the production process. In particular, during the manufacturing process, the manufacturing process adopts direct compression technology under a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0042] In an embodiment, disclose rextroamphetamine dimethanesulfonate orodispersible tablet.Herein, " rextroamphetamine dimethanesulfonate orodispersible tablet " and " rextroamphetamine dimethanesulfonate ODT (orally disintegrating tablets, Orally disintegrating tablets) " are hereinafter used interchangeably, without any restriction.Rextroamphetamine dimethanesulfonate orodispersible tablet comprises the rextroamphetamine dimethanesulfonate of approximately 8 % by weight to approximately 12 % by weight; The diluent of approximately 45 % by weight to approximately 55 % by weight; The binding agent of approximately 10 % by weight to approximately 20 % by weight; The buffer of approximately 8 % by weight to approximately 12 % by weight; The disintegrant of approximately 6 % by weight to approximately 10 % by weight; The sweetener of approximately 1 % by weight to approximately 4 % by weight; The antistatic agent of approximately 1 % by weight to approximately 2 % by weight; And the lubricant of approximately 1 % by weight to approximately 2 % by weight.

[0043] As used herein, lisdexamfetamine dimesylate is the active substance. Lisdexamfetamine dimesylate, the dimesylate of L-lysyl-d-amphetamine, has the molecular formula C 17 H 33 N3O7S2, also known by its chemical name as "(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]-hexanamide, dimethanesulfonate". The IUPAC name of lisdexamfetamine dimethanesulfonate is (2S)-2,6-diamino-N-[(2S)-1-phenylpropyl-2-yl]hexanamide; methanesulfonic acid.

[0044] The structural formula of resoxamfetamine dimesylate shows that the resoxamfetamine dimesylate molecule contains two chiral centers. Therefore, this compound has four possible enantiomers: (2S)-2,6-diamino-N-[(2S)-1-phenylpropyl-2-yl]hexanamide; (2R)-2,6-diamino-N-[(2S)-1-phenylpropyl-2-yl]hexanamide; (2S)-2,6-diamino-N-[(2R)-1-phenylpropyl-2-yl]hexanamide; and (2R)-2,6-diamino-N-[(2R)-1-phenylpropyl-2-yl]hexanamide.

[0045] Rexedamphetamine dimesylate is a white or almost white crystalline powder that is therapeutically classified as a CNS stimulant drug. It is also known as an amphetamine. Rexedamphetamine dimesylate is freely soluble in methanol; soluble in ethanol; very slightly soluble in acetone, chloroform, and toluene; and practically insoluble in tetrahydrofuran.

[0046] Typically, resorcinolone dimesylate is hygroscopic and is commonly used to treat attention deficit hyperactivity disorder (ADHD) and moderate to severe binge eating disorder (BED) in adults.

[0047] In one or more embodiments, the particle size of the rextroamphetamine dimesylate does not exceed 100 microns.

[0048] In one or more embodiments, the dosage of the rextroamphetamine 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.

[0049] In one or more embodiments, the diluent is Mannitol Granules 200SD.

[0050] As used herein, mannitol granules 200SD are used to prepare rextroamphetamine dimethanesulfonate orodispersible tablets. Mannitol granules 200SD are used to adjust the average weight of rextroamphetamine dimethanesulfonate orodispersible tablets. Mannitol granules 200SD also enhances the fluidity and mouth feel of rextroamphetamine dimethanesulfonate orodispersible tablets. Mannitol granules 200SD are divided into two parts to enhance the uniformity and distribution of the drug in the preparation. In one example, mannitol granules 200SD are 200SD.

[0051] In one or more embodiments, the binder is partially pregelatinized corn starch.

[0052] As used herein, partially pregelatinized corn starch is used to prepare resoxamfetamine dimethanesulfonate orodispersible tablets. Resoxamfetamine dimethanesulfonate as active substance is a molecule that is easily deliquescent, and by this property, when it is kept at room temperature, it can be converted into liquid form. Therefore, in order to maintain the solid form of active resoxamfetamine dimethanesulfonate, swellable partially pregelatinized corn starch is used in this resoxamfetamine dimethanesulfonate orodispersible tablet preparation. Partially pregelatinized corn starch improves the fluidity of powder, ensures uniformity. Pregelatinized corn starch can swell and trigger disintegration when contacting with aqueous dissolution medium (aqueous dissolution medium). It significantly reduces the adhesion (adhesion) of powder. In an example, partially pregelatinized corn starch is

[0053] In one or more embodiments, the buffering agent is microcrystalline cellulose.

[0054] As used herein, microcrystalline cellulose is used to prepare orodispersible tablets of lisdexamfetamine dimesylate. Microcrystalline cellulose is crystalline in nature. Microcrystalline cellulose enhances the flow of powders and aids in the compression of tablets to achieve the desired hardness. It also acts as a buffer. Due to the plastic properties of microcrystalline cellulose, it is often used as an excipient in tablet compression and granulation processes. Microcrystalline cellulose acts as a buffer to fill the spaces between particles and suppress the effects of the compression forces generated during the tableting process. In the examples, the microcrystalline cellulose is

[0055] In one or more embodiments, the disintegrant is crospovidone.

[0056] As used herein, crospovidone is used to prepare orodispersible tablets of lisdexamfetamine dimesylate. Crospovidone is a water-insoluble tablet disintegrant and dissolution agent. Crospovidone rapidly exhibits high capillary activity and significant hydration, and is unlikely to form a gel. In the example, crospovidone is

[0057] In one or more embodiments, the sweetener is sucralose.

[0058] As used herein, sucralose is used to prepare orodispersible tablets of lisdexamfetamine dimesylate. Sucralose is a white to off-white, free-flowing crystalline powder that is approximately 300-1000 times sweeter than sucrose and has no aftertaste.

[0059] In one or more embodiments, the antistatic agent is colloidal anhydrous silica.

[0060] As used herein, colloidal anhydrous silica is used to prepare orodispersible tablets of lisdexamfetamine dimesylate. Colloidal anhydrous silica is an adsorbent, an anticaking agent, and a glidant. It enhances the flow of the powder. In the examples, colloidal anhydrous silica is

[0061] In one or more embodiments, the lubricant is magnesium stearate.

[0062] As used herein, magnesium stearate is used to prepare dixamfetamine dimesylate orodispersible tablets. Magnesium stearate is an impalpable powder with low bulk density. It has a fine texture and is greasy, lightweight, white in color, and is naturally precipitated or ground. Functionally, it is used as a lubricant in the manufacture of capsules and tablets. Magnesium stearate powder is easy to adhere to the surface of tablets in the pharmaceutical industry to ensure that tablets are cleanly discharged without rupture or breakage due to its unique greasiness.

[0063] In one or more embodiments, the particle size of the drug particles used to form the tablet does not exceed 400 microns.

[0064] 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 flakes), and the hardness is from about 30N to about 70N.

[0065] In one or more embodiments, the dissolution rate exceeds 85% within 15 minutes.

[0066] As used herein, the dissolution medium was 900 ml of 0.1 N hydrochloric acid, the temperature was 37° C.±0.5° C., and the withdrawal time was 15 minutes.

[0067] In another embodiment, the present disclosure provides a method for preparing resoxamfetamine dimethanesulfonate orodispersible tablets. The method includes screening resoxamfetamine dimethanesulfonate, a binder, and a diluent together; dry mixing and blending the screened resoxamfetamine dimethanesulfonate, a binder, and a diluent to prepare a blended dry blend; screening and blending a diluent, a buffer, a disintegrant, a sweetener, and an antistatic agent together to prepare an intermediate blend; blending the blended dry blend and the intermediate blend; lubricating the blended dry blend and the intermediate blend to form standby compressed drug granules; and compressing the standby compressed drug granules to form compressed resoxamfetamine dimethanesulfonate orodispersible tablets.

[0068] Reference Figure 1, method 100 relates to a method for preparing rextroamphetamine dimethanesulfonate orodispersible tablets. In step 102, method 100 comprises screening rextroamphetamine dimethanesulfonate, adhesive and diluent together. In step 104, method 100 comprises dry mixing and blending the rextroamphetamine dimethanesulfonate, adhesive and diluent through screening to form a dry blend through blending. In step 106, method 100 comprises screening and blending diluent, buffer, disintegrant, sweetener and antistatic agent together to prepare an intermediate blend. In step 108, method 100 comprises blending the dry blend through blending and an intermediate blend. In step 110, method 100 comprises lubricating the dry blend through blending and an intermediate blend, to form standby compressed drug granules. In step 112, method 100 comprises compressing the standby compressed drug granules to form compressed rextroamphetamine dimethanesulfonate orodispersible tablets. The compressed orodispersible tablets of lisdexamfetamine dimesylate are then packaged in moisture-proof ALU peel-off blister packs / ALU-ALU packs. The moisture-proof ALU peel-off blister packs / ALU-ALU packs facilitate humidity-controlled manufacturing processes and packaging.

[0069] Figure 1 Method steps 102 and 104 in Figure 2 Described in detail in. Figure 1 Method steps 106 and 108 in Figure 3 Described in detail in. Figure 1 Method step 112 in Figure 4 Described in detail in.

[0070] Refer again Figure 1 In step 102, method 100 relates to sieve dimesylate, adhesive and diluent altogether, wherein dimesylate is active pharmaceutical ingredient (API). Adhesive is the corn starch of part pregelatinization. Diluent is mannitol granules 200SD. In step 104, method 100 relates to dry mixing and blending the dimesylate granules of sieved, the corn starch of part pregelatinization and mannitol granules 200SD without agglomerate (agglomerate free mass), to form the dry blend of blending. Figure 1 Method steps 102 and 104 in Figure 2 Described in detail in.

[0071] Reference Figure 2 In step 202, the granules 200SD of resoxamfetamine dimesylate, partially pregelatinized corn starch, and mannitol are sieved to obtain agglomerates. The sieved granules 200SD of resoxamfetamine dimesylate, partially pregelatinized corn starch, and mannitol are collected to obtain agglomerates.

[0072] Reference Figure 2 At step 204, the sieved lisdexamfetamine dimesylate, partially pregelatinized corn starch, and the agglomerate-free mannitol granules 200SD are loaded into a conta blender for dry blending and agglomeration-free blending in the conta blender to obtain a blended dry blend. Thereafter, at step 206, the blended dry blend is unloaded.

[0073] Refer again Figure 1 At step 106, the next step in method 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 silicon dioxide. Figure 1 Method step 106 in Figure 3 Described in detail in.

[0074] Reference Figure 1 , at step 108 , the next step of method 100 involves blending the blended dry blend obtained at step 204 and the intermediate blend obtained at step 304 . Figure 1 Step 108 in Figure 3 Described in detail in.

[0075] Refer again Figure 1 The next step in method 100 involves lubricating the blended dry blend and intermediate blend at step 110 to form drug granules ready for compression. Figure 1 Step 110 in Figure 3 Described in detail in.

[0076] Reference Figure 3 In step 302, mannitol granules 200SD, microcrystalline cellulose, crospovidone, sucralose, and colloidal anhydrous silicon dioxide are co-sieved through a 36-mesh vibrating screen to remove agglomerates. In step 304, the sieved material obtained in step 302 is blended in a Quantachrome blender at 8 RPM for 30 minutes to obtain an intermediate blend. Thereafter, in step 306, 50% of the intermediate blend obtained in step 304 is unloaded.

[0077] Refer again Figure 3 , method step 308 includes adding Figure 2 The blended dry blend obtained in step 204 is added to the 50% intermediate blend obtained in step 304. In addition, the unloaded 50% intermediate blend obtained in step 306 is added to the blender tank containing the 50% intermediate blend and the blended dry blend. In addition, in step 310, the above-added mixture obtained in step 308 is blended.

[0078] Refer again Figure 3 At step 312, the blended mixture obtained at step 308 is lubricated with a lubricant. Here, the lubricant is magnesium stearate. The magnesium stearate is sieved through a vibrating screen and added to the blended mixture in the Quantamix blender to obtain a lubricated blended mixture. At step 314, the lubricated blended mixture is further blended to obtain pharmaceutical granules ready for compression. The compressed pharmaceutical granules ready for compression are unloaded. Thereafter, the compressed pharmaceutical granules ready for compression are conveyed.

[0079] In one or more embodiments, the compressing step utilizes direct compression techniques at a controlled humidity level of NMT 40% to reduce exposure to moisture.

[0080] Refer again Figure 1 At step 112 , method 100 involves compressing the drug granules ready for compression to form compressed orodispersible tablets of rextroamphetamine dimesylate. Figure 1 Step 112 in Figure 4 Detailed description in . Figure 4 In step 402, the ready-to-compress drug granules obtained in step 314 are compressed by a compressor to obtain compressed orodispersible tablets of lixisenatide dimesylate. The compression used herein is a direct compression technique at a controlled humidity level of NMT 40% during the manufacturing process to reduce exposure to moisture.

[0081] After compression rexroyl dimethanesulfonate orodispersible tablets, in step 404, the compressed tablets (bulkcompressed tablet) in bulk are stored in the black double-lined plastic bag in the HDPE bucket, comprise silica gel bag as desiccant in the bag.Bucket is stored with the temperature lower than 25 ℃ in the isolation zone before initial packaging.In step 406, packing compressed rexroyl dimethanesulfonate orodispersible bulk tablets.In embodiments, compressed rexroyl dimethanesulfonate orodispersible tablets are packaged in moisture-proof ALU peeling blister packing.In another embodiment, compressed rexroyl dimethanesulfonate orodispersible tablets are packaged in moisture-proof ALU-ALU packing.

[0082] Herein, the compression yield is greater than 95%.

[0083] In one or more embodiments, compressed orodispersible tablets of lixisenatide dimesylate are packaged in moisture-proof (ALU) peel-off blister packs / ALU-ALU packs using a blister packaging machine. Moisture-proof ALU peel-off blister packs / ALU-ALU packs facilitate humidity-controlled manufacturing processes and packaging.

[0084] The weight percentages of API and excipients for the presented batches are described in Table 1.

[0085] Table 1

[0086]

[0087] The following non-limiting examples further illustrate dimethicone orodispersible tablets and preparation methods thereof. Those skilled in the art will recognize that the specific examples are intended to illustrate rather than limit the scope of this disclosure.

[0088] The physical characteristics of 10, 20, 30, 40, 50, 60, and 70 mg / tablet rextroamphetamine dimesylate orodispersible tablets are described in Table 2 (in mg / tablet).

[0089] Table 2

[0090]

[0091] Example 1

[0092] In Example 1, a method for preparing orodispersible tablets of rextroamphetamine dimesylate is described. Specifically, a method for preparing orodispersible tablets of rextroamphetamine dimesylate having a strength of 10 mg per tablet is described.

[0093] The amounts of API and excipients (in mg / tablet) for rextroamphetamine dimesylate (10 mg) orodispersible tablets are described in Table 3.

[0094] Table 3

[0095]

[0096] This technique begins by sieving dimesyamphetamine, part pregelatinized corn starch and mannitol granules 200SD together.Particularly, the dimesyamphetamine of 10mg, the mannitol granules 200SD of 25mg and the part pregelatinized corn starch of 15mg are sieved and obtained without agglomerates by vibratory screening machine.Collected the dimesyamphetamine through sieving, part pregelatinized corn starch and mannitol granules 200SD without agglomerates.

[0097] Thereafter, the sieved rextroamphetamine dimesylate, partially pregelatinized corn starch, and agglomerate-free mannitol granules 200SD were loaded into a Quanta blender to dry blend and blend the agglomerates-free in the Quanta blender to obtain a blended dry blend, and the blended dry blend was unloaded.

[0098] Next, 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 silicon dioxide were sieved through a vibrating sieve to remove agglomerates. The sieved material was then blended in a Quantachrome blender to obtain an intermediate blend. 50% of the intermediate blend was then unloaded.

[0099] In the next step, the blended dry blend is added to the blender bin of the conta blender containing 50% of the intermediate blend, and the unloaded 50% of the intermediate blend is added to the blender bin containing 50% of the intermediate blend and the blended dry blend to blend the mixture.

[0100] Then, 1.25 mg of magnesium stearate was sieved through a vibrating screen and added to the blended mixture in the Quantamix blender to obtain a lubricated blended mixture. The lubricated blended mixture was further blended to obtain drug granules ready for compression. The drug granules ready for compression were unloaded and conveyed for compression.

[0101] Finally, the drug granules of standby compression are compressed by compressor, to obtain compressed rextroamphetamine dimesylate (10mg) orodispersible tablets.The compression used herein is the direct compression technology under the controlled humidity level of NMT 40% during manufacturing process, to reduce exposure to moisture.

[0102] The product instructions for compressed orodispersible tablets of lisdexamfetamine dimesylate (10 mg) are described in Table 3A.

[0103] Table 3A

[0104]

[0105] The physical characteristics of compressed orodispersible tablets of rextroamphetamine dimesylate (10 mg) are described in Table 3B.

[0106] Table 3B

[0107]

[0108] Example 2

[0109] In Example 2, a method for preparing orodispersible tablets of rextroamphetamine dimesylate is described. Specifically, a method for preparing orodispersible tablets of rextroamphetamine dimesylate having a strength of 20 mg per tablet is described.

[0110] The amounts of API and excipients (in mg / tablet) for rextroamphetamine dimesylate (20 mg) orodispersible tablets are described in Table 4.

[0111] Table 4

[0112]

[0113] This technique begins by sieving dimesyamphetamine, mannitol granules 200SD and the pregelatinized corn starch of part together.Particularly, the dimesyamphetamine of 20mg, the mannitol granules 200SD of 50.0mg and the pregelatinized corn starch of 30.0mg are sieved to obtain without agglomerates by vibratory sieve.Collected the dimesyamphetamine through sieving, 200SD mannitol granules and the pregelatinized corn starch of part without agglomerates.

[0114] Thereafter, the sieved rextroamphetamine dimesylate, mannitol granules 200SD and agglomerate-free of partially pregelatinized corn starch were loaded into a Quanta blender to dry mix and blend the agglomerates-free in the Quanta blender to obtain a blended dry blend and the blended dry blend was unloaded.

[0115] Next, 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 Silicon Dioxide were co-sieved through a vibrating sieve to remove agglomerates. The sieved material was then blended in a Quantachrome blender to obtain an intermediate blend. 50% of the intermediate blend was then unloaded.

[0116] In the next step, the blended dry blend was added to the blender box of the Quanta blender containing 50% of the intermediate blend, and the unloaded 50% of the intermediate blend was added to the blender box containing 50% of the intermediate blend and the blended dry blend to blend the mixture.

[0117] Then, 2.5 mg of magnesium stearate was sieved through a vibrating screen and added to the blended mixture in the Quantamix blender to obtain a lubricated blended mixture. The lubricated blended mixture was further blended to obtain drug granules ready for compression. The drug granules ready for compression were unloaded and conveyed for compression.

[0118] Finally, the drug granules of standby compression are compressed by compressor, to obtain compressed rextroamphetamine dimesylate (20mg) orodispersible tablet.Compression used herein is the direct compression technique during manufacturing process, under the controlled humidity level of NMT 40%, to reduce exposure to moisture.

[0119] The product instructions for compressed orodispersible tablets of lisdexamfetamine dimesylate (20 mg) are described in Table 4A.

[0120] Table 4A

[0121]

[0122] The physical characteristics of compressed orodispersible tablets of rextroamphetamine dimesylate (20 mg) are described in Table 4B.

[0123] Table 4B

[0124]

[0125] Example 3

[0126] In Example 3, a method for preparing orodispersible tablets of rextroamphetamine dimesylate is described. Specifically, a method for preparing orodispersible tablets of rextroamphetamine dimesylate having a strength of 30 mg per tablet is described.

[0127] The amounts of API and excipients (in mg / tablet) for rextroamphetamine dimesylate (30 mg) orodispersible tablets are described in Table 5.

[0128] Table 5

[0129]

[0130] This technique begins by sieving dimesyamphetamine, mannitol granules 200SD and the pregelatinized corn starch of part together.Particularly, the dimesyamphetamine of 30mg, the mannitol granules 200SD of 75mg and the pregelatinized corn starch of 45mg are sieved and obtained without agglomerates by vibratory screening machine.Collected the dimesyamphetamine through sieving, 200SD mannitol granules and the pregelatinized corn starch of part without agglomerates.

[0131] Thereafter, the sieved rextroamphetamine dimesylate, mannitol granules 200SD and agglomerate-free of partially pregelatinized corn starch were loaded into a Quanta blender to dry mix and blend the agglomerate-free in the Quanta blender to obtain a blended dry blend and the blended dry blend was unloaded.

[0132] Next, 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 Silicon Dioxide were co-sieved through a vibrating sieve to remove agglomerates. The sieved material was then blended in a Quantachrome blender to obtain an intermediate blend. 50% of the intermediate blend was then unloaded.

[0133] In the next step, the blended dry blend was added to the blender box of the Quanta blender containing 50% of the intermediate blend, and the unloaded 50% of the intermediate blend was added to the blender box containing 50% of the intermediate blend and the blended dry blend to blend the mixture.

[0134] Then, 3.75 mg of magnesium stearate was sieved through a vibrating screen and added to the blended mixture in the Quanta blender to obtain a lubricated blended mixture. The lubricated blended mixture was further blended to obtain drug granules ready for compression. The drug granules ready for compression were unloaded and conveyed for compression.

[0135] At last, the drug granules of standby compression are compressed by compressor, to obtain compressed rextroamphetamine dimesylate (30mg) orodispersible tablet.The compression used herein is the direct compression technology under the controlled humidity level of NMT 40% during manufacturing process, to reduce exposure to moisture.

[0136] The amounts of API and excipients (in mg / tablet) for rextroamphetamine dimesylate (30 mg) orodispersible tablets are described in Table 5A.

[0137] Table 5A

[0138]

[0139] The physical characteristics of compressed orodispersible tablets of rextroamphetamine dimesylate (30 mg) are described in Table 5B.

[0140] Table 5B

[0141]

[0142] Example 4

[0143] In Example 4, a method for preparing orodispersible tablets of rextroamphetamine dimesylate is described. Specifically, a method for preparing orodispersible tablets of rextroamphetamine dimesylate having a strength of 40 mg per tablet is described.

[0144] The amounts of API and excipients (in mg / tablet) for rextroamphetamine dimesylate (40 mg) orodispersible tablets are described in Table 6.

[0145] Table 6

[0146]

[0147] This technique begins by sieving dimesyamphetamine, mannitol granules 200SD and the pregelatinized corn starch of part together.Particularly, the dimesyamphetamine of 40mg, the mannitol granules 200SD of 100mg and the pregelatinized corn starch of 60mg are sieved and obtained without agglomerates by vibratory screening machine.Collected the dimesyamphetamine through sieving, 200SD mannitol granules and the pregelatinized corn starch of part without agglomerates.

[0148] Thereafter, the sieved rextroamphetamine dimesylate, mannitol granules 200SD, and the agglomerate-free portion of pregelatinized corn starch were loaded into a Quanta blender to dry mix and blend the agglomerate-free portion in the Quanta blender to obtain a blended dry blend, and the blended dry blend was unloaded.

[0149] Next, 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 Silicon Dioxide were co-sieved through a vibrating sieve to remove agglomerates. The sieved material was then blended in a Quantachrome blender to obtain an intermediate blend. 50% of the intermediate blend was then unloaded.

[0150] In the next step, the blended dry blend was added to the blender box of the Quanta blender containing 50% of the intermediate blend, and the unloaded 50% of the intermediate blend was added to the blender box containing 50% of the intermediate blend and the blended dry blend to blend the mixture.

[0151] Then, 5 mg of magnesium stearate was sieved through a vibrating screen and added to the blended mixture in the Quanta blender to obtain a lubricated blended mixture. The lubricated blended mixture was further blended to obtain drug granules ready for compression. The drug granules ready for compression were unloaded and conveyed for compression.

[0152] Finally, the drug granules of standby compression are compressed by compressor, to obtain compressed rextroamphetamine dimesylate (40mg) orodispersible tablets.The compression used herein is the direct compression technology under the controlled humidity level of NMT 40% during manufacturing process, to reduce exposure to moisture.

[0153] The product instructions for compressed orodispersible tablets of lisdexamfetamine dimesylate (40 mg) are described in Table 6A.

[0154] Table 6A

[0155]

[0156] The physical characteristics of compressed orodispersible tablets of rextroamphetamine dimesylate (40 mg) are described in Table 6B.

[0157] Table 6B

[0158]

[0159] Example 5

[0160] In Example 5, a method for preparing orodispersible tablets of rextroamphetamine dimesylate is described. Specifically, a method for preparing orodispersible tablets of rextroamphetamine dimesylate having a strength of 50 mg per tablet is described.

[0161] The amounts of API and excipients (in mg / tablet) for rextroamphetamine dimesylate (50 mg) orodispersible tablets are described in Table 7.

[0162] Table 7

[0163]

[0164] This technique begins by sieving dimesyamphetamine, mannitol granules 200SD and the pregelatinized corn starch of part together.Particularly, the dimesyamphetamine of 50mg, the mannitol granules 200SD of 125mg and the pregelatinized corn starch of 75mg are sieved and obtained without agglomerates by vibratory screening machine.Collected the dimesyamphetamine through sieving, 200SD mannitol granules and the pregelatinized corn starch of part without agglomerates.

[0165] Thereafter, the sieved rextroamphetamine dimesylate, mannitol granules 200SD and the agglomerate-free portion of pregelatinized corn starch were loaded into a Quanta blender to dry mix and blend the agglomerate-free portion in the Quanta blender to obtain a blended dry blend, and the blended dry blend was unloaded.

[0166] Next, 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 silicon dioxide were co-sieved through a vibrating sieve to remove agglomerates. The sieved material was then blended in a Quantachrome blender to obtain an intermediate blend. 50% of the intermediate blend was then unloaded.

[0167] In the next step, the blended dry blend was added to the blender box of the Quanta blender containing 50% of the intermediate blend, and the unloaded 50% of the intermediate blend was added to the blender box containing 50% of the intermediate blend and the blended dry blend to blend the mixture.

[0168] Then, 6.25 mg of magnesium stearate was sieved through a vibrating screen and added to the blended mixture in the Quantamix blender to obtain a lubricated blended mixture. The lubricated blended mixture was further blended to obtain drug granules ready for compression. The drug granules ready for compression were unloaded and conveyed for compression.

[0169] Finally, the drug granules for subsequent compression are compressed by compressor, to obtain compressed rextroamphetamine dimesylate (50mg) orodispersible tablets. The compression used herein is the direct compression technology under the controlled humidity level of NMT 40% during manufacturing process, to reduce exposure to moisture.

[0170] The product instructions for compressed orodispersible tablets of lisdexamfetamine dimesylate (50 mg) are described in Table 7A.

[0171] Table 7A

[0172]

[0173] The physical characteristics of compressed orodispersible tablets of rextroamphetamine dimesylate (50 mg) are described in Table 7B.

[0174] Table 7B

[0175]

[0176] Example 6

[0177] In Example 6, a method for preparing orodispersible tablets of rextroamphetamine dimesylate is described. Specifically, a method for preparing orodispersible tablets of rextroamphetamine dimesylate having a strength of 60 mg per tablet is described.

[0178] The amounts of API and excipients (in mg / tablet) for rextroamphetamine dimesylate (60 mg) orodispersible tablets are described in Table 8.

[0179] Table 8

[0180]

[0181] This technique begins by sieving dimesyamphetamine, mannitol granules 200SD and the pregelatinized corn starch of part together.Particularly, the dimesyamphetamine of 60mg, the mannitol granules 200SD of 150mg and the pregelatinized corn starch of 90mg are sieved and obtained without agglomerates by vibratory screening machine.Collected the dimesyamphetamine through sieving, 200SD mannitol granules and the pregelatinized corn starch of part without agglomerates.

[0182] Thereafter, the sieved rextroamphetamine dimesylate, mannitol granules 200SD, and the agglomerate-free portion of pregelatinized corn starch were loaded into a Quanta blender to dry mix and blend the agglomerates in the Quanta blender to obtain a blended dry blend, and the blended dry blend was unloaded.

[0183] Next, 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 silicon dioxide were co-sieved through a vibrating sieve to remove agglomerates. The sieved material was then blended in a Quantachrome blender to obtain an intermediate blend. A 50% intermediate blend was then obtained.

[0184] In the next step, the blended dry blend was added to the blender box of the Quanta blender containing 50% of the intermediate blend, and the unloaded 50% of the intermediate blend was added to the blender box containing 50% of the intermediate blend and the blended dry blend to blend the mixture.

[0185] Then, 7.5 mg of magnesium stearate was sieved through a vibrating screen and added to the blended mixture in the Quantamix blender to obtain a lubricated blended mixture. The lubricated blended mixture was further blended to obtain drug granules ready for compression. The drug granules ready for compression were unloaded and conveyed for compression.

[0186] Finally, the drug granules for subsequent compression are compressed by compressor, to obtain compressed rextroamphetamine dimesylate (60mg) orodispersible tablets. The compression used herein is the direct compression technique under the controlled humidity level of NMT 40% during manufacturing process, to reduce exposure to moisture.

[0187] The product instructions for compressed orodispersible tablets of lisdexamfetamine dimesylate (60 mg) are described in Table 8A.

[0188] Table 8A

[0189]

[0190] The physical characteristics of compressed orodispersible tablets of rextroamphetamine dimesylate (60 mg) are described in Table 8B.

[0191] Table 8B

[0192]

[0193] Example 7

[0194] In Example 7, a method for preparing orodispersible tablets of rextroamphetamine dimesylate is described. Specifically, a method for preparing orodispersible tablets of rextroamphetamine dimesylate having a strength of 70 mg per tablet is described.

[0195] The amounts of API and excipients (in mg / tablet) for rextroamphetamine dimesylate (70 mg) orodispersible tablets are described in Table 9.

[0196] Table 9

[0197]

[0198] This technique begins by sieving dimesyamphetamine, mannitol granules 200SD and the pregelatinized corn starch of part together.Particularly, the dimesyamphetamine of 70mg, the mannitol granules 200SD of 175mg and the pregelatinized corn starch of 105mg are sieved and obtained without agglomerates by vibratory screening machine.Collected the dimesyamphetamine through sieving, 200SD mannitol granules and the pregelatinized corn starch of part without agglomerates.

[0199] Thereafter, the sieved rextroamphetamine dimesylate, mannitol granules 200SD and agglomerate-free of partially pregelatinized corn starch were loaded into a Quanta blender to dry mix and blend the agglomerates-free in the Quanta blender to obtain a blended dry blend and the blended dry blend was unloaded.

[0200] Next, 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 silicon dioxide were co-sieved through a vibrating sieve to remove agglomerates. The sieved material was then blended in a Quantachrome blender to obtain an intermediate blend. 50% of the intermediate blend was then unloaded.

[0201] In the next step, the blended dry blend was added to the blender box of the Quanta blender containing 50% of the intermediate blend, and the unloaded 50% of the intermediate blend was added to the blender box containing 50% of the intermediate blend and the blended dry blend to blend the mixture.

[0202] Then, 8.75 mg of magnesium stearate was sieved through a vibrating screen and added to the blended mixture in the Quanta blender to obtain a lubricated blended mixture. The lubricated blended mixture was further blended to obtain drug granules ready for compression. The drug granules ready for compression were unloaded and conveyed for compression.

[0203] Finally, the drug granules of standby compression are compressed by compressor, to obtain compressed rextroamphetamine dimesylate (70mg) orodispersible tablets.The compression used herein is the direct compression technology under the controlled humidity level of NMT 40% during manufacturing process, to reduce exposure to moisture.

[0204] The product instructions for compressed orodispersible tablets of lisdexamfetamine dimesylate (70 mg) are described in Table 9A.

[0205] Table 9A

[0206]

[0207] The physical characteristics of compressed orodispersible tablets of rextroamphetamine dimesylate (70 mg) are described in Table 9B.

[0208] Table 9B

[0209]

[0210] The present invention discloses a rextroamphetamine dimethanesulfonate oral dispersible composition and a preparation method thereof, wherein the composition is a rextroamphetamine dimethanesulfonate orodispersible tablet form. The rextroamphetamine dimethanesulfonate orodispersible tablet developed by the inventor is an orally disintegrating tablet, which allows the drug to be quickly released from particles and allows rapid absorption in vivo after administration. Further, the present disclosure provides stable, palatable and fast-disintegrating rextroamphetamine dimethanesulfonate orodispersible tablets. The present disclosure also provides a low process time and a low production cost manufacturing method for preparing the rextroamphetamine dimethanesulfonate oral dispersible composition. In addition, the present disclosure also provides a manufacturing process with controlled humidity, so that the exposure of deliquescent materials to moisture is minimized during the production process.

[0211] test:

[0212] The data included in the test results show the readings related to the moisture controlled tablet composition, i.e., tablets related to the deliquescence of the API, in other words, it shows how the exact combination of drug and all the different excipients results in a formulation / composition with no or insignificant deliquescence.

[0213] In order to demonstrate that compositions comprising resoxaban dimesylate do not exhibit hygroscopic properties, a series of tests have been performed with the aim of evaluating the stability, durability and resistance to various forms of degradation of tablet compositions comprising resoxaban dimesylate.

[0214] These tests were: accelerated aging testing to assess resistance to degradation over time; chemical resistance testing / compatibility testing to assess the suitability of excipient materials with rextroamphetamine dimesylate tablets; and hygroscopicity testing to show that tablets including rextroamphetamine dimesylate did not experience a significant increase in moisture absorption.

[0215] Accelerated aging test

[0216] Tablet compositions are subjected to accelerated stability conditions (such as, 40 degrees Celsius of high temperature and 75%RH humidity exposure) to simulate long-term environmental exposure. Before and after aging, the performance of the tablet comprising dexamfetamine dimesylate is evaluated to assess its degradation resistance over time.

[0217] In Table 10, the results of accelerated aging tests performed on tablet compositions comprising rextroamphetamine dimesylate are described.

[0218] Table 10

[0219]

[0220] The results showed that the hardness of the tablet composition including lisdexamfetamine dimesylate did not change. The hardness of the tablets did not decrease or change, which confirms the mechanical properties of the material and its ability to withstand stress and deformation without showing signs of deliquescence.

[0221] Chemical resistance test / compatibility test

[0222] Tablet compositions were exposed to a range of chemicals commonly used in ODT formulations to evaluate the tablets' resistance to chemical attack, including changes in appearance, physical properties, or structural integrity.

[0223] For compatibility studies, tablets were exposed to a temperature of 40 degrees Celsius and a humidity of 75% RH in both open and closed conditions, and to a temperature of 25 degrees Celsius and a humidity of 75% RH in both open and closed conditions.

[0224] The results indicate a positive interpretation, demonstrating a high degree of compatibility between the tablet composition including lisdexamfetamine dimesylate and chemistries commonly used in ODT formulations. Positive results from the compatibility study provide strong evidence supporting the suitability of the excipient material for its intended application.

[0225] Moisture absorption test

[0226] To determine the ability of tablet compositions comprising rexedam ​​dimesylate to resist moisture absorption, a controlled humidity or water soak test was performed. The amount of moisture absorbed by the tablets was measured and its effect on dimensional stability, strength, and other relevant properties was evaluated.

[0227] The tablet compositions comprising rexropheniramine dimesylate were analyzed under different storage conditions of 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% by using a KF analyzer.

[0228] The results show that the absorption of moisture by the tablet composition comprising lisdexamfetamine dimesylate remains unchanged. In short, the absorption level of moisture by the tablet is not significantly increased.

[0229] In Table 11, the results of the moisture absorption test of the tablet composition comprising rextroamphetamine dimesylate of Batch 1 are described.

[0230] Table 11

[0231]

[0232] In Table 12, the results of the moisture absorption test of Batch 2 tablet compositions comprising rextroamphetamine dimesylate are described.

[0233] Table 12

[0234]

[0235] In Table 13, the results of the moisture absorption test of Batch 3 of the tablet composition comprising rextroamphetamine dimesylate are described.

[0236] Table 13

[0237]

[0238] The stability report of batch 1, batch 2 and batch 3 has emphasized the non-deliquescent property of diamethanesulfonate rexropheniramine oral dispersion composition.Can illustrate from stability data (shown in table 11, table 12 and table 11), under the above-mentioned storage condition of mentioning, water content does not significantly increase.Therefore, in other words, it is stable to be able to draw a conclusion that diamethanesulfonate rexropheniramine oral dispersion tablet composition.

[0239] The present disclosure provides the synergistic combination of API and excipient with specific ratio to solve the deliquescence property (delinquent nature) of resoxamfetamine dimesylate.The synergistic combination has increased the disintegration time of orodispersible tablets.The present disclosure has also given the improved palatability of the tablet formulation of resoxamfetamine dimesylate.The present disclosure provides a kind of humidity-controlled manufacturing method, wherein, tablet formulation is manufactured in the environment of controlled humidity, so that the exposure of deliquescent material to moisture during production process is minimized.Especially, during manufacturing process, manufacturing process adopts direct compression technology under the controlled humidity level of NMT 40%, to reduce exposure to moisture.

[0240] The present disclosure provides the orally disintegrating tablet of the rextroamphetamine dimethanesulfonate composition that overcomes capsule and chewable tablet shortcoming.API and excipient are carried out synergistic combination to solve the deliquescent character of rextroamphetamine dimethanesulfonate by specific ratio, and stable rextroamphetamine dimethanesulfonate composition is provided.In 15 minutes, the dissolution rate of rextroamphetamine dimethanesulfonate orally dispersible tablet composition was greater than 85%.

[0241] The foregoing descriptions of specific embodiments of the present disclosure have been presented for the purposes of illustration and description. They are not intended to be exhaustive or to limit the present disclosure to the precise form disclosed, and it is apparent that many modifications and variations are possible in light of the foregoing teachings. The embodiments have been selected in order to best explain the present principles of the present disclosure and their practical application, thereby enabling those skilled in the art to best use the present disclosure and the various embodiments with various modifications to suit the intended specific use. It should be understood that various omissions and equivalent substitutions may be suggested or provided as appropriate, and that these are intended to cover application or implementation without departing from the spirit or scope of the claims of the present disclosure.

Claims

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

2. Lisdexamfetamine dimesylate orodispersible tablets according to claim 1, wherein The dosage of the dixamfetamine 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.

3. The orodispersible tablets of rixetamine dimesylate according to claim 1, wherein The diluent was mannitol granules 200SD, and the binder was partially pregelatinized corn starch.

4. The orodispersible tablets of rixetamine dimesylate according to claim 1, wherein The buffering agent is microcrystalline cellulose, the disintegrant is crospovidone, the sweetener is sucralose, the antistatic agent is colloidal anhydrous silicon dioxide, and the lubricant is magnesium stearate.

5. The orodispersible tablets of lisdexamfetamine dimesylate according to claim 1, wherein The particle size of the drug particles used to form the orodispersible tablets of rextroamphetamine dimesylate does not exceed 400 microns.

6. The orodispersible tablets of rixetamine dimesylate according to claim 1, wherein The friability is less than 2%, the disintegration time is less than 3 minutes at 37°C ± 2°C (without flakes), and the hardness is from about 30N to about 70N.

7. The orodispersible tablets of lisdexamfetamine dimesylate according to claim 1, wherein The dissolution rate exceeded 85% within 15 minutes.

8. The orodispersible tablets of lisdexamfetamine dimesylate according to claim 1, wherein The particle size of the resorcinol dimesylate is no more than 100 microns.

9. A method for preparing orodispersible tablets of lisdexamfetamine dimesylate, comprising: Co-screening of lisdexamfetamine dimesylate, binders, and diluents; dry mixing and blending the sieved rextroamphetamine dimesylate, the binder, and the diluent to form a blended dry blend; Co-sieving and blending the diluent, buffer, disintegrant, sweetener, and antistatic agent to prepare an intermediate blend; blending the blended dry blend and the intermediate blend; lubricating the blended dry blend and the intermediate blend to form drug granules ready for compression; and The drug granules ready for compression are compressed to form compressed orodispersible tablets of rextroamphetamine dimesylate.

10. The method according to claim 9, wherein: The dosage of the dixamfetamine 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. The method according to claim 9, wherein The diluent was mannitol granules 200SD, and the binder was partially pregelatinized corn starch.

12. The method according to claim 9, wherein The buffering agent is microcrystalline cellulose, the disintegrant is crospovidone, the sweetener is sucralose, the antistatic agent is colloidal anhydrous silicon dioxide, and the lubricant is magnesium stearate.

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

14. The method according to claim 9, wherein The compression step utilizes direct compression technology at a controlled humidity level of NMT 40% to reduce exposure to moisture.

15. The method according to claim 9, wherein The method further includes packaging the compressed orodispersible tablets of dexamfetamine dimesylate in a moisture-proof ALU peel-off blister pack.

16. The method according to claim 9, wherein The method further comprises packaging the compressed orodispersible tablets of lisdexamfetamine dimesylate in a moisture-proof ALU-ALU package.

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